bluuebunny/crossref_metadata_2025 huggingface dataset:
1599-P: Understanding the Paradoxical Rise in Blood Glucose in the Context of a Low-Carbohydrate Diet
Authors: DERU LANDON , BAILEY BRUCE W. , BIKMAN BENJAMIN
Published: June 2024

Introduction and Objective: Conventional medicine places markers of glycemic control as a key diagnostic and therapeutic target for metabolic disorders. Long-term adherence to a low-carbohydrate diet may improve glycemic control but may also cause a unique hormonal response to macronutrients that keeps blood glucose elevated. The purpose of this study was to identify an endocrine pattern explaining the phenomenon of elevated glucose on a subset of people that adhere to a carbohydrate-restricted diet.

Methods: Each participant (13 female, 11 male) completed three interventions which consisted of consuming an isovolumetric 300 kcal drink of either whey protein (PRO), dextrose (CHO), or olive oil (FAT) mixed in water. Blood was taken immediately prior to drink consumption and then every 30 minutes afterwards for 2 hours in each condition. Continuous glucose monitoring took place during each intervention.

Results: Glucagon was not different between FAT/CHO conditions (p = 0.28), but elevated in the PRO condition comparted to both FAT and CHO conditions (p < 0.01). Insulin was not different between PRO/FAT (p = 0.22) or PRO/CHO (p = 0.30), but was higher in the CHO compared to the FAT condition (p < 0.01). GLP-1 was not different between FAT/CHO conditions (p = 0.37), but was elevated in the PRO condition compared to the CHO and FAT conditions (p < 0.01). GIP was different between all three conditions (p<0.01). Glucose was not different between FAT/PRO conditions (p = 0.44), but was elevated in the CHO condition compared to the FAT and PRO conditions (p<0.01).

Conclusion: The glucose load significantly raised plasma glucose, GIP, and insulin while decreasing glucagon, relative to the fat and protein loads. The protein load, in contrast, uniquely raised GLP-1 and glucagon relative to the other drinks. Adherence to a carbohydrate-restricted diet may result in an exaggerated glucagon response to PRO which may explain elevated glucose in this population.

Disclosure

L. Deru: None. B.W. Bailey: None. B. Bikman: None.

Funding

This work is supported by funds from Levels Health, Inc.
1620-P: Vagus Nerve Integrity Is Critical for GLP-1 (7-36) Safeness against Hypoglycemia
Authors: LOBATO CAROLINA B. , HOLST JENS J.
Published: June 2024

Introduction & Objective: GLP-1 optimizes glycemic control mostly by stimulating insulin and suppressing glucagon secretion. During hypoglycemia, the glucagon suppressing activity is abolished through unclear pathways. The parasympathetic nervous system, via the vagus nerve, modulates the pancreatic hormone secretion during hypoglycemia. The vagus nerve fibers run along the esophagus and stomach walls, and innervate the pancreas distally. We investigated the role of the vagus nerve anatomical integrity in modulating pancreatic endocrine response to cholinergic activity and GLP-1 under hypoglycemia.

Methods: In situ, isolated rat pancreas (A); and pancreas and stomach (B) were perfused at severe hypoglycemia (glucose 1.5mM). Ach 1 µM, Ach 1 µM + GLP-1 (7-36) 1nM and GLP-1 (7-36) 1nM were sequentially infused (A: n = 6; B: n = 6). L-Arginine 10 mM was infused at the end of all experiments (positive control). Glucagon and SST levels were measured. Total hormone output was calculated. Statistical significance was settled at p<0.05.

Results: During hypoglycemia, cholinergic stimulation suppresses SST and stimulates glucagon secretion. Active GLP-1 (7-36) overrides cholinergic activity by potentiating SST and suppressing glucagon secretion in the isolated pancreas (A), but GLP-1 (7-36) has no effect if the vagus nerve integrity is preserved (B). Once cholinergic stimulation is discontinued, GLP-1 (7-36) suppresses glucagon and stimulates SST secretion in both preparations.

Conclusion: Pancreatic cholinergic activity stimulates glucagon secretion during hypoglycemia through suppression of somatostatin secretion. Cholinergic signaling that is delivered through the gastric intramural autonomic ganglia and/or vagus nerve efferents to the pancreas is crucial for blunting GLP-1 (7-36) activity under hypoglycemia. These findings improve our understanding of GLP-1 physiology and shine light on the requirements to target vagal nerve function in optimizing pancreatic endocrine secretion.

Disclosure

C.B. Lobato: Research Support; Dexcom, Inc. J.J. Holst: Advisory Panel; Novo Nordisk A/S, Merck Sharp & Dohme Corp., Kallyope. Board Member; Antag Therapeutics.

Funding

Danish Diabetes Academy (NNF17SA0031406); "la Caixa" Foundation (LCF/BQ/EU21/11890081).
1639-P: Tirzepatide and Efruxifermin Demonstrate Therapeutic Benefits for NASH in a Preclinical Metabolic Syndrome Animal Model, B6-Alms1-del Mice
Authors: CHEN ZHONG , SHEN YANFEI , WANG HONGYAN , WANG HONGYU , LIANG JUAN , ZHAO JING , GAO XIANG , GAO MAOMAO
Published: June 2024

The escalating prevalence of metabolic syndrome has led to NAFLD and its severe form, nonalcoholic steatohepatitis (NASH), becoming a major public health concern. While numerous anti-NAFLD/NASH agents have entered development pipelines, only Resmetirom has advanced to the NDA stage. There remains a high demand for novel therapies in the NAFLD/NASH field.We tested two promising anti-NASH agents, Tirzepatide and Efruxifermin in the B6-Alms1-del mice, which develop NASH spontaneously. B6-Alms1-del mice at 16 weeks of age received twice a week treatment of vehicle, 30 nmol/kg Tirzepatide or 30 nmol/kg Efruxifermin subcutaneously for 6 weeks. Our finding revealed that, compared with vehicle treatment, both Tirzepatide and Efruxifermin treatment significantly decreased body weight, plasma ALT and AST, fasting blood glucose and blood lipid. However, Efruxifermin demonstrated a significantly greater inhibitory effect on body weight than Tirzepatide treatment. Additionally, Tirzepatide significantly reduced the food intake of mice, while the effect of Efruxifermin on food intake was not significant. The results of metabolic parameters suggested that Efruxifermin's metabolic benefits on B6-Alms1-del mice did not mainly rely on reduced energy intake. Morphology analysis indicated that liver hypertrophy observed in B6-Alms1-del mice was marked reduced upon treatment with both Tirzepatide and Efruxifermin. Particularly, treatment with Efruxifermin nearly restored the liver weight of B6-Alms1-del mice to that of B6J mice. Consistently, Efruxifermin treatment exhibited more significant NASH resolution than Tirzepatide treatment.In summary, we demonstrated the therapeutic effects of Tirzepatide and Efruxifermin in B6-Alms1-del mice, which aligned with recent clinical observations. Consequently, B6-Alms1-del mice could serve as a valuable model for preclinical studies of anti-NASH agents targeting GLP-1R/GIPR and FGF21.

Disclosure

Z. Chen: None. Y. Shen: None. H. Wang: None. H. Wang: None. J. Liang: None. J. Zhao: None. X. Gao: None. M. Gao: None.
1685-P: Dapiglutide Is a Dual Agonist on Human GLP-1- and GLP-2-Receptors with a Biased and Prolonged Signaling Profile at the GLP-1R
Authors: GJELSTRUP LOUISE , KERSTIN LUNDHOLT BETINA , LARSEN BJARNE D. , JOHANSEN NICKLAS J. , OLSEN MINNA B. , MATHIESEN JESPER M.
Published: June 2024

Dapiglutide, a potential first-in-class therapy targeting obesity and low-grade inflammation, is designed for activating both GLP-1 and GLP-2 receptors. In a MAD trial, healthy participants receiving once-weekly s.c. injections of dapiglutide up to 6 mg for 4 weeks showed dose-dependent body weight loss up to a mean 4.3%, and dose-dependent reductions of plasma glucose and insulin. At the cellular level, GLP-1R activation by native GLP-1 induces formation of its major second messenger cAMP and recruitment of β-arrestin. Recent studies hypothesized that biased agonists displaying lack of β-arrestin recruitment at the GLP-1R are beneficial in controlling blood glucose and body weight loss in DIO rats. Here we investigated the in vitro profile of dapiglutide, emphasizing on GLP-1R signaling bias and functional consequences.

Binding assays using 125-iodinated radioligands were used to estimate binding affinities of dapiglutide for human GLP-1R and GLP-2R. The human GLP-1R in vitro signaling profile was investigated in a kinetic cAMP formation assay and for recruitment of β-arrestin in HEK293 cells.

Initial in vitro characterization indicated that dapiglutide is more potent for binding to GLP-1R over GLP-2R, with estimated binding affinities of 38 nM and 102 nM, respectively.​ At the GLP-1R, dapiglutide showed signaling bias, displaying full agonist activity in cAMP formation, whilst having significantly blunted response to β-arrestin recruitment. Further in vitro characterization showed that dapiglutide-induced cAMP formation kinetics persisted for up to 12 hours unlike native GLP-1, potentially reflecting signal bias, lack of receptor desensitization, and a promising efficacy profile in the MAD trial.

Dapiglutide, a dual GLP-1/GLP-2 agonist, has a unique GLP-1R biased agonism signaling profile that combined with additional GLP-2R activity may translate into an efficacious weight management therapy in individuals with obesity.

Disclosure

L. Gjelstrup: Employee; Zealand Pharma A/S. B. Lundholt: Employee; Zealand Pharma A/S. B.D. Larsen: None. N.J. Johansen: Employee; Zealand Pharma A/S. M.B. Olsen: None. J.M. Mathiesen: Employee; Zealand Pharma A/S.
1710-P: Weight Stigma and Discrimination among Hispanics and Non-Hispanic Whites and Blacks with Obesity and Diabetes in the U.S.
Authors: GALINDO RODOLFO J. , ZABALA ZOHYRA , AREVALO GIULIANA , MOAZZAMI BOBAK , LECUBE ALBERT , RASHIED AMMAR A. , UMPIERREZ GUILLERMO
Published: June 2024

Introduction: People with obesity experience stigma and discrimination for their physical appearance and weight. Data is limited among stigmatization and prejudices among Hispanics (HISP) and non-Hispanic Whites (NHW) and Blacks (NHB) with obesity and diabetes in the U.S. We compare prejudices, stigma and internal negative bias in these groups.

Methods: Observational study conducted at two academic centers, including adults > 18ys, and BMI ≥30 kg/m2. We assessed prejudices with Anti-Fat Attitudes (AFA), stigmatizing experiences with Brief Stigmatizing Situations Inventory (SSI-B), and internalization of negative weight bias with Weight Bias Internalization Scale (WBIS) surveys.

Results: Among 233 participants (age 55.3±13 years, 62% females, BMI 37±6.4, 48% HISP, 10% NHW, 42% NHB), 73% and 22% had the perception of being individuals with overweight (OW) and obesity (OB), respectively. HISP had a higher AFA score (p<0.001) compared to NHW and NHB. SSI-B score was similar across groups. NHW had a higher WBIS score compared to HISP and NHB (p=0.01).

Conclusions: Adults with obesity and diabetes in the U.S., HISP had higher aversion/prejudices towards people with obesity, NHW had higher internalization of negative bias, while stigmatizing experiences were not different across groups.

Table 1. Demographic Characteristics and Surveys Scores among Adults with Obesity and Diabetes

Disclosure

R.J. Galindo: Consultant; Abbott. Other Relationship; Dexcom, Inc. Consultant; Bayer Inc. Other Relationship; Novo Nordisk, Eli Lilly and Company. Consultant; Boehringer-Ingelheim, AstraZeneca. Z. Zabala: None. G. Arevalo: None. B. Moazzami: None. A. Lecube: None. A.A. Rashied: None. G. Umpierrez: Research Support; Abbott, Bayer Inc., Dexcom, Inc., AstraZeneca. Advisory Panel; Dexcom, Inc.

Funding

National Institutes of Health (P30DK111024 (RJG, GEU), and K23DK123384 (RJG) and R03DK138255 (RJG))
1729-P: Hypertonicity Mediates Glucose-Induced First-Phase Insulin Secretion
Authors: KAMAT VARUN , SWEET IAN
Published: June 2024

Biphasic insulin secretion is an intrinsic characteristic of the pancreatic islet and has clinical relevance due to the loss of first phase in patients with Type 2 diabetes. As it has long been shown both in vitro and in vivo that first phase insulin secretion only occurs in response to rapid, but not gradual, changes in glucose, we tested the hypothesis that hypertonicity is driving first phase insulin secretion. The hypothesis was tested with perifusion analysis of rat. mouse and human islets by counterbalancing increases in D-glucose with decreases in L-glucose (a membrane impermeable form of glucose) so that insulin secretion rate (ISR) and other parameters associated with its regulation (NAD(P)H, calcium, cAMP production rate (cAMP PR)) could be measured in response to D-glucose in the absence of a change in tonicity. In response to a rapid rise in D-glucose, biphasic increases were observed for all 4 measured parameters. Remarkably, the appearance of the first phase component was wholly dependent on changes in tonicity: no first phase in NAD(P)H, cytosolic calcium, cAMP PR, or ISR was observed when increased D-glucose concentration was counterbalanced by decreases in either L-glucose (or another membrane-impermeable compound mannitol). Notably, rapid increases in L-glucose without any change in D-glucose resulted in first phase responses in all measured parameters that were kinetically similar to those observed in response to D-glucose. The effects of changes in osmolarity on calcium and ISR were blocked by a specific inhibitor of L-type calcium channels. Taken together, it appears that first phase insulin secretion is a result of a short-lived hypertonicity occurring during rapidly increasing glucose that enhances glucose metabolism, activation of L-type calcium channels and elevation of cAMP, that briefly augments the same mechanisms mediating second phase insulin secretion.

Disclosure

V. Kamat: None. I. Sweet: Employee; EnTox Sciences, Inc. Advisory Panel; Regenerative Medical Solutions.

Funding

National Institutes of Health (R01 GM148741); The Helmsley Foundation (#FA218303); National Institutes of Health IIDP Technology Resource Award (TRA2023)
1733-P: Foxo3 and Heterogeneity of Dedifferentiating ß-Cells
Authors: SON JINSOOK , ACCILI DOMENICO
Published: June 2024

Type 2 diabetes is associated with β-cell dedifferentiation. This process is linked to a loss of Foxo1 function and can be recapitulated by genetic inactivation of Foxo1. Notably, β-cell dedifferentiation is heterogeneous, with distinct cells in the same islet exhibiting different stages of dedifferentiation. To understand the heterogeneity of β-cell dedifferentiation, we purified islets from β-cell-specific Foxo1 knockout mice and separated them by flow cytometry using an insulin promoter (Rip-Cre)-driven Rosa26 tdTomato reporter to select β-cells. Surprisingly, tdTomato-positive (β-) cells partitioned into two distinct clusters based on signal intensity. Both clusters were Foxo1-deficient. The subpopulation characterized by low levels of tdTomato expression (Tlow β-cells), increased from 2 to ~13% of the total β-cell population as animals aged from 3- to 24-months, and was absent in WT controls. Strikingly, this subpopulation was characterized by a compensatory increase of Foxo3 expression. To assess the function of Tlow β-cells, we performed glucose-stimulated insulin secretion assays on sorted pseudo-islets. Tlow β-cells exhibited enhanced glucose-dependent insulin secretion compared to Foxo1 knockout β-cells that failed to increase Foxo3 expression. Gene Ontology (GO) analyses of RNA-seq data revealed that the main difference between Foxo1 knockout cells without Foxo3 compensation and Tlow β-cells was in the oxidative phosphorylation and ATP synthesis-coupled electron transport pathways. This study illuminates β-cell heterogeneity in diabetic islets and suggests a role of Foxo3 compensation in the heterogeneity of β-cell dedifferentiation and in age-dependent changes of β-cell function.

Disclosure

J. Son: None. D. Accili: None.

Funding

National Institutes of Health (DK134848); National Institutes of Health (DK64819)
1752-P: Mechanistic Effects of Intermittent Hypoxia ?(IH) on? ß-Cells, Glucose Homeostasis, and Predisposition to Type 2 Diabetes (T2D)
Authors: BAKER TESS A. , ANDRADE LOUZADA NETO RUY , PUNJABI NARESH M. , BERNAL-MIZRACHI ERNESTO
Published: June 2024

The capacity of pancreatic β-cells to adapt to insulin resistance or stress conditions is the major determinant of developing Type 2 diabetes (T2D). Obstructive sleep apnea (OSA), a prevalent disorder associated with T2D, causes chronic intermittent hypoxia (IH). The mechanisms through which OSA/chronic IH cause abnormalities in glucose levels and T2DM are not known. Mechanistic responses to hypoxia in other tissues involve alterations in AMPK and mTORC1 signaling, but how these alterations affect tissues responsible for glucose homeostasis, including β-cells, is not known. It was hypothesized that IH leads to alterations in glucose homeostasis by inducing β-cell function via upregulation of mTORC1 signaling in β-cells. To examine the role of IH in glucose homeostasis and β-cell function, we used a system to induce IH in both in vivo and in vitro models. The fractional inspired O2 between 21% and 5% in 30 second intervals (~ 60 episodes/hr), for 12hrs/day for 7, 14, and 28-days in C57B6J mice. IH resulted in improved glucose tolerance and insulin sensitivity. Evidence of hypoxia at the β-cell level was seen by an increase in a common target of hypoxia inducible factor (HIF1), adrenomedullin, and an increase of the Hypoxyprobe marker, pimonidazole. At the mechanistic level, β-cells from IH exposed mice and islets exposed to IH in vitro displayed increase in mTORC1 activation, via activation of its downstream target pS6(240). Taken together, the current evidence showed that IH can induce improvements in glucose tolerance and insulin secretion, and this was associated to augmented mTORC1 signaling.

Disclosure

T.A. Baker: None. R. Andrade Louzada Neto: None. N.M. Punjabi: None. E. Bernal-Mizrachi: None.

Funding

R01 DK073716/DK/NIDDK
1753-P: Alteration of Splice Type in Type 2 Ryanodine Receptor Causes Impaired Insulin Secretion in Mice
Authors: MAKINO MAI , UCHIYAMA TOMOKO , OSHIMA YU , DAIKOKU TAKIKO , YAMAMOTO YASUHIKO , OKAMOTO HIROSHI , NAKAMURA SHUHEI , TAKASAWA SHIN
Published: June 2024

Increase of intracellular Ca2+ concentration is essential for glucose-induced insulin secretion. Type 2 ryanodine receptor (RyR2) is a Ca2+ release channel that mobilizes Ca2+ from the endoplasmic reticulum to the cytosol. Unlike RyR2 mRNA expressed in heart, RyR2 mRNA expressed in pancreatic β cells lacks exon 75, probably due to a unique splice donor site “gg” of intron 75 in RyR2 gene. We previously reported that the alteration of splicing in RYR2 caused impaired insulin biosynthesis in human 1.1B4 β cells. Here, to further investigate the significance of RyR2 alternative splicing in vivo, especially glucose-induced insulin secretion, we generated the homozygous genome-modified mice, named RyR2Ex75KI/Ex75KI, in which exon 75-containing RyR2 is expressed systemically including pancreatic β cells by using CRISPR/Cas9 system. Immunohistochemical analysis of pancreas from 15-week-old RyR2Ex75KI/Ex75KI and control wild-type (WT) mice revealed that the size of islets in RyR2Ex75KI/Ex75KI mice was almost the same as that in WT mice, while the insulin-positive area per islet was significantly decreased (0.44-fold, P=0.005). Isolated islets from 9- to 12-week-old mice of each genotype were stimulated by low (2.8 mmol/L) or high (20 mmol/L) glucose for 1 h and secreted insulin was measured by ELISA. Insulin secretion after low glucose treatment from RyR2Ex75KI/Ex75KI islets was significantly higher than that from WT islets (5.27-fold, P=0.019), and insulin secretion after high glucose stimulation was not increased (0.77-fold relative to low glucose stimulation). Intraperitoneal glucose tolerance test (2 g/kg) for 120 min on 14- to 19-week-old mice revealed that blood glucose levels did not differ between genotypes and serum insulin levels at 60-120 min after the glucose challenge were slightly higher in RyR2Ex75KI/Ex75KI mice. Taken together, our results suggest that the WT splice variant of RyR2 would have a crucial role in glucose-induced insulin secretion in vivo.

Disclosure

M. Makino: None. T. Uchiyama: None. Y. Oshima: None. T. Daikoku: None. Y. Yamamoto: None. H. Okamoto: None. S. Nakamura: None. S. Takasawa: None.

Funding

JSPS KAKENHI Grant Number JP21K15375
1759-P: Delta Cell Potentiates Secretion of Insulin and Glucagon in a Novel Model of Islet Paracrine Interactions
Authors: RODRIGUEZ DIAZ RAYNER , TAMAYO ALEJANDRO M. , PEREIRA ELIZABETH
Published: June 2024

The islet δ-cell secretes SST, a peptide which is a strong paracrine inhibitor of insulin and glucagon secretion. It is conceivable, that the δ-cell, as an inner homeostatic element in the islet to prevent the spillover of both hormones.There are insufficient data to ascertain the intraislet mechanisms governing the δ-cell activity and its impact on the islet secretory output. We aimed to 1) study the correlation between insulin and somatostatin secretion in human islets from healthy and diabetic donors as well as mice fed control or high fat diet; and 2) mechanistic studies to dissect the role the δ-cell plays in the islet secretory output using transgenic mouse models. Our data allows us to propose a revised model of intraislet paracrine interactions that challenges the view of the δ-cell solely as a suppressive element on islet secretion. We propose that δ-cells paradoxically may enhance the secretion of both glucoregulatory hormones through short and sharp events inhibition driven by its pulsatile secretion, besides its canonical inhibiting role. δ-cell activation leads to peaks of somatostatin secretion appears to cause asynchronous off-responses secretory responses of neighboring α- and β- cells after somatostatin falloff, prompting a net increase in the magnitude of insulin and glucagon secretions. This model provides a comprehensive explanation for our contradictory results of the effects manipulating δ-cells has on the mouse glucose metabolism, such as, the improved glucose metabolic readouts upon activation, inhibition or even ablation of the δ-cells. Our findings emphasize the importance of understanding the mechanism that link δ-cells to pathological events in the natural history of Diabetes.

Disclosure

R. Rodriguez Diaz: None. A.M. Tamayo: None. E. Pereira: None.

Funding

National Institutes of Health (R01 DK124527)
1864-LB: Comparative Safety and Effectiveness of GLP-1RA and SGLT2i Use in Adults with Type 2 Diabetes in U.S. Clinical Practice
Authors: HOFFMAN SARAH R. , LANES STEPHAN , QUIMBO TRACEY , PAPAZIAN AANAHIT , WHITE JEFF , FISHER VICKI , CZIRAKY MARK J. , CROWLEY MATTHEW J. , WILLEY VINCENT
Published: June 2024

GLP-1 RA use has risen sharply, a shift prompted by trial evidence and guideline recommendations in T2D and use in obesity. To inform safe prescribing for T2D, this study assessed the real-world effects of GLP-1 RA and SGLT2i on the incidence of serious clinical events. Adults with T2D who initiated a GLP-1 RA or SGLT2i agent from 1/1/16 to 9/30/23 were identified from the Healthcare Integrated Research Database (HIRD), a large national US claims database. Outcomes included GI, psychiatric, hepatic and CV events, thyroid cancer and all-cause mortality. Inverse probability of treatment weighting was used to control confounding and incidence rates and rate ratios (RR) were estimated. Differences between new users of GLP-1 RA (n=311,574) and SGLT2i (n=255,146) were observed in age, sex, prevalent conditions (obesity, ASCVD, HF, CKD and anxiety) and insulin use. After weighting, characteristics were well balanced between groups. Rates and RR are displayed in the Table. Among serious events, only GI hospitalizations occurred more frequently in GLP-1 RA users, while acute liver injury was less common. Psychiatric events, thyroid cancer and all-cause mortality rates were similar between groups, as were CV event rates in these groups having broad heterogeneity in baseline CV risk. These real-world data complement trial data and should inform GLP-1 RA prescribing decisions in T2D.

Disclosure

S.R. Hoffman: Other Relationship; Carelon Research. S. Lanes: None. T. Quimbo: None. A. Papazian: None. J. White: None. V. Fisher: None. M.J. Cziraky: Other Relationship; Carelon Research. M.J. Crowley: None. V. Willey: Other Relationship; Carelon Research.
1865-LB: Exploring Incretin-Based Therapies as Adjunctive Treatment for Type 1 Diabetes—Real-World Insights and Future Directions
Authors: ALMARZOOQI IHSAN , ZAKARIA HALA , CACCELLI MILENA , SAID YOUSEF , HASHEMI ALI
Published: June 2024

Incretin-based therapies, known for their efficacy in Type 2 diabetes management, are increasingly explored in the context of Type 1 diabetes due to their ability to modulate insulin and glucagon secretion. This shift in focus has prompted investigations into the potential benefits of Tirzepatide and Semaglutide, a glucagon-like peptide-1 receptor agonist, in managing Type 1 Diabetes. This case series study investigates Tirzepatide and Semaglutide's potential benefits in Type 1 Diabetes management.Our study included 10 T1D patients (30-47 years) using a hybrid care model with physical encounters and remote data monitoring. Patients on insulin were initiated on Semaglutide or Tirzepatide over three months. Data, including baseline characteristics and continuous glucose monitoring (CGM) metrics, were collected. Patients showed a substantial reduction in prandial and basal insulin doses (-25.24%, -29.16%). HbA1c improved from 8.28% to 6.95% in 3 months. Time in Range increased significantly (+42.11%, p=0.002). Overweight/obese patients lost -5.64 kg (p<0.001). The initiation of incretin therapy led to a substantial decrease in both bolus and basal insulin requirements, along with noteworthy improvements in HbA1c levels, weight and TIR. These reductions in alignment with ADA recommendations for T1D patients underscore the potential benefits of incretin-based therapies. Dose adjustments, continuous monitoring, and avoiding hypoglycemia were crucial.Preliminary findings suggest incretin therapy as an adjunct to insulin in T1D management, showing reduced insulin requirements, improved glycemic control, and positive weight impacts. However, comprehensive, randomized clinical trials with a larger cohort are needed to validate these outcomes.

Disclosure

I. Almarzooqi: None. H. Zakaria: None. M. Caccelli: None. Y. Said: None. A. Hashemi: None.
1873-LB: Comparison of Adherence and Persistence between Oral Semaglutide and Once-Weekly Semaglutide Injection at 12-Month Follow-up in Japanese Real-World Data
Authors: HORII TAKESHI , MASUDO CHIKAKO , MIHARA KIYOSHI
Published: June 2024

This retrospective, observational study aimed to compare 12-month adherence and persistence between oral semaglutide (O-SEMA) and matched Once-Weekly semaglutide Injection (SEMA-I) using real-world administrative claims data from the MDV database. The study included patients with T2D who initiated O-SEMA or SEMA-I between January 2018 and December 2022. SEMA-I initiators were 1:1 propensity-score matched to O-SEMA initiators (9,238 pairs each). Non-adherence was defined as a Proportion of Days Covered (PDC) <0.8. Logistic regression analysis was used with medication adherence (PDC <0.8) as the dependent variable. Persistence rates were compared using Cox regression analysis, with discontinuation of SEMA as the event. Baseline characteristics were balanced, with a mean age of 58 years and 50% females. More O-SEMA initiators were adherent compared to SEMA-I (92.5% vs. 89.8%). The odds ratio for non-adherence significantly increased with SEMA-I compared to SEMA-O (OR: 1.41). More O-SEMA initiators were persistent on therapy compared to SEMA-I (91.7% vs. 82.9%). The hazard ratio for treatment discontinuation, with O-SEMA as the reference, was 1.97 (95% CI 0.81-2.15) for SEMA-I. However, during the first 100 days of treatment, the hazard ratio for SEMA-I compared to O-SEMA was 0.67 (95% CI 0.60-0.76). O-SEMA initiators showed significantly higher adherence and greater persistence on their therapy than SEMA-I initiators in 12-month. On the other hand, it is important to be cautious of the risk of treatment discontinuation in the early stages of O-SEMA administration, as the complexity of management and the method of administration may be influencing factors.

Disclosure

T. Horii: None. C. Masudo: None. K. Mihara: None.
1875-LB: Adjuvant Glucagon-Like Peptide 1 Receptor Agonist (GLP-1 RA) Use in HNF1A- and HNF4A-MODY
Authors: BROOME DAVID , MEHDI ALINA Z. , FOSS-FREITAS MARIA C. , CHASE COLBY , GREGG BRIGID , ORAL ELIF A. , HERMAN WILLIAM H.
Published: June 2024

Introduction: Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes. Although sulfonylurea treatment is effective early in the disease course for HNF1A-MODY and HNF4A-MODY, patients often experience sulfonylurea treatment failure. Glucagon-like peptide-1 Receptor Agonists (GLP-1 RA) have previously been used in HNF1A-MODY and HNF4A-MODY, but there is a lack of evidence for their effectiveness as adjuvant treatment.

Methods: We compiled a case series study of University of Michigan MODY patients to examine the effect of adjuvant GLP-1 RA treatment in patients with HNF1A-MODY and HNF4A-MODY treated with sulfonylureas.

Results: Of 87 patients with genetically confirmed MODY (76 HNF4A-MODY, 11 HNF1A-MODY), there were 4 patients identified who were treated with a GLP-1 RA as adjuvant treatment to a sulfonylurea. All patients were White, 3 were female, 3 had HNF1A-MODY and all patients were from different pedigrees. The average HbA1c prior to initiation of GLP-1 RA was 7.7 + 0.4%, and the average BMI was 28.5 kg/m2. After GLP-1 RA initiation, there was an average decrease in HbA1c of 1.3 + 0.4%, with an average body weight loss of 15.8 + 10.7 lbs (BMI change of -2.6 kg/m2). Patients had the following information (sex, current age, mutation, sulfonylurea dose reduction, administration & type of GLP-1 RA, dose, treatment duration): F, 47, HNF1A-MODY, glimepiride 6 mg/day reduction, oral semaglutide, 7 mg once daily, 22 mos.; F, 55, HNF1A-MODY, glipizide 5 mg/day reduction, subcutaneous dulaglutide, 1.5 mg once weekly, 21.5 mos.; 56, F, HNF1A-MODY, glipizide 10 mg/day reduction, subcutaneous semaglutide, 0.5 mg once weekly, 24 mos.; 43, M, HNF4A-MODY, glipizide 10 mg/day reduction, subcutaneous dulaglutide, 1.5 mg once weekly, 47.5 mos.

Conclusions: These 4 patients (3 HNF1A-MODY, 1 HNF4A-MODY) demonstrate that adjuvant treatment with GLP-1 RA lowers HbA1c, body weight, and sulfonylurea dose requirements in patients with HNF1A- and HNF4A-MODY.

Disclosure

D. Broome: Research Support; Novo Nordisk, Fractyl Health, Inc., Rhythm Pharmaceuticals, Inc., T1D Exchange. Consultant; Tayco, Inc. M.C. Foss-Freitas: Research Support; Amryt Pharma Plc. Advisory Panel; PTC Pharmaceuticals. C. Chase: None. B. Gregg: Consultant; CVS Caremark. E.A. Oral: Consultant; Akcea Thearpeutics, Inc. Research Support; Akcea Thearpeutics, Inc. Consultant; Regeneron Pharmaceuticals Inc. Research Support; Regeneron Pharmaceuticals Inc., Amryt Pharma Plc. Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals. Research Support; Ionis Pharmaceuticals, Rhythm Pharmaceuticals, Inc., Novo Nordisk, GI Dynamics, Fractyl Health, Inc. W.H. Herman: Consultant; Merck Sharp & Dohme Corp. Advisory Panel; American Diabetes Association. Other Relationship; National Institutes of Health. Advisory Panel; National Committee for Quality Assurance.
1883-LB: ATR-258 Is a Precision Modulator of ß2-AR Signaling That Improves Glucose Homeostasis and Is Safe in Humans
Authors: KALINOVICH ANASTASIA , WAARA ERIK , DE JONG JASPER M.A. , PELCMAN BENJAMIN , BENGTSSON TORE
Published: June 2024

Introduction & Objective: Stimulation of β2-adrenergic receptors (β2-AR) in skeletal muscle improves glucose uptake capacity and is a promising avenue in the treatment of type 2 diabetes (T2D). To circumvent common β2-AR-associated cardiovascular side-effects through cAMP activation, we have developed a novel β2-AR agonist, ATR-258, with low cAMP induction but improved glucose tolerance and insulin sensitivity in preclinical models. Here we present preclinical efficacy data and phase 1 safety data for our candidate drug ATR-258.

Methods: We have used various in vitro models to analyze the functional characteristics of ATR-258. These include receptor selectivity, downstream signaling profiles, cAMP induction and glucose uptake. We assessed the in vivo effects of ATR-258 on glucose tolerance and insulin sensitivity in diet-induced obese C57BL/6 mice and diabetic Goto-Kakizaki rats. To test safety in humans, we performed single and multiple ascending dose studies in a total of 46 healthy male volunteers. In a third cohort, 23 male patients with T2D received either placebo (n = 8) or 2.5 mg ATR-258 (n = 15) once daily for 28 days. Safety profiles, PK, and PD variables such as HbA1c and glucose tolerance were measured.

Results: ATR-258 displayed limited cAMP induction and no promotion of β-arrestin recruitment or receptor desensitization, but a maintained ability to induce glucose uptake compared to classical β2-AR agonists in vitro. ATR-258 improved glucose tolerance and insulin sensitivity in a dose-dependent manner in mouse and rat models of obesity and diabetes. Our first-in-human phase 1 data showed that ATR-258 is safe and well-tolerated in healthy volunteers and T2D patients.

Conclusion: ATR-258 is a β2-AR agonist with a preferential signaling and safety profile resulting in beneficial effects on glucose homeostasis in preclinical models and a promising safety profile in humans. ATR-258 could lead the way of a new class of adrenergic agonists to

treat T2D.

Disclosure

A. Kalinovich: Employee; Atrogi AB. Stock/Shareholder; Atrogi AB. E. Waara: Employee; Atrogi. J.M.A. de Jong: Employee; Atrogi AB. B. Pelcman: Consultant; Atrogi AB. T. Bengtsson: Stock/Shareholder; Atrogi, Sigrid therapeutics.
19-OR: Sucralose Consumption Decreases Insulin Sensitivity and Modifies the Gut Microbiota in Healthy Individuals
Authors: ROMO-ROMO ALONSO , SANCHEZ-TAPIA MONICA , TORRES NIMBE , AGUILAR-SALINAS CARLOS A. , MARTAGON ALEXANDRO J. , GUADALUPE LÓPEZ-CARRASCO MARÍA , GUILLÉN-PINEDA LUZ E. , GOMEZ-AVILES PAOLA , BRITO GRISELDA X. , GÓMEZ-PEREZ FRANCISCO J. , ALMEDA-VALDES PALOMA
Published: June 2024

Introduction: Sucralose is a non-nutritive sweetener that has shown to decrease insulin sensitivity through mechanisms including changes in intestinal microbiota.

Objective: To determine the impact of sucralose on insulin sensitivity and gut microbiota in healthy individuals.

Methods: Parallel triple-blind randomized clinical trial including 24 healthy individuals, not habitual users of nonnutritive sweeteners. Individuals were instructed to maintain dietary and physical activity habits and randomized to consume capsules with 30% of the acceptable daily intake of sucralose or placebo for 30 days. Hyperinsulinemic euglycemic clamp was performed before and after the intervention, M/I value change was calculated and compared. Stool samples were taken at baseline and the final visit, DNA extraction was carried out with a QIAamp DNA stool Mini Kit.

Results: The M/I value adjusted for free fat mass decreased in the sucralose group vs placebo (p<0.01). Reduction in the alpha diversity of gut microbiota (p<0.0002) was observed in sucralose consuming group vs placebo (p=0.2369) and an increase in the Gram (-) bacteria Bacteroides fragilis associated to a significant increase in serum LPS were documented.

Conclusion: Sucralose consumption causes a significant decrease in insulin sensitivity associated to changes in gut microbiota composition and endotoxemia in healthy individuals.

Disclosure

A. Romo-Romo: None. M. Sanchez-Tapia: None. N. Torres: None. C.A. Aguilar-Salinas: None. A.J. Martagon: None. M. López-Carrasco: None. L.E. Guillén-Pineda: None. P. Gomez-Aviles: None. G.X. Brito: None. F.J. Gómez-Perez: None. P. Almeda-Valdes: None.

Funding

CONAHCYT Ciencia de Frontera 2019/316514
1972-LB: Timing of Overt Diabetes Diagnosis and Pregnancy Outcomes
Authors: REICHELT ANGELA J. , DE CAMPOS MARIA A. , GUERRA GIULIA L. , HIRAKATA VÂNIA N. , OPPERMANN MARIA LÚCIA R.
Published: June 2024

Introduction and Objective: Overt diabetes is becoming frequent in pregnancy. We aim to describe pregnancy outcomes in women with overt diabetes according to the timing of diagnosis.

Methods: From a retrospective cohort of 646 women with diabetes, we selected those with hyperglycemia diagnosed for the first time in pregnancy. We evaluated baseline characteristics, prenatal care, and pregnancy outcomes comparing women diagnosed up to 13 gestational weeks (GW), between 13 - 20 GW, and after 20 GW. We used ANOVA with post-hoc Tukey test to compare groups.

Results: Overt diabetes was diagnosed in 217 women (33.6%, 95% CI 30.0%-37.0%) (Table). An earlier diagnosis led to fewer maternal hospital admission, less weight gain and a lower third trimester HbA1c compared to the diagnosis in the third trimester. Pregnancy outcomes were similar among the groups.

Conclusions: Women with overt diabetes diagnosed up to the 13th gestational week attained better metabolic control. Nevertheless, timing of diagnosis did not impact on pregnancy outcomes in this cohort.

Disclosure

A.J. Reichelt: None. M.A. de Campos: None. V.N. Hirakata: None.
1988-LB: Effects of Alcohol Consumption among Patients with Hepatic Steatosis and Prediabetes or Diabetes
Authors: BANTU SRAVANI S. , PETRIE ERIN , GRAY MEAGAN , BRIL FERNANDO
Published: June 2024

In December of 2023, a multisociety Delphi consensus on fatty liver disease nomenclature was published renaming nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD) and introduced the term MetALD, which identifies patients with MASLD, who also are moderate consumers of alcohol. However, the effects of moderate alcohol consumption among patients with hepatic steatosis and prediabetes/diabetes are not well known.In order to better understand the effects of alcohol consumption in these patients, we analyzed data from NHANES 2017-2020 including self-report alcohol intake, and transient elastography (TE). Hepatic steatosis was defined based on controlled attenuation parameter ≥ 288 dB/m.A total of 1,757 patients with diabetes (47%) or prediabetes (53%) were included in the study (age: 55 ± 15 years; Sex: 44% female; BMI: 34.0 ± 7.0 kg/m2; A1c: 6.5 ± 1.4%). Based on self-reporting, patients were divided in 7 groups according to alcohol grams consumed per week (no alcohol consumption, 0-10, 10-50, 50-100, 100-200, 200-500, >500). Increasing alcohol consumption was associated with decreased insulin resistance by HOMA-IR (from 6.9 ± 6.0 to 3.7 ± 1.9, p=0.042) and A1c (from 6.7 ± 1.5 to 5.7 ± 0.5%, p<0.001), but increased BP (SBP: from 129 ± 19 to 137 ± 17 mmHg, p=0.006; DBP: from 76 ± 12 to 85 ± 11 mmHg, p<0.001), TG (from 153 ± 118 to 209 ± 193 mg/dL, p=0.056), and HDL-C (from 47 ± 11 to 57 ± 18 mg/dL, p<0.001). Alcohol consumption was associated with worse liver enzymes (AST, ALT, and GGT, all p<0.001) without concomitant changes in hepatic steatosis or fibrosis by imaging.In patients with hepatic steatosis and prediabetes or diabetes, moderate alcohol consumption was associated with improvement in insulin sensitivity, but worsening of other cardiometabolic risk factors (i.e., blood pressure and triglycerides). This can result in an overclassification of patients with MetALD, even in patients where alcohol may be the only driver of the disease.

Disclosure

S.S. Bantu: None. E. Petrie: None. M. Gray: Consultant; Novo Nordisk. F. Bril: Consultant; Novo Nordisk.
199-OR: Beta-Cell IRS1 Deficiency Predisposes Female Mice to Developing Gestational Diabetes
Authors: WANG XINGCHUN , USMAN TAOFEEK , CHHETRI GOMA , QUAN ZHENG WEN , YEH HSUAN , WHITE MORRIS F. , HENRY DONG H.
Published: June 2024

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without previously diagnosed diabetes. To understand the mechanism of GDM, we characterized the role of IRS1 in β-cell compensation for pregnancy. We generated β-cell conditional IRS1-knockout (βIRS1-KO) mice. While virgin βIRS1-KO mice maintained normal metabolism, pregnant βIRS1-KO mice developed GDM, culminating in the onset of fasting hyperglycemia and glucose intolerance at gestational day 15.5. These effects were attributable to the reduction of glucose-stimulated insulin secretion in pregnant βIRS1-KO mice. Anti-insulin immunohistochemistry revealed that pregnant βIRS1-KO vs. WT mice had significantly diminished islet size and reduced β-cell mass. Anti-Ki67 immunostaining showed that βIRS1-KO vs. WT mice had minimal β-cell replication during pregnancy. Islet RNA transcriptome analysis demonstrated that IRS1-deficient islets were associated with a significant downregulation of GATA4 and its targets Reg1 and Reg3a, key factors critical for β-cell replication. In pregnant WT mice, β-cell IRS1 along with GATA4, Reg1 and Reg3a was upregulated in islets, coinciding with the physiological induction of β-cell mass expansion during pregnancy. These effects were totally abolished in IRS1-deficient islets, correlating with impaired β-cell compensation in pregnant βIRS1-KO mice. Mechanistically, IRS1 underwent prolactin-stimulated phosphorylation at Tyr632. This effect correlated with the induction of GATA4, Reg1 and Reg3a expression in islets of pregnant WT mice. We recapitulated these findings in INS1 cells in response to prolactin. Our studies uncovered a new IRS1-GATA4-Reg1/Reg3a signaling cascade in integrating gestational hormones to β-cell compensation, an adaptive mechanism that acts to overcome maternal insulin resistance and protect against GDM.

Disclosure

X. Wang: None. T. Usman: None. G. Chhetri: None. W. Zheng: None. H. Yeh: None. M.F. White: Board Member; Housey Pharmaceutical Research Laboratories. H. Dong: None.
1994-LB: Metabolites Link Infections to Type 2 Diabetes in the Multiethnic Study of Atherosclerosis (MESA)
Authors: WOOD ALEXIS , GOODARZI MARK O. , CHEN ZSU-ZSU , GUO XIUQING , RICH STEPHEN S. , CLISH CLARY B. , GERSZTEN ROBERT E. , ROTTER JEROME I. , TAYLOR KENT
Published: June 2024

Introduction & Objective: Prior to T2D, patients experience increased infections, yet no pathways account for this immune/endocrine system cross-talk. We aimed to identify metabolites that link pathogens to T2D.

Methods: Using plasma from 4,424 adults (61 ±9 y; 53% female), taxonomic classification was conducted on reads from sequencing that aligned with a microbial reference panel, and metabolites quantified. Incident T2D (ADA 2003 criteria) was assessed over ~18 y. A cox-proportional hazard model identified baseline microbes as ‘variables of importance’ to incident T2D, with a penalty function to minimize sparse data bias. Metabolome-wide associations identified metabolites shared between T2D-related microbes at baseline, and incident T2D. All models adjusted for age, gender, race/ethnicity, education, and AHA’s Life’s Simple 8 score.

Results: Total microbes differed by race/ethnicity (X2= 30.4, df = 9, P= 3.8*10-4), but not any other covariates (all P>.05). Incident T2D was associated with 2 microbes: Rahnella (HR=1.90 (1.09-3.30), P=.02) and Plasmodium falciparum (HR=1.34 (1.05-1.73), P=.02). 23 metabolites were associated with incident T2D (P<.05 after an FDR-correction) and at least one of these microbes (P<.05; Fig).

Conclusions: These analyses indicate molecules linking exposure to, and / or continued presence in the plasma of, infectious microbes, and increased risk of T2D.

Disclosure

A. Wood: Research Support; Beef Checkoff. Consultant; Lundquist. M.O. Goodarzi: Advisory Panel; Nestlé Health Science, Organon. Z. Chen: None. X. Guo: None. S.S. Rich: None. C.B. Clish: None. R.E. Gerszten: None. J.I. Rotter: None. K. Taylor: None.

Funding

USDA/ARS cooperative agreement (#58-3092-5-001). Advancing Translational Sciences (UL1TR001420, UL1TR001881).
1996-LB: Relative Contributions of Glycosylated Hemoglobin and Glycemic Variability to the Development of Microvascular Outcomes from DCCT Study
Authors: ZHANG JIE , SONG ZHENQIANG , LI MINGZHEN , ZHU HONG , GAO SHAN , LIU YUFU
Published: June 2024

Introduction and Object: As two key profiles for blood glucose control and complications, the relative contributions of glycosylated hemoglobin (HbA1c) and glycemic variability (GV) to microvascular outcomes are explored in type 1 diabetes mellitus in Diabetes Control and Complications Trial (DCCT) study.

Methods: Measures of GVs included the SD, mean amplitude of glycemic excursions (MAGE), coefficient of variation (CV) within and between quarterly 7-point glucose profiles and HbA1c.The generalized boosted models were used to analysis the relative effects of HbA1c and GV.

Results: Mean HbA1c accounted for 57%-62% /55%-57%for the development/progression of retinopathy, and GV accounted for 38%-43%/43%-57%, even similar in subgroup analysis including gender, age, duration, triglyceride and changes of nephropathy. HbA1c accounted for 46.5% for the occurrence of microalbuminuria, as for GV, 53.5% respectively. MAGE and SD accounted more in patients with duration of more than 10years. GV contributed more in subgroup with serum triglyceride≤55mg/dL and non-deteriorated retinopathy (58%-61%, 59%-67% respectively) in microalbuminuria.

Conclusion: Our finding showed that GV contributed equally as HbA1c, or more for microvascular outcomes in type 1 diabetes, especially for microalbuminuria. Refined and comprehensive blood glucose management would be needed for health care provides.

Disclosure

J. Zhang: None. Z. Song: None. M. Li: None. H. Zhu: None. S. Gao: None. Y. Liu: None.
20-PUB: Intensification of Human Insulin Therapy with SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus
Authors: DZIDA GRZEGORZ J. , GAJDA PIOTR , MASIEREK MALGORZATA
Published: June 2024

Treatment intensification with SGLT2 inhibitors added to insulin therapy is recommended in many T2DM guidelines as well as registered indications. The aim of the study was the assessment of the efficacy and safety of SGLT2 inhibitors with human insulin combinations in comparison with the general treatment options in T2DM patients onwith human insulins therapy. The data were collected in non-interventional multicenter observational open label study recruiting 4384 T2DM patients treated with human insulin (Gensulin®) injected with the same device (Gensupen®2 ). Combinations including SGLT2 inhibitors was observed in 1079 (24,6%). Triple combination of human insulin+metformin+SGLT2 inhibitors was the most commonly used (632 patients, 14,4%). SGLT2 inhibitors treatment intensification was found in 40,1% of patients with diagnosed HF (those with HFrEF in 59,65%), history of MI 40,4% and CKD in 30,25%. Patients age, gender, BMI nor history of stroke did not affect the frequency of SGLT2 inhibitors use. The decrease of A1c in 6 months observation period in SGLT2 group was 0,8% while 0,7% in the general treatment group. A1c after 6 months was similar in both groups (7,7% and 7,8%). The percentage of patients achieving target A1c less than 7% was also similar ( 5,6% and 21,3% after 6 months vs. 5,8% and 18,9% respectively). Median insulin daily dose didn’t differ between groups (35,2U vs 34U ) as well as insulin dose per kg (0,4U/kg vs.0,4U/kg) at the study end. The confirmed hypoglycaemia rate was very low and did not differ between groups as well as percentage of patients not reporting hypogylaemia in 6 month period ( 82,7% vs. 84%). The intensification of human insulin treatment in T2DM patients with SGLT2 inhibitors did not affect significantly glucose control efficacy and safety. HF, history of MI and CKD were the strongest indications for SGLT2 inhibitors choice. The optimalization of insulin dose seems to be a crucial intervention needed to achieve appropriate glucose control.

Disclosure

G.J. Dzida: None. P. Gajda: None. M. Masierek: Employee; BIOTON.