Β-cell Response Research Articles

Syntaxin 4 Enrichment in β-Cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice.

Syntaxin 4 (STX4), a plasma membrane-localized SNARE protein, regulates human islet β-cell insulin secretion and preservation of β-cell mass. We found that human type 1 diabetes (T1D) and NOD mouse islets show reduced β-cell STX4 expression, consistent with decreased STX4 expression, as a potential driver of T1D phenotypes. To test this hypothesis, we generated inducible β-cell-specific STX4-expressing NOD mice (NOD-iβSTX4). Of NOD-iβSTX4 mice, 73% had sustained normoglycemia vs. <20% of control NOD (NOD-Ctrl) mice by 25 weeks of age. At 12 weeks of age, before diabetes conversion, NOD-iβSTX4 mice demonstrated superior whole-body glucose tolerance and β-cell glucose responsiveness than NOD-Ctrl mice. Higher β-cell mass and reduced β-cell apoptosis were also detected in NOD-iβSTX4 pancreata compared with pancreata of NOD-Ctrl mice. Single-cell RNA sequencing revealed that islets from NOD-iβSTX4 had markedly reduced interferon-γ signaling and tumor necrosis factor-α signaling via nuclear factor-κB in islet β-cells, including reduced expression of the chemokine CCL5; CD4+ regulatory T cells were also enriched in NOD-iβSTX4 islets. These results provide a deeper mechanistic understanding of STX4 function in β-cell protection and warrant further investigation of STX4 enrichment as a strategy to reverse or prevent T1D in humans or protect β-cell grafts.

Time restricted eating for the prevention of type 2 diabetes.

Type 2 diabetes can potentially be prevented by targeted lifestyle and weight loss interventions. Time restricted eating (TRE) is a form of intermittent fasting that has emerged as a novel diet strategy to reduce body weight and improve glycaemic control. TRE involves eating within a certain window of time (usually 4 to 10h), and water-fasting for the remaining hours of the day. The purpose of this review is to summarize the effects of TRE on body weight and markers of glycaemic control in human subjects. We also aim to provide mechanistic insights into the effect of TRE on insulin sensitivity and glucose tolerance. Results to date reveal that TRE produces mild weight loss (1%-4% from baseline) and energy restriction, when food consumption is restricted to 4-10h/day. TRE also reduces fasting insulin and improves insulin sensitivity in individuals with prediabetes and those with obesity. Moreover, TRE improves glucose tolerance and decreases serum glucose excursions. The possible mechanisms underlying these benefits include increased autophagic flux, mild elevations in ketone bodies, a reduction in oxidative stress, and the stimulation of β-cell responsiveness. While these preliminary results offer promise for the use of TRE in the prevention of type 2 diabetes, larger and longer-term human trials will be needed to confirm these findings.

From Pancreatic β-Cell Gene Networks to Novel Therapies for Type 1 Diabetes

Completion of the Human Genome Project enabled a novel systems- and network-level understanding of biology, but this remains to be applied for understanding the pathogenesis of type 1 diabetes (T1D). We propose that defining the key gene regulatory networks that drive β-cell dysfunction and death in T1D might enable the design of therapies that target the core disease mechanism, namely, the progressive loss of pancreatic β-cells. Indeed, many successful drugs do not directly target individual disease genes but, rather, modulate the consequences of defective steps, targeting proteins located one or two steps downstream. If we transpose this to the T1D situation, it makes sense to target the pathways that modulate the β-cell responses to the immune assault—in relation to signals that may stimulate the immune response (e.g., HLA class I and chemokine overexpression and/or neoantigen expression) or inhibit the invading immune cells (e.g., PDL1 and HLA-E expression)—instead of targeting only the immune system, as it is usually proposed. Here we discuss the importance of a focus on β-cells in T1D, lessons learned from other autoimmune diseases, the “alternative splicing connection,” data mining, and drug repurposing to protect β-cells in T1D and then some of the initial candidates under testing for β-cell protection.

Incidence of diabetic retinopathy in newly diagnosed subjects with type 2 diabetes mellitus over 5 years: Contribution of Β-cell function

AimsIdentifying and modulating risk factors is essential to prevent visual impairment due to diabetic retinopathy (DR). This study examines incident DR with metabolic and hormonal factors in newly-diagnosed, treatment naïve, individuals with Type2 Diabetes Mellitus (T2DM), over a 5 year period from diagnosis. Methods233 T2DM subjects underwent serial DR screening using digital photography and standardised Meal Tolerance Tests at diagnosis and after 1, 2 and 5 years. Subjects (179) with no DR throughout the 5-year study period were compared with those who developed DR (54). ResultsOf 233 subjects, 54(23.2%) developed DR by 5 years, background DR in 50(93%) and exudative maculopathy in 4(7%) individuals. Of these subjects, 12(22%) developed DR after 1 year, 15(28%) after 2 years and 27(50%) after 5 years.At baseline, those with DR at 5 years had higher HbA1c (p = 0.017), higher fasting plasma glucose (PG) (p = 0.031) and postprandial PG (p = 0.009). They were associated with reduced basal β-cell secretory function (M0) (p = 0.025), lower (p = 0.000) postprandial β-cell responsiveness (M1) and β-cell function (HOMA-B) (p = 0.044). ConclusionsThere is an independent association between glycaemic control and β-cell dysfunction at the time of diagnosis of T2DM, with incident DR over a follow-up period of 5 years.

Differential loss of β-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study

AimsTo compare OGTT-derived estimates of β-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE. MethodsYouth (n = 89) and adults (n = 132) were randomized to 3 months glargine followed by 9 months metformin (G/M) or 12 months metformin (MET). Insulin sensitivity and β-cell responses were estimated from 3-hour OGTTs over 21 months. Linear mixed models tested for differences by time and age group within each treatment arm. ResultsAfter treatment withdrawal, HbA1c increased in both youth and adults with a larger net increase in G/M youth vs. adults at 21 months. Among youth, β-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, β-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline β-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms. ConclusionsAfter treatment withdrawal youth demonstrated progressive decline in β-cell function after stopping treatment with either G/M or MET. In contrast, β-cell function in adults remained stable despite an increase in HbA1c over time.ClinicalTrials.gov Identifier: NCT01779375 and NCT01779362 at clinical trials.gov.

An Autonomous Cannabinoid System in Islets of Langerhans.

While endocannabinoids (ECs) and cannabis were primarily studied for their nervous system effects, it is now clear that ECs are also produced in the periphery where they regulate several physiological processes, including energy storage, glucose and lipid metabolism, insulin secretion and synthesis, and hepatocyte function. Within islet of Langerhans there is an autonomous EC system (ECS). Beta (β)-cells contain all the enzymes necessary for EC synthesis and degradation; ECs are generated in response to cellular depolarization; their paracrine influence on β-cells is mostly through the cannabinoid 1 receptor (CB1R) that is present on all β-cells; they modulate basal and glucose- and incretin-induced insulin secretion, and β-cell responses to various stressors. Furthermore, there is now accumulating evidence from preclinical studies that the autonomous islet ECS is a key player in obesity-induced inflammation in islets, and β-cell damage and apoptosis from many causes can be mitigated by CB1R blockers. We will thoroughly review the literature relevant to the effects of ECs and their receptors on β-cells and the other cell types within islets. Therapeutic potential of agents targeting EC/CB1R and CB2R is highly relevant because the receptors belong to the druggable G protein-coupled receptor superfamily. Present research in the ECS must be considered preliminary, especially with regards to human islet physiology, and further research is needed in order to translate basic cellular findings into clinical practice and the use of safe, clinically approved CBR modulators with and without glucose lowering combinations presently in therapeutic use for diabetes and obesity needs to be studied.

Serum fatty acid-binding protein 4 levels and responses of pancreatic islet \u03b2-cells and \u03b1-cells in patients with type 2 diabetes

BackgroundSerum fatty acid-binding protein 4 (FABP4), as an intracellular lipid chaperone and adipokine, was reported to be related to the incidence of type 2 diabetes (T2D) and diabetic complications, but its association with pancreatic islet β-cell and α-cell functions has not been fully elucidated. So the present study was to investigate the serum FABP4 levels and responses of islet β-cells and α-cells in patients with T2D.Methods115 patients with T2D and 89 healthy controls (HC), who received serum FABP4 levels test, were recruited to participate in this study. Moreover, 75-g oral glucose tolerance test (OGTT) was performed in T2D patients to evaluate islet β-cell and α-cell functions. Systemic insulin sensitivity and overall insulin secretion of islet β-cell function were assessed by Matsuda index using C peptide (ISIM-cp) and ratio of the area under the C peptide curve to the glucose curve (AUCcp/glu) during OGTT, respectively. Fasting glucagon (Gluca0min) and postchallenge glucagon assessed by the area under the glucagon curve (AUCgluca) were determined during OGTT to evaluate islet α-cell function. And other various clinical variables were also measured in all participants. Skewed variables were natural log-transformed (ln), such as lnFABP4.ResultsThe serum FABP4 levels in T2D patients were significantly higher than those in HC (p < 0.05). And after partially adjusting for fasting plasma glucose, serum lnFABP4 levels were negatively correlated with lnISIM-cp (r = − 0.332, p < 0.001) and positively correlated with lnAUCcp/glu (r = 0.324, p < 0.001), lnGluca0min (r = 0.200, p = 0.040) and lnAUCgluca (r = 0.311, p < 0.001), respectively, in patients with T2D. Furthermore, when multiple linear regression analyses were applied to adjust for other various clinical variables, serum lnFABP4 levels were found to remain associated with lnISIM-cp (β = − 0.296, t = − 2.900, p = 0.005), lnAUCcp/glu (β = 0.223, t = 2.038, p = 0.046), lnGluca0min (β = 0.272, t = 2.330, p = 0.024) and lnAUCgluca (β = 0.341, t = 3.065, p = 0.004), respectively.ConclusionIncreased serum FABP4 levels were closely associated with blunted insulin sensitivity, increased insulin secretion, and elevated fasting and postchallenge glucagon levels in patients with T2D.

Human Islet Expression Levels of Prostaglandin E2 Synthetic Enzymes, But Not Prostaglandin EP3 Receptor, Are Positively Correlated with Markers of β-Cell Function and Mass in Nondiabetic Obesity.

Elevated islet production of prostaglandin E2 (PGE2), an arachidonic acid metabolite, and expression of prostaglandin E2 receptor subtype EP3 (EP3) are well-known contributors to the β-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE2 production and signaling pathway influences nondiabetic β-cell function. In this work, plasma arachidonic acid and PGE2 metabolite levels were quantified in a cohort of nondiabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation. In order to link these findings to processes happening at the islet level, cadaveric human islets were subject to gene expression and functional assays. Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA levels, but not those of EP3, positively correlated with donor body mass index (BMI). IL-6 expression also strongly correlated with the expression of COX-2 and other PGE2 synthetic pathway genes. Insulin secretion assays using an EP3-specific antagonist confirmed functionally relevant upregulation of PGE2 production. Yet, islets from obese donors were not dysfunctional, secreting just as much insulin in basal and stimulatory conditions as those from nonobese donors as a percent of content. Islet insulin content, on the other hand, was increased with both donor BMI and islet COX-2 expression, while EP3 expression was unaffected. We conclude that upregulated islet PGE2 production may be part of the β-cell adaption response to obesity and insulin resistance that only becomes dysfunctional when both ligand and receptor are highly expressed in T2D.

Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.

OBJECTIVETo identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study.RESEARCH DESIGN AND METHODSA total of 91 youth (10–19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline).RESULTSGlycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05–0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05).CONCLUSIONSGlycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

263-OR: Higher Glycemic Threshold for Glucagon Suppression in Impaired Fasting Glucose and Impaired Glucose Tolerance

Impaired glucagon suppression is an overlooked contributor to the transition of prediabetes to type 2 diabetes. Graded Glucose Infusion (GGI) is a technique used to assess Insulin Secretion Rate (ISR) in response to rising glucose concentrations. We used GGI to examine the relationship of ISR and Glucagon Secretion Rate (GSR) with rising glucose. We studied 32 nondiabetic, weight-stable individuals (54 ± 2 yrs, 29 ± 1 Kg/M2) categorized on the basis of fasting and glucose tolerance status following a 75g OGTT at the time of screening. After an overnight fast, at 07:00 a variable insulin infusion was used to maintain glucose at ~4.4 mmol/L (until 08:30) enabling the subsequent measurement of the glycemic threshold for ISR and GSR. At 09:00 GGI commenced, starting at 1 mg/kg/min and doubling every 60 min until 13:00. GSR and ISR were calculated by nonparametric deconvolution from plasma concentrations of glucagon and c-peptide respectively. β-cell responsivity (Φ) was estimated from the relationship of ISR to glucose. The glycemic threshold for glucagon suppression was higher in subjects with impaired fasting glucose (IFG) than normal fasting glucose (NFG), 10.9 ± 0.8 vs. 8.3 ± 0.5 mmol/L, p&amp;lt;0.01, IFG vs. NFG respectively. This was also the case in subjects with impaired glucose tolerance (IGT) compared to normal glucose tolerance (NGT), 10.3 ± 0.7 vs. 8.5 ± 0.7 mmol/L, p=0.05. Φ did not differ in subjects with IGT vs. NGT (p=0.33) or in subjects with IFG vs. NFG (p=0.48). The glycemic threshold for stimulation of ISR was higher in subjects with IFG than NFG, 5.7 +/- 0.3 vs. 5.0 +/- 0.1 mmol/L, p&amp;lt;0.01, IFG vs. NFG respectively, but no different in subjects with IGT vs. NGT, 5.3 +/- 0.2 vs. 5.0 +/- 0.1 mmol/L, p=0.06, IGT vs. NGT respectively. These data show that in nondiabetic humans, IFG but not IGT is associated with a higher glycemic threshold for insulin secretion, and both IFG and IGT are associated with a higher glycemic threshold for glucagon suppression. Disclosure J. D. Kohlenberg: None. M. C. Laurenti: None. A. M. Egan: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Research Support; Self; Novo Nordisk. Funding Endocrine Fellows Foundation (DK078646DK116231)

1104-P: Normative Fasting C-Peptide Values in Adolescents in the National Health and Nutrition Examination Surveys (NHANES)

Background: C-peptide values are used for evaluation of residual β-cell function as well as endpoints in clinical trials. Therefore, it is crucial to have normative standards as a reference. This study aims to report normative fasting C-peptide values and variations across demographics in healthy adolescents included in the NHANES dataset. Materials and Methods: In this analysis, we used fasting C-peptide data (n=2063) from the 1999-2004 NHANES dataset for participants ages 12 to &amp;lt; 18 yrs old. Results: The mean ± SE age of participants was 14.99 ± 0.06; 992 were females and 1071 were males. The majority (&amp;gt;80%) of females and males had a BMI percentile (%ile) &amp;lt;85%. Among males, geometric mean C-peptide levels increased from 0.52 nmol/L at age 12, to 0.66 nmol/L at age 15 yrs. Mean values decreased slightly at age 16 and increased back to 0.66 nmol/L at age 17 yrs. Among females, C-peptide levels fluctuated around a geometric mean of 0.67 nmol/L and age did not have a significant effect on C-peptide (p=0.15). Females had significantly higher mean log-transformed C-peptide concentrations than males (p&amp;lt;0.0001) after adjusting for age, race, and BMI %ile category. After adjusting for age and BMI %ile category, we found that in males, non-Hispanic blacks had significantly lower C-peptide levels than non-Hispanic whites (p=0.0026), Mexican Americans (p&amp;lt;0.0001) and other races including multiracial (p=0.0186). Similarly, in females, non-Hispanic blacks had significantly lower concentrations than non-Hispanic whites (p=0.0093), Mexican Americans (p&amp;lt;0.0001), and other Hispanics (p=0.0187). BMI %ile category was positively correlated with C-peptide levels in both males and females after adjusting for age and race. Conclusions: Here we describe normative fasting C-peptide in a healthy adolescent population. These data will provide novel information which can be used in assessing residual β-cell function and response to intervention therapy. Disclosure P. Y. Soni: None. Y. Wang: None. G. J. Eckert: None. H. M. Ismail: None.

206-LB: Indian Americans as Compared with Indians Exhibit Increased Beta-Cell Responsivity and Insulin Clearance in Absence of Changes in Insulin Sensitivity

Studies suggest that Indian Americans (IA) living in US have higher basal insulin resistance than other ethnic groups thereby increasing risk for T2DM. To characterize glucose metabolism between IA to Indians (I) living in India, we studied thirty-one Indians recruited at the Chellaram Hospital in Pune, India and twenty Indian Americans at Mayo Clinic, MN. All underwent a 3-hour 9-point OGTT with analyses of glucose, insulin and C-peptide. The oral minimal model was used to estimate β-cell function (φtotal) and insulin sensitivity (SI), with assessment of β-cell responsivity (Disposition Index: DI). Insulin clearance was calculated as AUC of insulin secretion rate over insulin concentrations. Both I and IA were similar with respect to age (33±7 vs. 39±13y), BMI (25.0±1.8 vs. 24.7± 3.2kg/m2) and sex (13F and 9F) respectively. Results are in fig 1. Fasting and iAUC glucose did not differ between groups (p=0.478), while integrated C-peptide and Insulin concentrations were higher in I than IA (p Disclosure V. Purandare: None. A. Galderisi: None. M. Maertino: None. A. Basu: None. C. Cobelli: None. A. Unnikrishnan: Advisory Panel; Self; Sanofi-Aventis, Other Relationship; Self; Novo Nordisk A/S, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes. R. Basu: None. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.)

1184-P: Return to Normal Glucose Control by Weight Loss in Nonobese People with Type 2 Diabetes: The ReTUNE Study

Type 2 diabetes (T2D) in the non-obese has been regarded as etiologically distinct from that in obese people. However, clinical observation suggests that loss of fat mass above a personal fat threshold brings about remission in the same way. ReTUNE aimed to determine what proportion of T2D people with BMI &amp;lt;27kg/m2 could achieve remission, and to assess the fat threshold for this. 25 participants have been studied to date (T2D: 4M/10F, 58.3±2.1years, BMI 24.5±0.6kg/m2; matched nondiabetic controls: n=11). Other types of diabetes were excluded by anti-islet cell antibodies and MODY gene tests (2/14). From baseline, weight loss of 5% was achieved in 2-4 weeks using low calorie diet (800 kcal/day), then 6 weeks of weight maintenance. The cycle of weight loss plus maintenance was repeated 2-3 times until the clinical end point of remission was reached (HbA1c &amp;lt; 6.5%). Only 2 cycles (~10% weight loss) were required in 8/12 participants. The planned decrease in weight (baseline to clinical endpoint: 69.0±3.5 to 60.8±2.9kg, p&amp;lt;0.001) decreased total body fat from 33.1±1.9 to 27.4±2.0% (p&amp;lt;0.001). Fasting plasma glucose decreased from 7.3±0.3 to 6.3±0.3 mmol/l, p&amp;lt;0.05). HbA1c decreased from 7.1±0.2 to 6.5±0.1%, p&amp;lt;0.05 with 8/12 in remission (&amp;lt;6.5%). Fasting plasma insulin decreased (52.2±9.5 to 23.7±3.6 pmol/L, p=0.007) as did plasma triglyceride (1.6±0.2 to 1.0±0.1mmol/L, p=0.002). Liver fat fell from 4.4±0.8 to 1.4±0.1% (p=0.004) becoming similar to 11 matched healthy controls (1.9%). Pancreas fat content in T2D fell (5.1± 0.6 to 4.5±0.6%, p=0.026) towards control levels (3.3±0.3%, p=0.029 vs. T2D at baseline). Post meal insulin sensitivity (Si) and insulin secretion (disposition index and β-cell responsivity Φtot) improved after weight loss. In conclusion, 2/14 people with BMI &amp;lt;27kg/m2 were found to have other diagnoses, and weight loss brought about remission in 8/12 people accompanied by pathophysiological changes similar to those seen during remission in obesity-associated T2D. Disclosure A. Al-mrabeh: None. A. C. Barnes: None. K. M. Irvine: None. T. L. Kelly: Employee; Self; Diabetes Digital Media. K. G. Hollingsworth: None. D. Romeres: None. C. Cobelli: None. R. Taylor: Speaker's Bureau; Self; Novartis AG. Funding Diabetes UK (17/0005645)

1258-P: Il-1ß-Induced Transcription of Nf-kB Target Genes Is Repressed by Bet Bromodomain Inhibitors in Pancreatic ß-Cells

Autoimmune diabetes is characterized by chronic inflammation of pancreatic islets which ultimately destroys insulin-producing β-cells. In the islet, elevated proinflammatory cytokines lead to increased transcription of inducible nitric oxide synthase (iNOS) and its downstream product, nitric oxide (NO). Elevated levels of NO for prolonged periods lead to β-cell apoptosis. The exact causes of autoimmune diabetes are not well defined and, although genetic predisposition is a factor, low concordance rates of autoimmune diabetes among monozygotic twins indicates a role for epigenetic factors. Recent studies suggest that the bromodomain and extraterminal domain (BET) family of epigenetic regulatory proteins contribute to the onset and progression of autoimmune diabetes. BET proteins are epigenetic readers of sites of lysine acetylation found commonly on histones and have emerged as promising drug targets for a wide variety of diseases. We hypothesize that BET proteins increase proinflammatory cytokine-induced transcription in β-cells leading to β-cell damage and that selective inhibition of BET bromodomains with small molecules will prevent or reverse the progression of autoimmune diabetes. Here, we show that BET bromodomain inhibitors decrease the β-cell response to proinflammatory cytokines in an insulinoma β-cell line (INS832/13) and primary rat islets. BET inhibitors attenuated cytokine-induced transcription of inflammatory mediators, including iNOS. This decreased transcription is mediated through inhibition of the NF-κB signaling pathway by BET inhibitors. Using knockdown of individual BET proteins in a β-cell line, we identified the importance of individual BET family members in the altered transcriptional profile characteristic of autoimmune diabetes. This work uncovers important mechanisms of disease onset and progression of autoimmune diabetes, laying the groundwork for more targeted treatments with drug-like small molecules. Disclosure J. Nord: None. S. Wynia-smith: None. B. C. Smith: None. R. Jones lipinski: None. Funding American Diabetes Association (1-18-IBS-068 to B.C.S.); National Institutes of Health (R01DK119359, T32HL134643)

Liver Fat Reduction After Gastric Banding and Associations with Changes in Insulin Sensitivity and β-Cell Function.

The aim of this study was to examine the relationship between changes in liver fat and changes in insulin sensitivity and β-cell function 2 years after gastric banding surgery. Data included 23 adults with the surgery who had prediabetes or type 2 diabetes for less than 1 year and BMI 30 to 40 kg/m2 at baseline. Body adiposity measures including liver fat content (LFC), insulin sensitivity (M/I), and β-cell responses (acute, steady-state, and arginine-stimulated maximum C-peptide) were assessed at baseline and 2 years after surgery. Regression models were used to assess associations adjusted for age and sex. Two years after surgery, all measures of body adiposity, LFC, fasting and 2-hour glucose, and hemoglobin A1c significantly decreased; M/I significantly increased; and β-cell responses adjusted for M/I did not change significantly. Among adiposity measures, reduction in LFC had the strongest association with M/I increase (r = -0.61, P = 0.003). Among β-cell measures, change in LFC was associated with change in acute C-peptide response to arginine at maximal glycemic potentiation adjusted for M/I (r = 0.66, P = 0.007). Significant reductions in glycemic measures and increase in M/I were observed in individuals with LFC loss >2.5%. Reduction in LFC after gastric banding surgery appears to be an important factor associated with long-term improvements in insulin sensitivity and glycemic profiles in adults with obesity and prediabetes or early type 2 diabetes.

Early Impairment of Insulin Sensitivity, β-Cell Responsiveness, and Insulin Clearance in Youth with Stage 1 Type 1 Diabetes.

Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a presymptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D). The aim was to explore the metabolic phenotypes of β-cell function and insulin sensitivity and clearance in normoglycemic youth with Stage 1 T1D and compare them with healthy nonrelated peers during a 3-hour oral glucose tolerance test (OGTT). Twenty-eight lean youth, 14 with ≥2 islet autoantibodies (cases) and 14 healthy controls underwent a 3-hour 9-point OGTT with measurement of glucose, C-peptide, and insulin. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI=φtotal×SI). Fasting insulin clearance (CL0) was calculated as the ratio between the fasting insulin secretion rate (ISR) and plasma insulin levels (ISR0/I0), while postload clearance (CL180) was estimated by the ratio of AUC of ISR over the plasma insulin AUC for the 3-hour OGTT (ISRAUC/IAUC). Participants with impaired fasting glucose, impaired glucose tolerance, or any OGTT glucose concentration ≥200 mg/dL were excluded. Cases (10.5 years [8, 15]) exhibited reduced DI (P < .001) due to a simultaneous reduction in both φtotal (P < 0.001) and SI (P = .008) compared with controls (11.5 years [10.4, 14.9]). CL0 and CL180 were lower in cases than in controls (P = .005 and P = .019). Presymptomatic Stage 1 T1D in youth is associated with reduced insulin sensitivity and lower β-cell responsiveness, and the presence of blunted insulin clearance.

Analysis of the formation of dysglycemia in the substantiation of early pathogenetic therapy of diabetes mellitus

Introduction. To control carbohydrate metabolism disorders (CMD), which are closely related to the effect on the prognosis of cardiovascular diseases (CVD), their early, pathogenetically substantiated and prognosis-oriented therapy is required with a view to positive metabolic memory. The choice of drugs is based on the analysis of the formation of pre-nosological CMD - variants of prediabetes. The indices of the homeostatic model HOMA and the TyG family are most often used to assess the main links in the pathogenesis of CMD, IR and the secretory capacity of β-cells.Objective: to assess the basic pathogenetic links in prenosological CMD in comparison with type 2 diabetes mellitus (DM2) using a cohort of postmenopausal women: parameters of IR and secretory capacity of β-cells according to the TyG and HOMA-2 indices. Materials and methods. The examined 94 postmenopausal women 58.0 (53.0; 63.0) years old were divided into groups by history and HbA1c levels (%). Group 1 consisted of patients with T2DM (7.20: 6.60; 7.98) with a duration of 4.0 (2.0; 7.0) years; women with two-fold fasting normoglycemia without a history of CMD were classified according to their HbA1c levels into group 2 (prediabetes) and 3 (without CMD) twice: according to WHO criteria - 6.15 (6.03; 6.30) and 5.45 (5.20; 5.80); and ADA - 6.00 (5.80; 6.23) and 5.35 (5.05; 5.40), respectively. The indices TyG, HOMA2-IR, HOMA2-%S, and HOMA2-%B were determined (based on C-peptide calculations).Results and discussion. The performed analysis confirms the contribution of IR/insulin sensitivity to the progression of CMD with the participation of the phenomenon of lipoglucotoxicity at the prenosological stage of their formation, starting with HbA1c ≥ 5.7% levels. The inadequate secretory response of β-cells reflects an early decline in their functional abilities even at the stage of prediabetes. This limits the effectiveness of the classical stepwise scheme for intensifying glucose-lowering therapy with a T2DM duration of less than 10 years.Conclusions. Along with the timely diagnosis of dysglycemia, to control the cardiometabolic risk, it is advisable to use drug combinations early in terms of their effect on the key links in the pathogenesis of CMD: insulin resistance and β-cell dysfunction. Pioglitazone has been substantiated as an insulin sensitizer, which has a proven effect on the regression of early CMD and a decrease in the risk of cardiovascular events. In order to eliminate incretin dysfunction, which is closely related to the adequacy of the secretory capabilities of β-cells to the needs of impaired glucose homeostasis, a rational combination with an inhibitor of dipeptidyl peptidase-4.

BET bromodomain inhibitors diminish IL‐1B‐induced transcription of NF‐κB target genes

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β-cells, thought to be a result of chronic inflammation of pancreatic islets. Elevated proinflammatory cytokine levels in the islet results in increased nitric oxide production through increased transcription of inducible nitric oxide synthase (iNOS), reduced glucose responsiveness, and ultimately selective destruction of insulin-producing β-cells. The exact causes of T1D are poorly understood and although genetic predisposition is a factor, low concordance rates of autoimmune diabetes among monozygotic twins suggests an, as yet undetermined role for epigenetic factors. Recent studies have shown that epigenetic regulatory proteins contribute to the onset and progression of autoimmune diabetes. The bromodomain and extraterminal domain (BET) family of proteins (Brd2, Brd3, Brd4 and BrdT) have emerged as promising drug targets for a wide variety of diseases. Bromodomain-containing proteins are epigenetic “readers” of histone acetylation and we hypothesize they regulate proinflammatory cytokine induced transcription in β-cells. Uniquely, the BET family proteins contain two bromodomains (BD1 and BD2), which affords BET proteins the capacity to simultaneously bind two acetylated histones and/or other nuclear proteins such as DNA-binding factors to modulate transcription in a cell-type specific manner. Here, we show that BET bromodomain inhibitors decrease the β-cell response to proinflammatory cytokines in insulinoma β-cell line (INS832/13) and primary rat islets. We found that BET inhibitors mitigated cytokine-induced transcription of inflammatory mediators, including iNOS, which is known to damage β-cells. This decrease is mediated through inhibition of the NF-κB pathway by BET inhibitors. Furthermore, using knockdown of BET proteins in insulinoma β-cell lines, we identified key mechanisms through which this altered transcriptional profile occurs. This work provides important mechanistic insights into the disease onset and progression of autoimmune diabetes for which current therapies are ineffective.

Adipose tissue lipolysis, plasma fatty acids, and glucose homeostasis in people with obesity: New pieces that help solve the puzzle

Insulin is the key regulator of plasma glucose concentration, because it potently suppresses hepatic glucose production and stimulates tissue glucose uptake. Obesity is often associated with both insulin resistance and hyperinsulinemia. The concurrence of the two is commonly thought to reflect a homeostatic feedback loop in which the insulin resistance-mediated increase in plasma glucose stimulates insulin secretion from β-cells to maintain euglycemia [1]. Continuous overstimulation of β-cells leads to β-cell dysfunction, i.e., an insufficient β-cell response to the rise in glucose, resulting in hyperglycemia despite hyperinsulinemia and ultimately type 2 diabetes (T2D) [1].

A parallax view of type 1 diabetes

The year 2021 marks the 100th anniversary of the discovery of insulin, a therapy that transformed type 1 diabetes (T1D) from a once fatal diagnosis into a chronic condition that can be successfully managed with exogenous insulin administration. In this article, we celebrate the remarkable journey that led to the discovery of insulin and our subsequent understanding of T1D as a disease of immune-mediated β-cell destruction. Further, we discuss an alternative and parallax view of disease development, highlighting maladaptive β-cell responses that act to amplify immune responses and have been implicated in diabetes development.