Nonalcoholic Steatohepatitis (NASH) Is Associated with a Decline in Pancreatic Beta Cell (β-Cell) Function

Type 1 diabetes (T1D) is a chronic autoimmune disease accompanied by the immune-mediated destruction of pancreatic β-cells. In this study, we aimed to explore the regulatory effects of Vitamin D (VD) supplementation on pancreatic β-cell function by altering the expression of bioinformatically identified cathepsin G (CatG) in T1D model mice. A T1D mouse model was established in non-obese diabetic (NOD) mice, and their islets were isolated and purified. Pancreatic mononuclear cells (MNCs) were collected, from which CD4+ T cells were isolated. The levels of interleukin (IL)-2, IL-10, tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ) in the supernatant of mouse pancreatic tissue homogenate were assessed using ELISA. Immunohistochemistry and TUNEL staining were conducted to evaluate the effects of VD supplementation on pancreatic tissues of T1D mice. The pancreatic beta-cell line MIN6 was used for in vitro substantiation of findings in vivo. VD supplementation reduced glucose levels and improved glucose tolerance in T1D mice. Further, VD supplementation improved pancreatic β-cell function and suppressed immunological and inflammatory reactions in the T1D mice. We documented overexpression of CatG in diabetes tissue samples, and then showed that VD supplementation normalized the islet immune microenvironment through down-regulating CatG expression in T1D mice. Experiments in vitro subsequently demonstrated that VD supplementation impeded CD4+ T activation by down-regulating CatG expression, and thereby enhanced pancreatic β-cell function. Results of the present study elucidated that VD supplementation can down-regulate the expression of CatG and inhibit CD4+ T cell activation, thereby improving β-cell function in T1D.

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Correction to: Mixed Meal and Intravenous L-Arginine Tests Both Stimulate Incretin Release Across Glucose Tolerance in Man: Lack of Correlation with β Cell Function by Ruetten H, MD, PhD, Gebauer M, PhD, Raymond RH, MS, Calle RA, MD, Cobelli C, PhD, Ghosh A, PhD, Robertson RP, MD, Shankar SS, MD, Staten MA, MD, Stefanovski D, PhD, Vella A, MD, Wright K, MS, and Fryburg DA, MD; on behalf of the Foundation for the NIH Biomarkers Consortium Beta Cell Project Team Metab Syndr Relat Disord 2018;16:406–415 DOI 10.1089/met.2018.0022

Metabolic Syndrome and Related Disorders ◽

10.1089/met.2018.0022.correx ◽

2019 ◽

Vol 17 (2) ◽

pp. 128-128

Keyword(s):

Glucose Tolerance ◽

Beta Cell ◽

Cell Function ◽

Project Team ◽

Β Cell ◽

Mixed Meal ◽

Β Cell Function

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The role of long non-coding RNAs in the regulation of pancreatic beta cell identity

Biochemical Society Transactions ◽

10.1042/bst20210207 ◽

2021 ◽

Author(s):

Maya E. Wilson ◽

Timothy J. Pullen

Keyword(s):

Cell Function ◽

Pancreatic Beta Cell ◽

Nucleotide Polymorphisms ◽

Β Cell ◽

Developmentally Regulated ◽

Specific Expression ◽

Cell Identity ◽

Continental Population ◽

Β Cell Function ◽

Non Coding Rnas

Type 2 diabetes (T2D) is a widespread disease affecting millions in every continental population. Pancreatic β-cells are central to the regulation of circulating glucose, but failure in the maintenance of their mass and/or functional identity leads to T2D. Long non-coding RNAs (lncRNAs) represent a relatively understudied class of transcripts which growing evidence implicates in diabetes pathogenesis. T2D-associated single nucleotide polymorphisms (SNPs) have been identified in lncRNA loci, although these appear to function primarily through regulating β-cell proliferation. In the last decade, over 1100 lncRNAs have been catalogued in islets and the roles of a few have been further investigated, definitively linking them to β-cell function. These studies show that lncRNAs can be developmentally regulated and show highly tissue-specific expression. lncRNAs regulate neighbouring β-cell-specific transcription factor expression, with knockdown or overexpression of lncRNAs impacting a network of other key genes and pathways. Finally, gene expression analysis in studies of diabetic models have uncovered a number of lncRNAs with roles in β-cell function. A deeper understanding of these lncRNA roles in maintaining β-cell identity, and its deterioration, is required to fully appreciate the β-cell molecular network and to advance novel diabetes treatments.

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Large birth size, infancy growth pattern, insulin resistance and β-cell function

Acta Endocrinologica ◽

10.1530/eje-20-1332 ◽

2021 ◽

Author(s):

Rong Huang ◽

Yu Dong ◽

Anne Monique Nuyt ◽

Emile Levy ◽

Shu-Qin Wei ◽

...

Keyword(s):

Insulin Resistance ◽

Beta Cell ◽

Gestational Age ◽

Growth Pattern ◽

Beta Cell Function ◽

Cell Function ◽

Birth Size ◽

Model Assessment ◽

Β Cell ◽

Β Cell Function

Objective: Large birth size programs an elevated risk of type 2 diabetes in adulthood, but data are absent concerning glucose metabolic health impact in infancy. We sought to determine whether large birth size is associated with insulin resistance and β-cell function in infancy, and evaluate the determinants. Design and Participants: In the Canadian 3D birth cohort, we conducted a nested matched (1:2) study of 70 large-for-gestational-age (LGA, birth weight >90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) control infants. The primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) at age 2-years. Results: HOMA-IR and HOMA-β were similar in LGA and OGA infants. Adjusting for maternal and infant characteristics, decelerated growth in length during early infancy (0-3 months) was associated a 25.8% decrease (95% confidence intervals 6.7-41.0%) in HOMA-β. During mid-infancy (3-12 months), accelerated growth in weight was associated with a 25.5% (0.35-56.9%) increase in HOMA-IR, in length with a 69.3% increase (31.4-118.0%) in HOMA-IR and a 24.5% (0.52-54.3%) increase in HOMA-β. Decelerated growth in length during late infancy (1-2 years) was associated with a 28.4% (9.5-43.4%) decrease in HOMA-IR and a 21.2% (3.9-35.4%) decrease in HOMA-β. Female sex was associated with higher HOMA-β, Caucasian ethnicity with lower HOMA-IR, and maternal smoking with lower HOMA-β. Conclusions: The study is the first to demonstrate that large birth size is not associated with insulin resistance and β-cell function in infancy, but infancy growth pattern matters. Decelerated infancy growth may be detrimental to beta-cell function.

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Effect of linagliptin on glucose metabolism and pancreatic beta cell function in patients with persistent prediabetes after metformin and lifestyle

Scientific Reports ◽

10.1038/s41598-021-88108-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mildred Fátima de la Luz Alvarez-Canales ◽

Sara Stephania Salazar-López ◽

Diana Farfán-Vázquez ◽

Yosceline Estrella Martínez-López ◽

Jessica Noemí González-Mena ◽

...

Keyword(s):

Glucose Tolerance ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Disposition Index ◽

Oral Glucose ◽

Pancreatic Β Cell ◽

Β Cell ◽

Double Blind ◽

Glucose Levels ◽

Β Cell Function

AbstractThe goal of the study was to evaluate the effect of adding linagliptin to metformin and lifestyle on glucose levels and pancreatic β-cell function in patients with persistent impaired glucose tolerance (IGT) after 12 months of metformin and lifestyle. A single center parallel double-blind randomized clinical trial with 6 months of follow-up was performed in patients with persistent IGT after 12 months of treatment with metformin and lifestyle; patients were randomized to continue with metformin 850 mg twice daily (M group, n = 12) or linagliptin/metformin 2.5/850 mg twice daily (LM group, n = 19). Anthropometric measurements were obtained by standard methods and by bioelectrical impedance; glucose was measured by dry chemistry, insulin by chemiluminescence, and pancreatic β-cell function was calculated with the disposition index using glucose and insulin values during oral glucose tolerance test (OGTT) and adjusting by insulin sensitivity. The main outcomes were glucose levels during OGTT and pancreatic β-cell function. Patients in the LM group had a reduction in weight (−1.7 ± 0.6, p < 0.05) and body mass index (BMI, −0.67 ± 0.2, p < 0.05). Glucose levels significantly improved in LM group with a greater reduction in the area under the glucose curve during OGTT (AUCGluc0_120min) as compared to the M group (−4425 ± 871 vs −1116 ± 1104 mg/dl/120 min, p < 0.001). Pancreatic β-cell function measured with the disposition index, improved only in LM group (2.3 ± 0.23 vs 1.7 ± 0.27, p 0.001); these improvements persisted after controlling for OGTT glucose levels. The differences in pancreatic β-cell function persisted also after pairing groups for basal AUCGluc0_120min. The addition of linagliptin to patients with persistent IGT after 12 months of treatment with metformin and lifestyle, improved glucose levels during OGTT and pancreatic β-cell function after 6 months of treatment.Trial registration: Clinicaltrials.gov with the ID number NCT04088461

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The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome

Endocrine Connections ◽

10.1530/ec-17-0217 ◽

2017 ◽

Vol 6 (8) ◽

pp. 811-816 ◽

Cited By ~ 2

Author(s):

Thozhukat Sathyapalan ◽

Anne-Marie Coady ◽

Eric S Kilpatrick ◽

Stephen L Atkin

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Cell Function ◽

Polycystic Ovary ◽

Pancreatic Beta Cell ◽

Controlled Study ◽

Β Cell ◽

Ovary Syndrome ◽

Increased Risk ◽

Β Cell Function

Background There is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS), and there is evidence that statins improve metabolic parameters in these patients. However, there are some data to show that statins increase the risk of incipient diabetes. Materials and methods We have previously shown that 12 weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double-blind placebo controlled study, 40 medication-naïve patients with PCOS were randomised to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. Results There was a significant reduction in HOMA-β (240 ± 3.2 vs 177 ± 2.3; P value <0.01) after 12 weeks of atorvastatin treatment, which was maintained by metformin in the subsequent 12 weeks. There were no changes in HOMA-β after the placebo or after subsequent metformin treatment. There was no linear correlation between reduction in HOMA-β with improvement of free androgen index (FAI) (r2 = 0.02; P = 0.72), testosterone (r2 = 0.13; P = 0.49), SHBG (r2 = 0.22; P = 0.48), hsCRP (r2 = 0.19; P = 0.64), triglycerides (r2 = 0.09; P = 0.12), total cholesterol (r2 = 0.11; P = 0.32) or LDL-C (r2 = 0.19; P = 0.38). Conclusion Treatment with atorvastatin for 12 weeks in women with PCOS significantly reduced HOMA-β. This could be potentially due to fall in β-cell requirement with improvement of insulin resistance rather than a reduction of β-cell function.

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Adipokines as key players in β cell function and failure

Clinical Science ◽

10.1042/cs20190523 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2317-2327 ◽

Cited By ~ 3

Author(s):

Nicolás Gómez-Banoy ◽

James C. Lo

Keyword(s):

Metabolic Diseases ◽

Cell Function ◽

Whole Body ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Axis ◽

Β Cell Function ◽

Prevalence Of Obesity ◽

Specific Factors ◽

Whole Body Metabolism

Abstract The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the “classic” adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose–pancreatic β cell axis.

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