# Venom Peptides, Polyphenols and Alkaloids: Are They the Next Antidiabetics That Will Preserve β-Cell Mass and Function in Type 2 Diabetes?

Michele Lodato, Valérie Plaisance, Valérie Pawlowski, Maxime Kwapich, Alexandre Barras, Emeline Buissart, Stéphane Dalle, Sabine Szunerits, Jérôme Vicogne, Rabah Boukherroub, et al.

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## ► To cite this version:

Michele Lodato, Valérie Plaisance, Valérie Pawlowski, Maxime Kwapich, Alexandre Barras, et al. "Venom Peptides, Polyphenols and Alkaloids: Are They the Next Antidiabetics That Will Preserve β-Cell Mass and Function in Type 2 Diabetes?". Cells, 2023, 12 (6), pp.940. 10.3390/cells12060940. hal-04062633

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Review

# Venom Peptides, Polyphenols and Alkaloids: Are They the Next Antidiabetics That Will Preserve β-Cell Mass and Function in Type 2 Diabetes?

Michele Lodato<fnref n="1" />, Valérie Plaisance<fnref n="1" />, Valérie Pawlowski<fnref n="1" />, Maxime Kwapich <fnref n="1" />,<fnref n="2" />, Alexandre Barras <fnref n="1" /> ID,
Emeline Buissart <fnref n="1" />, Stéphane Dalle<fnref n="3" />, Sabine Szunerits <fnref n="1" /> ID, Jérôme Vicogne <fnref n="4" /> ID, Rabah Boukherroub <fnref n="1" /> ID
and Amar Abderrahmani <fnref n="1" />,* ID

**Abstract:** Improvement of insulin secretion by pancreatic β-cells and preservation of their mass are the current challenges that future antidiabetic drugs should meet for achieving efficient and long-term glycemic control in patients with type 2 diabetes (T2D). The successful development of glucagon-like peptide 1 (GLP-1) analogues, derived from the saliva of a lizard from the *Helodermatidae* family, has provided the proof of concept that antidiabetic drugs directly targeting pancreatic β-cells can emerge from venomous animals. The literature reporting on the antidiabetic effects of medicinal plants suggests that they contain some promising active substances such as polyphenols and alkaloids, which could be active as insulin secretagogues and β-cell protectors. In this review, we discuss the potential of several polyphenols, alkaloids and venom peptides from snake, frogs, scorpions and cone snails. These molecules could contribute to the development of new efficient antidiabetic medicines targeting β-cells, which would tackle the progression of the disease.

**Keywords:** diabetes; insulin secretagogues; pancreatic beta cell; venom; polyphenols; alkaloids; peptides

## 1. Introduction

Humanity has always been inspired and guided by plants and animals for its healthcare [1], as cited by Hippocrates: "Nature itself is the best physician". Plants have been able to offer efficient analgesics (morphine and codeine), anti-cancer (taxol), antiparasite (artemisinin) as well as anti-inflammatory (salicylic acid) drugs. In addition to bacteria and fungi, many analgesics, vaccines (hepatitis A, influenza), inflammation modulators and anti-venom drugs are from the animal origin [2]. Antidiabetic drugs have also been supplied from plants and animals. For example, dog insulin enabled Sir Frederik Banting to reveal the therapeutic activity of this hormone, and to treat the first patient with type 1 diabetes [3]. Before genetic engineering was possible, insulin, used to treat millions of patients, was from bovine and pig origin. For patients with type 2 diabetes (T2D), the most prominent type of diabetes with 90% of all diagnosed cases, several current antidiabetic drugs are from plant and animal origins: metformin, sodium glucose co-transporter type 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Metformin is currently the most popular antidiabetic drug and the first line of medication in T2D. Metformin is a biguanide derivative, whose antidiabetic activity was originally described in the Middle Age with the use of the *Galega officinalis*,

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check for
updates

**Citation:** Lodato, M.; Plaisance, V.; Pawlowski, V.; Kwapich, M.; Barras, A.; Buissart, E.; Dalle, S.; Szunerits, S.; Vicogne, J.; Boukherroub, R.; et al. Venom Peptides, Polyphenols and Alkaloids: Are They the Next Antidiabetics That Will Preserve β-Cell Mass and Function in Type 2 Diabetes? *Cells* **2023**, *12*, 940. https://doi.org/10.3390/cells12060940

Academic Editor: Thierry Coppola

Received: 14 February 2023

Revised: 9 March 2023

Accepted: 17 March 2023

Published: 20 March 2023

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**Copyright:** © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

<footnote n="1">¹ University Lille, CNRS, Centrale Lille, University Polytechnique Hauts-de-France, UMR 8520, IEMN, F-59000 Lille, France</footnote>

<footnote n="2">² Service de Diabétologie et d'Endocrinologie, CH Dunkerque, 59385 Dunkirk, France</footnote>

<footnote n="3">³ Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094 Montpellier, France</footnote>

<footnote n="4">⁴ University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France</footnote>

<footnote>* Correspondence: amar.abderrahmani@univ-lille.fr; Tel.: +33-362531704</footnote>
also known as “French lilac”, plant [4]. Metformin acts as an insulin sensitizer, which
together with lifestyle changes, improves glucose uptake of patients, and thereby
reduces hyperglycemia [4]. The antidiabetic effect mostly relies on the inhibition of
hepatic gluconeogenesis [5,6]. With metformin, the SGLT2i antidiabetic class of T2D
is becoming very popular [7]. Besides their glucose-lowering effect, SGLT2is reduce
the risk of cardiovascular diseases and hospitalization caused by heart failure [8,9].
SGLT2is lower glucose blood levels by reducing renal glucose reabsorption and by
promoting urinary glucose excretion [7]. Historically, SGLT2is originate from phlorizin,
a naturally occurring glucoside found in various plants, such as the root bark of apple
and other fruit trees [10]. While phlorizin was initially used for treating fever, infectious
diseases and malaria, the substance could lead to glucosuria and polyuria [11]. Because
phlorizin is poorly absorbed into the gastrointestinal tract and acts in other tissues
by inhibiting SGLT1 (primarily found in the gastrointestinal tract), the molecule has
never been used as a medication for the treatment of T2D. To circumvent these concerns,
analogs of phlorizin have been developed. Another drug used for the treatment of
T2D is GLP-1RA which improves insulin secretion in patients. Indeed, T2D develops
when insulin secretion from pancreatic β-cells of the islet of Langerhans, the only cells
in the body specialized in the production of insulin, is insufficient for coping insulin
resistance [12]. GLP-1RA alleviates hyperglycemia by potentiating nutrient-induced
insulin secretion [13]. Therefore, GLP-1RAs are of high value as they do not cause
hypoglycemia. In addition, they are considered as very promising since they are the
only antidiabetics that could slow and/or prevent the degradation of β-cell mass of
patients, as revealed by preclinical studies [14]. In fact, β-cell mass in a T2D patient
is only 40-60% of that of a body mass index-matched non-diabetic person [15,16].
Progressive reduction of β-cell mass contributes to the poor glycemic control of patients
over time. This reduction is suggested to degenerate, as the remaining β-cells are
functioning at very likely only half their capacity [17]. The first GLP-1RA was originally
discovered by an American team through the search for molecules from arthropod and
reptile venoms that activate G-protein coupled receptors (GPCRs) involved in pancreatic
amylase secretion. The most potent molecule came from the venom of the Gila monster
(Heloderma suspectum), in which resides the GLP-1RA Exendin 4 [18,19]. The half-life
of the GLP-1RA has been extended by chemical modification, leading to exenatide
and many other derived drugs so far [20]. Unfortunately, GLP-1RAs are heterogenous
in terms of efficiency for achieving short- and mid-time glycemic control [21]. Their
efficiency can even be reduced over time [22,23]. In addition, some patients are non-
respondent to GLP-1RAs [24]. A randomized controlled trial, performed in a small
cohort of 40 subjects with early T2D, were treated for 6 months with the GLP-1RA
exenatide, but it had no effect on β-cell mass [25,26].

Similarly, the sulfonylureas (SUs) and glinides, two popular classes of oral antidiabetics which directly enhance insulin secretion, are unable to achieve long-term glycemic control, and thereby cannot be used as therapeutic alternative [27,28]. The concern is that these drugs do not preserve functional β-cell mass, which continues to deteriorate over time, worsening insulin deficiency. SUs can even participate in the functional β-cell mass demise by accelerating β-cell apoptosis and β-cell exhaustion or desensitization [29,30]. In addition, SUs and glinides stimulate insulin secretion in the absence of glucose or food uptake, which can cause hypoglycemia, a major side effect that can limit their use for some patients. Moreover, weight gain, nausea, erythema multiforme, exfoliative dermatitis and also, more rarely, photosensitivity are some of the secondary effects of these drugs [31,32]. Occasionally, they can cause also cardiac dysfunction, hyponatremia and abnormalities in liver function [33].

Therefore, it is urgent to develop insulin secretagogue drugs with long duration effi-
ciencies that are capable to preserve functional β-cell mass by protecting them from death
caused by the diabetogenic environment (cytokines, chronic hyperglycemia, chronic
hyperlipidemia and amyloid deposits). To this end, it is essential that future drugs
not only target the key cellular mechanisms that stimulate insulin secretion, but also
promote β-cell survival in this detrimental environment. With approximately 8.7 mil-
lion plant and animal species worldwide, including 6.5 million species living on earth
and 2.2 million in the seas [34], it is highly possible to tackle this medical challenge.
Indeed, there are accumulating data evidencing that animal venom peptides and plant
substances including polyphenols and alkaloids are potential candidates. This review
reports these molecules and provides an original and consistent presentation of their
potential for targeting the mechanisms of insulin secretion and β-cell protection, the
expected requirement of future antidiabetics.

**2. Peptides and Substances Stimulating Insulin Secretion**

2.1. *Key Pathways Regulating Glucose-Induced Insulin Secretion*

Under physiological conditions, in the presence of non-stimulatory concentrations of glucose, low levels of insulin are secreted by β-cells. Basal insulin secretion results from the low rate of glucose metabolism, leading the opening of ATP-dependent potassium channels (K⁺ATP channels). The potassium efflux counteracts depolarizing currents which thereby maintains the membrane's steady-state potential at more negative values and the closure of the voltage-dependent Ca²⁺ channels. When the concentration of glucose increases, it enters into the cell and its metabolization through the glycolysis pathway and tricarboxylic acid cycle (TCA) is accelerated (Figure 1). This results in elevated mitochondrial ATP generation and a decrease in ADP concentration, which induces the closure of K⁺ATP channels [35]. The closure of K⁺ATP, induced by higher a ATP/ADP ratio, prevents the K⁺ efflux and thereby causes membrane depolarization. Subsequently, the membrane depolarization leads to the opening of voltage-dependent calcium channels (VDCCs) and the influx of Ca²⁺. Finally, the rise of intracellular Ca²⁺ accounts for the insulin export through a soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated (SNAREs) fusion of a readily releasable pool of insulin-containing vesicles with the plasma membrane [36–38]. This triggering mechanism involving K⁺ATP is responsible for the first phase of the insulin secretory response. This phase occurs during the first 5–10 min. The second phase, termed as the amplifying pathway, is more sustained and is achieved over a period of 30–60 min. This second phase relies on a K⁺ATP-independent mechanism [39]. This mechanism involves several metabolites including TCA intermediates, such as NADPH and NADH, and associated products (anaplerosis), such as glutamate, malonyl-CoA, phospholipase C/protein kinase C (PKC) signaling, alterations in intracellular levels of lipids and/or elevation in cAMP levels, together enhancing cytosolic Ca²⁺ concentrations and insulin exocytosis (Figure 1).
<figure><img src="image_5.png" /><figcaption>**Figure 1.** Triggering and amplifying pathways coupling glucose to insulin secretion. Glucose enters via glucose transporters (GLUTs) and increases the ATP/ADP ratio by glycolytic and TCA metabolism. Then, ATP promotes the closure of $K^+$ channels, which stops the $K^+$ efflux. This leads to membrane depolarization and the opening of voltage-dependent calcium channels (VDCCs). The entry of $Ca^+$ could activate the mitogen-activated kinases ERK/2, which together fosters the fusion of insulin-containing granules with the plasma membrane, and finally the release of insulin into the extracellular compartment. The triggering pathway is followed by the amplifying pathways which involve GLP-1R and other $G_s$-protein coupled receptors (GPCRs), and several metabolites including NADH/NADPH, radical species, $H_2O_2$, and lipidic metabolites. All of these can promote the granule docking, fusion and finally, insulin exocytosis. Granule fusion entails the pairing of the (v)-SNARE (VAMP2) and t-SNAREs (SNAP-25/23 and Syntaxin) proteins, forming a binary cognate target membrane receptor complex. After insulin release, the membrane repolarization involves Kv and Kc channels. GCK: glucokinase, Kv: voltage-dependent potassium channel, Kc: calcium-activated potassium channel, G6P: glucose-6 phosphate, AC: adenylate cyclase, PKA: Protein Kinase A, ERK1/2: extracellular signal-regulated kinases 1/2. VAMP2: vesicle-associated membrane protein 2, SNAP23/25: synaptosome-associated proteins 23/25 kDa.</figcaption></figure>

## 2.2. Peptides from Animal Venoms That Act as Insulin Secretagogues

Within the animal kingdom, several strategies are used for defense and hunting. One consists of using poisons and venoms to subdue and/or kill prey or predators. Unlike poisons that induce their toxicity by ingestion or external contact, venoms have to be parenterally administrated via specialized apparatus (e.g., fangs, stingers, teeth, nematocysts). Some animals including snake, lizards, frogs, spiders, scorpions and cone snails, for example, produce and secrete venoms. Venoms contain a mixture of substances mainly enriched with proteins called "toxins". In fact, toxins include enzymes (e.g., oxidases, hydrolases, proteases and phospholipases), non-enzymatic proteins (e.g., disintegrins) and peptides. Many of venom peptides modulate ion channels and receptors in a broad variety of species including humans [40]. Thanks to their mode of action, toxins from venoms are used in a wide-range of pharmaceutical and cosmeceutical activities [41]. Indeed, several drugs based on peptide toxins, including captopril (hypertension), ziconotide (chronic pain), eptifibatide (cardiovascular diseases), lepirudin (thrombosis, stroke) and cobratoxin
(pain), are currently in clinical use [42]. Venoms can contain peptides that stimulate the production of hormones and growth factors, as illustrated by the venom from the snake *Bothrops jararaca* [43]. This venom contains prothrombin and factor X activators that can elicit the generation of hepatocyte growth factor/scatter factor (HGF/SF), a regenerative growth factor that is considered a therapeutic target in T2D [44]. Finally, some peptides from venom can mimic human hormones and thereby can be potentially used as medicines. This is illustrated by Exendin-4 which has led to the development of new generations of GLP-1RAs with longer half-lives [45]. The Exendin-4 story has been pivotal for supporting the idea that other peptides from venoms can be considered for developing antidiabetic medicines. Two decades of research have enabled the identification of other peptides capable of triggering insulin secretion. Some of these peptides are GLP-1RA, $K^+$*ATP* blockers or modulators of major channels regulating the triggering and/or amplifying pathways of glucose-induced insulin secretion (GSIS).

### 2.2.1. Venom Peptides as New GLP-1RAs

Venom peptides target a wide variety of membrane-bound protein channels and receptors. GLP-1RA, that elevates cAMP levels by activating the G-protein coupled receptor (GPCR), supports the concept that molecules capable of modifying the β-cell membrane depolarization and/or modulating the key intracellular partners of the triggering and amplifying pathways are good insulin secretagogue candidates [46,47]. The discovery of Exendin-4 in the venomous saliva of the Gila monster and the multiple health benefits of GLP-1RAs [13], beyond lowering plasma glucose, have opened up new avenues of research for analogues from other animal species. The 13-amino-acid peptide (RK-13) isolated from the skin of *Agalychnis calcarifer* frogs might act as a GLP-1RA, although the binding to GLP-1R and the downstream receptor signaling have not yet been directly demonstrated [48]. Currently, efforts are focused on the identification of analogues with more selective therapeutic effects than those of Exendin-4 and native GLP-1. In particular, GLP-1 analogues, also called GLP-1 receptor-biased agonists (GLP-1RBAs), are expected to be the future drugs of this class. While GLP-1RBAs act through the same GLP-1 receptor, it improves the durability of the effect on insulin secretion [49]. Two GLP-1RBAs have been discovered in venoms of platypuses (*Ornithorhynchus anatinus*) and short-beaked echidnas (*Tachyglossus aculeatus*), two mammals of the monotreme order living in Australia and New Guinea [50]. The two GLP-1RBAs are structurally analogous to Exendin-4, although they differ by 12 amino acids in their sequence [50]. The affinity of both peptides for the human GLP-1 receptor is lower than native GLP-1 [50]. Nonetheless, these novel analogues stimulate insulin secretion in response to glucose through the preferential activation of one of the MAPK signaling pathways (ERK1/2) [50]. In addition, both peptides are more resistant to digestion by dipeptidyl peptidase-4 (DPP-4) than Exendin-4 [50], thus confirming the feasibility for the development of new GLP-1 analogues with longer-lasting and more specific effects.

### 2.2.2. $K^+$*ATP* Channel Inhibitor Peptides from Venom

The closure and opening of $K^+$*ATP* channel are pivotal for controlling insulin secretion. This channel consists of four sulfonylurea receptors (SURs) surrounding four pore-forming subunits named Kir6.1 or Kir6.2 [51]. Channel activity involves the interaction of ATP or ADP with the two nucleotide-binding sites of SUR. When glucose concentration rises in plasma, it is sensed by the β-cell thanks to its facilitated passage into cytoplasm via the low $K_m$ glucose transporters (GLUT2). The increase in glucose metabolism promotes ATP synthesis. ATP binding to SUR1 causes $K^+$*ATP* channel closure, inhibition of the $K^+$ efflux, β-cell membrane depolarization, calcium influx and finally insulin secretion [51]. SUs can also directly stimulate insulin exocytosis by penetrating into β-cells and triggering its secretory machinery [52]. SUs cause a maximum channel blocking of ~50–80% [53], thereby stimulating insulin secretion. The first members of SUs for treating T2D were tolbutamide, chlorpropamide, acetohexamide and tolazamide [54]. Second-generation and third-
generation SUs were developed later including glyburide, glipizide and glimepiride [55,56]. Another class of oral antidiabetic targeting K⁺ATP channels is the glinides [57]. Like SUs, all glinides promote closure of the K⁺ATP channels. However, unlike SUs, glinides bind directly to the Kir6.1 subunit [57]. Glinides, including repaglinide (RPG), meglitinide, mitiglinide and nateglinide, are widely prescribed, because of their good safety and efficacy for controlling postprandial blood glucose by stimulating insulin secretion. However, glinides can also provoke hypoglycemia as they elicit insulin secretion in a glucose-independent manner. Nonetheless, the release of SU and glinides has been instrumental for serving as models for identifying other therapeutic peptides capable of blocking K⁺ATP channels by activating the Kir6.1 subunit or SUR. At the present time, several insulin secretagogue peptides from animal venom inducing the closure of the K⁺ATP channel have been identified (Table 1). However, unlike SUs and glinides, for most peptides, their effects on the K⁺ATP channels seem to be indirect. This is the case for mastoparan, tigerinin and secretory phospholipase 2 [58–60]. Only the protein toxin dubbed SpTx1, isolated from the venom of desert centipede *Scolopendra polymorpha*, has been shown to directly interact with the K⁺ATP channel [61]. In addition, SpTx1 inhibits K⁺ATP channels by blocking the ion-conduction pore [62]. However, the usage of this peptide as K⁺ATP inhibitor should raise the question of their safety. Besides the risk of hypoglycemia, the same drawbacks as SUs and glinides, the K⁺ATP channel inhibitor peptides might affect cardiomyocytes, where the channel is abundantly expressed. This hypothesis is supported by SUs, which might increase the risk of cardiovascular events by targeting the K⁺ATP channel [63]. The search for K⁺ATP channel inhibitor peptides as insulin secretagogues definitely requires further investigations of their effects in heart function.

<table><caption>**Table 1.** K⁺ATP inhibitor peptides that stimulate insulin secretion.</caption><thead><tr><th>Compounds</th><th>Specie</th><th>In Vitro Models</th><th>In Vivo Models</th><th>Reference(s)</th></tr></thead><tbody><tr><td>SpTx1</td><td>Scolopendra polymorpha</td><td>Isolated mouse islets</td><td>Wild type mice</td><td>[62]</td></tr><tr><td>Mastoparan</td><td>Vespula lewisii</td><td>Rat RINm5F, hamster HIT-T15, mouse αTC3 cells, rat INS-1 cells isolated rat and human islets</td><td>ND</td><td>[58,64–66]</td></tr><tr><td>Secretory phospholipase 2</td><td>Naja mossambica</td><td>Isolated mouse islets and single β-cells</td><td>ND</td><td>[60]</td></tr><tr><td>Tigerinin-1R and analogs</td><td>Indian frog Hoplobatrachus tigerinus</td><td>BRIN-BD11 cells</td><td>HFD-induced Swiss obese mice</td><td>[59,67,68]</td></tr></tbody></table>

ND: Not Done, High Fat Diet: HFD.

### 2.2.3. Venom Peptides Inhibiting Voltage-Dependent (Kv) and Calcium-Activated (Kc) Potassium Channels

Another strategy for stimulating GSIS is to inhibit β-cell membrane repolarization controlled by voltage-dependent (Kv) and calcium-activated (Kc) high conductance K⁺ channels. Kv and Kc open upon membrane depolarization and mediate outwardly rectifying K⁺ currents, which act to repolarize action potentials [69]. Kv and Kc channels are a homo- or heterotetrameric complex of α-subunits of the same family. Kv2.1 is the major β-cell Kv channel isoform. Some peptides from venoms of striated cones, tarantulas and scorpions have been identified to be capable of inhibiting Kv channel activity (Table 2). These peptides are supposed to maintain the β-cell in a depolarized state, which would prolong insulin secretion only in the presence of glucose. However, Kv and Kc are also expressed in bladder and other excitable cells of the neuronal and cardiovascular systems [70,71]. Therefore, further investigations are required for controlling the side effect of peptides in clinical applications.
<table><caption>**Table 2.** Calcium-dependent potassium ($K_C$) or voltage-dependent potassium channels ($K_V$) inhibitor peptides that stimulate insulin secretion.</caption><thead><tr><th>Compounds</th><th>Specie</th><th>Class of the Active Substance</th><th>In Vitro Models</th><th>In Vivo Models</th><th>Reference(s)</th></tr></thead><tbody><tr><td>Conkunitzin-S1</td><td>Striated Cone (<i>Conus striatus</i>)</td><td>Inhibitor of K<sub>V1.7</sub></td><td>Isolated rat islets</td><td>ND</td><td>[72]</td></tr><tr><td>Guangxitoxin-1 (GxTX-1)</td><td>Chinese Fawn Tarentula (<i>Chilobrachys Guangxiensis</i>)</td><td>Inhibitor of K<sub>V2.1</sub> and K<sub>V2.2</sub></td><td>Isolated mouse islets</td><td>ND</td><td>[67]</td></tr><tr><td>Hanatoxin (HaTX)</td><td>Chilean Rose Tarentula (<i>Grammostola rosea</i>)</td><td>Inhibitor of K<sub>V2.1</sub></td><td>Isolated human islets</td><td>ND</td><td>[73]</td></tr><tr><td>Iberiotoxin</td><td>Eastern Indian Scorpion (<i>Hottentotta tamulus</i>)</td><td>Inhibitor of K<sub>C</sub></td><td>Isolated human islets, mouse MIN6 cells</td><td>ND</td><td>[74,75]</td></tr></tbody></table>

ND: Not Done.

### 2.2.4. Peptides That Stimulate Insulin Secretion in a Not Yet Identified Mechanisms

A large number of toxins are ion channel modulators that can inhibit or activate metabolic enzymes. If the venom peptides act as ligands of ion channels, they also possess other favorable characteristic features such as small size with high stability, cationicity and hydrophobicity. For example, cationicity promotes peptide-cell membrane interactions and subsequent internalization. These physicochemical characteristics provide peptides some key advantages as antimicrobial agents [76,77]. Some of these peptides have led to Captopril, an angiotensin converting enzyme inhibitor, which is derived from the venom of the *Bothrops jararaca* viper [78]. Captopril is prescribed for the treatment of hypertension, diabetic nephropathy and heart failure [79]. Several cationic venom peptides with insulin secretagogue activity have been identified (Table 3). However, the mechanisms through which they stimulate insulin secretion are not elucidated. Thanks to their cationicity, it is suggested that these peptides penetrate membranes and enter into cells to stimulate insulin secretion via mechanisms that do not require $K^+_{ATP}$. These peptides that can enter into cells include bombesin [80]; crotamine [81] members from *Pipidae* and *Ranidae* families isolated from the skin of amphibians [82]; Brevinin-2-related peptide (B2RP), a peptide of the northern frog (*Lithobates septentrionalis*); Alyteserin-2a of the midwife toad (*Alytes obstetricans*); Hymenochirin-1b of the African dwarf frog (*Hymenochirus boettgeri*); Magainin-AM1 and AM2 of *xenopus amieti*; and Esculentin-2Cha of the Chiricahua leopard frog (*Lithobates chiricahuensis*). The peptides enter into the cells, depolarize the β-cell membrane and stimulate insulin secretion [83]. These peptides could pave the way for the development of a new class of antidiabetic drugs, although they may also lead to hypoglycemia.

<table><caption>**Table 3.** Peptides stimulating insulin secretion with unknown mechanisms.</caption><thead><tr><th>Compounds</th><th>Specie</th><th>In Vitro Models</th><th>In Vivo Models</th><th>Reference(s)</th></tr></thead><tbody><tr><td>Agelaia MP-I (AMP-I)</td><td>Vespid wasp (<i>Agelaia pallipes pallipes</i>)</td><td>Isolated mouse islets</td><td>ND</td><td>[84]</td></tr><tr><td>Alyteserin-2a</td><td>Midwife toad (<i>Alytes obstetricans</i>)</td><td>BRIN-BD11 cells</td><td>High-fat-diet-induced obese Swiss mice</td><td>[85]</td></tr><tr><td>Amolopin</td><td>Frog (<i>Amolops loloensis</i>)</td><td>Rat INS-1 cells</td><td>ND</td><td>[86]</td></tr><tr><td>Bombesin</td><td>Frog (<i>Bombina bombina</i>)</td><td>HIT-T15 cells, isolated rat islets</td><td>Wild type baboon, wild type rats</td><td>[87–92]</td></tr><tr><td>Brevinin-2-related peptide (B2RP)</td><td>Mink frog (<i>Lithobates septentrionalis</i>)</td><td>BRIN-BD11 cells</td><td>HFD-induced obese Swiss mice</td><td>[93]</td></tr><tr><td>Caerulein-related peptides</td><td>Frog (<i>Xenopus borealis</i> and <i>Xenopus amieti</i>)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[94]</td></tr></tbody></table>
<table><caption>**Table 3. Cont.**</caption><thead><tr><th>Compounds</th><th>Specie</th><th>In Vitro Models</th><th>In Vivo Models</th><th>Reference(s)</th></tr></thead><tbody><tr><td>Crotamine</td><td>Rattlesnake (Crotalus durrisus terrificus)</td><td>Isolated rat islets</td><td>ND</td><td>[95]</td></tr><tr><td>Dermaseptin B-IV</td><td>Frog (Phyllomedusa trinitatis)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[96]</td></tr><tr><td>Esculentin-2CHa</td><td>Chiricahua leopard frog (Lithobates chiricahuensis)</td><td>BRIN-BD11 cells</td><td>Wild type and HFD-induced obese Swiss mice</td><td>[97,98]</td></tr><tr><td>Hymenochirin-1b</td><td>Frog Hymenochirus boettgeri</td><td>BRIN-BD11 cells</td><td>Wild type Swiss mice</td><td>[99,100]</td></tr><tr><td>Magainin-AM1</td><td>Volcano clawed frog (Xenopus amieti)</td><td>BRIN-BD11 cells</td><td>Wild type and HFD-induced obese Swiss mice</td><td>[101]</td></tr><tr><td>Magainin-AM2</td><td>Volcano clawed frog (Xenopus amieti)</td><td>BRIN-BD11 cells</td><td>Wild type and HFD-induced obese Swiss mice</td><td>[101]</td></tr><tr><td>Melittin</td><td>Honeybee (Apis mellifera)</td><td>Isolated mouse and rat islets</td><td>ND</td><td>[102,103]</td></tr><tr><td>Ocellatin-L2</td><td>Bullfrog (Lithobates catesbeianus)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[104]</td></tr><tr><td>Palustrin-2CBa</td><td>Bullfrog (Lithobates catesbeianus)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[105]</td></tr><tr><td>Peptide Glycine-Leucine-Amide (PGLa)-AM1</td><td>Frog (Xenopus amieti)</td><td>BRIN-BD11 cells and isolated mouse islets</td><td>ND</td><td>[106,107]</td></tr><tr><td>Plasticin-L1</td><td>Frog (Leptodactylus laticeps)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[82]</td></tr><tr><td>Pseudin-2</td><td>frog (Pseudis paradoxa)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[108]</td></tr><tr><td>Ranatuerin-2CBd</td><td>Bullfrog (Lithobates catesbeianus)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[105]</td></tr><tr><td>Temporin-1OE, -1Va, -1Vb 1-Vc; -1DRb, -1TGb</td><td>Frog (Rana Ornativentris, Rana virgatipes, Rana draytonii, Rana Tagoi)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[109]</td></tr><tr><td>Xenopsin and Xenopsin-AM2</td><td>Frog (Xenopus borealis and Xenopus amieti)</td><td>BRIN-BD11 cells</td><td>ND</td><td>[94]</td></tr></tbody></table>

HFD: High Fat Diet; ND: Not Done.

## 2.3. Polyphenols and Alkaloids from Plants Stimulating Insulin Secretion

Medicinal plants have been a major focus of research due to the presence of bioactive compounds that may provide the foundation for drug design. The World Health Organization lists almost 21,000 plants used for medicinal purposes worldwide [110]. Bioactive substances include mostly polyphenols and alkaloids. Polyphenols are secondary polyhydroxy phytochemicals metabolites resulting from the shikimic acid and phenylpropanoid pathways of plants. These metabolites mediate plant defenses against pathogenic aggression and ultraviolet radiation [111]. They are also key for plant adaptation against stressful environments and cues [112]. These phenolic substances share a common phenolic ring structure, with one or more phenolic rings linked to more than one hydroxyl group [113].
Polyphenols are classified into several subgroups (Figure 2) with flavonoids being the largest one [114].

<figure><img src="image_6.png" /><figcaption>**Figure 2.** Classification of Polyphenols.</figcaption></figure>

Alkaloids are nitrogenous compounds derived from the metabolism of amino acids, such as tyrosine, lysine, ornithine, phenylalanine and tryptophan. They contain at least one nitrogen atom in a heterocyclic ring. In addition, most alkaloids contain oxygen. The term alkaloid refers to the basic (alkaline) nature of the structure. There are several groups of alkaloids (Figure 3), which are mainly found as salts or as N oxides in seed-bearing plants, in berries, bark, fruits, roots and leaves. They are also found in marine algae [115] and in the skin of amphibians along with other toxins [116]. Among more than twenty thousand alkaloids, several dozen are currently used as medical drugs as exemplified by morphine and codeine [117]. An application of alkaloids and polyphenols for the treatment of diabetes is possible. The literature reports a plethora of studies confirming some direct effects of polyphenols and alkaloids on insulin secretion. Some of them inhibit insulin secretion, as exemplified by colchicine [118], scopolamine [119,120], melatonin [121,122], atropine [123], cystisine [124] and serotonine [125]. For some others, there are still some debates and conflicting results. For example, according to the concentration, nicotine [124,126,127], some quinoline members (e.g., quinine and quinidine) [128,129] and some isoquinoline members (e.g., berberine) [130–132] can either stimulate or inhibit insulin secretion. Nonetheless, numerous polyphenols and alkaloids have been identified as direct insulin secretagogues. However, the molecular mechanisms of their effects are different. While some polyphenols, such as resveratrol, cyanidin and rutin, stimulate insulin secretion via an increase in glucose metabolism or a direct augmentation of Ca²⁺ influx [133–135], other polyphenol substances and alkaloids enhance insulin secretion via other pathways. Some molecules can directly trigger the closure of K⁺ATP (Table 4), although it is unclear if they directly close the K⁺ATP channels by binding to SUR or Kir6.2 and/or indirectly induce the closure through an increase in ATP production. Other molecules promote the rise of cAMP levels similar to GLP-1RAs (Table 5). Unlike myricetin, the mechanism through which compounds such as vanillic acid stimulate the rise of cAMP is not well understood. Curcumin could also induce the rise of cAMP via the inhibition of phosphodiesterase activity [136], whereas genistein and daidzein seem to directly stimulate adenylate cyclase activity similar to forskolin [137]. Quercetin may activate β-adrenergic receptors [138], whereas the alkaloid morphine could involve opioid receptors [139].
<figure><img src="image_7.png" /><figcaption>**Figure 3.** Classification of Alkaloids.</figcaption></figure>

<table><caption>**Table 4.** Polyphenols and alkaloids that stimulate insulin secretion in a mechanism that requires the closure of K<sup>+</sup><sub>ATP</sub> channels.</caption><thead><tr><th>Compounds</th><th>Class</th><th>Group of the Active Substance</th><th>In Vitro Models</th><th>In Vivo Models</th><th>Reference(s)</th></tr></thead><tbody><tr><td>Astragalin</td><td>Flavonol</td><td>Polyphenol</td><td>Isolated rat islets</td><td>ND</td><td>[140]</td></tr><tr><td>Caffeine</td><td>Purine</td><td>Alkaloid</td><td>ND</td><td>NMRI and BALB/c mice transplanted with mouse islets</td><td>[141–143]</td></tr><tr><td>Ellagic acid</td><td>Tannin</td><td>Polyphenol</td><td>Isolated mouse islets</td><td>ND</td><td>[144,145]</td></tr><tr><td>Kaempferol</td><td>Flavonol</td><td>Polyphenol</td><td>ND</td><td>ND</td><td>[146]</td></tr><tr><td>Lupanine</td><td>Quinolizidine</td><td>Alkaloid</td><td>Isolated rat islets</td><td>ND</td><td>[147]</td></tr><tr><td>Nuciferin</td><td>Aporphine</td><td>Alkaloid</td><td>Isolated mouse CD1 islets and INS-1 cells</td><td>ND</td><td>[148]</td></tr><tr><td>Quercetin</td><td>Flavonol</td><td>Polyphenol</td><td>Rat INS-1 cells</td><td>ND</td><td>[149]</td></tr><tr><td>Resveratrol</td><td>Stilbene</td><td>Polyphenol</td><td>MIN6 cells, HIT-T15, and RIN-m5F cells</td><td>Wistar Rats</td><td>[150]</td></tr><tr><td>Schisandrol A, schisandrol B and schisandrin C</td><td>Lignan</td><td>Polyphenol</td><td>Rat INS-1 cells</td><td>ND</td><td>[151]</td></tr><tr><td>Sparteine</td><td>Quinolizidine</td><td>Alkaloid</td><td>HIT-T15 cells</td><td>ND</td><td>[152]</td></tr><tr><td>2R, 3R taxifolin 3-O-rhamnoside</td><td>Flavanonol</td><td>Polyphenol</td><td>ND</td><td>Wild type mice</td><td>[153]</td></tr><tr><td>Vindoline</td><td>Indole</td><td>Alkaloid</td><td>Mouse MIN6 cells and isolated mouse islets</td><td>db/db mice and STZ/HFD-induced type 2 diabetic rats</td><td>[154]</td></tr></tbody></table>

ND: Not Done.
<table><caption>**Table 5.** Polyphenols and alkaloids that stimulate insulin secretion via a rise in cAMP levels.</caption><thead><tr><th>Compounds</th><th>Subclass</th><th>Class of the Active Substance</th><th>In Vitro Models</th><th>In Vivo Models</th><th>Reference(s)</th></tr></thead><tbody><tr><td>Curcumin</td><td>Curcuminoid</td><td>Polyphenol</td><td>Mouse MIN6 cells and isolated human islets</td><td>ND</td><td>[136]</td></tr><tr><td>Daidzein</td><td>Isoflavone</td><td>Polyphenol</td><td>Rat INS-1 cells and isolated mouse islets</td><td>ND</td><td>[155,156]</td></tr><tr><td>Genistein</td><td>Isoflavone</td><td>Polyphenol</td><td>Rat INS-1 cells, mouse MIN6 cells and isolated mouse islets, isolated human islets</td><td>Streptozotocin-induced diabetic mice</td><td>[137,157,158]</td></tr><tr><td>Morphine</td><td>Isoquinoline</td><td>Alkaloid</td><td>Isolated rat islets</td><td>ND</td><td>[139,159]</td></tr><tr><td>Myricetin</td><td>Flavonol</td><td>Polyphenol</td><td>Isolated rat islets</td><td>Wistar Rats</td><td>[160]</td></tr><tr><td>Vanillic acid</td><td>Benzoic acid</td><td>Polyphenol</td><td>Rat INS-1 cells and isolated rat islets</td><td>ND</td><td>[161]</td></tr></tbody></table>

ND: Not done.

### 3. Venom Peptides, Polyphenols and Alkaloids Protecting β-Cells against Death Induced by Diabetogenic Environments

#### 3.1. Preserving β-Cell Mass in T2D by Antagonizing ER Stress, Oxidative Stress and Autophagy as the Paradigm for Achieving Long-Term Glycemic Control in T2D

In T2D, β-cell death is the leading cause in the reduction of β-cell mass [16,162] although the increase of β-cell senescence [163] and dedifferentiation [164] are also involved. Nowadays, there is evidence that β-cell death results from activation of several pathways including Endoplasmic Reticulum (ER) stress [165], oxidative stress (OS) [166] and autophagy [167,168], which intersect with one another. Amyloid deposits, pro-inflammatory cytokines, hyperlipidemia (cholesterol and saturated fatty acids) and hyperglycemia are, individually and in combination, involved in the induction of ER stress, OS and autophagy [169,170]. When compared to SUs, glinides and gliptines, the GLP-1RAs are the only antidiabetic drugs that can antagonize the deleterious effects of ER stress [14], oxidative stress [171] and autophagy in β-cells [172]. Although the preclinical data are exciting, in clinical setting, the long-term benefits of some GLP-1RAs are debated as many patients are non-responders to GLP-1RAs and switch to insulin therapy [173]. One explanation is that the expression of GLP-1 receptor (GLP-1R) is decreased in patients with T2D [174,175]. The insufficient GLP-1R levels in β-cells could reduce the biological effects of GLP-1RAs and thereby limit their use in some patients. Therefore, there is an urgent need that the next generation of antidiabetics that targets β-cells not only improve insulin secretion, but also protect them against death caused by stress-induced pathways.

#### 3.2. Survival Proteins of β-Cells Revealed by GLP-1RAs

Intensive studies have tried to unravel the mechanism through which GLP-1RAs antagonize the deleterious effects of ER stress [14], oxidative stress [171] and autophagy [172]. These mechanisms have been instrumental for identifying the key targets required for β-cell protection. These proteins are listed in the Table 6 and are considered as key players in the β-cell protection elicited by GLP-1RAs when they meet the following criteria: (1) they are activated and/or their expression induced by GLP-1RAs in β-cells and (2) their inhibition and/or suppression attenuate the protective effect of GLP-1RAs on cell death induced by pro-apoptotic stressors. All these proteins belong to the GLP-1RA signaling cascade and are therefore connected with each other, as exemplified by the IB1/JIP1/JNK3 pathway [176]. Therefore, targeting these proteins using GLP-1RAs represents a relevant therapeutic strategy for improving β-cell mass in T2D.
<table><caption>**Table 6.** β-cell survival proteins induced by GLP-1RAs.</caption><thead><tr><td>Protein Name</td><td>Protein Role</td><td>Reference(s)</td></tr></thead><tbody><tr><td>AKT, also called PKB</td><td>AKT is a serine/threonine kinase which activates CREB, PDX1 and mammalian target of rapamycin (mTOR) complex 1. It inhibits glycogen synthase kinase 3 (GSK3β), caspase-9, FoxO1 and Bcl-2-associated death promoter (Bad)</td><td>[177,178]</td></tr><tr><td>MAK8IP1 also called Islet Brain 1/JIP1</td><td>Scaffold protein that tethers MAP3K/MAP2K/JNK.MAPK8IP1 is involved in the anti-apoptotic JNK signaling pathway</td><td>[179–181]</td></tr><tr><td>MAPK10/JNK3</td><td>Anti-apoptotic with unidentified targets. JNK3 is regulated by MAP8IP1/JIP-1/IB1</td><td>[176]</td></tr><tr><td>CREB</td><td>Transcription factor that positively regulates the expression of insulin receptor substrate 2, a key component of IGF-1 and insulin receptor signaling leading to AKT activation</td><td>[182]</td></tr><tr><td>ERK1/2</td><td>Ras-dependent extracellular signal-regulated kinase 1 (ERK1)/2 mitogen-activated protein (MAP) kinase pathway regulates cell survival</td><td>[183–185]</td></tr><tr><td>SERCA2b</td><td>P-type ATPase that regulates endoplasmic reticulum (ER) Ca<sup>2+</sup> stores.</td><td>[186,187]</td></tr><tr><td>PDX-1</td><td>Transcription factor that determines endocrine cell fate and controls β-cell differentiation</td><td>[188]</td></tr><tr><td>PKA</td><td>Protein kinase A that phosphorylates transcription factor CREB</td><td>[14,185]</td></tr><tr><td>NKX6.1</td><td>Transcription factor that determines the specification of progenitor cells into mature functional β-cells. It maintains the function of adult pancreatic β-cells.</td><td>[189,190]</td></tr><tr><td>FoxO1</td><td>Forkhead transcription factor (Fox) of the O subclass. FoxO1 is a transcriptional effector of IGF signaling that controls β-cell mass through Pdx1</td><td>[191,192]</td></tr><tr><td>NRF2</td><td>The nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a leucine zipper (bZip) transcription factor that regulates oxidant levels</td><td>[193,194]</td></tr><tr><td>MAFA</td><td>While v-Maf musculoaponeurotic fibrosarcoma transcription factor A (MAFA) controls β-cell differentiation, it maintains the mature phenotype and viability of β-cells</td><td>[195]</td></tr><tr><td>XBP-1</td><td>X-box binding protein 1 (XBP1) is leucine zipper (bZIP) transcription factor that promotes ER biogenesis and activates the expression of ER chaperone genes</td><td>[196,197]</td></tr><tr><td>ERα</td><td>Estrogen receptor α (ERα) is a nuclear receptor that maintains the mitochondrial fission/fusion–mitophagy dynamics</td><td>[198,199]</td></tr><tr><td>Glucokinase</td><td>Transferase that phosphorylates glucose</td><td>[200]</td></tr><tr><td>PPARγ</td><td>Nuclear factor that regulates components of β-cell function and survival</td><td>[201,202]</td></tr><tr><td>AMPK</td><td>AMP-activated protein kinase that regulates β-cell survival via the mTOR pathway</td><td>[203,204]</td></tr><tr><td>Bcl2</td><td>Mitochondrial membrane protein that inhibits apoptosis</td><td>[205]</td></tr></tbody></table>

### 3.3. Peptides from Venoms That Protect β-Cells against Death by Targeting β-Cell Survival Proteins

Despite the identification of venom peptides that can act as insulin secretagogues, there are few in vitro and preclinical studies stating a direct protective effect of these peptides in β-cell death. In addition, most studies did not validate the direct role of the peptides in β-cell viability and/or β-cell mass, although plasma glucose, insulin level and blood biomarkers have been investigated [82]. In fact, only considering the in vitro and in vivo studies that have directly investigated β-cell viability, very few peptides from venoms have been tested among those exhibiting an insulin secretagogue activity. Temporins A and F protect BRIN-BD11 cells against death [206]. However, the mechanism through which temporins trigger β-cell protection has not been elucidated thus far. A protective role of esculentin-2Cha and PGLa-AM1 in an in vitro model of β-cells, possibly via the induction
of PDX1, has been described [106,207]. Nonetheless, these results still need to be confirmed
in human islets and islets of animal models of T2D.

3.4. *Polyphenols and Alkaloids That Protect β-Cells against Death by Targeting the β-Cell Survival Proteins*

Unlike the peptides from venom, the literature is more substantial regarding studies investigating the protective effect of polyphenols and alkaloids on β-cell death. Dozens of these plant substances (Table 7), mostly polyphenols, have been directly tested for their capacity to counteract the toxicity induced by diabetogenic factors and exploring the underlying mechanisms. Besides stimulating insulin secretion (see Section 2.3), curcumin, cyanidin, kaempferol, quercetin, myricetin, genistein, silibilin and resveratrol, seem to directly protect β-cells similar to GLP-1RAs. It is noteworthy that the protective effect of flavonol, curcuminoid, flavone, isoflavone, flavinolignan and stilbenes on β-cells could also rely on their phytoestrogen activity in a mechanism involving estrogen receptors (ER). Indeed, as phytoestrogens, the members of the six polyphenol subclasses can bind to both types of ERα receptors and ERβ receptors, mimicking the effect of estradiol [208–210]. Estradiol prevents β-cells death induced by OS [211]. However, the estradiol-mimicking effect of these polyphenols in β-cell protection remains to be confirmed. In addition, at the present time, evidence supporting the role of polyphenols and alkaloids for reducing hyperglycemia and improving β-cell mass and function in human are missing. Resveratrol fails to restore glycemia and to improve insulin secretion in a clinical trial of diet-controlled patients with T2D treated for 5 weeks with stilbene [212]. In other clinical trials, although promising, the data are incomplete as only mixtures of polyphenol-enriched extracts were used. Using either polyphenol-rich drinks [213] or polyphenol-enriched plant extracts, the clinical studies showed an improvement in fasting and/or postprandial glycemia in healthy individuals or people with metabolic syndrome or with T2D [214–216]. In a 3-month period trial, curcumin administrated in patients with T2D improved glycemia and plasma insulin levels [217]. Among alkaloids, berberine is one of the most intensively studied [218]. Besides the improvement of insulin sensitivity, hepatic lipid metabolism and adipose fibrosis, this isoquinoline might also alleviate hyperglycemia by protecting β-cells against death induced by lipotoxicity in a mechanism involving SIRT1 [219]. Although berberine seems convincing as a promising antidiabetic, the temporary adverse gastrointestinal events observed in one third of patients treated with the alkaloid in a trial of 59 patients [220], has restrained the medical community from using it for clinical purposes. This worry is further supported by the inconsistent bioavailability of berberine after oral ingestion, as shown by a randomized, double-blind, placebo-controlled investigation [221]. In addition, as mentioned above (see Section 2.3), there are conflicting results of the effect of berberine on insulin secretion [130,132]. Therefore, future experimental and clinical studies are required for confirming the effectiveness of berberine on insulin secretion and its long-term safety in a consistent cohort of patients.
<table><caption>**Table 7.** Polyphenols and alkaloids targeting β-cell survival proteins.</caption><thead><tr><th>Compounds</th><th>Class</th><th>Group of the Active Substance</th><th>Target Protein</th><th>In Vitro Models</th><th>In Vivo Models</th><th>Reference(s)</th></tr></thead><tbody><tr><td>Curcumin</td><td>Curcuminoid</td><td>Polyphenol</td><td>AKT, FoxO1, SIRT1</td><td>Mouse MIN6 cells</td><td>ND</td><td>[222,223]</td></tr><tr><td>Epigallocatechin (EGCG)</td><td>Flavonol</td><td>Polyphenol</td><td>AKT, PDX1, FoxO1, Bcl2, AMPK</td><td>Rat RINm5F</td><td>ND</td><td>[224]</td></tr><tr><td>Anthocyanins</td><td>Anthocyanidins</td><td>Polyphenol</td><td>AMPK, Bcl2, PDX1</td><td>ND</td><td>KKAy diabetic mice STZ-induced diabetic rats</td><td>[225,226]</td></tr><tr><td>Dephinidin</td><td>Anthocyanidins</td><td>Polyphenol</td><td>AMPK</td><td>Rat RINm5F</td><td>ND</td><td>[227]</td></tr><tr><td>Cyanidin (Cyanidin-3-glucoside)</td><td>Anthocyanidins</td><td>Polyphenol</td><td>PPARγ, AKT, Bcl2</td><td>Mouse MIN6 and rat INS-1 cells</td><td>ND</td><td>[228–230]</td></tr><tr><td>Apigenin</td><td>Flavone</td><td>Polyphenol</td><td>AKT</td><td>Hamster HIT-T15 and rat RINm5F cells</td><td>ND</td><td>[231–233]</td></tr><tr><td>Luteolin</td><td>Flavone</td><td>Polyphenol</td><td>AKT, MAFA</td><td>Rat INS-1 cells, MIN6 cells and isolated mouse islets</td><td>Alloxan-induced diabetic rats</td><td>[234–236]</td></tr><tr><td>Kaempferol</td><td>Flavonol</td><td>Polyphenol</td><td>AKT, Bcl2, PKA, PDX1</td><td>Isolated human islets and INS-1 cells</td><td>ND</td><td>[146]</td></tr><tr><td>Quercetin</td><td>Flavonol</td><td>Polyphenol</td><td>ERK1/2, AKT</td><td>Rat RINm5F and INS-1 cells</td><td>ND</td><td>[232,237]</td></tr><tr><td>Myricetin</td><td>Flavonol</td><td>Polyphenol</td><td>PDX1, AKT</td><td>Rat RINm5F and INS-1 cells</td><td>ND</td><td>[238,239]</td></tr><tr><td>Naringenin</td><td>Flavonol</td><td>Polyphenol</td><td>AKT</td><td>INS-1 cells</td><td>ND</td><td>[237]</td></tr><tr><td>Genistein</td><td>Isoflavone</td><td>Polyphenol</td><td>ERK1/2, cAMP</td><td>Isolated human islets and INS-1 cells</td><td>STZ-induced diabetic rats</td><td>[240]</td></tr><tr><td>Silibinin</td><td>Flavinolignan</td><td>Polyphenol</td><td>PKA, PDX1</td><td>ND</td><td>STZ-induced diabetic rats</td><td>[241–243]</td></tr><tr><td>Resveratrol</td><td>Stilbene</td><td>Polyphenol</td><td>PDX1, FoxO1</td><td>Isolated human islets, isolated rat islets and INS-1 cells</td><td>HFD-induced diabetic mice</td><td>[244–246]</td></tr><tr><td>Berberine</td><td>Isoquinoline</td><td>Alkaloid</td><td>Nrf2</td><td>Rat INS-1 cells, MIN6 cells</td><td>ND</td><td>[131,219]</td></tr></tbody></table>

ND: Not Done, STZ: Streptozotocin.

4. Conclusions

The fight against diabetes epidemic worldwide requires efficient drugs that not only improve β-cell function, but also preserve their mass [247]. This review underlines that only polyphenols and one alkaloid, berberine, have been clearly studied as insulin secretagogues and β-cell protectors, whereas the effects of animal venom peptides in the preservation of β-cell are largely under investigated. Flavonols, curcuminoids, flavones, isoflavones, flavinolignans and stilbenes can be considered as the most promising drugs, as exemplified by curcumin, resveratrol, silibilin, genistein, myricetin, quercetin, EGCG and apigenin. In addition, as phytoestrogens, all these polyphenols could provide several additional benefits for patients. Phytoestrogens are reported to lower the risk of menopausal symptoms, cardiovascular diseases, brain function disorders and several cancers such as breast, bowel, uterine and prostate cancers [248]. Nonetheless, the interest in these polyphenols for clinical use will only be approved if future studies at least confirm their safety in terms of infertility risks and increased risks of cancer in estrogen-sensitive organs. The careful attention to their safety is further supported by the fact that polyphenols also target a large number of receptors and non-receptor tyrosine kinases and serine-threonine kinases, which play key pleiotropic roles in cellular signaling and physiology [249,250]. Besides their safety, there is still a need for additional preclinical studies to confirming their bioavailability,
pharmacokinetics and efficiency upon delivery by an oral route. Successful delivery of polyphenols and alkaloids via this route could offer some metabolic advantages as these compounds might directly stimulate GLP-1 secretion in the gut. Curcumin, delphinidin, EGCG and genistein, for example, are able to stimulate GLP-1 secretion in in vitro and rodent diabetic models [251]. In the gut, the polyphenols could also be beneficial by acting as prebiotics for stimulating the production of *Akkermansia muciniphila*, a bacteria that improves the glucose metabolism of patients with T2D [252], as shown by a previous study using polyphenol-rich extracts [253]. However, oral administration of polyphenols is challenging as it compromises the stability of the substances in the gastrointestinal tract and their proper absorption. Polyphenols are not well assimilated by the gut if they are delivered as glycosides, esters or polymers [254]. In addition, they can be modified by intestinal bacteria and trigger some side effects including nausea, headache and nasopharyngitis, even though the available data from clinical studies are rather optimistic, showing that polyphenols are overall safe and cause marginal side effects [255].

Encapsulation of peptides, polyphenols and alkaloids into biocompatible nanoparticles/nanocapsules will increase their apparent solubility, bioavailability and intestinal permeability and reduce their side effects [256-258]. Optimal formulation of these substances with nanoparticles and their preclinical validation are required before proceeding to clinical trials. The latter should be randomized and performed in large cohorts of patients receiving the therapeutic substances for periods of over 6 months. In addition, for validating the properties of the substances on β-cell mass and function, it is essential that trials include the current methods for monitoring β-cell function and mass such as arginine-induced insulin secretion, mixed meal tolerance tests, oral glucose tolerance tests and/or intravenous glucose tolerance tests [259].

**Author Contributions:** Conceptualization, A.A.; Funding acquisition, A.A.; project administration, A.A.; Writing—original draft, A.A., M.L., V.P. (Valérie Plaisance), V.P. (Valérie Pawlowski), M.K., A.B., E.B., S.D., S.S., J.V. and R.B.; Writing—review and editing, A.A., M.L., V.P., V.P. (Valérie Pawlowski), M.K., A.B., E.B., S.D., S.S., J.V. and R.B.; M.L., V.P. (Valérie Plaisance) and V.P. (Valérie Pawlowski) contributed equally to the work. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding. The APC was covered by the full waiver from the journal.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** This research was supported by the Centre National de la Recherche Scientifique, the University of Lille, I-SITE-ULNE, the region des Hauts-de-France and the Agence Nationale pour la Recherche ANR-22-CE09-0016-01.

**Conflicts of Interest:** The authors declare no conflict of interest.

## References

1. Bungau, S.; Popa, V.-C. Between Religion and Science: Some Aspects: Concerning Illness and Healing in Antiquity. *Transylv. Rev.* **2015**, *XXIV*, 3-19.

2. Newman, D.J.; Cragg, G.M. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. *J. Nat. Prod.* **2020**, *83*, 770-803. [CrossRef] [PubMed]

3. Tan, S.Y.; Merchant, J. Frederick Banting (1891-1941): Discoverer of Insulin. *Singap. Med. J.* **2017**, *58*, 2-3. [CrossRef] [PubMed]

4. Bailey, C.J. Metformin: Historical Overview. *Diabetologia* **2017**, *60*, 1566-1576. [CrossRef]

5. Drzewoski, J.; Hanefeld, M. The Current and Potential Therapeutic Use of Metformin—The Good Old Drug. *Pharmaceuticals* **2021**, *14*, 122. [CrossRef]

6. Yang, X.; Xu, Z.; Zhang, C.; Cai, Z.; Zhang, J. Metformin, beyond an Insulin Sensitizer, Targeting Heart and Pancreatic β Cells. *Biochim. Biophys. Acta Mol. Basis Dis.* **2017**, *1863*, 1984-1990. [CrossRef]

7. Bays, H. Sodium Glucose Co-Transporter Type 2 (SGLT2) Inhibitors: Targeting the Kidney to Improve Glycemic Control in Diabetes Mellitus. *Diabetes Ther.* **2013**, *4*, 195-220. [CrossRef]
8. Zannad, F.; Ferreira, J.P.; Pocock, S.J.; Anker, S.D.; Butler, J.; Filippatos, G.; Brueckmann, M.; Ofstad, A.P.; Pfarr, E.; Jamal, W.; et al. SGLT2 Inhibitors in Patients with Heart Failure with Reduced Ejection Fraction: A Meta-Analysis of the EMPEROR-Reduced and DAPA-HF Trials. *Lancet* **2020**, *396*, 819–829. [CrossRef]

9. Vaduganathan, M.; Docherty, K.F.; Claggett, B.L.; Jhund, P.S.; de Boer, R.A.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; Martinez, F.; et al. SGLT-2 Inhibitors in Patients with Heart Failure: A Comprehensive Meta-Analysis of Five Randomised Controlled Trials. *Lancet* **2022**, *400*, 757–767. [CrossRef]

10. White, J.R., Jr. Apple Trees to Sodium Glucose Co-Transporter Inhibitors: A Review of SGLT2 Inhibition. *Clin. Diabetes* **2010**, *28*, 5–10. [CrossRef]

11. Stiles, P.G.; Lusk, G. On the Action of Phlorhizin. *Am. J. Physiol.-Leg. Content* **1903**, *10*, 67–79. [CrossRef]

12. Abderrahmani, A.; Jacovetti, C.; Regazzi, R. Lessons from Neonatal β-Cell Epigenomic for Diabetes Prevention and Treatment. *Trends Endocrinol. Metab.* **2022**, *S1043-2760(22)00054-6*. [CrossRef]

13. Iorga, R.A.; Bacalbasa, N.; Carsote, M.; Bratu, O.G.; Stanescu, A.M.A.; Bungau, S.; Pantis, C.; Diaconu, C.C. Metabolic and Cardiovascular Benefits of GLP-1 Agonists, besides the Hypoglycemic Effect (Review). *Exp. Ther. Med.* **2020**, *20*, 2396–2400. [CrossRef]

14. Yusta, B.; Baggio, L.L.; Estall, J.L.; Koehler, J.A.; Holland, D.P.; Li, H.; Pipeleers, D.; Ling, Z.; Drucker, D.J. GLP-1 Receptor Activation Improves Beta Cell Function and Survival Following Induction of Endoplasmic Reticulum Stress. *Cell Metab.* **2006**, *4*, 391–406. [CrossRef]

15. Rahier, J.; Guiot, Y.; Goebbels, R.M.; Sempoux, C.; Henquin, J.C. Pancreatic Beta-Cell Mass in European Subjects with Type 2 Diabetes. *Diabetes Obes. Metab.* **2008**, *10* (Suppl S4), 32–42. [CrossRef]

16. Butler, A.E.; Janson, J.; Bonner-Weir, S.; Ritzel, R.; Rizza, R.A.; Butler, P.C. Beta-Cell Deficit and Increased Beta-Cell Apoptosis in Humans with Type 2 Diabetes. *Diabetes* **2003**, *52*, 102–110. [CrossRef]

17. Garvey, W.T.; Olefsky, J.M.; Griffin, J.; Hamman, R.F.; Kolterman, O.G. The Effect of Insulin Treatment on Insulin Secretion and Insulin Action in Type II Diabetes Mellitus. *Diabetes* **1985**, *34*, 222–234. [CrossRef]

18. Raufman, J.P.; Jensen, R.T.; Sutliff, V.E.; Pisano, J.J.; Gardner, J.D. Actions of Gila Monster Venom on Dispersed Acini from Guinea Pig Pancreas. *Am. J. Physiol.* **1982**, *242*, G470–G474. [CrossRef]

19. Göke, R.; Fehmann, H.C.; Linn, T.; Schmidt, H.; Krause, M.; Eng, J.; Göke, B. Exendin-4 Is a High Potency Agonist and Truncated Exendin-(9-39)-Amide an Antagonist at the Glucagon-like Peptide 1-(7-36)-Amide Receptor of Insulin-Secreting Beta-Cells. *J. Biol. Chem.* **1993**, *268*, 19650–19655. [CrossRef]

20. Abderrahmani, A.; Szunerits, S.; Dalle, S.; Boukherroub, R. Chapter 3: Optimizing the Current Type 2 Diabetes Antidiabetics with Nanotechnologies: Where Do We Stand? In *Nanotechnology for Diabetes Management*; Abderrahmani, A., Dalle, S., Szunerits, S., Boukherroub, B., El Ouaamari, A., Eds.; Royal Society of Chemistry: London, UK, 2022; pp. 92–112. [CrossRef]

21. Nauck, M.A.; Quast, D.R.; Wefers, J.; Meier, J.J. GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes–State-of-the-Art. *Mol. Metab.* **2021**, *46*, 101102. [CrossRef]

22. Grant, R.W.; Pirraglia, P.A.; Meigs, J.B.; Singer, D.E. Trends in Complexity of Diabetes Care in the United States from 1991 to 2000. *Arch. Intern. Med.* **2004**, *164*, 1134–1139. [CrossRef] [PubMed]

23. MacLean, C.D.; Littenberg, B.; Kennedy, A.G. Limitations of Diabetes Pharmacotherapy: Results from the Vermont Diabetes Information System Study. *BMC Fam. Prac.* **2006**, *7*, 50. [CrossRef] [PubMed]

24. Imai, K.; Tsujimoto, T.; Goto, A.; Goto, M.; Kishimoto, M.; Yamamoto-Honda, R.; Noto, H.; Kajio, H.; Noda, M. Prediction of Response to GLP-1 Receptor Agonist Therapy in Japanese Patients with Type 2 Diabetes. *Diabetol. Metab. Syndr.* **2014**, *6*, 110. [CrossRef] [PubMed]

25. Gudipaty, L.; Rosenfeld, N.K.; Fuller, C.S.; Gallop, R.; Schutta, M.H.; Rickels, M.R. Effect of Exenatide, Sitagliptin, or Glimepiride on β-Cell Secretory Capacity in Early Type 2 Diabetes. *Diabetes Care* **2014**, *37*, 2451–2458. [CrossRef]

26. Kahn, S.E.; Carr, D.B.; Faulenbach, M.V.; Utzschneider, K.M. An Examination of Beta-Cell Function Measures and Their Potential Use for Estimating Beta-Cell Mass. *Diabetes Obes. Metab.* **2008**, *10* (Suppl S4), 63–76. [CrossRef]

27. Pontiroli, A.E.; Calderara, A.; Pozza, G. Secondary Failure of Oral Hypoglycaemic Agents: Frequency, Possible Causes, and Management. *Diabetes Metab. Rev.* **1994**, *10*, 31–43. [CrossRef]

28. U.K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16. Overview of 6 Years' Therapy of Type II Diabetes: A Progressive Disease. *Diabetes* **1995**, *44*, 1249–1258. [CrossRef]

29. Hambrock, A.; de Oliveira Franz, C.B.; Hiller, S.; Osswald, H. Glibenclamide-Induced Apoptosis Is Specifically Enhanced by Expression of the Sulfonylurea Receptor Isoform SUR1 but Not by Expression of SUR2B or the Mutant SUR1(M1289T). *J. Pharmacol. Exp. Ther.* **2006**, *316*, 1031–1037. [CrossRef]

30. Iwakura, T.; Fujimoto, S.; Kagimoto, S.; Inada, A.; Kubota, A.; Someya, Y.; Ihara, Y.; Yamada, Y.; Seino, Y. Sustained Enhancement of Ca(2+) Influx by Glibenclamide Induces Apoptosis in RINm5F Cells. *Biochem. Biophys. Res. Commun.* **2000**, *271*, 422–428. [CrossRef]

31. Sola, D.; Rossi, L.; Schianca, G.P.C.; Maffioli, P.; Bigliocca, M.; Mella, R.; Corlianò, F.; Fra, G.P.; Bartoli, E.; Derosa, G. Sulfonylureas and Their Use in Clinical Practice. *Arch. Med. Sci.* **2015**, *11*, 840–848. [CrossRef]

32. Khunti, K.; Chatterjee, S.; Gerstein, H.C.; Zoungas, S.; Davies, M.J. Do Sulphonylureas Still Have a Place in Clinical Practice? *Lancet Diabetes Endocrinol.* **2018**, *6*, 821–832. [CrossRef]
33. Del Prato, S.; Pulizzi, N. The Place of Sulfonylureas in the Therapy for Type 2 Diabetes Mellitus. *Metabolism* **2006**, *55*, S20-S27.
[CrossRef]

34. Corrêa, A.S.; Vinson, C.C.; Braga, L.S.; Guedes, R.N.C.; Oliveira, L.O. de Ancient Origin and Recent Range Expansion of the Maize Weevil Sitophilus Zeamais, and Its Genealogical Relationship to the Rice Weevil S. Oryzae. *Bull. Entomol. Res.* **2017**, *107*, 9-20.
[CrossRef]

35. Henquin, J.-C. Glucose-Induced Insulin Secretion in Isolated Human Islets: Does It Truly Reflect β-Cell Function in Vivo? *Mol. Metab.* **2021**, *48*, 101212.
[CrossRef]

36. Williams, D.; Vicôgne, J.; Zaitseva, I.; McLaughlin, S.; Pessin, J.E. Evidence That Electrostatic Interactions between Vesicle-Associated Membrane Protein 2 and Acidic Phospholipids May Modulate the Fusion of Transport Vesicles with the Plasma Membrane. *Mol. Biol. Cell.* **2009**, *20*, 4910-4919.
[CrossRef]

37. Gaisano, H.Y. Recent New Insights into the Role of SNARE and Associated Proteins in Insulin Granule Exocytosis. *Diabetes Obes. Metab.* **2017**, *19* (Suppl. S1), 115-123.
[CrossRef]

38. Abderrahmani, A.; Plaisance, V.; Lovis, P.; Regazzi, R. Mechanisms Controlling the Expression of the Components of the Exocytotic Apparatus under Physiological and Pathological Conditions. *Biochem. Soc. Trans.* **2006**, *34*, 696-700.
[CrossRef]

39. Kalwat, M.A.; Cobb, M.H. Mechanisms of the Amplifying Pathway of Insulin Secretion in the β Cell. *Pharmacol. Ther.* **2017**, *179*, 17-30.
[CrossRef]

40. Mobli, M.; Undheim, E.A.B.; Rash, L.D. Modulation of Ion Channels by Cysteine-Rich Peptides: From Sequence to Structure. *Adv. Pharmacol.* **2017**, *79*, 199-223.
[CrossRef]

41. Bordon, K.d.C.F.; Cologna, C.T.; Fornari-Baldo, E.C.; Pinheiro-Júnior, E.L.; Cerni, F.A.; Amorim, F.G.; Anjolette, F.A.P.; Cordeiro, F.A.; Wiezel, G.A.; Cardoso, I.A.; et al. From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery. *Front. Pharmacol.* **2020**, *11*, 1132.
[CrossRef]

42. Coulter-Parkhill, A.; McClean, S.; Gault, V.A.; Irwin, N. Therapeutic Potential of Peptides Derived from Animal Venoms: Current Views and Emerging Drugs for Diabetes. *Clin. Med. Insights Endocrinol. Diabetes* **2021**, *14*, 11795514211006072.
[CrossRef]
[PubMed]

43. Prezoto, B.C.; Kato, E.E.; Gonçalves, L.R.C.; Sampaio, S.C.; Sano-Martins, I.S. Elevated Plasma Levels of Hepatocyte Growth Factor in Rats Experimentally Envenomated with Bothrops Jararaca Venom: Role of Snake Venom Metalloproteases. *Toxicon* **2019**, *162*, 9-14.
[CrossRef]
[PubMed]

44. Oliveira, A.G.; Araújo, T.G.; Carvalho, B.D.M.; Rocha, G.Z.; Santos, A.; Saad, M.J.A. The Role of Hepatocyte Growth Factor (HGF) in Insulin Resistance and Diabetes. *Front. Endocrinol. (Lausanne)* **2018**, *9*, 503.
[CrossRef]
[PubMed]

45. Furman, B.L. The Development of Byetta (Exenatide) from the Venom of the Gila Monster as an Anti-Diabetic Agent. *Toxicon* **2012**, *59*, 464-471.
[CrossRef]
[PubMed]

46. Tomas, A.; Jones, B.; Leech, C. New Insights into Beta-Cell GLP-1 Receptor and CAMP Signaling. *J. Mol. Biol.* **2020**, *432*, 1347-1366.
[CrossRef]

47. Dalle, S.; Burcelin, R.; Gourdy, P. Specific Actions of GLP-1 Receptor Agonists and DPP4 Inhibitors for the Treatment of Pancreatic β-Cell Impairments in Type 2 Diabetes. *Cell. Signal.* **2013**, *25*, 570-579.
[CrossRef]

48. Abdel-Wahab, Y.H.A.; Marenah, L.; Orr, D.F.; Shaw, C.; Flatt, P.R. Isolation and Structural Characterisation of a Novel 13-Amino Acid Insulin-Releasing Peptide from the Skin Secretion of Agalychnis Calcarifer. *Diabetologia* **2005**, *386*, 581-587.
[CrossRef]

49. Jones, B.; McGlone, E.R.; Fang, Z.; Pickford, P.; Corrêa, I.R.; Oishi, A.; Jockers, R.; Inoue, A.; Kumar, S.; Görlitz, F.; et al. Genetic and Biased Agonist-Mediated Reductions in β-Arrestin Recruitment Prolong CAMP Signalling at Glucagon Family Receptors. *J. Biol. Chem.* **2020**.
[CrossRef]

50. Tsend-Ayush, E.; He, C.; Myers, M.A.; Andrikopoulos, S.; Wong, N.; Sexton, P.M.; Wootten, D.; Forbes, B.E.; Grutzner, F. Monotreme Glucagon-like Peptide-1 in Venom and Gut: One Gene-Two Very Different Functions. *Sci. Rep.* **2016**, *6*, 37744.
[CrossRef]

51. Tucker, S.J.; Gribble, F.M.; Zhao, C.; Trapp, S.; Ashcroft, F.M. Truncation of Kir6.2 Produces ATP-Sensitive K+ Channels in the Absence of the Sulphonylurea Receptor. *Nature* **1997**, *387*, 179-183.
[CrossRef]

52. Kamp, F.; Kizilbash, N.; Corkey, B.E.; Berggren, P.-O.; Hamilton, J.A. Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism. *Diabetes* **2003**, *52*, 2526-2531.
[CrossRef]

53. Gribble, F.M.; Reimann, F. Sulphonylurea Action Revisited: The Post-Cloning Era. *Diabetologia* **2003**, *46*, 875-891.
[CrossRef]

54. Seltzer, H.S. Efficacy and Safety of Oral Hypoglycemic Agents. *Annu. Rev. Med.* **1980**, *31*, 261-272.
[CrossRef]

55. Kreisberg, R.A. The Second-Generation Sulfonylureas: Change or Progress? *Ann. Intern. Med.* **1985**, *102*, 125-126.
[CrossRef]

56. Campbell, R.K. Glimepiride: Role of a New Sulfonylurea in the Treatment of Type 2 Diabetes Mellitus. *Ann. Pharmacother.* **1998**, *32*, 1044-1052.
[CrossRef]

57. Dornhorst, A. Insulinotropic Meglitinide Analogues. *Lancet* **2001**, *358*, 1709-1716.
[CrossRef]

58. Eddlestone, G.T.; Komatsu, M.; Shen, L.; Sharp, G.W. Mastoparan Increases the Intracellular Free Calcium Concentration in Two Insulin-Secreting Cell Lines by Inhibition of ATP-Sensitive Potassium Channels. *Mol. Pharmacol.* **1995**, *47*, 787-797.

59. Ojo, O.O.; Srinivasan, D.K.; Owolabi, B.O.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Beneficial Effects of Tigerinin-1R on Glucose Homeostasis and Beta Cell Function in Mice with Diet-Induced Obesity-Diabetes. *Biochimie* **2015**, *109*, 18-26.
[CrossRef]
60. Juhl, K.; Efanov, A.M.; Olsen, H.L.; Gromada, J. Secretory Phospholipase A2 Is Released from Pancreatic β-Cells and Stimulates Insulin Secretion via Inhibition of ATP-Dependent K+ Channels. *Biochem. Biophys. Res. Commun.* **2003**, *310*, 274-279.
[CrossRef]

61. Ramu, Y.; Xu, Y.; Lu, Z. A Novel High-Affinity Inhibitor against the Human ATP-Sensitive Kir6.2 Channel. *J. Gen. Physiol.* **2018**, *150*, 969-976. [CrossRef]

62. Ramu, Y.; Yamakaze, J.; Zhou, Y.; Hoshi, T.; Lu, Z. Blocking Kir6.2 Channels with SpTx1 Potentiates Glucose-Stimulated Insulin Secretion from Murine Pancreatic β Cells and Lowers Blood Glucose in Diabetic Mice. *Elife* **2022**, *11*, e77026. [CrossRef] [PubMed]

63. Simpson, S.H.; Lee, J.; Choi, S.; Vandermeer, B.; Abdelmoneim, A.S.; Featherstone, T.R. Mortality Risk among Sulfonylureas: A Systematic Review and Network Meta-Analysis. *Lancet Diabetes Endocrinol.* **2015**, *3*, 43-51. [CrossRef] [PubMed]

64. Straub, S.G.; James, R.F.; Dunne, M.J.; Sharp, G.W. Glucose Augmentation of Mastoparan-Stimulated Insulin Secretion in Rat and Human Pancreatic Islets. *Diabetes* **1998**, *47*, 1053-1057. [CrossRef] [PubMed]

65. Komatsu, M.; McDermott, A.M.; Gillison, S.L.; Sharp, G.W. Mastoparan Stimulates Exocytosis at a Ca(2+)-Independent Late Site in Stimulus-Secretion Coupling. Studies with the RINm5F Beta-Cell Line. *J. Biol. Chem.* **1993**, *268*, 23297-23306. [CrossRef] [PubMed]

66. Amin, R.H.; Chen, H.-Q.; Veluthakal, R.; Silver, R.B.; Li, J.; Li, G.; Kowluru, A. Mastoparan-Induced Insulin Secretion from Insulin-Secreting BetaTC3 and INS-1 Cells: Evidence for Its Regulation by Rho Subfamily of G Proteins. *Endocrinology* **2003**, *144*, 4508-4518. [CrossRef]

67. Herrington, J.; Zhou, Y.-P.; Bugianesi, R.M.; Dulski, P.M.; Feng, Y.; Warren, V.A.; Smith, M.M.; Kohler, M.G.; Garsky, V.M.; Sanchez, M.; et al. Blockers of the Delayed-Rectifier Potassium Current in Pancreatic Beta-Cells Enhance Glucose-Dependent Insulin Secretion. *Diabetes* **2006**, *55*, 1034-1042. [CrossRef]

68. Ojo, O.O.; Srinivasan, D.K.; Owolabi, B.O.; McGahon, M.K.; Moffett, R.C.; Curtis, T.M.; Conlon, J.M.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Molecular Mechanisms Mediating the Beneficial Metabolic Effects of [Arg4]Tigerinin-1R in Mice with Diet-Induced Obesity and Insulin Resistance. *Biol. Chem.* **2016**, *397*, 753-764. [CrossRef]

69. MacDonald, P.E.; Wheeler, M.B. Voltage-Dependent K(+) Channels in Pancreatic Beta Cells: Role, Regulation and Potential as Therapeutic Targets. *Diabetologia* **2003**, *46*, 1046-1062. [CrossRef]

70. Dwenger, M.M.; Raph, S.M.; Baba, S.P.; Moore, J.B.; Nystoriak, M.A. Diversification of Potassium Currents in Excitable Cells via Kvβ Proteins. *Cells* **2022**, *11*, 2230. [CrossRef]

71. Patel, N.H.; Johannesen, J.; Shah, K.; Goswami, S.K.; Patel, N.J.; Ponnalagu, D.; Kohut, A.R.; Singh, H. Inhibition of BKCa Negatively Alters Cardiovascular Function. *Physiol. Rep.* **2018**, *6*, e13748. [CrossRef]

72. Finol-Urdaneta, R.K.; Remedi, M.S.; Raasch, W.; Becker, S.; Clark, R.B.; Strüver, N.; Pavlov, E.; Nichols, C.G.; French, R.J.; Terlau, H. Block of Kv1.7 Potassium Currents Increases Glucose-Stimulated Insulin Secretion. *EMBO Mol. Med.* **2012**, *4*, 424-434. [CrossRef]

73. Herrington, J.; Sanchez, M.; Wunderler, D.; Yan, L.; Bugianesi, R.M.; Dick, I.E.; Clark, S.A.; Brochu, R.M.; Priest, B.T.; Kohler, M.G.; et al. Biophysical and Pharmacological Properties of the Voltage-Gated Potassium Current of Human Pancreatic Beta-Cells. *J. Physiol.* **2005**, *567*, 159-175. [CrossRef]

74. Braun, M.; Ramracheya, R.; Bengtsson, M.; Zhang, Q.; Karanauskaite, J.; Partridge, C.; Johnson, P.R.; Rorsman, P. Voltage-Gated Ion Channels in Human Pancreatic Beta-Cells: Electrophysiological Characterization and Role in Insulin Secretion. *Diabetes* **2008**, *57*, 1618-1628. [CrossRef]

75. MacDonald, P.E.; Sewing, S.; Wang, J.; Joseph, J.W.; Smukler, S.R.; Sakellaropoulos, G.; Wang, J.; Saleh, M.C.; Chan, C.B.; Tsushima, R.G.; et al. Inhibition of Kv2.1 Voltage-Dependent K+Channels in Pancreatic β-Cells Enhances Glucose-Dependent Insulin Secretion*. *J. Biol. Chem.* **2002**, *277*, 44938-44945. [CrossRef]

76. Yacoub, T.; Rima, M.; Karam, M.; Sabatier, J.-M.; Fajloun, Z. Antimicrobials from Venomous Animals: An Overview. *Molecules* **2020**, *25*, 2402. [CrossRef]

77. Park, C.B.; Kim, H.S.; Kim, S.C. Mechanism of Action of the Antimicrobial Peptide Buforin II: Buforin II Kills Microorganisms by Penetrating the Cell Membrane and Inhibiting Cellular Functions. *Biochem. Biophys. Res. Commun.* **1998**, *244*, 253-257. [CrossRef]

78. Lewis, R.J.; Garcia, M.L. Therapeutic Potential of Venom Peptides. *Nat. Rev. Drug Discov.* **2003**, *2*, 790-802. [CrossRef]

79. Damasceno, A.; Ferreira, B.; Patel, S.; Sevene, E.; Polónia, J. Efficacy of Captopril and Nifedipine in Black and White Patients with Hypertensive Crisis. *J. Hum. Hypertens.* **1997**, *11*, 471-476. [CrossRef]

80. Jiménez-Mancilla, N.; Ferro-Flores, G.; Santos-Cuevas, C.; Ocampo-García, B.; Luna-Gutiérrez, M.; Azorín-Vega, E.; Isaac-Olivé, K.; Camacho-López, M.; Torres-García, E. Multifunctional Targeted Therapy System Based on (99m) Tc/(177) Lu-Labeled Gold Nanoparticles-Tat(49-57)-Lys(3) -Bombesin Internalized in Nuclei of Prostate Cancer Cells. *J. Labelled Comp. Radiopharm.* **2013**, *56*, 663-671. [CrossRef]

81. Kerkis, A.; Kerkis, I.; Rádis-Baptista, G.; Oliveira, E.B.; Vianna-Morgante, A.M.; Pereira, L.V.; Yamane, T. Crotamine Is a Novel Cell-Penetrating Protein from the Venom of Rattlesnake Crotalus Durissus Terrificus. *FASEB J.* **2004**, *18*, 1407-1409. [CrossRef]
82. Conlon, J.M.; Mechkarska, M.; Abdel-Wahab, Y.H.; Flatt, P.R. Peptides from Frog Skin with Potential for Development into Agents for Type 2 Diabetes Therapy. *Peptides* **2018**, *100*, 275-281. [CrossRef] [PubMed]

83. Amatya, R.; Park, T.; Hwang, S.; Yang, J.; Lee, Y.; Cheong, H.; Moon, C.; Kwak, H.D.; Min, K.A.; Shin, M.C. Drug Delivery Strategies for Enhancing the Therapeutic Efficacy of Toxin-Derived Anti-Diabetic Peptides. *Toxins* **2020**, *12*, 313. [CrossRef] [PubMed]

84. Baptista-Saidemberg, N.B.; Saidemberg, D.M.; Ribeiro, R.A.; Arcuri, H.A.; Palma, M.S.; Carneiro, E.M. Agelaia MP-I: A Peptide Isolated from the Venom of the Social Wasp, Agelaia Pallipes Pallipes, Enhances Insulin Secretion in Mice Pancreatic Islets. *Toxicon* **2012**, *60*, 596-602. [CrossRef] [PubMed]

85. Ojo, O.O.; Abdel-Wahab, Y.H.A.; Flatt, P.R.; Conlon, J.M. Insulinotropic Actions of the Frog Skin Host-Defense Peptide Alyteserin-2a: A Structure-Activity Study. *Chem. Biol. Drug. Des.* **2013**, *82*, 196-204. [CrossRef] [PubMed]

86. Mo, G.-X.; Bai, X.-W.; Li, Z.-J.; Yan, X.-W.; He, X.-Q.; Rong, M.-Q. A Novel Insulinotropic Peptide from the Skin Secretions of Amolops Loloensis Frog. *Nat. Prod. Bioprospect.* **2014**, *4*, 309-313. [CrossRef]

87. Swope, S.L.; Schonbrunn, A. Bombesin Stimulates Insulin Secretion by a Pancreatic Islet Cell Line. *Proc. Natl. Acad. Sci. USA* **1984**, *81*, 1822-1826. [CrossRef]

88. Woods, S.C.; Stein, L.J.; Figlewicz, D.P.; Porte, D. Bombesin Stimulates Insulin Secretion and Reduces Food Intake in the Baboon. *Peptides* **1983**, *4*, 687-691. [CrossRef]

89. Martindale, R.; Levin, S.; Alfin-Slater, R. Effects of Caerulein and Bombesin on Insulin and Glucagon Secretion from the Isolated, Perfused Rat Pancreas. *Regul. Pept.* **1982**, *3*, 313-324. [CrossRef]

90. Swope, S.L.; Schonbrunn, A. The Biphasic Stimulation of Insulin Secretion by Bombesin Involves Both Cytosolic Free Calcium and Protein Kinase C. *Biochem. J.* **1988**, *253*, 193-202. [CrossRef]

91. Schöfl, C.; Rössig, L.; Leitolf, H.; Mader, T.; von zur Mühlen, A.; Brabant, G. Generation of Repetitive Ca2+ Transients by Bombesin Requires Intracellular Release and Influx of Ca2+ through Voltage-Dependent and Voltage Independent Channels in Single HIT Cells. *Cell. Calcium* **1996**, *19*, 485-493. [CrossRef]

92. Greeley, G.H.; Spannagel, A.; Trowbridge, J.; Thompson, J.C. Effect of Bombesin and Gastrin-Releasing Peptide on the Release of Gastric Inhibitory Polypeptide and Insulin in Rats. *Proc. Soc. Exp. Biol. Med.* **1986**, *182*, 540-542. [CrossRef]

93. Abdel-Wahab, Y.H.A.; Patterson, S.; Flatt, P.R.; Conlon, J.M. Brevinin-2-Related Peptide and Its [D4K] Analogue Stimulate Insulin Release In Vitro and Improve Glucose Tolerance in Mice Fed a High Fat Diet. *Horm. Metab. Res.* **2010**, *42*, 652-656. [CrossRef]

94. Zahid, O.K.; Mechkarska, M.; Ojo, O.O.; Abdel-Wahab, Y.H.A.; Flatt, P.R.; Meetani, M.A.; Conlon, J.M. Caerulein-and Xenopsin-Related Peptides with Insulin-Releasing Activities from Skin Secretions of the Clawed Frogs, Xenopus Borealis and Xenopus Amieti (Pipidae). *Gen. Comp. Endocrinol.* **2011**, *172*, 314-320. [CrossRef]

95. Toyama, M.H.; Carneiro, E.M.; Marangoni, S.; Barbosa, R.L.; Corso, G.; Boschero, A.C. Biochemical Characterization of Two Crotamine Isoforms Isolated by a Single Step RP-HPLC from Crotalus Durissus Terrificus (South American Rattlesnake) Venom and Their Action on Insulin Secretion by Pancreatic Islets. *Biochim. Biophys. Acta* **2000**, *1474*, 56-60. [CrossRef]

96. Marenah, L.; Mcclean, S.; Flatt, P.R.; Orr, D.F.; Shaw, C.; Abdel-wahab, Y.H.A. Novel Insulin-Releasing Peptides in the Skin of *Phyllomedusa trinitatis* Frog Include 28 Amino Acid Peptide From Dermaseptin Biv Precursor. *Pancreas* **2004**, *29*, 110-115. [CrossRef]

97. Vasu, S.; McGahon, M.K.; Moffett, R.C.; Curtis, T.M.; Conlon, J.M.; Abdel-Wahab, Y.H.A.; Flatt, P.R. Esculinin-2CHa(1-30) and Its Analogues: Stability and Mechanisms of Insulinotropic Action. *J. Endocrinol.* **2017**, *232*, 423-435. [CrossRef]

98. Ojo, O.O.; Srinivasan, D.K.; Owolabi, B.O.; Vasu, S.; Conlon, J.M.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Esculinin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance. *PLoS ONE* **2015**, *10*, e0141549. [CrossRef]

99. Owolabi, B.O.; Ojo, O.O.; Srinivasan, D.K.; Conlon, J.M.; Flatt, P.R.; Abdel-Wahab, Y.H.A. In Vitro and in Vivo Insulinotropic Properties of the Multifunctional Frog Skin Peptide Hymenochirin-1B: A Structure-Activity Study. *Amino Acids* **2016**, *48*, 535-547. [CrossRef]

100. Owolabi, B.O.; Ojo, O.O.; Srinivasan, D.K.; Conlon, J.M.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Glucoregulatory, Endocrine and Morphological Effects of [P5K]Hymenochirin-1B in Mice with Diet-Induced Glucose Intolerance and Insulin Resistance. *Naunyn-Schmiedeberg's Arch. Pharmacol.* **2016**, *389*, 769-781. [CrossRef]

101. Ojo, O.O.; Srinivasan, D.K.; Owolabi, B.O.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Magainin-Related Peptides Stimulate Insulin-Release and Improve Glucose Tolerance in High Fat Fed Mice. *Protein Pept. Lett.* **2014**, *22*, 256-263. [CrossRef]

102. Morgan, N.G.; Rumford, G.M.; Montague, W. Studies on the Mechanism by Which Melittin Stimulates Insulin Secretion from Isolated Rat Islets of Langerhans. *Biochim. Biophys. Acta* **1985**, *845*, 526-532. [CrossRef] [PubMed]

103. Pace, C.S. Glucose Dose-Related Influence of Phospholipase C and Melittin on Insulin Release from Perifused Rat Islets. *Res. Commun. Chem. Pathol. Pharmacol.* **1988**, *62*, 295-308. [PubMed]

104. Conlon, J.M.; Abdel-Wahab, Y.H.A.; Flatt, P.R.; Leprince, J.; Vaudry, H.; Jouenne, T.; Condamine, E. A Glycine-Leucine-Rich Peptide Structurally Related to the Plasticins from Skin Secretions of the Frog Leptodactylus Laticeps (Leptodactylidae). *Peptides* **2009**, *30*, 888-892. [CrossRef] [PubMed]

105. Mechkarska, M.; Ojo, O.O.; Meetani, M.A.; Coquet, L.; Jouenne, T.; Abdel-Wahab, Y.H.A.; Flatt, P.R.; King, J.D.; Conlon, J.M. Peptidomic Analysis of Skin Secretions from the Bullfrog Lithobates Catesbeianus (Ranidae) Identifies Multiple Peptides with Potent Insulin-Releasing Activity. *Peptides* **2011**, *32*, 203-208. [CrossRef] [PubMed]
106. Musale, V.; Moffett, R.C.; Conlon, J.M.; Flatt, P.R.; Abdel-Wahab, Y.H. Beneficial Actions of the [A14K] Analog of the Frog Skin Peptide PGLa-AM1 in Mice with Obesity and Degenerative Diabetes: A Mechanistic Study. *Peptides* **2021**, *136*, 170472. [CrossRef]

107. Owolabi, B.O.; Musale, V.; Ojo, O.O.; Moffett, R.C.; McGahon, M.K.; Curtis, T.M.; Conlon, J.M.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Actions of PGLa-AM1 and Its [A14K] and [A20K] Analogues and Their Therapeutic Potential as Anti-Diabetic Agents. *Biochimie* **2017**, *138*, 1–12. [CrossRef]

108. Abdel-Wahab, Y.H.A.; Power, G.J.; Ng, M.T.; Flatt, P.R.; Conlon, J.M. Insulin-Releasing Properties of the Frog Skin Peptide Pseudin-2 and Its [Lys18]-Substituted Analogue. *Biol. Chem.**2008**, *389*, 143–148. [CrossRef]

109. Abdel-Wahab, Y.H.A.; Marenah, L.; Flatt, P.R.; Conlon, J.M. Insulin Releasing Properties of the Temporin Family of Antimicrobial Peptides. *Protein Pept. Lett.* **2007**, *14*, 702–707. [CrossRef]

110. Kumar, S.; Mittal, A.; Babu, D.; Mittal, A. Herbal Medicines for Diabetes Management and Its Secondary Complications. *Curr. Diabetes Rev.* **2020**, *17*, 437–456. [CrossRef]

111. Beckman, C.H. Phenolic-Storing Cells: Keys to Programmed Cell Death and Periderm Formation in Wilt Disease Resistance and in General Defence Responses in Plants? *Physiol. Mol. Plant Pathol.* **2000**, *57*, 101–110. [CrossRef]

112. Sureda, A.; Tejada, S.; Bibiloni, d.M.; Tur, J.A.; Pons, A. Polyphenols: Well beyond the Antioxidant Capacity: Polyphenol Supplementation and Exercise-Induced Oxidative Stress and Inflammation. *Curr. Pharm. Biotechnol.* **2014**, *15*, 373–379. [CrossRef]

113. Tsao, R. Chemistry and Biochemistry of Dietary Polyphenols. *Nutrients* **2010**, *2*, 1231–1246. [CrossRef]

114. Scalbert, A.; Williamson, G. Dietary Intake and Bioavailability of Polyphenols. *J. Nutr.* **2000**, *130*, 2073S–2085S. [CrossRef]

115. Souza, C.R.M.; Bezerra, W.P.; Souto, J.T. Marine Alkaloids with Anti-Inflammatory Activity: Current Knowledge and Future Perspectives. *Mar. Drugs* **2020**, *18*, 147. [CrossRef]

116. Daly, J.W.; Garraffo, H.M.; Spande, T.F.; Decker, M.W.; Sullivan, J.P.; Williams, M. Alkaloids from Frog Skin: The Discovery of Epibatidine and the Potential for Developing Novel Non-Opioid Analgesics. *Nat. Prod. Rep.* **2000**, *17*, 131–135. [CrossRef]

117. Heinrich, M.; Mah, J.; Amirkia, V. Alkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity—An Update and Forward Look. *Molecules* **2021**, *26*, 1836. [CrossRef]

118. Boyd, A.E.; Bolton, W.E.; Brinkley, B.R. Microtubules and Beta Cell Function: Effect of Colchicine on Microtubules and Insulin Secretion in Vitro by Mouse Beta Cells. *J. Cell. Biol.* **1982**, *92*, 425–434. [CrossRef]

119. Malta, A.; de Souza, A.A.; Ribeiro, T.A.; Francisco, F.A.; Pavanello, A.; Prates, K.V.; Tófolo, L.P.; Miranda, R.A.; de Oliveira, J.C.; Martins, I.P.; et al. Neonatal Treatment with Scopolamine Butylbromide Prevents Metabolic Dysfunction in Male Rats. *Sci. Rep.* **2016**, *6*, 30745. [CrossRef]

120. Grill, V.; Ostenson, C.G. Muscarinic Receptors in Pancreatic Islets of the Rat. Demonstration and Dependence on Long-Term Glucose Environment. *Biochim. Biophys. Acta* **1983**, *756*, 159–162. [CrossRef]

121. Tuomi, T.; Nagorny, C.L.F.; Singh, P.; Bennet, H.; Yu, Q.; Alenkvist, I.; Isomaa, B.; Östman, B.; Söderström, J.; Pesonen, A.-K.; et al. Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. *Cell. Metab.* **2016**, *23*, 1067–1077. [CrossRef]

122. Picinato, M.C.; Haber, E.P.; Cipolla-Neto, J.; Curi, R.; de Oliveira Carvalho, C.R.; Carpinelli, A.R. Melatonin Inhibits Insulin Secretion and Decreases PKA Levels without Interfering with Glucose Metabolism in Rat Pancreatic Islets. *J. Pineal Res.* **2002**, *33*, 156–160. [CrossRef] [PubMed]

123. Henderson, J.R.; Jefferys, D.B.; Jones, R.H.; Stanley, D. The Effect of atropine on the insulin release caused by oral and intravenous glucose in human subjects. *Eur. J. Endocrinol.* **1976**, *83*, 772–780. [CrossRef] [PubMed]

124. Yoshikawa, H.; Hellström-Lindahl, E.; Grill, V. Evidence for Functional Nicotinic Receptors on Pancreatic Beta Cells. *Metabolism* **2005**, *54*, 247–254. [CrossRef] [PubMed]

125. Zern, R.T.; Bird, J.L.; Feldman, J.M. Effect of Increased Pancreatic Islet Norepinephrine, Dopamine and Serotonin Concentration on Insulin Secretion in the Golden Hamster. *Diabetologia* **1980**, *18*, 341–346. [CrossRef] [PubMed]

126. Tjälve, H.; Popov, D. Effect of Nicotine and Nicotine Metabolites on Insulin Secretion from Rabbit Pancreas Pieces. *Endocrinology* **1973**, *92*, 1343–1348. [CrossRef]

127. Chapal, J.; Loubatières-Mariani, M.M. [Effect of nicotine on insulin secretion in the isolated perfused rat pancreas]. *C. R. Seances Soc. Biol. Fil.* **1978**, *172*, 156–160.

128. Henquin, J.C.; Horemans, B.; Nenquin, M.; Verniers, J.; Lambert, A.E. Quinine-Induced Modifications of Insulin Release and Glucose Metabolism by Isolated Pancreatic Islets. *FEBS Lett.* **1975**, *57*, 280–284. [CrossRef]

129. Herchuelz, A.; Lebrun, P.; Carpinelli, A.; Thonnart, N.; Sener, A.; Malaisse, W.J. Regulation of Calcium Fluxes in Rat Pancreatic Islets. Quinine Mimics the Dual Effect of Glucose on Calcium Movements. *Biochim. Biophys. Acta* **1981**, *640*, 16–30. [CrossRef]

130. Bai, M.; Liu, Y.; Zhou, F.; Zhang, Y.; Zhu, Q.; Zhang, L.; Zhang, Q.; Wang, S.; Zhu, K.; Wang, X.; et al. Berberine Inhibits Glucose Oxidation and Insulin Secretion in Rat Islets. *Endocr. J.* **2018**, *65*, 469–477. [CrossRef]

131. Lv, X.; Zhao, Y.; Yang, X.; Han, H.; Ge, Y.; Zhang, M.; Zhang, H.; Zhang, M.; Chen, L. Berberine Potentiates Insulin Secretion and Prevents β-Cell Dysfunction Through the MiR-204/SIRT1 Signaling Pathway. *Front. Pharmacol.* **2021**, *12*, 720866. [CrossRef]

132. Zhao, M.-M.; Lu, J.; Li, S.; Wang, H.; Cao, X.; Li, Q.; Shi, T.-T.; Matsunaga, K.; Chen, C.; Huang, H.; et al. Berberine Is an Insulin Secretagogue Targeting the KCNH6 Potassium Channel. *Nat. Commun.* **2021**, *12*, 5616. [CrossRef]
133. Suantawee, T.; Elazab, S.T.; Hsu, W.H.; Yao, S.; Cheng, H.; Adisakwattana, S. Cyanidin Stimulates Insulin Secretion and Pancreatic β-Cell Gene Expression through Activation of I-Type Voltage-Dependent Ca2+ Channels. *Nutrients* **2017**, *9*, 814. [CrossRef]

134. Kappel, V.D.; Frederico, M.J.S.; Postal, B.G.; Mendes, C.P.; Cazarolli, L.H.; Silva, F.R.M.B. The Role of Calcium in Intracellular Pathways of Rutin in Rat Pancreatic Islets: Potential Insulin Secretagogue Effect. *Eur. J. Pharmacol.* **2013**, *702*, 264–268. [CrossRef]

135. Vetterli, L.; Brun, T.; Giovannoni, L.; Bosco, D.; Maechler, P. Resveratrol Potentiates Glucose-Stimulated Insulin Secretion in INS-1E Beta-Cells and Human Islets through a SIRT1-Dependent Mechanism. *J. Biol. Chem.* **2011**, *286*, 6049–6060. [CrossRef]

136. Rouse, M.; Younès, A.; Egan, J.M. Resveratrol and Curcumin Enhance Pancreatic β-Cell Function by Inhibiting Phosphodiesterase Activity. *J. Endocrinol.* **2014**, *223*, 107–117. [CrossRef]

137. Liu, D.; Zhen, W.; Yang, Z.; Carter, J.D.; Si, H.; Reynolds, K.A. Genistein Acutely Stimulates Insulin Secretion in Pancreatic Beta-Cells through a CAMP-Dependent Protein Kinase Pathway. *Diabetes* **2006**, *55*, 1043–1050. [CrossRef]

138. Pavan, B.; Capuzzo, A.; Forlani, G. Quercetin and Quercetin-3-O-Glucoside Interact with Different Components of the CAMP Signaling Cascade in Human Retinal Pigment Epithelial Cells. *Life Sci.* **2015**, *121*, 166–173. [CrossRef]

139. Green, I.C.; Ray, K.; Perrin, D. Opioid Peptide Effects on Insulin Release and C-AMP in Islets of Langerhans. *Horm. Metab. Res.* **1983**, *15*, 124–128. [CrossRef]

140. Rey, D.; Miranda Sulis, P.; Alves Fernandes, T.; Gonçalves, R.; Silva Frederico, M.J.; Costa, G.M.; Aragon, M.; Ospina, L.F.; Mena Barreto Silva, F.R. Astragalin Augments Basal Calcium Influx and Insulin Secretion in Rat Pancreatic Islets. *Cell. Calcium* **2019**, *80*, 56–62. [CrossRef]

141. Mao, X.; Chai, Y.; Lin, Y.-F. Dual Regulation of the ATP-Sensitive Potassium Channel by Caffeine. *Am. J. Physiol. Cell Physiol.* **2007**, *292*, C2239–C2258. [CrossRef]

142. Shi, C.L. Effects of Caffeine and Acetylcholine on Glucose-Stimulated Insulin Release from Islet Transplants in Mice. *Cell. Transplant.* **1997**, *6*, 33–37. [CrossRef] [PubMed]

143. Johnston, K.L.; Clifford, M.N.; Morgan, L.M. Coffee Acutely Modifies Gastrointestinal Hormone Secretion and Glucose Tolerance in Humans: Glycemic Effects of Chlorogenic Acid and Caffeine. *Am. J. Clin. Nutr.* **2003**, *78*, 728–733. [CrossRef] [PubMed]

144. Fatima, N.; Hafizur, R.M.; Hameed, A.; Ahmed, S.; Nisar, M.; Kabir, N. Ellagic Acid in Emblica Officinalis Exerts Anti-Diabetic Activity through the Action on β-Cells of Pancreas. *Eur. J. Nutr.* **2017**, *56*, 591–601. [CrossRef] [PubMed]

145. Mathew, A.J.; Raj, N.N.; Sugappriya, M.; Priyadarshini, S.M. Modeling of ATP-Sensitive Inward Rectifier Potassium Channel 11 and Inhibition Mechanism of the Natural Ligand, Ellagic Acid, Using Molecular Docking. *Adv. Exp. Med. Biol.* **2010**, *680*, 489–495. [CrossRef] [PubMed]

146. Zhang, Y.; Liu, D. Flavonol Kaempferol Improves Chronic Hyperglycemia-Impaired Pancreatic Beta-Cell Viability and Insulin Secretory Function. *Eur. J. Pharmacol.* **2011**, *670*, 325–332. [CrossRef]

147. García López, P.M.; de la Mora, P.G.; Wysocka, W.; Maiztegui, B.; Alzugaray, M.E.; Del Zotto, H.; Borelli, M.I. Quinolizidine Alkaloids Isolated from Lupinus Species Enhance Insulin Secretion. *Eur. J. Pharmacol.* **2004**, *504*, 139–142. [CrossRef]

148. Nguyen, K.H.; Ta, T.N.; Pham, T.H.M.; Nguyen, Q.T.; Pham, H.D.; Mishra, S.; Nyomba, B.L.G. Nuciferine Stimulates Insulin Secretion from Beta Cells—An in Vitro Comparison with Glibenclamide. *J. Ethnopharmacol.* **2012**, *142*, 488–495. [CrossRef]

149. Kittl, M.; Beyreis, M.; Tumurkhuu, M.; Fürst, J.; Helm, K.; Pitschmann, A.; Gaisberger, M.; Glasl, S.; Ritter, M.; Jakab, M. Quercetin Stimulates Insulin Secretion and Reduces the Viability of Rat INS-1 Beta-Cells. *CPB* **2016**, *39*, 278–293. [CrossRef]

150. Chen, W.-P.; Chi, T.-C.; Chuang, L.-M.; Su, M.-J. Resveratrol Enhances Insulin Secretion by Blocking K(ATP) and K(V) Channels of Beta Cells. *Eur. J. Pharmacol.* **2007**, *568*, 269–277. [CrossRef]

151. Lee, D.; Kim, Y.-M.; Kim, H.W.; Choi, Y.-K.; Park, B.J.; Joo, S.H.; Kang, K.S. Schisandrin C Affects Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells and Glucose Uptake in Skeletal Muscle Cells. *Molecules* **2021**, *26*, 6509. [CrossRef]

152. Ashcroft, F.M.; Kerr, A.J.; Gibson, J.S.; Williams, B.A. Amantadine and Sparteine Inhibit ATP-Regulated K-Currents in the Insulin-Secreting Beta-Cell Line, HIT-T15. *Br. J. Pharmacol.* **1991**, *104*, 579–584. [CrossRef]

153. Balamurugan, R.; Vendan, S.E.; Aravinthan, A.; Kim, J.-H. Isolation and Structural Characterization of 2R, 3R Taxifolin 3-O-Rhamnoside from Ethyl Acetate Extract of Hydnocarpus Alpina and Its Hypoglycemic Effect by Attenuating Hepatic Key Enzymes of Glucose Metabolism in Streptozotocin-Induced Diabetic Rats. *Biochimie* **2015**, *111*, 70–81. [CrossRef]

154. Yao, X.; Chen, F.; Li, P.; Quan, L.; Chen, J.; Yu, L.; Ding, H.; Li, C.; Chen, L.; Gao, Z.; et al. Natural Product Vindoline Stimulates Insulin Secretion and Efficiently Ameliorates Glucose Homeostasis in Diabetic Murine Models. *J. Ethnopharmacol.* **2013**, *150*, 285–297. [CrossRef]

155. Horiuchi, H.; Usami, A.; Shirai, R.; Harada, N.; Ikushiro, S.; Sakaki, T.; Nakano, Y.; Inui, H.; Yamaji, R. S-Equol Activates CAMP Signaling at the Plasma Membrane of INS-1 Pancreatic β-Cells and Protects against Streptozotocin-Induced Hyperglycemia by Increasing β-Cell Function in Male Mice. *J. Nutr.* **2017**, *147*, 1631–1639. [CrossRef]

156. Jonas, J.C.; Plant, T.D.; Gilon, P.; Detimary, P.; Nenquin, M.; Henquin, J.C. Multiple Effects and Stimulation of Insulin Secretion by the Tyrosine Kinase Inhibitor Genistein in Normal Mouse Islets. *Br. J. Pharmacol.* **1995**, *114*, 872–880. [CrossRef]

157. Ohno, T.; Kato, N.; Ishii, C.; Shimizu, M.; Ito, Y.; Tomono, S.; Kawazu, S. Genistein Augments Cyclic Adenosine 3′5′-Monophosphate(CAMP) Accumulation and Insulin Release in MIN6 Cells. *Endocr. Res.* **1993**, *19*, 273–285. [CrossRef]

158. Fu, Z.; Liu, D. Long-Term Exposure to Genistein Improves Insulin Secretory Function of Pancreatic Beta-Cells. *Eur. J. Pharmacol.* **2009**, *616*, 321–327. [CrossRef]
159. Green, I.C.; Perrin, D.; Pedley, K.C.; Leslie, R.D.; Pyke, D.A. Effect of Enkephalins and Morphine on Insulin Secretion from Isolated Rat Islets. *Diabetologia* **1980**, *19*, 158–161. [CrossRef]

160. Li, Y.; Zheng, X.; Yi, X.; Liu, C.; Kong, D.; Zhang, J.; Gong, M. Myricetin: A Potent Approach for the Treatment of Type 2 Diabetes as a Natural Class B GPCR Agonist. *FASEB J.* **2017**, *31*, 2603–2611. [CrossRef]

161. Mahendra, V.P.; Haware, D.J.; Kumar, R. CAMP-PKA Dependent ERK1/2 Activation Is Necessary for Vanillic Acid Potentiated Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells. *J. Funct. Foods* **2019**, *56*, 110–118. [CrossRef]

162. Rhodes, C.J. Type 2 Diabetes-a Matter of Beta-Cell Life and Death? *Science* **2005**, *307*, 380–384. [CrossRef] [PubMed]

163. Aguayo-Mazzucato, C.; Andle, J.; Lee, T.B.; Midha, A.; Talemal, L.; Chipashvili, V.; Hollister-Lock, J.; van Deursen, J.; Weir, G.; Bonner-Weir, S. Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes. *Cell. Metab.* **2019**, *30*, 129–142. [CrossRef] [PubMed]

164. Talchai, C.; Xuan, S.; Lin, H.V.; Sussel, L.; Accili, D. Pancreatic β-Cell Dedifferentiation As Mechanism Of Diabetic β-Cell Failure. *Cell.* **2012**, *150*, 1223–1234. [CrossRef]

165. Lee, J.-H.; Lee, J. Endoplasmic Reticulum (ER) Stress and Its Role in Pancreatic β-Cell Dysfunction and Senescence in Type 2 Diabetes. *Int. J. Mol. Sci.* **2022**, *23*, 4843. [CrossRef] [PubMed]

166. Ježek, P.; Jabůrek, M.; Plecitá-Hlavatá, L. Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes. *Antioxid. Redox Signal.* **2019**, *31*, 722–751. [CrossRef]

167. Masini, M.; Bugliani, M.; Lupi, R.; del Guerra, S.; Boggi, U.; Filipponi, F.; Marselli, L.; Masiello, P.; Marchetti, P. Autophagy in Human Type 2 Diabetes Pancreatic Beta Cells. *Diabetologia* **2009**, *52*, 1083–1086. [CrossRef]

168. Bugliani, M.; Mossuto, S.; Grano, F.; Suleiman, M.; Marselli, L.; Boggi, U.; De Simone, P.; Eizirik, D.L.; Cnop, M.; Marchetti, P.; et al. Modulation of Autophagy Influences the Function and Survival of Human Pancreatic Beta Cells Under Endoplasmic Reticulum Stress Conditions and in Type 2 Diabetes. *Front. Endocrinol. (Lausanne)* **2019**, *10*, 52. [CrossRef]

169. Cerf, M.E. Developmental Programming and Glucolipotoxicity: Insights on Beta Cell Inflammation and Diabetes. *Metabolites* **2020**, *10*, 444. [CrossRef]

170. Lytrivi, M.; Castell, A.-L.; Poitout, V.; Cnop, M. Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes. *J. Mol. Biol.* **2020**, *432*, 1514–1534. [CrossRef]

171. Oh, Y.S.; Jun, H.-S. Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling. *Int. J. Mol. Sci.* **2017**, *19*, 26. [CrossRef]

172. Zummo, F.P.; Cullen, K.S.; Honkanen-Scott, M.; Shaw, J.A.M.; Lovat, P.E.; Arden, C. Glucagon-Like Peptide 1 Protects Pancreatic β-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function. *Diabetes* **2017**, *66*, 1272–1285. [CrossRef]

173. Montvida, O.; Klein, K.; Kumar, S.; Khunti, K.; Paul, S.K. Addition of or Switch to Insulin Therapy in People Treated with Glucagon-like Peptide-1 Receptor Agonists: A Real-World Study in 66 583 Patients. *Diabetes Obes. Metab.* **2017**, *19*, 108–117. [CrossRef]

174. Xu, G.; Kaneto, H.; Laybutt, D.R.; Duvivier-Kali, V.F.; Trivedi, N.; Suzuma, K.; King, G.L.; Weir, G.C.; Bonner-Weir, S. Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia: Possible Contribution to Impaired Incretin Effects in Diabetes. *Diabetes* **2007**, *56*, 1551–1558. [CrossRef]

175. Mitchell, R.K.; Mondragon, A.; Chen, L.; Mcginty, J.A.; French, P.M.; Ferrer, J.; Thorens, B.; Hodson, D.J.; Rutter, G.A.; Da Silva Xavier, G. Selective Disruption of Tcf7l2 in the Pancreatic β Cell Impairs Secretory Function and Lowers β Cell Mass. *Hum. Mol. Genet.* **2015**, *24*, 1390–1399. [CrossRef]

176. Ezanno, H.; Pawlowski, V.; Abdelli, S.; Boutry, R.; Gmyr, V.; Kerr-Conte, J.; Bonny, C.; Pattou, F.; Abderrahmani, A. JNK3 Is Required for the Cytoprotective Effect of Exendin 4. *J. Diabetes Res.* **2014**, *2014*, 814854. [CrossRef]

177. Kapodistria, K.; Tsilibary, E.-P.; Kotsopoulou, E.; Moustardas, P.; Kitsiou, P. Liraglutide, a Human Glucagon-like Peptide-1 Analogue, Stimulates AKT-Dependent Survival Signalling and Inhibits Pancreatic β-Cell Apoptosis. *J. Cell. Mol. Med.* **2018**, *22*, 2970–2980. [CrossRef]

178. Camaya, I.; Donnelly, S.; O'Brien, B. Targeting the PI3K/Akt Signaling Pathway in Pancreatic B-cells to Enhance Their Survival and Function: An Emerging Therapeutic Strategy for Type 1 Diabetes. *J. Diabetes* **2022**, *14*, 247–260. [CrossRef]

179. Weston, C.R.; Davis, R.J. The JNK Signal Transduction Pathway. *Curr. Opin. Cell. Biol.* **2007**, *19*, 142–149. [CrossRef]

180. Tenenbaum, M.; Plaisance, V.; Boutry, R.; Pawlowski, V.; Jacovetti, C.; Sanchez-Parra, C.; Ezanno, H.; Bourry, J.; Beeler, N.; Pasquetti, G.; et al. The Map3k12 (Dlk)/JNK3 Signaling Pathway Is Required for Pancreatic Beta-Cell Proliferation during Postnatal Development. *Cell. Mol. Life Sci.* **2021**, *78*, 287–298. [CrossRef]

181. Ferdaoussi, M.; Abdelli, S.; Yang, J.-Y.; Cornu, M.; Niederhauser, G.; Favre, D.; Widmann, C.; Regazzi, R.; Thorens, B.; Waeber, G.; et al. Exendin-4 Protects Beta-Cells from Interleukin-1 Beta-Induced Apoptosis by Interfering with the c-Jun NH2-Terminal Kinase Pathway. *Diabetes* **2008**, *57*, 1205–1215. [CrossRef]

182. Jhala, U.S.; Canettieri, G.; Screaton, R.A.; Kulkarni, R.N.; Krajewski, S.; Reed, J.; Walker, J.; Lin, X.; White, M.; Montminy, M. CAMP Promotes Pancreatic Beta-Cell Survival via CREB-Mediated Induction of IRS2. *Genes. Dev.* **2003**, *17*, 1575–1580. [CrossRef] [PubMed]

183. Blandino-Rosano, M.; Perez-Arana, G.; Mellado-Gil, J.M.; Segundo, C.; Aguilar-Diosdado, M. Anti-Proliferative Effect of pro-Inflammatory Cytokines in Cultured Beta Cells Is Associated with Extracellular Signal-Regulated Kinase 1/2 Pathway Inhibition: Protective Role of Glucagon-like Peptide-1. *J. Mol. Endocrinol.* **2008**, *41*, 35–44. [CrossRef] [PubMed]
184. Costes, S.; Broca, C.; Bertrand, G.; Lajoix, A.-D.; Bataille, D.; Bockaert, J.; Dalle, S. ERK1/2 Control Phosphorylation and Protein Level of CAMP-Responsive Element-Binding Protein: A Key Role in Glucose-Mediated Pancreatic Beta-Cell Survival. *Diabetes* **2006**, *55*, 2220–2230. [CrossRef] [PubMed]

185. Quoyer, J.; Longuet, C.; Broca, C.; Linck, N.; Costes, S.; Varin, E.; Bockaert, J.; Bertrand, G.; Dalle, S. GLP-1 Mediates Antiapoptotic Effect by Phosphorylating Bad through a Beta-Arrestin 1-Mediated ERK1/2 Activation in Pancreatic Beta-Cells. *J. Biol. Chem.* **2010**, *285*, 1989–2002. [CrossRef]

186. Tong, X.; Kono, T.; Anderson-Baucum, E.K.; Yamamoto, W.; Gilon, P.; Lebeche, D.; Day, R.N.; Shull, G.E.; Evans-Molina, C. SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity. *Diabetes* **2016**, *65*, 3039–3052. [CrossRef]

187. Lee, W.-Y. New Potential Targets of Glucagon-Like Peptide 1 Receptor Agonists in Pancreatic β-Cells and Hepatocytes. *Endocrinol. Metab.* **2017**, *32*, 1–5. [CrossRef]

188. Li, Y.; Cao, X.; Li, L.-X.; Brubaker, P.L.; Edlund, H.; Drucker, D.J. Beta-Cell Pdx1 Expression Is Essential for the Glucoregulatory, Proliferative, and Cytoprotective Actions of Glucagon-like Peptide-1. *Diabetes* **2005**, *54*, 482–491. [CrossRef]

189. Aigha, I.I.; Abdelalim, E.M. NKX6.1 Transcription Factor: A Crucial Regulator of Pancreatic β Cell Development, Identity, and Proliferation. *Stem Cell. Res. Ther.* **2020**, *11*, 459. [CrossRef]

190. Li, Y.; Dong, Y.; Shilun, L.; Xue, P. Liraglutide Inhibits Endoplasmic Reticulum Stress in Pancreatic Beta Cells via Regulation of the Homeodomain Transcription Factor Nkx6.1. *Diabetes* **2018**, *67*, 2146-P. [CrossRef]

191. Buteau, J.; Spatz, M.L.; Accili, D. Transcription Factor FoxO1 Mediates Glucagon-like Peptide-1 Effects on Pancreatic Beta-Cell Mass. *Diabetes* **2006**, *55*, 1190–1196. [CrossRef]

192. Kitamura, T.; Nakae, J.; Kitamura, Y.; Kido, Y.; Biggs, W.H.; Wright, C.V.E.; White, M.F.; Arden, K.C.; Accili, D. The Forkhead Transcription Factor Foxo1 Links Insulin Signaling to Pdx1 Regulation of Pancreatic Beta Cell Growth. *J. Clin. Investig.* **2002**, *110*, 1839–1847. [CrossRef] [PubMed]

193. Ma, Q. Role of Nrf2 in Oxidative Stress and Toxicity. *Annu. Rev. Pharmacol. Toxicol.* **2013**, *53*, 401–426. [CrossRef] [PubMed]

194. Fernández-Millán, E.; Martín, M.A.; Goya, L.; Lizárraga-Mollinedo, E.; Escrivá, F.; Ramos, S.; Álvarez, C. Glucagon-like Peptide-1 Improves Beta-Cell Antioxidant Capacity via Extracellular Regulated Kinases Pathway and Nrf2 Translocation. *Free Radic. Biol. Med.* **2016**, *95*, 16–26. [CrossRef] [PubMed]

195. Nishimura, W.; Iwasa, H.; Tumurkhuu, M. Role of the Transcription Factor MAFA in the Maintenance of Pancreatic β-Cells. *Int. J. Mol. Sci.* **2022**, *23*, 4478. [CrossRef] [PubMed]

196. Cunha, D.A.; Ladrière, L.; Ortis, F.; Igoillo-Esteve, M.; Gurzov, E.N.; Lupi, R.; Marchetti, P.; Eizirik, D.L.; Cnop, M. Glucagon-Like Peptide-1 Agonists Protect Pancreatic β-Cells From Lipotoxic Endoplasmic Reticulum Stress Through Upregulation of BiP and JunB. *Diabetes* **2009**, *58*, 2851–2862. [CrossRef]

197. Lee, A.-H.; Iwakoshi, N.N.; Glimcher, L.H. XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response. *Mol. Cell. Biol.* **2003**, *23*, 7448–7459. [CrossRef]

198. Zhou, Z.; Ribas, V.; Rajbhandari, P.; Drew, B.G.; Moore, T.M.; Fluitt, A.H.; Reddish, B.R.; Whitney, K.A.; Georgia, S.; Vergnes, L.; et al. Estrogen Receptor α Protects Pancreatic β-Cells from Apoptosis by Preserving Mitochondrial Function and Suppressing Endoplasmic Reticulum Stress. *J. Biol. Chem.* **2018**, *293*, 4735–4751. [CrossRef]

199. Fuselier, T.; Mota de Sa, P.; Qadir, M.M.F.; Xu, B.; Allard, C.; Meyers, M.M.; Tiano, J.P.; Yang, B.S.; Gelfanov, V.; Lindsey, S.H.; et al. Efficacy of Glucagon-like Peptide-1 and Estrogen Dual Agonist in Pancreatic Islets Protection and Pre-Clinical Models of Insulin-Deficient Diabetes. *Cell. Rep. Med.* **2022**, *3*, 100598. [CrossRef]

200. Park, J.-H.; Kim, S.-J.; Park, S.-H.; Son, D.-G.; Bae, J.-H.; Kim, H.K.; Han, J.; Song, D.-K. Glucagon-Like Peptide-1 Enhances Glucokinase Activity in Pancreatic β-Cells through the Association of Epac2 with Rim2 and Rab3A. *Endocrinology* **2012**, *153*, 574–582. [CrossRef]

201. Marinho, T.d.S.; Martins, F.F.; Cardoso, L.E.d.M.; Aguila, M.B.; Mandarim-de-Lacerda, C.A. Pancreatic Islet Cells Disarray, Apoptosis, and Proliferation in Obese Mice. The Role of Semaglutide Treatment. *Biochimie* **2022**, *193*, 126–136. [CrossRef]

202. Gupta, D.; Kono, T.; Evans-Molina, C. The Role of Peroxisome Proliferator-Activated Receptor Gamma in Pancreatic Beta Cell Function and Survival: Therapeutic Implications for the Treatment of Type 2 Diabetes Mellitus. *Diabetes Obes. Metab.* **2010**, *12*, 1036–1047. [CrossRef]

203. Rourke, J.L.; Hu, Q.; Screaton, R.A. AMPK and Friends: Central Regulators of β Cell Biology. *Trends Endocrinol. Metab.* **2018**, *29*, 111–122. [CrossRef]

204. Li, R.; Sun, X.; Li, P.; Li, W.; Zhao, L.; Zhu, L.; Zhu, S. GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux. *Front. Cell. Dev. Biol.* **2021**, *9*, 646113. [CrossRef]

205. Buteau, J.; El-Assaad, W.; Rhodes, C.J.; Rosenberg, L.; Joly, E.; Prentki, M. Glucagon-like Peptide-1 Prevents Beta Cell Glucolipotoxicity. *Diabetologia* **2004**, *47*, 806–815. [CrossRef]

206. Musale, V.; Casciaro, B.; Mangoni, M.L.; Abdel-Wahab, Y.H.A.; Flatt, P.R.; Conlon, J.M. Assessment of the Potential of Temporin Peptides from the Frog Rana Temporaria (Ranidae) as Anti-Diabetic Agents. *J. Pept. Sci.* **2018**, *24*, e3065. [CrossRef]

207. Vasu, S.; Ojo, O.O.; Moffett, R.C.; Conlon, J.M.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Anti-Diabetic Actions of Esculentin-2CHa(1-30) and Its Stable Analogues in a Diet-Induced Model of Obesity-Diabetes. *Amino Acids* **2017**, *49*, 1705–1717. [CrossRef]
208. Sirotkin, A.V.; Harrath, A.H. Phytoestrogens and Their Effects. *Eur. J. Pharmacol.* **2014**, *741*, 230–236. [CrossRef]

209. Bachmeier, B.E.; Mirisola, V.; Romeo, F.; Generoso, L.; Esposito, A.; Dell'eva, R.; Blengio, F.; Killian, P.H.; Albini, A.; Pfeffer, U. Reference Profile Correlation Reveals Estrogen-like Transcriptional Activity of Curcumin. *Cell. Physiol. Biochem.* **2010**, *26*, 471–482. [CrossRef]

210. Desmawati, D.; Sulastri, D. Phytoestrogens and Their Health Effect. *Open Access Maced. J. Med. Sci.* **2019**, *7*, 495. [CrossRef]

211. Le May, C.; Chu, K.; Hu, M.; Ortega, C.S.; Simpson, E.R.; Korach, K.S.; Tsai, M.-J.; Mauvais-Jarvis, F. Estrogens Protect Pancreatic β-Cells from Apoptosis and Prevent Insulin-Deficient Diabetes Mellitus in Mice. *Proc. Natl. Acad. Sci. USA* **2006**, *103*, 9232–9237. [CrossRef]

212. Thazhath, S.S.; Wu, T.; Bound, M.J.; Checklin, H.L.; Standfield, S.; Jones, K.L.; Horowitz, M.; Rayner, C.K. Administration of Resveratrol for 5 Wk Has No Effect on Glucagon-like Peptide 1 Secretion, Gastric Emptying, or Glycemic Control in Type 2 Diabetes: A Randomized Controlled Trial. *Am. J. Clin. Nutr.* **2016**, *103*, 66–70. [CrossRef] [PubMed]

213. Castro-Acosta, M.L.; Stone, S.G.; Mok, J.E.; Mhajan, R.K.; Fu, C.-I.; Lenihan-Geels, G.N.; Corpe, C.P.; Hall, W.L. Apple and Blackcurrant Polyphenol-Rich Drinks Decrease Postprandial Glucose, Insulin and Incretin Response to a High-Carbohydrate Meal in Healthy Men and Women. *J. Nutr. Biochem.* **2017**, *49*, 53–62. [CrossRef] [PubMed]

214. Tasic, N.; Jakovljevic, V.L.J.; Mitrovic, M.; Djindjic, B.; Tasic, D.; Dragisic, D.; Citakovic, Z.; Kovacevic, Z.; Radoman, K.; Zivkovic, V.; et al. Black Chokeberry Aronia Melanocarpa Extract Reduces Blood Pressure, Glycemia and Lipid Profile in Patients with Metabolic Syndrome: A Prospective Controlled Trial. *Mol. Cell. Biochem.* **2021**, *476*, 2663–2673. [CrossRef] [PubMed]

215. Chavanelle, V.; Otero, Y.F.; Le Joubioux, F.; Ripoche, D.; Bargetto, M.; Vluggens, A.; Montaurier, C.; Pickering, G.; Ducheix, G.; Dubray, C.; et al. Effects of Totum-63 on Glucose Homeostasis and Postprandial Glycemia: A Translational Study. *Am. J. Physiol. Endocrinol. Metab.* **2021**, *320*, E1119–E1137. [CrossRef]

216. Derosa, G.; Cicero, A.F.G.; D'Angelo, A.; Maffioli, P. Ascophyllum Nodosum and Fucus Vesiculosus on Glycemic Status and on Endothelial Damage Markers in Dysglycemic Patients. *Phytother. Res.* **2019**, *33*, 791–797. [CrossRef]

217. Panahi, Y.; Khalili, N.; Sahebi, E.; Namazi, S.; Simental-Mendía, L.E.; Majeed, M.; Sahebkar, A. Effects of Curcuminoids Plus Piperine on Glycemic, Hepatic and Inflammatory Biomarkers in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blind Placebo-Controlled Trial. *Drug. Res. (Stuttg)* **2018**, *68*, 403–409. [CrossRef]

218. Xu, X.; Yi, H.; Wu, J.; Kuang, T.; Zhang, J.; Li, Q.; Du, H.; Xu, T.; Jiang, G.; Fan, G. Therapeutic Effect of Berberine on Metabolic Diseases: Both Pharmacological Data and Clinical Evidence. *Biomed. Pharmacother.* **2021**, *133*, 110984. [CrossRef]

219. Li, M.; She, J.; Ma, L.; Ma, L.; Ma, X.; Zhai, J. Berberine Protects against Palmitate Induced Beta Cell Injury via Promoting Mitophagy. *Genes Genomics* **2022**, *44*, 867–878. [CrossRef]

220. Yin, J.; Xing, H.; Ye, J. Efficacy of Berberine in Patients with Type 2 Diabetes Mellitus. *Metabolism* **2008**, *57*, 712–717. [CrossRef]

221. Moon, J.M.; Ratliff, K.M.; Hagele, A.M.; Stecker, R.A.; Mumford, P.W.; Kerksick, C.M. Absorption Kinetics of Berberine and Dihydroberberine and Their Impact on Glycemia: A Randomized, Controlled, Crossover Pilot Trial. *Nutrients* **2021**, *14*, 124. [CrossRef]

222. Cao, Z.; Wu, Z.; Duan, T.; Tang, C.; Huang, D.; Hu, X. Curcumin Ameliorates HO-Induced Injury through SIRT1-PERK-CHOP Pathway in Pancreatic Beta Cells. *Acta Biochim. Biophys. Sin.* (Shanghai) **2022**, *54*, 370–377. [CrossRef]

223. Hao, F.; Kang, J.; Cao, Y.; Fan, S.; Yang, H.; An, Y.; Pan, Y.; Tie, L.; Li, X. Curcumin Attenuates Palmitate-Induced Apoptosis in MIN6 Pancreatic β-Cells through PI3K/Akt/FoxO1 and Mitochondrial Survival Pathways. *Apoptosis* **2015**, *20*, 1420–1432. [CrossRef]

224. Cai, E.P.; Lin, J.-K. Epigallocatechin Gallate (EGCG) and Rutin Suppress the Glucotoxicity through Activating IRS2 and AMPK Signaling in Rat Pancreatic Beta Cells. *J. Agric. Food Chem.* **2009**, *57*, 9817–9827. [CrossRef]

225. Takikawa, M.; Inoue, S.; Horio, F.; Tsuda, T. Dietary Anthocyanin-Rich Bilberry Extract Ameliorates Hyperglycemia and Insulin Sensitivity via Activation of AMP-Activated Protein Kinase in Diabetic Mice. *J. Nutr.* **2010**, *140*, 527–533. [CrossRef]

226. Nizamutdinova, I.T.; Jin, Y.C.; Chung, J.I.; Shin, S.C.; Lee, S.J.; Seo, H.G.; Lee, J.H.; Chang, K.C.; Kim, H.J. The Anti-Diabetic Effect of Anthocyanins in Streptozotocin-Induced Diabetic Rats through Glucose Transporter 4 Regulation and Prevention of Insulin Resistance and Pancreatic Apoptosis. *Mol. Nutr. Food Res.* **2009**, *53*, 1419–1429. [CrossRef]

227. Delphinidin-Induced Autophagy Protects Pancreatic <bold>β</bold> Cells against Apoptosis Resulting from High-Glucose Stress via AMPK Signaling Pathway. *ABBSS* **2019**, *1242–1249*. [CrossRef]

228. Lee, J.S.; Kim, Y.R.; Park, J.M.; Kim, Y.E.; Baek, N.I.; Hong, E.K. Cyanidin-3-Glucoside Isolated from Mulberry Fruits Protects Pancreatic β-Cells against Glucotoxicity-Induced Apoptosis. *Mol. Med. Rep.* **2015**, *11*, 2723–2728. [CrossRef]

229. Lee, J.S.; Kim, Y.R.; Song, I.G.; Ha, S.-J.; Kim, Y.E.; Baek, N.-I.; Hong, E.K. Cyanidin-3-Glucoside Isolated from Mulberry Fruit Protects Pancreatic β-Cells against Oxidative Stress-Induced Apoptosis. *Int. J. Mol. Med.* **2015**, *35*, 405–412. [CrossRef]

230. Choi, K.-H.; Park, M.H.; Lee, H.A.; Han, J.-S. Cyanidin-3-Rutinoside Protects INS-1 Pancreatic β Cells against High Glucose-Induced Glucotoxicity by Apoptosis. *Z. Naturforsch. C* **2018**, *73*, 281–289. [CrossRef]

231. Suh, K.S.; Oh, S.; Woo, J.-T.; Kim, S.-W.; Kim, J.-W.; Kim, Y.S.; Chon, S. Apigenin Attenuates 2-Deoxy-D-Ribose-Induced Oxidative Cell Damage in HIT-T15 Pancreatic β-Cells. *Biol. Pharm. Bull.* **2012**, *35*, 121–126. [CrossRef]

232. Kim, E.-K.; Kwon, K.-B.; Song, M.-Y.; Han, M.-J.; Lee, J.-H.; Lee, Y.-R.; Lee, J.-H.; Ryu, D.-G.; Park, B.-H.; Park, J.-W. Flavonoids Protect against Cytokine-Induced Pancreatic Beta-Cell Damage through Suppression of Nuclear Factor KappaB Activation. *Pancreas* **2007**, *35*, e1–e9. [CrossRef] [PubMed]
233. Wang, N.; Yi, W.J.; Tan, L.; Zhang, J.H.; Xu, J.; Chen, Y.; Qin, M.; Yu, S.; Guan, J.; Zhang, R. Apigenin Attenuates Streptozotocin-Induced Pancreatic β Cell Damage by Its Protective Effects on Cellular Antioxidant Defense. *In Vitro Cell. Dev.Biol.-Anim.* **2017**, *53*, 554–563. [CrossRef] [PubMed]

234. Youl, E.; Bardy, G.; Magous, R.; Cros, G.; Sejalon, F.; Virsolvy, A.; Richard, S.; Quignard, J.F.; Gross, R.; Petit, P.; et al. Quercetin Potentiates Insulin Secretion and Protects INS-1 Pancreatic β-Cells against Oxidative Damage via the ERK1/2 Pathway. *Br. J. Pharmacol.* **2010**, *161*, 799–814. [CrossRef] [PubMed]

235. Ding, Y.; Shi, X.; Shuai, X.; Xu, Y.; Liu, Y.; Liang, X.; Wei, D.; Su, D. Luteolin Prevents Uric Acid-Induced Pancreatic β-Cell Dysfunction. *J. Biomed. Res.* **2014**, *28*, 292–298. [CrossRef]

236. Ojo, O.A.; Grant, S.; Amanze, J.C.; Oni, A.I.; Ojo, A.B.; Elebiyo, T.C.; Obafemi, T.O.; Ayokunle, D.I.; Ogunlakin, A.D. Annona Muricata L. Peel Extract Inhibits Carbohydrate Metabolizing Enzymes and Reduces Pancreatic β-Cells, Inflammation, and Apoptosis via Upregulation of PI3K/AKT Genes. *PLoS ONE* **2022**, *17*, e0276984. [CrossRef]

237. Lin, C.-Y.; Ni, C.-C.; Yin, M.-C.; Lii, C.-K. Flavonoids Protect Pancreatic Beta-Cells from Cytokines Mediated Apoptosis through the Activation of PI3-Kinase Pathway. *Cytokine* **2012**, *59*, 65–71. [CrossRef]

238. Karunakaran, U.; Elumalai, S.; Moon, J.S.; Jeon, J.H.; Kim, N.D.; Park, K.G.; Won, K.C.; Leem, J.; Lee, I.K. Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5. *Diabetes Metab. J.* **2019**, *43*, 192–205. [CrossRef]

239. Ding, Y.; Zhang, Z.-F.; Dai, X.-Q.; Li, Y. Myricetin Protects against Cytokine-Induced Cell Death in RIN-M5f β Cells. *J. Med. Food* **2012**, *15*, 733–740. [CrossRef]

240. Fu, Z.; Zhang, W.; Zhen, W.; Lum, H.; Nadler, J.; Bassaganya-Riera, J.; Jia, Z.; Wang, Y.; Misra, H.; Liu, D. Genistein Induces Pancreatic Beta-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice. *Endocrinology* **2010**, *151*, 3026–3037. [CrossRef]

241. Wang, Q.; Liu, M.; Liu, W.-W.; Hao, W.-B.; Tashiro, S.; Onodera, S.; Ikejima, T. In Vivo Recovery Effect of Silihinin Treatment on Streptozotocin-Induced Diabetic Mice Is Associated with the Modulations of Sirt-1 Expression and Autophagy in Pancreatic β-Cell. *J. Asian Nat. Prod. Res.* **2012**, *14*, 413–423. [CrossRef]

242. Yang, J.; Sun, Y.; Xu, F.; Liu, W.; Mai, Y.; Hayashi, T.; Hattori, S.; Ushiki-Kaku, Y.; Onodera, S.; Tashiro, S.-I.; et al. Silihinin Ameliorates Amylin-Induced Pancreatic β-Cell Apoptosis Partly via Upregulation of GLP-1R/PKA Pathway. *Mol. Cell. Biochem.* **2019**, *452*, 83–94. [CrossRef]

243. Chen, K.; Zhao, L.; He, H.; Wan, X.; Wang, F.; Mo, Z. Silihinin Protects β Cells from Glucotoxicity through Regulation of the Insig-1/SREBP-1c Pathway. *Int. J. Mol. Med.* **2014**, *34*, 1073–1080. [CrossRef]

244. Keshtkar, S.; Kaviani, M.; Jabbarpour, Z.; Al-Abdullah, I.H.; Aghdaei, M.H.; Nikeghbalian, S.; Shamsaeefar, A.; Geramizadeh, B.; Azarpira, N.; Ghahremani, M.H. Significant Reduction of Apoptosis Induced via Hypoxia and Oxidative Stress in Isolated Human Islet by Resveratrol. *Nutr. Metab. Cardiovasc. Dis.* **2020**, *30*, 1216–1226. [CrossRef]

245. Zhang, J.; Chen, L.; Zheng, J.; Zeng, T.; Li, H.; Xiao, H.; Deng, X.; Hu, X. The Protective Effect of Resveratrol on Islet Insulin Secretion and Morphology in Mice on a High-Fat Diet. *Diabetes Res. Clin. Pract.* **2012**, *97*, 474–482. [CrossRef]

246. Wu, L.; Zhou, L.; Lu, Y.; Zhang, J.; Jian, F.; Liu, Y.; Li, F.; Li, W.; Wang, X.; Li, G. Activation of SIRT1 Protects Pancreatic β-Cells against Palmitate-Induced Dysfunction. *Biochim. Biophys. Acta* **2012**, *1822*, 1815–1825. [CrossRef]

247. Magliano, D.J.; Boyko, E.J. IDF Diabetes Atlas 10th Edition Scientific Committee IDF Diabetes Atlas; IDF Diabetes Atlas, 10th ed.; International Diabetes Federation: Brussels, Belgium, 2021; ISBN 978-2-930229-98-0.

248. Rietjens, I.M.C.M.; Louisse, J.; Beekmann, K. The Potential Health Effects of Dietary Phytoestrogens. *Br. J. Pharmacol.* **2017**, *174*, 1263–1280. [CrossRef]

249. Kang, N.J.; Shin, S.H.; Lee, H.J.; Lee, K.W. Polyphenols as Small Molecular Inhibitors of Signaling Cascades in Carcinogenesis. *Pharmacol. Ther.* **2011**, *130*, 310–324. [CrossRef]

250. Sakle, N.S.; More, S.A.; Dhawale, S.A.; Mokale, S.N. Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-Tumor Drug Discovery. *Curr. Drug. Discov. Technol.* **2020**, *17*, 585–615. [CrossRef]

251. Wang, Y.; Alkhalidy, H.; Liu, D. The Emerging Role of Polyphenols in the Management of Type 2 Diabetes. *Molecules* **2021**, *26*, 703. [CrossRef]

252. Corb Aron, R.A.; Abid, A.; Vesa, C.M.; Nechifor, A.C.; Behl, T.; Ghitea, T.C.; Munteanu, M.A.; Fratila, O.; Andronie-Cioara, F.L.; Toma, M.M.; et al. Recognizing the Benefits of Pre-/Probiotics in Metabolic Syndrome and Type 2 Diabetes Mellitus Considering the Influence of Akkermansia Muciniphila as a Key Gut Bacterium. *Microorganisms* **2021**, *9*, 618. [CrossRef]

253. Anhê, F.F.; Pilon, G.; Roy, D.; Desjardins, Y.; Levy, E.; Marette, A. Triggering Akkermansia with Dietary Polyphenols: A New Weapon to Combat the Metabolic Syndrome? *Gut Microbes* **2016**, *7*, 146–153. [CrossRef] [PubMed]

254. Murota, K.; Nakamura, Y.; Uehara, M. Flavonoid Metabolism: The Interaction of Metabolites and Gut Microbiota. *Biosci. Biotechnol. Biochem.* **2018**, *82*, 600–610. [CrossRef] [PubMed]

255. Renaud, J.; Martinoli, M.-G. Considerations for the Use of Polyphenols as Therapies in Neurodegenerative Diseases. *Int. J. Mol. Sci.* **2019**, *20*, 1883. [CrossRef] [PubMed]

256. Fang, Z.; Bhandari, B. Encapsulation of Polyphenols—A Review. *Trends Food Sci. Technol.* **2010**, *21*, 510–523. [CrossRef]
257. Szunerits, S.; Melinte, S.; Barras, A.; Pagneux, Q.; Voronova, A.; Abderrahmani, A.; Boukherroub, R. The Impact of Chemical Engineering and Technological Advances on Managing Diabetes: Present and Future Concepts. *Chem. Soc. Rev.* **2021**, *50*, 2102–2146. [CrossRef]

258. Barras, A.; Mezzetti, A.; Richard, A.; Lazzaroni, S.; Roux, S.; Melnyk, P.; Betbeder, D.; Monfilliette-Dupont, N. Formulation and Characterization of Polyphenol-Loaded Lipid Nanocapsules. *Int. J. Pharm.* **2009**, *379*, 270–277. [CrossRef]

259. Hannon, T.; Kahn, S.; Utzschneider, K.; Buchanan, T.; Nadeau, K.; Zeitler, P.; Ehrmann, D.; Arslanian, S.; Caprio, S.; Edelstein, S.; et al. A Review of Methods for Measuring β-Cell Function: Design Considerations from the Restoring Insulin Secretion (RISE) Consortium. *Diabetes Obes. Metab.* **2018**, *20*, 14–24. [CrossRef]

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