Reduced Insulin Secretion Research Articles

Nickel Sulfate-Induced GSIS Injury in MIN6 Cells by Activating the JNK Pathway Through Oxidative Stress.

Nickel has an impact on human health, especially in the context of the new energy industries. Nickel's influence on glycemia remains controversial, and the effects and mechanisms of nickel on islet function still need further exploration. MIN6 cells were treated with different concentrations of nickel sulfate (NiSO4) (0, 75, 150, and 300µg/mL) for different durations (0, 12, 24, and 48h). The study measured cell cycle progression, apoptosis, reactive oxygen species (ROS) production, oxidative stress-related indexes (T-SOD, TBARS, 8-OHdG, and GSH), glucose-induced insulin secretion (GSIS), and the expression of JNK pathway-related proteins, pancreaticoduodenal homeobox-1 (PDX-1), glucose transporter 2 (GLUT2), and forkhead box protein O1 (FOXO1). NiSO4 damaged MIN6 cells in a time- and dose-dependent manner. NiSO4 blocked the cell cycle, induced apoptosis, and reduced insulin secretion in the GSIS experiment. NiSO4 also induced ROS production, increased oxidative stress-related indexes (TRABS and 8-OHdG), and decreased antioxidant stress-related indexes (GSH and T-SOD). In addition, NiSO4 activated the JNK pathway, upregulated FOXO1 protein expression, and inhibited PDX-1 and GLUT2 protein expression, affecting insulin release during GSIS. NiSO4 inhibited the proliferation of MIN6 cells through oxidative stress, aggravated apoptosis, caused functional impairment, upregulated the expression of FOXO1 by activating the JNK pathway, inhibited the expression of PDX-1 and GLUT2 proteins, and impaired the GSIS function of islets.

Maternal Low-Protein Diet During Nursing Leads to Glucose-Insulin Dyshomeostasis and Pancreatic-Islet Dysfunction by Disrupting Glucocorticoid Responsiveness in Male Rats.

Both perinatal malnutrition and elevated glucocorticoids are pivotal triggers of the growing global pandemic of metabolic diseases. Here, we studied the effects of metabolic stress responsiveness on glucose-insulin homeostasis and pancreatic-islet function in male Wistar offspring whose mothers underwent protein restriction during lactation. During the first two weeks after delivery, lactating dams were fed a low-protein (4% protein, LP group) or normal-protein diet (22.5% protein, NP group). At 90 days of age, male rat offspring were challenged with food deprivation (72 h of fasting), intracerebroventricular (icv) injection of dexamethasone (2 µL, 2.115 mmol/L) or chronic intraperitoneal injection of dexamethasone (1 mg/kg body weight/5 days). Body weight, food intake, intravenous glucose tolerance test (ivGTT) results, insulin secretion and biochemical parameters were assessed. LP rats did not display significant metabolic changes after long-term starvation (p > 0.05) or under the central effect of dexamethasone (p = 0.999). Chronic dexamethasone induced rapid hyperglycemia (~1.2-fold, p < 0.001) and hyperinsulinemia (NP: 65%; LP: 216%; p < 0.001), decreased insulin sensitivity (NP: ~2-fold; LP: ~4-fold; p < 0.001), reduced insulinemia (20%) and increased glycemia (35%) only in NP rats under ivGTT conditions (p < 0.001). Glucose and acetylcholine insulinotropic effects, as well as the muscarinic receptor antagonist response, were reduced by chronic dexamethasone only in pancreatic islets from NP rats (p < 0.05). The direct effect of dexamethasone on pancreatic islets reduced insulin secretion (NP: 60.2%, p < 0.001; LP: 33.8%, p < 0.001). Peripheral glucose-insulin dyshomeostasis and functional failure of pancreatic islets in LP rats, as evidenced by an impaired acute and chronic response to metabolic stress, may be due to excessive corticosterone action as a long-term consequence.

520 nm and 660 nm light-emitting diodes modulates pancreatic development and beta cell functions in zebrafish embryos.

Green and Red LEDs increase insulin production, but their comparative effects on pancreatic and beta cell development are unclear. Zebrafish embryos were divided into three groups: Control (n = 60), Green (G) (n = 60), and Red (R) (n = 60), then irradiated for three days (14 hours/day) with 0.5 W/cm2 G (λpeak = 520 nm, 180 mA) and R (λpeak = 660 nm, 210 mA). At the end of 72 h, pancreatic and beta cells, circadian rhythm, and oxidative stress gene were analyzed using RT-PCR. Malondialdehyde, nitric oxide, superoxide dismutase, and glutathione levels were also evaluated. In the Red group, pancreatic area increased by ~97.13% compared to the Control group and by approximately ~62.16% compared to the G group (both p < 0.0001), and no significant difference in beta cell area (p = 0.964). G group insulin expression increased 2.31-fold compared to R group (p < 0.0001). Red LED treatment increased MDA levels (p < 0.001), oxidative stress (fth1b, nqo1) (p < 0.0001), and per1b during the photophase (p < 0.0001) compared to G group. R LED treatment increases oxidative stress and disrupts circadian rhythm, leading to reduced insulin secretion. The positive effects of G LED treatment have potential for metabolic syndrome, diabetes, and pancreatic diseases.

Effect of Barley on Postprandial Blood Glucose Response and Appetite in Healthy Individuals: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background/Objectives: Barley dietary fiber (BDF), particularly β-glucan, has shown potential in modulating postprandial glycemic responses and improving metabolic health. This study aimed to assess the effects of Saechalssalbori (Hordeum vulgare L.), a glutinous barley variety rich in β-glucan, on postprandial blood glucose, insulin, glucagon, triglycerides, and appetite-related hormones in healthy adults. Methods: In this randomized, double-blind, placebo-controlled, crossover trial, healthy adults (n = 67) with fasting blood glucose levels below 126 mg/dL were assigned to consume either BDF or placebo (rice flour). Fasting and postprandial blood samples were collected at 30, 60, 120, and 180 min after consumption. Blood glucose, insulin, glucagon, triglycerides, and appetite-related hormones (ghrelin, PYY) were measured, and appetite was assessed using the visual analog scale (VAS). The study was approved by the Institutional Review Board (CHAMC 2022-08-040-007) and registered (KCT0009166). Results: BDF consumption significantly delayed the postprandial increase in blood glucose compared with placebo, reduced insulin secretion, and slightly increased glucagon and triglycerides. BDF also lowered hunger and increased satiety, with associated increases in ghrelin and PYY levels. Conclusions: BDF consumption, particularly from β-glucan-rich barley, may improve postprandial glycemic control and suppress appetite, making it a promising dietary intervention for managing metabolic conditions such as diabetes. Further studies are needed to explore its long-term impact on glycemic variability.

Acute Inhibition of Adipose Triglyceride Lipase by NG497 Dysregulates Insulin and Glucagon Secretion from Human Islets.

Adipose triglyceride lipase (ATGL), which catalyzes the breakdown of triglycerides in lipid droplets (LDs), plays a critical role in releasing fatty acids to support insulin secretion in pancreatic beta cells. Based on genetic downregulation of ATGL in beta cells, multiple mechanisms are proposed that acutely or chronically regulate insulin secretion. Currently, the contribution of acute versus chronic mechanisms in the regulation of insulin secretion is unclear. Also, little is known whether ATGL affects alpha cell function. Using the human-specific ATGL inhibitor, NG497, this study investigates the impact of acute inhibition of ATGL on hormone secretion from human islets. When lipolysis by ATGL was assessed via morphological differences in LDs in confocal images of beta and alpha cells, beta cells exposed to NG497 showed notable increases in LD size and number under glucose-sufficient culture. The effect of NG497 on LD accumulation in alpha cells was more prominent under fasting-simulated conditions than glucose-sufficient conditions, pointing toward a critical role for ATGL lipolysis under conditions that stimulate hormone secretion in beta and alpha cells. When exposed to NG497 acutely, human islets reduced glucose-stimulated insulin secretion mildly, particularly first-phase insulin secretion, to an extent less pronounced than the impacts of chronic ATGL downregulation. Thus, chronic mechanisms play a predominant role in reducing insulin secretion when ATGL is downregulated. Acute exposure of human islets to NG497 significantly reduced glucagon secretion at low glucose concentration, highlighting an important potential role of ATGL lipolysis in promoting hormone secretion acutely from alpha cells.

Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion.

Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (miRNAs). However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs' miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs' miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus.

Environmental Heavy Metal Exposure and Associated Cardiovascular Diseases in Light of the Triglyceride Glucose Index.

Cardiovascular diseases (CVD), primarily ischemic heart disease and stroke, remain leading global health burdens. Environmental risk factors have a major role in the development of CVD, particularly exposure to heavy metals. The Triglyceride Glucose Index (TyG), a measure of insulin resistance and CVD risk, is the primary focus of this study, which summarizes the most recent findings on the effects of lead (Pb), arsenic (As), and cadmium (Cd) on CVD risk. A higher risk of CVD is correlated with an elevated TyG index, which has been linked to insulin resistance. Exposure to Cd is associated with disturbance of lipid metabolism and oxidative stress, which increases the risk of CVD and TyG. Exposure reduces insulin secretion and signaling, which raises the TyG index and causes dyslipidemia. Pb exposure increases the risk of CVD and TyG index via causing oxidative stress and pancreatic β-cell destruction. These results highlight the need of reducing heavy metal exposure by lifestyle and environmental modifications in order to lower the risk of CVD. To comprehend the mechanisms and create practical management plans for health hazards associated with heavy metals, more study is required.

8538 Pancreatic Islet Adaptations to Hyperglycemia Are Prevented by Glycolytic Inhibition and Amplified by Inhibiting Membrane Depolarization

Abstract Disclosure: N.B. Whitticar: None. B.P. List: None. N. Bruce: None. R. Bertram: None. C.S. Nunemaker: None. Long before type 2 diabetes ensues, pancreatic islets undergo functional changes to compensate for increasing insulin resistance. Primarily, the islets increase their ability to secrete insulin by augmenting the glucose-stimulated insulin secretion (GSIS) pathway. As metabolic syndrome worsens, islets become functionally exhausted, leading to cellular dysfunction and apoptosis. To avoid the negative consequences of this compensatory response, various steps of the GSIS pathway can be attenuated to restore normal functional levels before the islets fail. Determining which inhibitors can prevent the earliest adaptations to hyperglycemia may reveal the processes that play a causal role in islet failure. The chemicals mannoheptulose (MH), diazoxide (DZ), and nifedipine (NP) were chosen to inhibit the glucokinase enzyme, KATP-channel closure, and voltage-gated calcium channels, respectively. CD-1 mouse islets were placed in 20 mM glucose to simulate hyperglycemia along with a concentration of each inhibitory drug that reduced insulin secretion by 30-40%. After 48-hour treatment, glucose-stimulated calcium tests were performed to determine if the treatments could prevent the negative adaptation to hyperglycemia. Only islets treated with MH to reduce glycolytic activity maintained a normal calcium response. Islets in the MH group also retained a strong insulin response to glucose and were not depleted of insulin content. Unexpectedly, inhibition of calcium influx and insulin secretion with DZ or NF caused a substantial increase in basal insulin secretion compared to islets in standard culture (P&amp;lt;0.01, n=6; P=0.06, n=6, respectively). These results indicate that the signaling pathway that causes the adaptation to hyperglycemia lies upstream of KATP channels and downstream of glucokinase. Mathematical modeling using the Integrated Oscillator Model was able to replicate our results and suggests that high rates of glycolytic and mitochondrial metabolism are associated with the signal that adapts islets to hyperglycemia, and that reducing intracellular calcium in the face of high glucose further increases basal insulin secretion. Ongoing studies will determine if metabolic acceleration or altered membrane conductance are responsible for the earliest islet adaptations to hyperglycemia. Our results suggest that reducing metabolic activity, but not calcium influx, prevents adaptations to hyperglycemia in mouse islets. These findings can be applied to potentially prevent the progression of obesity and hyperinsulinemia into type 2 diabetes. Presentation: 6/2/2024

12439 Investigating The Regulation Of Islet Alpha-cell Function Mediated By The ISL1 And LDB1 Transcriptional Complex

Abstract Disclosure: I. Deeba: None. S. Poole: None. Y. Liu: None. C. Hunter: None. Glucose homeostasis is maintained by the action of insulin-secreting β-cells and glucagon-producing α-cells in the pancreatic islet. Diabetes, traditionally considered a dysglycemia centered on the β-cell, also has clear contributions by dysregulated α-cells. However, little is known of the key transcriptional regulators, including transcription factors (TFs) and interacting co-regulators, driving α-cell development and function. A published pancreas-wide knockout (KO) of the LIM-Homeodomain Islet-1 (ISL1) TF in mice led to a dominant β-cell phenotype, including glucose intolerance and reduced insulin secretion. However, significant reductions of glucagon (Gcg) and Arx mRNA and pancreatic GCG content were also noted, suggesting α-cell impacts. Furthermore, we demonstrated that pancreatic ISL1 activity involves interactions with the LDB1 scaffolding co-regulator. However, nothing is known of the comparative α-cell-specific target genes and functions of these protein partners. To first assess ISL1:LDB1 complexes in α-cells, we performed co-IP and proximity ligation assay (PLA) in mouse α-cell lines and found low-glucose stimulated ISL1 and LDB1 interactions. These observations led us to hypothesize that ISL1 and LDB1 complexes regulate transcription of target genes to drive α-cell function. To assess comparative DNA occupancy, we performed ChIP and observed significant ISL1 and LDB1 binding in conserved Gcg promoter and intronic domains. siRNA-mediated Isl1 or Ldb1 knockdown followed by RNA analysis revealed a similar differential expression of α-cell mRNAs (e.g., Gcg, IL6ra, Sox8, Cox5a, Atp5k, Atp5e), suggesting roles in α-cell function. To compare ISL1 and LDB1 importance in vivo, we developed two novel mouse α-cell ISL1 or LDB1 KO models using Gcg-Cre, termed Isl1Δα and Ldb1Δα, respectively. ISL1 and LDB1 loss was confirmed in α-cells by immunofluorescence. Significant fasting hypoglycemia and hypoglucagonemia were found in postnatal Isl1Δα and Ldb1Δα mice, along with decreased GCG+ cell numbers in Ldb1Δα mice, compared to controls. These findings underscore the crucial roles of these factors in regulating GCG production and secretion. Immunostaining for the MAFB α-cell TF in Ldb1Δα islets revealed potential heterogeneous MAFB expression, marked by MAFB+ cells lacking GCG, or co-expressing INS, each indicating a potential loss of α-cell identity. Our lineage tracing analysis revealed α-cell lineage labeled tomato+ cells in Isl1Δα mice appearing to co-express INS, suggesting transdifferentiation. Currently, inducible α-cell-specific KO mice are in development to investigate the role of ISL1 and LDB1 in adult α-cells. In the future, we will also explore the effects of α-cell-specific ISL1 or LDB1 deficiency during embryogenesis. Overall, our study will benefit efforts in identifying new molecular targets and cell-based therapies to combat diabetes. Presentation: 6/1/2024

Nicotinamide Mononucleotide (NMN) Ameliorates Free Fatty Acid-Induced Pancreatic β-Cell Dysfunction via the NAD+/AMPK/SIRT1/HIF-1α Pathway.

As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD+ and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD+/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD+ and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD+/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.

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

ObjectivesPlatelets, 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 β 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 β cell function have not been previously explored. MethodsIn 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 β cells. ResultsOur findings indicate that AG deficiency has little to no effect on pancreatic β 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. ConclusionsObtained data suggest that DGs, but not AGs, mediate the influence of platelets on pancreatic β cells, thereby modulating glucose metabolism.

A Randomized Trial of the Efficacy of Three Weight Loss Diet Interventions in Overweight/Obese with Polycystic Ovary Syndrome.

Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic β-cells. To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients. A total of 90 overweight/obese patients with PCOS were selected to receive an 8- week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods. After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8 cm2, 13.4 cm2 and 23.45 cm2, respectively, especially in group C (p <0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p <0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p <0.05), and the changes in SOD and MDA in group B and group C were more significant (p <0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p <0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p <0.05) and HOMA-IR index (r=0.422; p <0.01); SOD positively correlated with LMI/FFMI (r=0.195; p <0.05), negatively correlated with HOMA-IR index (r=-0.433; p <0.01). All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage.

IGFBP7 is upregulated in islets from T2D donors and reduces insulin secretion

Intra-islet crosstalk has become a focus area to fully understand the regulation of insulin secretion andimpaired β-cell function in type 2 diabetes (T2D). Here, we put forward evidence for insulin-like growth factor binding protein 7 (IGFBP7) as a potential protein involved in autocrine and paracrine β-cell regulation. We showed presence of IGFBP7 in granules of both human α- and β-cells and measured elevated gene expression as well as IGFBP7 protein in T2D. Insulin secretion was reduced in human islets, and the human β-cell line EndoC-βH1, after 72-h incubation with IGFBP7. Mechanistically reduced insulin secretion by IGFBP7 is attributed to reduced p21-activated kinase 1 (PAK1) protein, and decreased oxygen consumption and ATP-production. Knockdown of IGFBP7 in EndoC-βH1 cells verified reduced IGFBP7 levels in the medium, as well as improved insulin secretion. Finally, IGFBP7 knockdown in islets from T2D donors improved insulin secretion, making IGFBP7 a potential drug target in diabetes.

Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus.

Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012). Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes. This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB. Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia. Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E-140] and 0.98 (1.04/0.92; P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E-06), independently of age and diabetes. PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.

Global deletion of G protein-coupled receptor 55 impairs glucose homeostasis during obesity by reducing insulin secretion and β-cell turnover.

To investigate the effect of G protein-coupled receptor 55 (GPR55) deletion on glucose homeostasis and islet function following diet-induced obesity. GPR55-/- and wild-type (WT) mice were fed ad libitum either standard chow (SC) or a high-fat diet (HFD) for 20 weeks. Glucose and insulin tolerance tests were performed at 9/10 and 19/20 weeks of dietary intervention. Insulin secretion in vivo and dynamic insulin secretion following perifusion of isolated islets were also determined, as were islet caspase-3/7 activities and β-cell 5-bromo-20-deoxyuridine (BrdU) incorporation. GPR55-/- mice fed a HFD were more susceptible to diet-induced obesity and were more glucose intolerant and insulin resistant than WT mice maintained on a HFD. Islets isolated from HFD-fed GPR55-/- mice showed impaired glucose- and pcacahorbol 12-myristate 13-acetate-stimulated insulin secretion, and they also displayed increased cytokine-induced apoptosis. While there was a 5.6 ± 1.6-fold increase in β-cell BrdU incorporation in the pancreases of WT mice fed a HFD, this compensatory increase in β-cell proliferation in response to the HFD was attenuated in GPR55-/- mice. Under conditions of diet-induced obesity, GPR55-/- mice show impaired glucose handling, which is associated with reduced insulin secretory capacity, increased islet cell apoptosis and insufficient compensatory increases in β-cell proliferation. These observations support that GPR55 plays an important role in positively regulating islet function.

Effect of circadian clock disruption on type 2 diabetes.

Type 2 diabetes (T2D) is the predominant form of diabetes mellitus and is among the leading causes of death with an increasing prevalence worldwide. However, the pathological mechanism underlying T2D remains complex and unclear. An increasing number of studies have suggested an association between circadian clock disruption and high T2D prevalence. This review explores the physiological and genetic evidence underlying T2D symptoms associated with circadian clock disturbances, including insulin secretion and glucose metabolism. Notably, circadian clock disruption reduces insulin secretion and insulin sensitivity and negatively affects glucose homeostasis. The circadian clock regulates the hypothalamic-pituitary-adrenal axis, an important factor that regulates glucose metabolism and influences T2D progression. Therefore, circadian clock regulation is an attractive, novel therapeutic approach for T2D, and various circadian clock stabilizers play therapeutic roles in T2D. Lastly, this review suggests novel therapeutic and preventive approaches using circadian clock regulators for T2D.

Insulin sensitivity, disposition index and insulin clearance in cystic fibrosis: a cross-sectional study

Aims/hypothesisThe aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency.MethodsIn a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity.ResultsAmong 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001).Conclusions/interpretationIn individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance.Graphical

Clinical characteristics and complication risks in data-driven clusters among Chinese community diabetes populations.

Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data-driven analysis in Chinese community diabetes populations. We used K-means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic β-cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi-square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups. Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity-related and insulin-resistant diabetes (SOIRD), severe insulin-deficient diabetes (SIDD), mild age-associated diabetes mellitus (MARD), and mild insulin-deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease. The data-driven approach to differentiating the status of new-onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications.

Decreased β-cell volume and insulin secretion but preserved glucose tolerance in a growth hormone insensitive pig model

PurposeGrowth hormone (GH) is a central regulator of β-cell proliferation, insulin secretion and sensitivity. Aim of this study was to investigate the effect of GH insensitivity on pancreatic β-cell histomorphology and consequences for metabolism in vivo.MethodsPancreata from pigs with growth hormone receptor deficiency (GHR-KO, n = 12) were analyzed by unbiased quantitative stereology in comparison to wild-type controls (WT, n = 12) at 3 and 7–8.5 months of age. In vivo secretion capacity for insulin and glucose tolerance were assessed by intravenous glucose tolerance tests (ivGTTs) in GHR-KO (n = 3) and WT (n = 3) pigs of the respective age groups.ResultsUnbiased quantitative stereological analyses revealed a significant reduction in total β-cell volume (83% and 73% reduction in young and adult GHR-KO vs. age-matched WT pigs; p < 0.0001) and volume density of β-cells in the pancreas of GHR-KO pigs (42% and 39% reduction in young and adult GHR-KO pigs; p = 0.0018). GHR-KO pigs displayed a significant, age-dependent increase in the proportion of isolated β-cells in the pancreas (28% in young and 97% in adult GHR-KO vs. age-matched WT pigs; p = 0.0009). Despite reduced insulin secretion in ivGTTs, GHR-KO pigs maintained normal glucose tolerance.ConclusionGH insensitivity in GHR-KO pigs leads to decreased β-cell volume and volume proportion of β-cells in the pancreas, causing a reduced insulin secretion capacity. The increased proportion of isolated β-cells in the pancreas of GHR-KO pigs highlights the dependency on GH stimulation for proper β-cell maturation. Preserved glucose tolerance accomplished with decreased insulin secretion indicates enhanced sensitivity for insulin in GH insensitivity.

Hypovitaminosis D among type 2 diabetes patients and non-diabetics at Libreville

: Type 2 diabetes is resulting from insulin resistance and/or progressively reduced insulin secretion. Vitamin D nuclear receptor present on the β cells of the pancreas promotes the growth, synthesis and secretion of insulin. Furthermore, vitamin D deficiency has been associated with numerous disorders, such as type 2 diabetes, cardiovascular diseases, arterial hypertension, cancer, multiple sclerosis, depression, psychiatric diseases. Determine the frequency of hypovitaminosis D among type 2 diabetes patients and those without diabetes in Libreville. The study population was composed of 92 type 2 diabetes patients (cases) and 100 non-diabetics (controls). The vitamin D and glycated hemoglobin were performed using 25 OH Vitamin D total kit and FIA8000 kit respectively. The blood glucose, calcemia and phosphorus were performed using standard spectrophotometric assay. Insufficient vitamin D (&amp;#60;30ng/mL) was found among 55.2% of the study population that was 57.0% of insufficient vitamin D in cases and 53.3% in controls. In the general population vitamin D was not correlated to blood glucose (r= -0.0270). Thus, with glycated hemoglobin, no correlation was found with vitamin D among cases. However, a weak negative correlation of vitamin D with blood glucose has been found in control group (r= -0.2798). High hypovitaminosis D was found among cases and controls. Therefore and in regards of studies based on vitamin D supplementation, with an appropriate concentration of vitamin D or calcitriol, glucose homeostasis may be maintained. Moreover, implementation of preventive measures should be done to avoid disastrous consequences of vitamin D insufficiency.