Chronic late gestation fetal hyperglucagonaemia results in lower insulin secretion, pancreatic mass, islet area and beta- and α-cell proliferation.

Fetal glucagon concentrations are elevated in the presence of a compromised intrauterine environment, as in cases of placental insufficiency and perinatal acidaemia. Our objective was to investigate the impact of late gestation fetal hyperglucagonaemia on in vivo insulin secretion and pancreatic islet structure. Chronically catheterized late gestation fetal sheep received an intravenous infusion of glucagon at low (5 ng/kg/min; GCG-5) or high (50 ng/kg/min; GCG-50) concentrations or a vehicle control (CON) for 8-10 days. Glucose-stimulated fetal insulin secretion (GSIS) was measured following 3 h (acute response) and 8-10 days (chronic response) of experimental infusions. Insulin, glucose and amino acid concentrations were measured longitudinally. The pancreas was collected at the study end for histology and gene expression analysis. Acute exposure (3 h) to GCG-50 induced a 3-fold increase in basal insulin concentrations with greater GSIS. Meanwhile, chronic exposure to both GCG-5 and GCG-50 decreased basal insulin concentrations 2-fold by day 8-10. Chronic GCG-50 also blunted GSIS at the study end. Fetal amino acid concentrations were decreased within 24 h of GCG-5 and GCG-50, while there were no differences in fetal glucose. Histologically, GCG-5 and GCG-50 had lower ß- and α-cell proliferation, as well as lower α-cell mass and pancreas weight, while GCG-50 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs ß-cell proliferation and insulin secretion, which has the potential to contribute to later-life diabetes risk. We speculate that the action of glucagon in lower circulating fetal amino acid concentrations may have a suppressive effect on insulin secretion. KEY POINTS: We have previously demonstrated in a chronically catheterized fetal sheep model that experimentally elevated glucagon in the fetus impairs placental function, reduces fetal protein accretion and lowers fetal weight. In the present study, we further characterized the effects of elevated fetal glucagon on fetal physiology with a focus on pancreatic development and ß-cell function. We show that experimentally elevated fetal glucagon results in lower ß- and α-cell proliferation, as well as decreased insulin secretion after 8-10 days of glucagon infusion. These results have important implications for ß-cell reserve and later-life predisposition to diabetes.

Impact of lifestyle intervention on vitamin D, Adiponectin, Insulin-like growth factor 1 and Proneurotensin in overweight individuals from the Middle East.

BACKGROUND: Immigrants from the Middle East (ME) have a higher prevalence of type 2 diabetes (T2D) compared to the native-born Swedish population. In individuals free from T2D, ME immigrants are more insulin resistant and have lower levels of adjusted insulin secretion (Disposition index, DIo) compared to Swedish-born individuals. The ethnic differences are not fully explained by traditional risk factors. This has raised the question as to whether hormonal factors other than insulin are involved, contributing to higher T2D risk in ME immigrants. AIMS: In ME immigrants at high risk of developing T2D, we aimed to study the effect of a randomized culturally adapted lifestyle intervention on the levels of Vitamin D (25(OH)D), insulin-like growth factor 1 (IGF-1), Pro-neurotensin (Pro-NT) and Adiponectin. Furthermore, we aimed to study if the effect of the intervention was associated to these hormones, or if a direct effect of the intervention remained after accounting for these. METHODS: In this culturally adapted randomized controlled trial of four months duration, eligible ME immigrants at high risk of developing T2D identified in the MEDIM cohort were invited to participate. The intervention group (N= 35) received a culturally adapted lifestyle intervention program consisting of seven group sessions and cooking classes. The control group (N= 32) were given treatment as usual with oral and written information to improve their lifestyle habits. Using mixed models' linear regression analysis, the changes in the levels of 25(OH)D, IGF-1, Adiponectin and Pro-NT were assessed by comparing the groups and we further studied the effects of the changes on insulin action and secretion. RESULTS: The adjusted levels of 25(OH)D significantly increased in the intervention group compared to the control group (ß for the effect of the intervention on 25(OH)D: 0.061, 95 % CI 0.009-0.113, P = 0.023). The increase in insulin sensitivity index (ISI) observed in the intervention compared to the control group was altered after adjusting for 25(OH)D: 0.129, 95 % CI -0.016-0.274, P = 0.078). IGF-1, Adiponectin and Pro-NT did not significantly influence the change over time concerning insulin secretion. CONCLUSION: Lifestyle intervention increases the adjusted levels of 25(OH)D. Moreover, the effect of the lifestyle intervention on insulin action and secretion was altered when adjusting for 25(OH)D.

2-Hydroxylation is a chemical switch linking fatty acids to glucose-stimulated insulin secretion.

Glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cells is metabolically regulated and progressively diminished during the development of type 2 diabetes (T2D). This dynamic process is tightly coupled with fatty acid metabolism, but the underlying mechanisms remain poorly understood. Fatty acid 2-hydroxylase (FA2H) catalyzes the conversion of fatty acids to chiral specific (R)-2-hydroxy fatty acids ((R)-2-OHFAs), which influences cell metabolism. However, little is known about its potential coupling with GSIS in pancreatic ß cells. Here, we showed that Fa2h knockout decreases plasma membrane localization and protein level of glucose transporter 2 (GLUT2), which is essential for GSIS, thereby controlling blood glucose homeostasis. Conversely, FA2H overexpression increases GLUT2 on the plasma membrane and enhances GSIS. Mechanistically, FA2H suppresses the internalization and trafficking of GLUT2 to the lysosomes for degradation. Overexpression of wild-type FA2H, but not its mutant with impaired hydroxylase activity in the pancreatic ß-cells, improves glucose tolerance by promoting insulin secretion. Levels of 2-OHFAs and Fa2h gene expression are lower in high-fat diet-induced obese mouse islets with impaired GSIS. Moreover, lower gene expression of FA2H is observed in a set of human T2D islets when the insulin secretion index is significantly suppressed, indicating the potential involvement of FA2H in regulating mouse and human GSIS. Collectively, our results identified an FA chemical switch to maintain the proper response of GSIS in pancreatic ß cells and provided a new perspective on the ß-cell failure that triggers T2D.

Notoginsenoside R1, a metabolite from Panax notoginseng (Burkill) F.H.Chen, stimulates insulin secretion through activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway.

Background: For ages, botanical medicine has been used in the treatment of diabetes mellitus (DM). Notoginsenoside R1 (NGR1), a Panax notoginseng (Burkill) F.H.Chen metabolite, has been documented to possess antidiabetic action in vivo. However, its precise molecular mechanism of action is not clear. Objectives: We evaluated NGR1's effects on blood glucose in vivo and then evaluated in vitro whether NGR1 has effects on insulin secretion and the probable molecular pathways involved in NGR1-induced insulin secretion. Methods: Diabetes was induced in mice by streptozotocin. Glucose tolerance test was performed before and after NGR1 was administered intraperitoneally to diabetic animals for 4 weeks. Static and perifusion experiments were performed using isolated female BALB/c mouse islets. Preproinsulin (Ins) mRNA expression was measured using q-PCR. Protein expression of PI3K/Akt pathway was assessed using the fully automated Wes™ capillary-based protein electrophoresis. Results: Treatment of diabetic mice with NGR1 improved their glucose intolerance. In vitro, NGR1 increased insulin secretion in a concentration-dependent manner. NGR1 initiated the secretion of insulin at 2 mM glucose and augmented glucose-stimulated insulin secretion which was sustained throughout NGR1 perifusion. NGR1-induced insulin secretion was not altered by a voltage gated calcium channel blocker or protein kinase A inhibitor. NGR1 did not significantly modulate Ins mRNA expression. However, NGR1 significantly increased the levels of phospho-Akt and phopho-p-85. Conclusion: In conclusion, this study has shown that NGR1 ameliorates hyperglycemia in diabetic mice. NGR1 has a direct insulin secretagogue activity on mouse islets, stimulates insulin secretion at both basal and postprandial glucose concentrations, and activates PI3K/Akt pathway to induce insulin secretion. These results suggest that NGR1 may provide an alternative therapy to manage DM.

Initial clinical manifestations in a young male with RFX6-variant-associated diabetes.

To date, heterozygous loss-of-function variants of RFX6 have been identified in 13 families with diabetes. Here, we present initial clinical information regarding a young male with diabetes who carried a heterozygous nonsense variant of RFX6 (p.Arg377Ter) previously reported in his family with diabetes. At 11 yr and 7 mo of age, the patient experienced severe thirst and hyperglycemia (331-398 mg/dL). Laboratory tests revealed elevated levels of glycated hemoglobin (HbA1c) (47 mmol/mL, 6.5%) and the Homeostatic Model for Insulin Resistance (HOMA-IR) (3.4). Blood glucose self-monitoring demonstrated grossly normal blood glucose levels, together with occasional postprandial hyperglycemia, and a few episodes of hypoglycemia. An oral glucose tolerance test revealed mild hyperglycemia and a delayed peak insulin level. His laboratory indices improved over two years with self-control of diet and exercise. These results indicate that the initial presentation of RFX6-variant-associated diabetes includes occasional hyperglycemia and hypoglycemia in response to changes in lifestyle. The possible association between RFX6 variants and mild insulin resistance requires further validation in future studies.

The L-type amino acid transporter 1 enhances drug delivery to the mouse pancreatic beta cell line (MIN6).

l-type amino acid transporter 1 (LAT1) is a membrane transporter responsible for carrying large, neutral l-configured amino acids as well as appropriate (pro)drugs into a cell. It has shown a great potential to improve drug delivery across the blood-brain barrier and to increase cell uptake into several brain and cancer cell types. However, besides the brain, the LAT1-utilizing compounds are also delivered more efficiently into the pancreas in vivo. In this study, we quantified the expression of LAT1 along several other membrane transporters in mouse pancreatic ß-cell line (MIN6). Furthermore, we studied the function of LAT1 in MIN6 cells, and its ability to deliver non-steroidal anti-inflammatory drug (NSAID)-derived prodrugs there. The results showed that LAT1 was highly abundant in MIN6 cells, with an even expression on cell pseudoislets. The l-leucine uptake as a probe substrate was efficient, with comparable affinity and capacity to previously studied immortalized mouse microglia (BV2). The NSAID-derived prodrugs utilized LAT1 for their delivery and were uptaken into MIN6 cells 2-300 times more efficiently when compared to their parent drugs. A similar increase in pancreatic delivery was observed also in vivo, where the pancreatic exposure was 2-10 times higher with selected prodrugs, indicating an excellent correlation between in vitro uptake and in vivo pancreatic delivery. Finally, the LAT1-utilizing prodrugs were able to reverse the effects of cytokines on insulin secretion in MIN6 cells, showing that improved delivery via LAT1 can enhance drug effects in the mouse pancreatic ß-cell line.

Dense but not alpha granules of platelets are required for insulin secretion from pancreatic ß cells.

OBJECTIVES: Platelets, originally described for their role in blood coagulation, are now also recognized as key players in modulating inflammation, tissue regeneration, angiogenesis, and carcinogenesis. Recent evidence suggests that platelets also influence insulin secretion from pancreatic ß cells. The multifaceted functions of platelets are mediated by the factors stored in their alpha granules (AGs) and dense granules (DGs). AGs primarily contain proteins, while DGs are rich in small molecules, and both types of granules are released during blood coagulation. Specific components stored in AGs and DGs are implicated in various inflammatory, regenerative, and tumorigenic processes. However, the relative contributions of AGs and DGs to the regulation of pancreatic ß cell function have not been previously explored. METHODS: In this study, we utilized mouse models deficient in AG content (neurobeachin-like 2 (Nbeal2) -deficient mice) and models with defective DG release (Unc13d-deficiency in bone marrow-derived cells) to investigate the impact of platelet granules on insulin secretion from pancreatic ß cells. RESULTS: Our findings indicate that AG deficiency has little to no effect on pancreatic ß cell function and glucose homeostasis. Conversely, mice with defective DG release exhibited glucose intolerance and reduced insulin secretion. Furthermore, Unc13d-deficiency in hematopoietic stem cells led to a reduction in adipose tissue gain in obese mice. CONCLUSIONS: Obtained data suggest that DGs, but not AGs, mediate the influence of platelets on pancreatic ß cells, thereby modulating glucose metabolism.

Vagal sensory neuron-derived FGF3 controls insulin secretion.

Vagal nerve stimulation has emerged as a promising modality for treating a wide range of chronic conditions, including metabolic disorders. However, the cellular and molecular pathways driving these clinical benefits remain largely obscure. Here, we demonstrate that fibroblast growth factor 3 (Fgf3) mRNA is upregulated in the mouse vagal ganglia under acute metabolic stress. Systemic and vagal sensory overexpression of Fgf3 enhanced glucose-stimulated insulin secretion (GSIS), improved glucose excursion, and increased energy expenditure and physical activity. Fgf3-elicited insulinotropic and glucose-lowering responses were recapitulated when overexpression of Fgf3 was restricted to the pancreas-projecting vagal sensory neurons. Genetic ablation of Fgf3 in pancreatic vagal afferents exacerbated high-fat diet-induced glucose intolerance and blunted GSIS. Finally, electrostimulation of the vagal afferents enhanced GSIS and glucose clearance independently of efferent outputs. Collectively, we demonstrate a direct role for the vagal afferent signaling in GSIS and identify Fgf3 as a vagal sensory-derived metabolic factor that controls pancreatic ß-cell activity.

Kinesin-1 mediates proper ER folding of the CaV1.2 channel and maintains mouse glucose homeostasis.

Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is a principal mechanism for systemic glucose homeostasis, of which regulatory mechanisms are still unclear. Here we show that kinesin molecular motor KIF5B is essential for GSIS through maintaining the voltage-gated calcium channel CaV1.2 levels, by facilitating an Hsp70-to-Hsp90 chaperone exchange to pass through the quality control in the endoplasmic reticulum (ER). Phenotypic analyses of KIF5B conditional knockout (cKO) mouse beta cells revealed significant abolishment of glucose-stimulated calcium transients, which altered the behaviors of insulin granules via abnormally stabilized cortical F-actin. KIF5B and Hsp90 colocalize to microdroplets on ER sheets, where CaV1.2 but not Kir6.2 is accumulated. In the absence of KIF5B, CaV1.2 fails to be transferred from Hsp70 to Hsp90 via STIP1, and is likely degraded via the proteasomal pathway. KIF5B and Hsc70 overexpression increased CaV1.2 expression via enhancing its chaperone binding. Thus, ER sheets may serve as the place of KIF5B- and Hsp90-dependent chaperone exchange, which predominantly facilitates CaV1.2 production in beta cells and properly enterprises GSIS against diabetes.

GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review.

Obesity and type 2 diabetes mellitus (T2DM) present major global health challenges, with an increasing prevalence worldwide. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a pivotal treatment option for both conditions, demonstrating efficacy in blood glucose management, weight reduction, cardiovascular disease prevention, and kidney health improvement. GLP-1, an incretin hormone, plays a crucial role in glucose metabolism and appetite regulation, influencing insulin secretion, insulin sensitivity, and gastric emptying. The therapeutic use of GLP-1RAs has evolved significantly, offering various formulations that provide different efficacy, routes of administration, and flexibility in dosing. These agents reduce HbA1c levels, facilitate weight loss, and exhibit cardiovascular protective effects, making them an integral component of T2DM and obesity management. This review will discuss the currently approved medication for T2DM and obesity, and will also highlight the advent of novel agents which are dual and triple hormonal agonists which represent the future direction of incretin-based therapy. Funding: National Institutes of HealthNIDDKU24 DK132733 (FCS), UE5 DK137285 (FCS), and P30 DK040561 (FCS).

The flavonoid resokaempferol improves insulin secretion from healthy and dysfunctional pancreatic ß-cells.

BACKGROUND AND PURPOSE: The pharmacology of flavonoids on ß-cell function is largely undefined especially in the context of defective secretion of insulin. We sought to identify flavonoids that increased the insulin-secreting function of ß-cells and to explore the underlying mechanisms. EXPERIMENTAL APPROACH: INS-1 ß-cells in culture and islets of Langerhans isolated from control and diabetic male rats were used for insulin secretion experiments. Pharmacological and electrophysiological approaches were used for mechanistic studies. KEY RESULTS: Among a set of flavonoids, exposure of INS-1 ß-cells to resokaempferol (ResoK) enhanced glucose-stimulated insulin secretion and therefore we further characterised its activity and its pharmacological mechanism. ResoK glucose-dependently enhanced insulin secretion in INS-1 ß-cells and pancreatic islets isolated from rats. Mechanistically, whole cell patch clamp recordings in INS-1 cells showed that ResoK rapidly and dose-dependently enhanced the L-type Ca2+ current whereas it was inactive towards T-type Ca2+ current. Accordingly, pharmacological inhibition of L-type Ca2+ current but not T-type Ca2+ current blocked the effects of ResoK on glucose-stimulated insulin secretion. ResoK was still active on dysfunctional ß-cells as it ameliorated glucose-stimulated insulin secretion in glucotoxicity-induced dysfunctional INS-1 cells and in pancreatic islets isolated from diabetic rats. CONCLUSION AND IMPLICATIONS: ResoK is a glucose-dependent activator of insulin secretion. Our results indicated that the effects of ResoK on insulin secretion involved its capacity to stimulate L-type Ca2+ currents in cultured ß-cells. As ResoK was also effective on dysfunctional ß-cells, our work provides a new approach to stimulating insulin secretion, using compounds based on the structure of ResoK.

Effects of glucokinase haploinsufficiency on the pancreatic ß-cell mass and function of long-term high-fat, high-sucrose diet-fed mice.

AIMS/INTRODUCTION: We previously showed that glucokinase haploinsufficiency improves the glucose tolerance of db/db mice by preserving pancreatic ß-cell mass and function. In the present study, we aimed to determine the effects of glucokinase haploinsufficiency on the ß-cell mass and function of long-term high-fat, high-sucrose (HFHS) diet-fed mice. MATERIALS AND METHODS: Four-week-old male glucokinase haploinsufficient (Gck+/-) mice and 4-week-old male wild-type (Gck+/+) mice (controls) were each divided into two groups: an HFHS diet-fed group and a normal chow-fed group, and the four groups were followed until 16, 40 or 60 weeks-of-age. Their glucose tolerance, glucose-stimulated insulin secretion and ß-cell mass were evaluated. In addition, islets were isolated from 40-week-old mice, and the expression of key genes was compared. RESULTS: Gck+/-HFHS mice had smaller compensatory increases in ß-cell mass and glucose-stimulated insulin secretion than Gck+/+HFHS mice, and their glucose tolerance deteriorated from 16 to 40 weeks-of-age. However, their ß-cell mass and glucose-stimulated insulin secretion did not decrease between 40 and 60 weeks-of-age, but rather, tended to increase, and there was no progressive deterioration in glucose tolerance. The expression of Aldh1a3 in pancreatic islets, which is high in several models of diabetes and is associated with an impairment in ß-cell function, was high in Gck+/+HFHS mice, but not in Gck+/-HFHS mice. CONCLUSIONS: Glucokinase haploinsufficiency prevents the progressive deterioration of pancreatic ß-cell mass/function and glucose tolerance in long-term HFHS diet-fed mice.

The flavonoid Sudachitin regulates glucose metabolism via PDE inhibition.

Sudachitin, a member of the flavonoid family, reportedly improves glucose metabolism after long-term administration, but details of the underlying mechanisms are unknown. We found that Sudachitin approximately doubles insulin secretion under high glucose concentrations in mouse pancreatic islets and MIN6 cells. When Sudachitin was orally administered to mice, early-phase insulin secretion was increased and a 30 % reduction in blood glucose levels was demonstrated 30 min after glucose loading. Insulin tolerance tests also showed Sudachitin to increase systemic insulin sensitivity. Additionally, we observed that Sudachitin raised intracellular cAMP levels in pancreatic islets. Phosphodiesterase (PDE) activity assays revealed Sudachitin to inhibit PDE activity and computer simulations predicted a high binding affinity between PDEs and Sudachitin. These findings suggest that Sudachitin enhances both insulin secretion and insulin sensitivity via an increase in intracellular cAMP resulting from PDE inhibition. These insights may facilitate understanding the mechanisms underlying the regulation of glucose metabolism by Sudachitin and other isoflavones.

Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified hundreds of type 2 diabetes loci, with the vast majority of signals located in non-coding regions; as a consequence, it remains largely unclear which 'effector' genes these variants influence. Determining these effector genes has been hampered by the relatively challenging cellular settings in which they are hypothesised to confer their effects. METHODS: To implicate such effector genes, we elected to generate and integrate high-resolution promoter-focused Capture-C, assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq datasets to characterise chromatin and expression profiles in multiple cell lines relevant to type 2 diabetes for subsequent functional follow-up analyses: EndoC-BH1 (pancreatic beta cell), HepG2 (hepatocyte) and Simpson-Golabi-Behmel syndrome (SGBS; adipocyte). RESULTS: The subsequent variant-to-gene analysis implicated 810 candidate effector genes at 370 type 2 diabetes risk loci. Using partitioned linkage disequilibrium score regression, we observed enrichment for type 2 diabetes and fasting glucose GWAS loci in promoter-connected putative cis-regulatory elements in EndoC-BH1 cells as well as fasting insulin GWAS loci in SGBS cells. Moreover, as a proof of principle, when we knocked down expression of the SMCO4 gene in EndoC-BH1 cells, we observed a statistically significant increase in insulin secretion. CONCLUSIONS/INTERPRETATION: These results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings. DATA AVAILABILITY: Raw and processed next-generation sequencing data for EndoC-BH1, HepG2, SGBS_undiff and SGBS_diff cells are deposited in GEO under the Superseries accession GSE262484. Promoter-focused Capture-C data are deposited under accession GSE262496. Hi-C data are deposited under accession GSE262481. Bulk ATAC-seq data are deposited under accession GSE262479. Bulk RNA-seq data are deposited under accession GSE262480.

NMDA Suppresses Pancreatic ABCA1 Expression through the MEK/ERK/LXR Pathway in Pancreatic Beta Cells.

Dysfunction or loss of pancreatic ß cells can cause insulin deficiency and impaired glucose regulation, resulting in conditions like type 2 diabetes. The ATP-binding cassette transporter A1 (ABCA1) plays a key role in the reverse cholesterol transport system, and its decreased expression is associated with pancreatic ß cell lipotoxicity, resulting in abnormal insulin synthesis and secretion. Increased glutamate release can cause glucotoxicity in ß cells, though the detailed mechanisms remain unclear. This study investigated the effect of N-methyl-D-aspartic acid (NMDA) on ABCA1 expression in INS-1 cells and primary pancreatic islets to elucidate the signaling mechanisms that suppress insulin secretion. Using Western blotting, microscopy, and biochemical analyses, we found that NMDA activated the mitogen-activated protein kinase (MEK)-dependent pathway, suppressing ABCA1 protein and mRNA expression. The MEK-specific inhibitor PD98059 restored ABCA1 promoter activity, indicating the involvement of the extracellular signal-regulated kinase (MEK/ERK) pathway. Furthermore, we identified the liver X receptor (LXR) as an effector transcription factor in NMDA regulation of ABCA1 transcription. NMDA treatment increased cholesterol and triglyceride levels while decreasing insulin secretion, even under high-glucose conditions. These effects were abrogated by treatment with PD98059. This study reveals that NMDA suppresses ABCA1 expression via the MEK/ERK/LXR pathway, providing new insights into the pathological suppression of insulin secretion in pancreatic ß cells and emphasizing the importance of investigating the role of NMDA in ß cell dysfunction.

Rationale and Design of the Study to Investigate the Metabolic Action of Imeglimin on Patients with Type 2 Diabetes Mellitus (SISIMAI).

INTRODUCTION: Imeglimin is a first-in-class, novel, oral glucose-lowering agent for the treatment of type 2 diabetes mellitus. The efficacy and safety of imeglimin as an antidiabetic agent have been investigated in clinical trials. However, its metabolic effects in humans have not yet been fully elucidated. METHODS: The Study to InveStIgate the Metabolic Action of Imeglimin on patients with type 2 diabetes mellitus (SISIMAI) is a single-arm intervention study. In this study, we have recruited 25 patients with type 2 diabetes to receive 2000 mg/day imeglimin for 20 weeks. We perform a 75-g oral glucose tolerance test (OGTT) with double-glucose tracers, a two-step hyperinsulinemic-euglycemic clamp with glucose tracer, ectopic fat measurement by proton magnetic resonance spectroscopy, visceral/subcutaneous fat area measurement by magnetic resonance imaging, muscle biopsy, and evaluation of fitness level by cycle ergometer before and after imeglimin administration. PLANNED OUTCOMES: The primary outcome is the change in area under the curve of glucose levels during the OGTT after 20 weeks of imeglimin treatment. We also calculate the endogenous glucose production, rate of oral glucose appearance, and rate of glucose disappearance from the data during the 75-g OGTT and compare them between pre- and post-treatment. Additionally, we will compare other parameters, such as the changes in tissue-specific insulin sensitivity, ectopic fat accumulation, visceral/subcutaneous fat area accumulation, and fitness level between each point. This is the first study to investigate the organ-specific metabolic action of imeglimin in patients with type 2 diabetes mellitus using the 75-g OGTT with the double tracer method. The results of this study are expected to provide useful information for drug selection based on the pathophysiology of individual patients with type 2 diabetes mellitus. TRIAL REGISTRATION: jRCTs031210600.

Preserving insulin function in diabetes: a case report.

BACKGROUND: This case report explores the long-term dynamics of insulin secretion and glycemic control in two patients with diabetes mellitus type 2 over 20 years. The observations underscore the impact of lifestyle interventions, including weight loss and calorie restriction, on insulin secretion patterns and glucose levels during 75 g oral glucose tolerance tests. Additionally, the role of hemoglobin A1c fluctuations, influenced by various factors such as body weight, exercise, and pharmacological interventions, is investigated. CASE PRESENTATION: Case 1 involves a Japanese woman now in her late 70s who successfully maintained her hemoglobin A1c below 7% for over two decades through sustained weight loss and lifestyle changes. Despite a gradual decline in the homeostasis model assessment of ß cell function, the patient exhibited remarkable preservation of insulin secretion patterns over the 20-year follow-up. In case 2, a Japanese woman, now in her early 70s, experienced an improvement in hemoglobin A1c to 6.3% after a period of calorie limitation due to a wrist fracture in 2018. This incident seemed to trigger a temporary rescue of pancreatic ß cell function, emphasizing the dynamic nature of insulin secretion. Both cases highlight the potential for pancreatic ß cell rescue and underscore the persistence of insulin secretion over the 20-year follow-up. Additionally, we have briefly discussed three additional cases with follow-ups ranging from 10 to 17 years, demonstrating similar trends in glucose and insulin ratios. CONCLUSIONS: Long-term lifestyle interventions, such as weight loss and calorie restriction, can preserve pancreatic ß cell function and maintain glycemic control in type 2 diabetes patients over 20 years. Two patients showed stable or improved insulin secretion and favorable hemoglobin A1c levels, challenging the traditional view of irreversible ß cell decline. The findings highlight the importance of personalized, nonpharmacological approaches, suggesting that sustained lifestyle changes can significantly impact diabetes management and potentially rescue ß cell function.

Carbohydrate response element-binding protein (ChREBP) mediates decreased SNAP25 expression in islets from diabetic Goto-Kakizaki (GK) rats.

SNAP25 plays an essential role in the glucose-stimulated insulin secretion (GSIS) of pancreatic ß-cells. Carbohydrate response element-binding protein (ChREBP) is an important transcription factor in ß-cells and, in this study, we aimed to explore whether ChREBP regulates SNAP25 expression in ß-cells. We show that diabetic Goto-Kakizaki (GK) rats exhibited impaired insulin secretion and hyperglycemia, along with decreased SNAP25 expression and ChREBP phosphorylation in islets. SNAP25 knockdown decreased GSIS in ß-cells, while SNAP25 overexpression increased GSIS in ß-cells. Activation or overexpression of ChREBP led to reduced SNAP25 expression and subsequent suppression of GSIS. Conversely, ChREBP knockdown mitigated the reduction in SNAP25 expression caused by high glucose. Mechanistically, the activation of ChREBP by high glucose increased its occupancy and decreased the level of H3K4me3 at the Snap25 promoter. Our findings reveal the novel regulatory mechanisms of SNAP25 expression in ß-cells and suggest that SNAP25 may be involved in the regulation of ß-cell secretory function controlled by ChREBP.

The stimulatory effect of HI 129, a novel indole derivative, on glucose-induced insulin secretion.

Indole derivatives exhibit a broad spectrum of beneficial effects, encompassing anti-inflammatory, antiviral, antimalarial, anti-diabetic, antioxidant, anti-hepatitis, and antidepressant properties. Here, we describe the potentiation of insulin secretion in pancreatic islets and INS-1 cells through methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-(pyrimidine-2-yl)-1H-indole-3-carboxylate (HI 129), a novel indole derivative. Treatment with HI 129 led to notably decreased ADP/ATP ratios in pancreatic islets and INS-1 cells compared to those in the vehicle-treated controls, indicating a shift in cellular ATP production. Moreover, the augmentation of insulin secretion by HI 129 was closely correlated with its ability to enhance the mitochondrial membrane potential and respiration, partly by reducing the phosphorylation levels of AMP-activated protein kinase (AMPK). Mechanistically, HI 129 enhanced the association between AMPK and ß-arrestin-1, critical molecules for glucose-induced insulin secretion. Furthermore, ß-arrestin-1 depletion attenuated the effect of HI 129 on glucose-induced insulin secretion, suggesting that HI 129 potentiates insulin secretion via ß-arrestin-1/AMPK signaling. These results collectively underscore the potential of HI 129 in enhancing insulin secretion as a novel candidate for improving glucose homeostasis in type 2 diabetes.