bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Intestine-Specific FFA3 Has Protective Effects Against Diet-Induced Obesity and Hyperglycemia in Mice on a Western Diet
Authors: Lednovich Kristen Roan , Gough Sophie , Priyadarshini Medha , Layden Brian T 
Published: May 2021

Abstract
Free fatty acid receptor 3 (FFA3) is a recently-deorphaned G protein-coupled receptor belonging to the free fatty acid receptor family. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients that play a diverse role in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA3 is broadly expressed in a multitude of tissues including the intestine, pancreas, and central nervous system, and is thought to contribute to metabolic homeostasis via a summation of its tissue-specific effects. Consequently, FFA3 has been identified as a potential drug target for metabolic diseases including obesity and type-2 diabetes. FFA3 is highly expressed in enteroendocrine cells (EECs) within the intestinal epithelium - the major site of SCFA generation - and is hypothesized to play a role in the secretion of postprandial incretin hormones, which are a group of specialized gut peptides that regulate a variety of metabolic and digestive functions following a meal. However, due to a paucity of data, the role of FFA3 within the intestine and its effects on physiology and metabolism is largely unclear. Previous in vivo studies involving this receptor have largely relied on global knockout mouse models, making it difficult to isolate its effects in EECs. To overcome this challenge, we have generated a novel intestine-specific knockout mouse model for FFA3, utilizing Cre-mediated recombination under the expression of the villin promoter. Here, we report the first in vivo characterization of FFA3 in the intestine and reveal novel insights into receptor function. Following model validation, we conducted a general metabolic assessment of male Villin-Cre-FFA3 mice on normal chow and observed no major congenital or time-dependent defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, a pilot study was performed on male Villin-Cre-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar “western diet.” Mice were placed on either normal chow (NC) or western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. Our data reveals that Villin-Cre-FFA3 mice on WD, but not NC, were protected from diet-induced metabolic dysfunction, and displayed significantly lower levels of fat mass as well as modestly improved glycemic control. Our findings suggest a novel role of FFA3 in mediating the metabolic consequences of a western diet - a state of high inflammation, dysbiosis and metabolic stress. Moreover, these data support an intestine-specific role of FFA3 in both glucose and lipid metabolism, and further suggest the receptor’s role in whole-body metabolic homeostasis and in the development of adiposity and hyperglycemia.
Tgm2-p62-p53 Complex May Function as an Autophagic Regulator Through Fyn and Involve in Diabetic Kidney Disease
Authors: Uehara Ryota , Yamada Eijiro , Uehara Masaya , Nakajima Yasuyo , Horiguchi Kazuhiko , Ishida Emi , Matsumoto Shunichi , Okada Shuichi , Yamada Masanobu 
Published: May 2021

Abstract
Diabetic kidney disease (DKD) is one of the major diabetic complications and the leading cause of the end stage renal disease. Recently autophagy was shown to regulate DKD. Previously we reported that Fyn regulates muscle mass by suppressing autophagy through Fyn-STAT3-VPS34 signaling pathway. More recently, we demonstrated that Fyn also down-regulates autophagy in HK2 cells, an in vitrocell model of renal proximal tubular epithelial cells (RPTC). Phospho-proteomic analysis revealed that Fyn phosphorylates Transglutaminase 2 (Tgm2), a known autophagic inhibitor, at Y369 and Y617. Moreover, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy. It has been reported that Tgm2 forms complexes with p53 and p62 (a known autophagy regulator) to mediate degradation of p53 at autophagosome in cancer cells and p53 functions as a DKD inducer. We found that p53 expression was decreased in Tgm2 knock-downed HK2 cells suggesting that Tgm2-p62-p53 complex also modulates autophagy in RPTC. We previously showed that Fyn and autophagy is regulated by energy status, therefore we next examined whether energy levels changed the subcellular localization of p53, p62 and Tgm2 in HK2 cells in vivousing the marker, Aquaporin 1. Confocal microscopic studies revealed that ad libitum-fed mice showed increased punctate of p62 in RPTC suggesting that autophagy was reduced. Fyn, Tgm2 and p53 shaped the dotted form mainly in the basement membrane of the cells. Interestingly, all these molecules moved to the cytoplasm in fasted state, where decreased p62 punctations were observed indicating increased autophagy. More importantly, in HFD fed mice, diet-induced rodent models of metabolic disorders, we found that protein expression of p53 was increased due to decreased levels of degradation with inhibition of autophagy implicated by decreased p62 punctations in RPTC. Taken together, these data suggest that the metabolic status may regulate Fyn to not only phosphorylate Tgm2 and modulates Tgm2-p62-p53 complex but also change their co-localizations of Fyn, p53 and Tgm2 in RPTC to regulate autophagy leading to pathogenesis of DKD.
The Short-Term Impact of Roux-en-Y Gastric Bypass on Enteroendocrine Hormone Distribution and Density in Rhesus Macaques
Authors: True Cadence , Kirigiti Melissa Ann , Lindsley Sarah Rene , Scamarone Jackelin , Bauman Leigh Ann , Kievit Paul 
Published: May 2021

Abstract
Roux-en-Y gastric bypass (RYGB) surgery results in profound weight loss and improvements in glucose homeostasis through a likely combination of malabsorption and changes in GI tract signaling. One component of GI tract signaling implicated in RYGB effects are enteroendocrine hormones, which are produced along the tract and regulate GI tract motility, pancreas exocrine and endocrine functions, including insulin release, and central nervous system control of feeding. While RYGB has been shown to cause post-prandial serum increases of several enteroendocrine hormones, the mechanism for how this occurs in the GI tract is still unknown. The current study examined GI tract tissue 13 weeks after RYGB or sham-surgery combined with pair-feeding (Sham/PF) in adult rhesus macaques. In situ hybridization analysis revealed no RYGB-induced changes compared to Sham/PF animals in the overall distribution of enteroendocrine hormones, with cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) cells found predominantly in the proximal small intestine and preglucagon, encoding glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine (PYY) cells found predominantly in the ileum and colon. Immunohistochemistry was performed to further characterize the impact of RYGB on enteroendocrine cell density. No differences were observed in CCK cell densities in the proximal tract following RYGB, nor were there any differences in PYY and GLP-1 densities in the distal intestine. The only observed difference was an increase in serotonin and chromogranin A cell densities in the ileum of the RYGB group compared to the Sham/PF group. Serotonin has diverse actions from regulating GI tract motility to central nervous system signaling via the vagus nerve. Additional studies are planned to investigate how this up-regulation of serotonin may impact metabolic physiology after RYGB.
High-Fat Diet Accelerates Pathological Progression and Intestinal Inflammation in a Type 2 Diabetes Rodent Model
Authors: Reilly Austin , Ren Hongxia 
Published: May 2021

Abstract
Insulin signaling lowers postprandial glucose by stimulating cell surface translocation of the insulin sensitive glucose transporter 4 (GLUT4). In order to better understand how insulin resistance contributes to the pathophysiological progression of type 2 diabetes, we generated human GLUT4 promoter-driven insulin receptor knockout (GIRKO) mice and characterized their metabolic features relative to control mice. Although the role of insulin resistance in diabetes is beyond dispute, our previous studies showed that GIRKO mice fed normal chow diet (NCD) had an unexpectedly low rate of frank diabetes despite severe insulin resistance in muscle, fat, and brain.
In the current study, we first sought to determine whether GIRKO mice would respond to high-fat diet (HFD) challenge with worsened glycemic outcome compared to control mice on HFD. Secondly, we sought to determine whether HFD-induced pathologies in GIRKO mice were caused by adaptations in the gastrointestinal (GI) tract and microbiome. We discovered that after beginning the HFD-feeding regimen, GIRKO mice rapidly developed hyperinsulinemia and hyperglycemia without excessive adiposity gain. Furthermore, GIRKO mice displayed dyslipidemia via increased hepatic lipid accumulation and serum lipid content. We used indirect calorimetry to characterize the metabolic features of single-housed mice. HFD-fed GIRKO mice had comparatively lower respiratory exchange ratio (RER), indicating relatively greater lipid metabolism compared to control mice on HFD. Despite having increased circulating incretins, GIRKO mice had impaired oral glucose tolerance and limited glucose-lowering benefit from Exendin-4 (Ex-4) injections. Since HFD promotes inflammation in the gastrointestinal (GI) tract, we performed gene expression analysis and pathway analysis of duodenal mRNAs to investigate whether inflammatory response, glucose transport, and lipid transport were altered in HFD-fed GIRKO mice. Among the top pathways discovered in pathway analysis were those involved with inflammatory signaling, carbohydrate transport, and xenobiotic metabolism, which supports that HFD-fed GIRKO mice have increased GI tract inflammation which may promote impaired glucose homeostasis.
In conclusion, our studies suggest that HFD increased intestinal inflammation and exacerbated insulin resistance, which catalyzed the pathological progression of diabetes. Future studies are necessary to identify the molecular and cellular signaling pathways which culminate in frank diabetes, which may lead to therapeutic targets for regulating glucose homeostasis in the context of insulin resistance.
Once Weekly Basal Insulin Fc (BIF) is Safe and Efficacious in Patients with Type 2 Diabetes Mellitus (T2DM) Previously Treated With Basal Insulin
Authors: Frias Juan Pablo , Chien Jenny , Zhang Qianyi , Chigutsa Emmanuel , Landschulz William , Wullenweber Paula , Haupt Axel , Kazda Christof 
Published: May 2021

Abstract
Basal insulin Fc (BIF; LY3209590) is a novel, once-weekly, long-acting IgG Fc-fusion protein that is being assessed for the treatment of diabetes mellitus. The presented study evaluated the safety and efficacy of BIF compared to insulin degludec over 32 weeks in patients with T2DM previously treated with oral antidiabetic drugs and a basal insulin. The study design included 2 different dosing algorithms for BIF (BIF-A1 and BIF-A2) with two different fasting glucose (FG) targets of ≤140 mg/dL (BIF-A1) and ≤120 mg/dL (BIF-A2). Insulin degludec was titrated to a FG target of ≤100mg/dL using a modified Riddle treat-to-target algorithm. Study participants (N=399) were randomized in a 1:1:1 ratio to 1 of 3 parallel treatment groups. The average age of participants was 60.2 years, baseline HbA1c was 8.1% and duration of diabetes 14.7 years. There were no statistically significant differences in demographics or baseline characteristics across the 3 treatment groups. Both BIF groups achieved non-inferiority (non-inferiority margin = 0.4%) for the primary endpoint of HbA1c change from baseline to Week 32 with a mean±SE reduction for BIF-A1, BIF-A2 and insulin degludec of 0.6±0.1%, 0.6±0.1% and 0.7±0.1%, respectively. In line with the different fasting serum glucose (FSG) targets, insulin degludec achieved greater FSG lowering from baseline as compared to the BIF arms. Similarly, both BIF dosing groups showed significantly fewer hypoglycemic events compared to insulin degludec (all documented events as well as nocturnal events) when assessing events ≤70 mg/dL (3.9 mmol/L). Hypoglycemic events &lt;54 mg/dL (3.0 mmol/L - all documented events as well as nocturnal events) were not significantly different between the three dosing groups. Two severe hypoglycemic events were reported in BIF-A2. The reported treatment-emergent adverse events and serious adverse events were balanced across the 3 treatment groups. Both BIF groups had a statistically significantly smaller increase in body weight compared to insulin degludec from baseline to Week 32. In summary, BIF, when administered weekly according to either dosing algorithm, was noninferior to insulin degludec for glycemic control as measured by change in HbA1c after 32 weeks with a lower rate of documented and nocturnal hypoglycemia ≤70 mg/dL and less weight gain. Additionally, no safety signals were detected. While higher FG targets were chosen in this first Phase 2 study with BIF, the safety and tolerability results allow assessment of lower target glucose ranges in future trials. The results from this study support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.
A Point-of-Care Interactive Decision Tool Reveals Variance Between Clinicians and Experts in Selecting Among GLP-1 RAs in T2D
Authors: Schwartz Zachary , Mir-Hudgeons Kiran , Roc Anne , Zimmerman Robert S , Peters Anne 
Published: May 2021

Abstract
Background: T2D management is shifting toward treating patients with therapies that align with their level of CV and end-organ risk. To this end, evidence-based guidelines now recommend glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for both glycemic and extraglycemic benefits. The great speed with which these recommendations change create immediate gaps in knowledge and competence, especially as they relate to managing patients with comorbid CV and/or renal disease. To help clinicians understand GLP-1 RA therapies and their novel characteristics in practice, we developed a decision support tool where choice of treatment among GLP-1 RAs is guided by a panel of experts.
Methods: We developed a decision support tool with guidance from 5 experts who provided therapy recommendations for 48 unique patient case scenarios based on patient variables including CVD, CKD, retinopathy, A1C level, and need for weight loss. Clinician learners are prompted to specify a patient scenario using these variables before selecting an intended therapy. After all questions are completed for a patient scenario, the tool displays what the panel of experts recommend and then asks the learner if this information changed their intended choice.
Results: From February through October 2020, 983 learners entered 1433 unique patient case scenarios. Of these, 365 were anonymous and 623 were authenticated, of which 70% (n = 437) were from the US; 50% (n = 310) were MDs; 22% (n = 135) were nurses, NPs, or PAs; and 19% (n = 121) were PharmDs.
The intended therapy of learners differed from the experts in 34% (n = 489) of cases and were limited to 3 categories: cases in which learners chose to use exenatide (17%), cases in which they chose to use a GLP-1 RA in conjunction with insulin (12%), or cases in which they were unsure (71%).
Of note, of the 93 cases in which learners chose exenatide, 68% (n = 63) were cases with CVD and/or CKD, where exenatide was not recommended by experts. Similarly, of the 89 cases in which learners chose insulin with a GLP-1 RA, 57% (n = 51) were cases with A1C &lt; 9%, where insulin was not recommended by experts.
Of cases in which learners’ intended therapy differed from the experts’ (and they indicated the impact of the tool), 52% indicated that they planned to change their treatment plan.
Conclusion: This tool highlights continuing gaps in clinicians’ ability to select among GLP-1 RAs for T2D. Using a decision support tool can positively influence practice behaviors: Learners can see if their intended treatment choice is congruent with a panel of experts and change plans as appropriate.
Comparing Quality of Life in Type 2 Diabetic Patients Using Dulaglutide and Liraglutide
Authors: Ghosh Aneesh 
Published: May 2021

Abstract
Background and Aims: WHO has defined quality of life as individuals perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. The quality of life evaluation is seen as an important aspect of care of diabetes mellitus 1. In this context it is imperative to study how new agents will affect the quality of life. In this study we have compared the quality of life of patients using dulaglutide and liraglutide. Deign and Method: We have used a simple self-administered patient centered quality of life (PCQoL) measure that is based on general and diabetes related life. This tool has shown to strongly correlate with the established reference scorings system, diabetes related quality of life (DQoL) score, developed for the Diabetes Control and Complications Trial 2,3. Sixty eligible patients on oral hypoglycaemic agents and Dulaglutide (N:30) or Liraglutide (N:30) formed the study group. All study subjects were on steady dose of GLP 1 RA for at least six months before they took two part quality of life (general and diabetes related) questionnaire during their hospital visit. In each part, subjects nominated five facets of life, judged to be important to them for quality of life (most important rated 5). Each aspect was then weighted by the patient for their current level of satisfaction on a five-point Likert scale (5, completely satisfied; 1, not at all satisfied), and a total score was calculated. Groups were matched for for age, sex, diabetes duration, comorbidities and HbA1C. The means were compared with Student’s t test.
Results: The quality of life scores were better for dulaglutide than for liraglutide treated subjects (mean [SD] PCQoL: 66 [61–70] vs 56 [52 - 60], p &lt; 0.05).
Discussion: In the diabetes management strategy, a primary therapeutic goal is to address and better the quality of life. In this study we have established that once weekly Dulaglutide offers better quality of life than daily injections of Liraglutide. PCQoL is a patient centered quality of life measurement is quick, simple, repeatable, sensitive, and valid in type 2 diabetes mellitus. References: 1.Rubin R, Peyrot M. Quality of life and diabetes. Diab Metab Res Rev. 1999;15(3):205–18. 2.Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes. N Engl J Med. 1993;329(14):977–86. 3.John C. Pickup, Anna Harris. Assessing Quality of Life for New Diabetes Treatments and Technologies: A Simple Patient-Centered Score. Journal of Diabetes Science and Technology. 2007;1(3):394–99.
In Obese Patients Without Diabetes, 12 Weeks of Time-Restricted Eating (TRE) Does Not Alter β-Cell Function: A Randomized Pilot Study
Authors: Lau Kheng Joe , Manoogian Emily N C , Alvear Alison , Wang Qi , Panda Satchidananda , Mashek Douglas G , Chow Lisa Senye 
Published: May 2021

Abstract
Impairment of β-cell function is a precursor to impaired glucose tolerance, which is a pathophysiological basis for the development of Type 2 Diabetes Mellitus (T2DM). Previous literature has reported varying effects of TRE on metabolic measures in different populations, yet the effect of TRE on β-cell function has not been well-characterized. We hypothesized that in obese patients without diabetes, 12 weeks of TRE (8-hour eating window) would improve β-cell function relative to baseline and the unrestricted eating group (non-TRE). Participants (17 women and 3 men; (mean ± SD); 45.5±12.1 years; BMI 34.1±7.5 kg/m2) with a prolonged eating window (15.4±0.9 hours) were randomized to either TRE (n=11) or non-TRE (n=9) for 12 weeks. Weight and 2-hour oral glucose tolerance (OGTT) were measured during at baseline and end-intervention. Β-cell function was assessed by multiple OGTT-based measures, including Glucose AUC, Insulin AUC, insulinogenic index, disposition index, QUICKI index, Matsuda index, Stumvoll index, and Avignon index. At baseline, these measures are within normal range across both groups. We found that TRE did not significantly alter these measures relative to baseline or the non-TRE group. In addition, the degree of eating window restriction did not correlate with any observed changes in β-cell function. We concluded that in obese patients without diabetes, TRE did not significantly alter β cell function; whether TRE may be beneficial in patients with dysglycemia warrants further investigation.
Patient-Specific Risk Factors and Clinical Correlates of Euglycemic Diabetic Ketoacidosis in Patients on Sodium-Glucose Co-Transporter-2 Inhibitors
Authors: Somagutta Manoj Reddy , Pormento Maria Kezia Lourdes L , Hange Namrata , Khan Muhammad Adnan , Jain Molly S , Hanan Saad , Batti Erkan , Kaur Jaspreet , Iloeje Obumneme Jude , Pagad Sukrut 
Published: May 2021

Abstract
Background: Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT-2i) association with euglycemic diabetic ketoacidosis (EDKA) has been well reported. The underlying mechanism is mainly enhanced lipolysis and ketone bodies’ reabsorption. They also stimulate the pancreatic alpha cells and inhibit the beta cells, thereby causing an imbalance in glucagon/insulin levels, further contributing to lipolysis and ketogenesis. SGLT-2i were also found to cause EDKA in all types of diabetes, even uncovering undiagnosed Latent Autoimmune Diabetes of the Adult (LADA).
Methods: Numerous electronic databases were systematically searched to identify patient-specific risk factors and clinical characteristics of EDKA in patients on SGLT-2i. The patient’s symptoms, clinical profile, laboratory results, and precipitants for EDKA were reviewed.
Results: A total of 96 case reports identifying 116 patients with EDKA was fully reviewed. EDKA was twice prevalent in females (66.3%) than males (33.6%); median age was 52.15 ± 13.47, BMI was 29.3 ± 7.0. Among the 116 DKA events in SGLT-2i 92 (79.3%) were associated with Type-2 DM, 15 (12.9%) were Type-1 DM, 8 (6.9%) in LADA. Common symptoms were nausea (48.7%), vomiting (47%), and abdominal pain (28.2%). Canagliflozin was the most common SGLT-2i (40.5%), followed by Empagliflozin (29.3%) and Dapagliflozin (25.9%). The most common precipitant was surgery (17.2%), followed by infection (14.7%), fasting (11.2%), and Keto Diet (9.5%); others being reduced insulin use, alcoholism, and cancer. At presentation, average blood glucose was 196.8 ± 96.5, pH 7.1 ± 0.16, HCO3 8.7 ± 5.7 mmol/L, potassium 4.3 ± 1.03, anion-gap 24.2 ± 6.8 mmol/L, and the average HbA1C was 9.24 ± 2.08. Urine Ketones were positive in 81.89% of patients. 17 patients had pancreatic autoantibodies testing, and 7 were positive (41.2%) for glutamic acid decarboxylase-65 antibodies (anti-GAD-65). As a result, 7 patients were newly diagnosed with LADA who were previously misdiagnosed with type-2 DM.
Conclusion: SGLT2i induced EDKA was found to be more predominant in females and type-2 DM. Diabetics should be educated on risk factors and consult physicians before commencing a dietary or exercise change. Physicians should be vigilant in diagnosing EDKA by thoughtful measurement of urine ketones and anti-GAD-65 testing can help diagnose underlying LADA.