Impaired Β-cell Function Research Articles

Smoking causes the disorder of glucose metabolism under different levels of blood pressure in male occupational population.

Smoking is an important modifiable factor in the risk of type 2 diabetes. Type 2 diabetes and hypertension overlap in the population. The present study investigated effects of smoking on glucose metabolism under different blood pressure (BP) levels in occupational population. A smoking survey among occupational groups was conducted in 2018. The general linear model was used to analyze the differences of glucose metabolism indexes and BP indexes influenced by different smoking intensity (never 0, mild <10, moderate <20, heavy ≥20 pack‐years). Odds ratios of developing diabetes and β‐cell deficiency were analyzed by using logistic regression model. BP was further taken into account in the relationship between smoking and glucose metabolism. As a result, 1730 male workers aged 21 to 60 years were included in the analysis finally. Compared to never smokers, heavy smokers had significantly increased fasting plasma glucose. Moderate and above smokers had significantly increased glycosylated hemoglobin, decreased fasting plasma insulin and β‐cell function, after adjustment for covariates. Further, smoking intensity was found to have a dose‐dependent relationship with impaired β‐cell function and diabetes. In conclusion, smoking has a positive dose‐dependent relationship with β‐cell deficiency and diabetes. Male smoking workers, especially the moderate or higher smoking, with high‐normal and high BP levels are at high risk of abnormal glucose metabolism.

The p66Shc Protein Mediates Insulin Resistance and Secretory Dysfunction in Pancreatic β-Cells Under Lipotoxic Conditions.

We evaluated the role of the p66Shc redox adaptor protein in pancreatic β-cell insulin resistance that develops under lipotoxic conditions and with excess body fat. Prolonged exposure to palmitate in vitro or the presence of overweight/obesity augmented p66Shc expression levels and caused an impaired ability of exogenous insulin to increase cellular insulin content and secreted C-peptide levels in INS-1E cells and human and murine islets. In INS-1E cells, p66Shc knockdown resulted in enhanced insulin-induced augmentation of insulin content and C-peptide secretion and prevented the ability of palmitate to impair these effects of insulin. Conversely, p66Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion in both the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by a p53-induced increase in p66Shc protein levels and JNK-induced p66Shc phosphorylation at Ser36 and appear to involve the phosphorylation of the ribosomal protein S6 kinase at Thr389 and of insulin receptor substrate 1 at Ser307, resulting in the inhibition of insulin-stimulated protein kinase B phosphorylation at Ser473. Thus, the p66Shc protein mediates the impaired β-cell function and insulin resistance induced by saturated fatty acids and excess body fat.

The Transcription Factor YY1 Is Essential for Normal DNA Repair and Cell Cycle in Human and Mouse β-Cells.

Identifying the mechanisms behind the β-cell adaptation to failure is important to develop strategies to manage type 2 diabetes (T2D). Using db/db mice at early stages of the disease process, we took advantage of unbiased RNA sequencing to identify genes/pathways regulated by insulin resistance in β-cells. We demonstrate herein that islets from 4-week-old nonobese and nondiabetic leptin receptor-deficient db/db mice exhibited downregulation of several genes involved in cell cycle regulation and DNA repair. We identified the transcription factor Yin Yang 1 (YY1) as a common gene between both pathways. The expression of YY1 and its targeted genes was decreased in the db/db islets. We confirmed the reduction in YY1 expression in β-cells from diabetic db/db mice, mice fed a high-fat diet (HFD), and individuals with T2D. Chromatin immunoprecipitation sequencing profiling in EndoC-βH1 cells, a human pancreatic β-cell line, indicated that YY1 binding regions regulate cell cycle control and DNA damage recognition and repair. We then generated mouse models with constitutive and inducible YY1 deficiency in β-cells. YY1-deficient mice developed diabetes early in life due to β-cell loss. β-Cells from these mice exhibited higher DNA damage, cell cycle arrest, and cell death as well as decreased maturation markers. Tamoxifen-induced YY1 deficiency in mature β-cells impaired β-cell function and induced DNA damage. In summary, we identified YY1 as a critical factor for β-cell DNA repair and cell cycle progression.

Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity: A Latent Class Trajectory Approach.

OBJECTIVEIn a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT).RESEARCH DESIGN AND METHODSLatent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and β-cell function were estimated by glucose, insulin, and C-peptide modeling.RESULTSFour latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and β-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and β-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in β-cell glucose sensitivity.CONCLUSIONSWe identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by β-cell glucose sensitivity.

Fatty Pancreas: Linking Pancreas Pathophysiology to Nonalcoholic Fatty Liver Disease.

Currently, scientific interest has focused on fat accumulation outside of subcutaneous adipose tissue. As various imaging modalities are available to quantify fat accumulation in particular organs, fatty pancreas has become an important area of research over the last decade. The pancreas has an essential role in regulating glucose metabolism and insulin secretion by responding to changes in nutrients under various metabolic circumstances. Mounting evidence has revealed that fatty pancreas is linked to impaired β-cell function and affects insulin secretion with metabolic consequences of impaired glucose metabolism, type 2 diabetes, and metabolic syndrome. It has been shown that there is a connection between fatty pancreas and the presence and severity of nonalcoholic fatty liver disease (NAFLD), which has become the predominant cause of chronic liver disease worldwide. Therefore, it is necessary to better understand the pathogenic mechanisms of fat accumulation in the pancreas and its relationship with NAFLD. This review summarizes the epidemiology, diagnosis, risk factors, and metabolic consequences of fatty pancreas and discusses its pathophysiology links to NAFLD.

Oral fat tolerance testing identifies abnormal pancreatic β-cell function and insulin resistance in individuals with normal glucose tolerance.

Insulin sensitivity and β-cell function are affected by lipid metabolism disorders, even before the onset of type 2 diabetes. People are in the postprandial state most of the time. Therefore, identifying postprandial hyperlipemia is important. This study aimed to assess patients with abnormalities in lipid metabolism, but with normal glucose tolerance, using oral fat tolerance testing (OFTT) to identify defects in insulin sensitivity and β-cell function. We included 248 volunteers with normal glucose tolerance who underwent OFTT. They were divided into three groups in accordance with their fasting and 4-h postprandial triglyceride (TG) concentrations. Their lipid concentrations during OFTT were compared. The disposition index (DI) was applied to estimate β-cell function, and the Matsuda insulin sensitivity index (ISIM ) was used to assess insulin sensitivity. We used multiple linear regression analysis to estimate the relationships of fasting and postprandial TG concentrations with β-cell function and insulin sensitivity . The changes in TG concentrations during OFTT were more marked than those in low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol or total cholesterol concentrations. As lipid metabolism deteriorated, the ISIM and the DI gradually decreased. Multiple linear regression analysis showed that fasting and 4-h postprandial TG concentrations affected LnISIM and LnDI. In individuals with normal glucose tolerance, β-cell function and insulin sensitivity gradually decrease with a deterioration in the lipid profile. Not only fasting TG, but also postprandial TG concentrations are independent risk factors for impaired β-cell function and insulin resistance.

The microRNA-29 family: role in metabolism and metabolic disease.

The microRNA-29 family members miR-29a-3p, miR-29b-3p, and miR-29c-3p are ubiquitously expressed and consistently increased in various tissues and cell types in conditions of metabolic disease, obesity, insulin resistance, and type 2 diabetes. In pancreatic β cells, miR-29a is required for normal exocytosis, but increased levels are associated with impaired β-cell function. Similarly, in liver, miR-29 species are higher in models of insulin resistance and type 2 diabetes, and either knock-out or depletion using a microRNA inhibitor improves hepatic insulin resistance. In skeletal muscle, miR-29 family upregulation is associated with insulin resistance and altered substrate oxidation, and similarly, in adipocytes, overexpression of miR-29a leads to insulin resistance. Blocking miR-29a using nucleic acid antisense therapeutics show promising results in preclinical animal models of obesity and type 2 diabetes, although the widespread expression pattern of miR-29 family members complicates the exploration of single target tissues. However, in fibrotic diseases, such as in late complications of diabetes and metabolic disease (diabetic kidney disease, nonalcoholic steatohepatitis), miR-29 species expression is suppressed by TGF-β allowing increased extracellular matrix collagen to form. In the clinical setting, circulating levels of miR-29a and miR-29b are consistently increased in type 2 diabetes and in gestational diabetes and are also possible prognostic markers for deterioration of glucose tolerance. In conclusion, miR-29 family miRNAs play an essential role in various organs relevant to intermediary metabolism and its upregulation contributes to impaired glucose metabolism, whereas it suppresses fibrosis development. Thus, a correct balance of levels of miR-29 family miRNA seems important for cellular and organ homeostasis in metabolism.

1047-P: To Assess the Physiological Changes of Glucose Metabolism Associated with Increased BMI in Pregnancy

Background: Maternal overweight is a risk factor for Gestational Diabetes Mellitus (GDM) . However, there is emerging evidence that increased maternal BMI has considerable impact on the development of large for gestational age (LGA) offspring even in women who do not develop GDM, possibly related to subtle impairments in glucose metabolism. This study aims to assess physiological changes associated with increased BMI. Methods: 21 women with overweight and 21 normal weight controls were included in this explorative study and received a metabolic assessment at early pregnancy (13.3 weeks) (Visit 1) , including a 60 min frequently sampled intravenous glucose tolerance test (FSIGT) . An OGTT was performed between 24 and 28 weeks of gestation (Visit 2) in women who remained normal glucose tolerant. Results: At V1 mothers with overweight showed significantly elevated fasting glucose and HbA1c values, a well as impaired insulin sensitivity at fasting condition and dynamically assessed during the FSIGT, whereby the Calculated Insulin Sensitivity index (CSI) was lower in the overweight group as compared to normal weight controls (3.5 vs. 6.7 10-4⋅[μU/mL]-1⋅min-1, p=0.025) . The Disposition Index (DI) as a parameter of β-cell function was significantly decreased in mothers with overweight. Likewise, maternal BMI was inversely related to fasting (rho=0.56, p=0.005) and dynamically assessed insulin sensitivity (rho=0.51, p=0.014) as well as the DI (rho=0.51, p=0.014) and the AUC of glucose (rho=0.66, p&amp;lt;0.001) and C-Peptide (rho=0.46, p=0.020) during the OGTT in mothers who remained normal glucose tolerant during pregnancy at V2. Conclusions: Increased maternal BMI is associated to insulin resistance and impaired β-cell function already at early pregnancy. We also observed that maternal BMI was associated with impaired glucose metabolism and especially elevated glucose levels during the OGTT at mid gestation in women who did not develop GDM and remained normal glucose tolerant. Disclosure T.Linder: None. D.Eppel: None. C.Monod: None. G.Kotzaeridi: None. A.Tura: None. C.S.Göbl: Research Support; Dexcom, Inc., Sanofi.

1312-P: Impaired Beta-Cell Function in Older Patients Corresponds to Changes in Salience Network Connectivity

The salience network (anterior cingulate cortex (ACC) —insula) plays an important role in regulating attention and memory in the context of decision making and has also been shown to be highly responsive to changes in peripheral glucose levels. Increased age is also associated with changes in glucose homeostasis and the salience network. To investigate these relationships, 40 healthy, cognitively normal, non-diabetic subjects (20 Young (age mean 28±1 years, BMI 28.1 ±1.1 kg/m2, HbA1c 5.3±0.1%) and 20 Old (age mean of 73±2 years, BMI 26.9±0.9 kg/m2, HbA1c 5.5±0.1%)) underwent an OGTT, resting state functional connectivity (FC) MRI brain scanning, and cognitive assessments (Cambridge Neuropsychological Test Automated Battery) . Despite similar BMI, HbA1C, and fasting glucose levels, older individuals had lower disposition index (young: 9±2, old: 3.3±0.4, p=0.005) indicating impaired β-cell function. There were no differences in measures of insulin sensitivity (HOMA-IR (p=0.38) or Matsuda index (p=0.70) . A seed-based analysis using a predefined cubic voxel in the ACC showed differences in FC between the ACC and the left insula (Main Effect by group, P&amp;lt;0.001) with lower connectivity values in Old compared to Young subjects. This connectivity value also correlated with errors on the Paired Associate Learning task, which tests attention and memory (r=-0.5, P=0.001) . Moreover, the connectivity values correlated with the disposition index in older subjects (r=0.49, P=0.03) but not younger subjects (P=0.9) . Thus, in our cohort of healthy, cognitively normal older subjects, impairments in beta-cell function are associated with altered functional connectivity within the salience network. These findings highlight the need for future investigations to determine whether mild age-related changes in glycemic control contribute to neurocognitive changes in older patients. Disclosure J.Deajon-jackson: None. C.Lacadie: None. C.Watt: None. D.Scheinost: None. J.J.Hwang: None. Funding Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342)

198-OR: Altered Prandial Glucose Metabolism in Nondiabetic Subjects with Spinal Cord Injury Is Associated with Impaired Insulin Secretion and Clearance

Patients with spinal cord injury (SCI) develop type 2 diabetes earlier and at 2-3 times higher frequency compared to the matched able-bodied persons (AB) . The difference in glucose abnormalities among SCI and AB cohorts remains after adjusting for known risk factors for DM, such as decreased physical activity, or lower body lean mass, or larger visceral fat mass. The mechanism for this dramatic effect of SCI on glucose metabolism is unknown but is consistent with endocrine-neurological alterations after injury. We hypothesized that SCI is associated with abnormalities in prandial glucose metabolism and β-cell function. To test this hypothesis glucose, insulin, and C-peptide levels were measured during 3-hr mixed meal tolerance test in 4 non-diabetic SCI (3M/1F, ages 33-61 years) and 6 age-matched AB with normal glucose tolerance test (2M/4F, ages 37-57 years) . SCI subjects had lower BMI (p=0.05) and A1C (p&amp;lt;0.05) than AB (SCI vs. AB; BMI range: 19-29 vs. 25-39 kg/m2; A1C range: 5.0-5.3 vs. 5.3-5.9%) . Fasting values of glucose, insulin, C-peptide, insulin sensitivity (HOMA-IR) , and insulin clearance (CP/insulin) were similar between SCI and AB. Prandial glucose (AUCGlucose3h) and insulin (AUCInsulin3h) responses, however, were greater in SCI than AB (p&amp;lt;0.01) . Despite larger prandial insulinemia β-cell output (AUCC-peptide3h) did not differ among 2 groups. This was consistent with a diminished insulin clearance (Total AUCC-peptide3h / Total AUCInsulin3h) in SCI compared to AB by 3-fold (p&amp;lt;0.05) . Oral glucose insulin sensitivity (OGIS) was similar between 2 groups while β-cell glucose sensitivity and disposition index were smaller in SCI than AB by 2-fold (p=0.08) . These findings indicate that among subjects with normal glucose tolerance, those with SCI have larger prandial glycemic concentration despite lower BMI and A1C. This glycemic effect of SCI is associated with impaired β-cell function as well as insulin clearance. Disclosure M.Trbovich: None. R.Dimas: None. M.Salehi: None.

13-OR: Cystic Fibrosis Donors Exhibit Striking Decrease in Pancreatic Islet and Exocrine Capillaries

Glucose intolerance and insulin deficiency are common features of cystic fibrosis (CF) , with nearly half of adult CF patients developing CF-related diabetes (CFRD) , but the underlying pathophysiology remains poorly understood. Extensive destruction of the exocrine pancreas occurs in most CF patients. However, islets are still readily detectable, suggesting β cell loss is not the major driver of impaired insulin release. Islets are normally highly vascularized, and islet capillaries are the source of key growth factors that maintain β cell health and function. Islet capillary morphology is altered in type 1 and type 2 diabetes, with increased capillary density and/or vessel thickening being observed. In the present study we aimed to determine whether islet capillaries are also disrupted in CF/CFRD. Pancreas sections (8 control and 8 CF/CFRD, age-matched) were stained for CD31, a marker of vascular endothelial cells. Islets in microscopy images were manually identified (17.8±2.8[SEM] per sample) and CD31-positive area within islet and exocrine was quantified. Mean islet cross-sectional area did not significantly differ between CF and non-CF pancreas specimens. CD31 positive area, expressed as a fraction of islet area, was significantly decreased in CF pancreas specimens (2.8±0.9% vs. 6.1±1.2%; p=0.05) . Islet capillary density (the number of CD31+ objects normalized to islet area) was also decreased (0.88±0.17x103/μm2 vs. 3.8±0.57x103/μm2; p=0.0004) , as was exocrine tissue CD31 positive area (0.17±0.03% vs. 1.5±0.23%; p&amp;lt;0.0001) . Our data demonstrate a significant deficit in islet and pancreatic vascularity in CF/CFRD. This contrasts markedly with the increase in islet capillary density seen in both T1D and T2D and underscores the presence of distinct features of islet morphology that characterize CF. Given that islet capillaries support β-cell function and survival, their loss likely contributes to impaired β-cell function. Disclosure J.J.Castillo: None. A.Aplin: None. R.Akter: None. R.L.Hull-meichle: Research Support; Casma Therapeutics. Funding Cystic Fibrosis Foundation Fellowship (CASTIL20F0)

1326-P: Baseline OGTT as a Predictor of Type 2 Diabetes Progression in the GRADE Study

Type 2 diabetes (T2D) is progressive, often requiring additional medications to maintain glycemic control. We assessed baseline β-cell function and insulin sensitivity as predictors of worsening glycemia (HbA1c) in the GRADE Study. Adults with T2D &amp;lt;y and HbA1c 6.8-8.5% were randomized to glimepiride, sitagliptin, insulin glargine 100 U/mL or liraglutide added to metformin monotherapy. Complete baseline OGTT data were available for 4586 of 5047 participants (Mean±SD: Age 57±y, 64% male, 5.0±1.3 y f/up) . Insulin sensitivity (HOMA2S) and early (C-peptide index (CPI) : ΔCP/ΔG 0-30 min) and total (incAUC-CP/G 0-120 min) C-peptide responses were used in Cox proportional hazard models to predict time to 1° (HbA1c ≥7%) and 2° (HbA1c &amp;gt;7.5%) glycemic outcomes and tested for treatment interaction. Given the inverse relationship with insulin sensitivity, C-peptide responses were adjusted for HOMA2S. Values determined at baseline (mean±SD) were: CPI 0.8±.nmol/g, incAUC CP/G 1.0±0.6 nmol/mg, HOMA2S 35±68 %, fasting glucose 152±31 mg/dl. Higher C-peptide responses predicted lower risk of 1° (CPI: HR±SE per 1 unit change =0.74±0.03, p&amp;lt;0.001; incAUC-CP/G: HR=0.68±0.02, p&amp;lt;0.001) and 2° glycemic outcomes (CPI: HR=0.71±0.03, p&amp;lt;0.001; incAUC-CP/G: HR=0.60±0.03, p&amp;lt;0.001) . Risks did not differ by treatment. There was interaction for HOMA2S and treatment; a 5 unit change in HOMA2S predicted lower risk of 1° and 2° outcomes with glimepiride and sitagliptin (HR=0.97±0.for both 1° outcomes; HR=0.96±0.for 2° outcome with glimepiride, HR=0.95±0.for 2° outcome with sitagliptin; all p&amp;lt;0.05) . A mg/dL change in fasting glucose predicted greater risk of 1° outcomes for all treatments, lowest for insulin glargine (HR=1.05±0.01) and highest for sitagliptin (HR=1.11±0.01) . Conclusions: Impaired β-cell function based on an OGTT predicted higher risk of T2D progression regardless of assigned treatment. This approach may identify cases that may benefit from earlier more aggressive therapy. Disclosure K.Utzschneider: Consultant; Nevro Corp. T.A.Elasy: None. W.Valencia: None. C.Ma: None. N.Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. W.Sivitz: n/a. Grade research group: n/a. N.Younes: None. N.M.Butera: None. A.Balasubramanyam: None. C.Desouza: Advisory Panel; AstraZeneca, Bayer AG, Novo Nordisk A/S, Consultant; Asahi Kasei Corporation. J.Krakoff: None. J.I.Barzilay: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc., Speaker’s Bureau; AstraZeneca. R.M.Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK098246, U34-DK-088043)

Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function.

Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. miRNAs are short, noncoding RNAs that silence gene expression vital for the development and function of β cells. We have previously shown that β cell-specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in β cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycemia in β cells. Here, we show that islet miR-125b-5p expression is upregulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose-stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased, high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human β-cell line EndoCβ-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in β cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg β cells contained enlarged lysosomal structures and had reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.

Knockout of Nur77 Leads to Amino Acid, Lipid, and Glucose Metabolism Disorders in Zebrafish.

Orphan nuclear receptor Nur77 has been reported to be implicated in a diverse range of metabolic processes, including carbohydrate metabolism and lipid metabolism. However, the detailed mechanism of Nur77 in the regulation of metabolic pathway still needs to be further investigated. In this study, we created a global nur77 knockout zebrafish model by CRISPR/Cas9 technique, and then performed whole-organism RNA sequencing analysis in wildtype and nur77-deficient zebrafish to dissect the genetic changes in metabolic-related pathways. We found that many genes involved in amino acid, lipid, and carbohydrate metabolism changed by more than twofold. Furthermore, we revealed that nur77−/− mutant displayed increased total cholesterol (TC) and triglyceride (TG), alteration in total amino acids, as well as elevated glucose. We also demonstrated that the elevated glucose was not due to the change of glucose uptake but was likely caused by the disorder of glycolysis/gluconeogenesis and the impaired β-cell function, including downregulated insb expression, reduced β-cell mass, and suppressed insulin secretion. Importantly, we also verified that targeted expression of Nur77 in the β cells is sufficient to rescue the β-cell defects in global nur77−/− larvae zebrafish. These results provide new information about the global metabolic network that Nur77 signaling regulates, as well as the role of Nur77 in β-cell function.

Epigallocatechin-3-gallate alleviates type 2 diabetes mellitus via β-cell function improvement and insulin resistance reduction.

Objective(s):Epigallocatechin-3-gallate (EGCG) has a good therapeutic effect on type 2 diabetes mellitus (T2DM). This work was designed to explore EGCG’s effectiveness in insulin resistance (IR) and pancreas islet β-cell function in a rat model of T2DM. Materials and Methods:Eight-week-old male Sprague Dawley rats were randomly divided into 6 groups, including the Control (normal diet), Diabetes (high-sucrose high-fat [HSHF] diet combined with tail vein injection of streptozotocin [STZ] for T2DM induction) and Treatment Diabetic rats which were treated with metformin [500 mg/kg/d] or EGCG [25, 50 or 100 mg/kg/d] intragastric administration for 10 weeks. With the exception of control animals, the other groups were fed the HSHF diet. EGCG’s effects on IR and insulin secretion were assessed by measuring body weights, and fasting blood glucose (FBG), postprandial blood glucose (PBG) and insulin levels. The morphological and molecular changes of pancreas islet β-cells were examined by hematoxylin-eosin (H&E) staining, transmission electron microscopy (TEM) and immunofluorescence.Results:Rats fed the HSHF diet combined with STZ treatment had increased body weights and blood glucose amounts, accompanied by IR and impaired β-cell function, induced T2DM, and EGCG dose-dependently restored the above indicators. Additionally, EGCG upregulated the pancreatic transcription factors pancreatic duodenal homeobox protein-1 (PDX-1) and musculoaponeurotic fibrosarcoma oncogene homolog A (MafA).Conclusion:These results suggest that EGCG reduces blood glucose amounts, and improve IR and islet β-cell disorder in T2DM.

IDF21-0393 Pancreatic beta cell CASK gene knockout aggravates beta cell aging and abnormal glucose metabolism in old mice

Background: The incidence of type 2 diabetes mellitus (T2DM) increased with advancing age. Older adults with T2DM were usually accompanied by gradual impairment of β-cell function and accumulation of senescent β-cells. However, the contribution of β cell senescence to diabetes has received little attention. Our previous study found that with increasing age of mice, knocking out the Cask gene in pancreatic islet β-cells leads to a gradual increase impairment in glucose profile and insulin secretion.

Pancreatic fat infiltration, β-cell function and insulin resistance: A study of the young patients with obesity

ObjectiveThis study aimed to investigate the relationship between pancreatic fat infiltration (PFI) and glucose metabolism disorder, β-cell function and insulin resistance in patients with obesity. MethodsPancreatic fat fraction (PFF) was quantified by MRI IDEAL-IQ technique. PFF greater than 6.2 % was defined as PFI, and 34 obese patients were divided into PFI and non-PFI groups. The 5-point plasma glucose and insulin values during oral glucose tolerance test (OGTT) were recorded. OGTT-derived indices of insulin resistance and β-cell function were calculated. ResultsGlucose values levels at 0–120 min during OGTT were significantly higher and β-cell function variables were lower in PFI group than non-PFI group. While indices of insulin resistance were not significantly different between two groups. Correlation analysis showed that PFF was positively correlated with glucose levels at 0, 30 and 60 min, negatively correlated with β-cell function variables and not significantly correlated with indices of insulin resistance. However, these associations of PFF with β-cell function and glucose levels were only present in type 2 diabetes mellitus (T2DM) group but not in non-T2DM group. ConclusionThere is an association between PFI and impaired β-cell function, and increased pancreatic fat may be a potential risk factor for the development of T2DM.

The Role of the Gut Microbiota in the Pathogenesis of Diabetes.

Diabetes mellitus is a significant clinical and therapeutic problem because it can lead to serious long-term complications. Its pathogenesis is not fully understood, but there are indications that dysbiosis can play a role in the development of diabetes, or that it appears during the course of the disease. Changes in microbiota composition are observed in both type 1 diabetes (T1D) and type 2 diabetes (T2D) patients. These modifications are associated with pro-inflammation, increased intestinal permeability, endotoxemia, impaired β-cell function and development of insulin resistance. This review summarizes the role of the gut microbiota in healthy individuals and the changes in bacterial composition that can be associated with T1D or T2D. It also presents new developments in diabetes therapy based on influencing the gut microbiota as a promising method to alter the course of diabetes. Moreover, it highlights the lacking data and suggests future directions needed to prove the causal relationship between dysbiosis and diabetes, both T1D and T2D.

Non-linear associations of body mass index with impaired fasting glucose, β-cell dysfunction, and insulin resistance in nondiabetic Chinese individuals: a cross-sectional study.

Identifying and managing patients with prediabetes is important. The study aims to investigate the association of body mass index (BMI) with impaired fasting glucose (IFG), β-cell dysfunction, and insulin resistance in nondiabetic Chinese individuals. This was a cross-sectional study of consecutive nondiabetic individuals enrolled between January 2014 and January 2015, divided into NFG [normal fasting glucose, fasting blood glucose (FBG) < 5.6 mmol/L) and IFG (n = 450; FBG ≥ 5.6 mmol/L) groups. Restricted cubic splines and piecewise-regression were used to model the association of IFG, impaired b-cell function, and insulin resistance with BMI. Stratified analyses were performed across sex and age. A total of 900 NFG and 450 IFG individuals were enrolled, with a median age of 41 (30-49) years and 1076 males (79.7%). After adjusting for age and sex, the restricted cubic splines showed that the risk of IFG was increasing rapidly until around 27.96 kg/m² of BMI and then started to plateau afterward (p for non-linearity = 0.010), which was similar in males and individuals ≤ 45 years old (p for nonlinearity < 0.001 and = 0.007, respectively). The risk of insulin resistance increased and β-cell dysfunction decreased as the BMI increased in all participants (bothp for non-linearity > 0.05), consistent with the results in males, females, and ≤ 45 and > 45 year olds. The risk of IFG does not rise linearly as the BMI increases, and higher BMI seems to decelerate the rise of the risk.

Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions.

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.