Targeting inhibition of CCR5 on improving obesity-associated insulin resistance and impairment of pancreatic insulin secretion in high fat-fed rodent models

AbstractCOP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1–CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2WT/K70E mice with partially disrupted binding of IP6, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4COP1 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4COP1 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2WT/K70E, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4COP1-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP6-assisted CSN-COP1 competition. Deregulation of the IP6-CSN-CRL4COP1-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.

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PPARα activation and increased dietary lipid oppose thyroid hormone signaling and rescue impaired glucose-stimulated insulin secretion in hyperthyroidism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90700.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. E1380-E1389 ◽

Cited By ~ 16

Author(s):

Mark J. Holness ◽

Gemma K. Greenwood ◽

Nicholas D. Smith ◽

Mary C. Sugden

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Thyroid Hormone ◽

Dietary Lipid ◽

High Fat ◽

Carbohydrate Diet ◽

Low Carbohydrate Diet ◽

Glucose Stimulated Insulin Secretion ◽

Glucose Responsiveness ◽

The Impact

The aim of the study was to investigate the impact of hyperthyroidism on the characteristics of the islet insulin secretory response to glucose, particularly the consequences of competition between thyroid hormone and peroxisome proliferator-activated receptor (PPAR)α in the regulation of islet adaptations to starvation and dietary lipid-induced insulin resistance. Rats maintained on standard (low-fat/high-carbohydrate) diet or high-fat/low-carbohydrate diet were rendered hyperthyroid (HT) by triiodothyronine (T3) administration (1 mg·kg body wt−1·day−1 sc, 3 days). The PPARα agonist WY14643 (50 mg/kg body wt ip) was administered 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed during hyperglycemic clamps or after acute glucose bolus injection in vivo and with step-up and step-down islet perifusions. Hyperthyroidism decreased the glucose responsiveness of GSIS, precluding sufficient enhancement of insulin secretion for the degree of insulin resistance, in rats fed either standard diet or high-fat diet. Hyperthyroidism partially opposed the starvation-induced increase in the glucose threshold for GSIS and decrease in glucose responsiveness. WY14643 administration restored glucose tolerance by enhancing GSIS in fed HT rats and relieved the impact of hyperthyroidism to partially oppose islet starvation adaptations. Competition between thyroid hormone receptor (TR) and PPARα influences the characteristics of GSIS, such that hyperthyroidism impairs GSIS while PPARα activation (and increased dietary lipid) opposes TR signaling and restores GSIS in the fed hyperthyroid state. Increased islet PPARα signaling and decreased TR signaling during starvation facilitates appropriate modification of islet function.

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Association between smoking, pancreatic insulin secretion and insulin resistance in Chinese subjects with or without glucose intolerance

Chinese Medical Journal ◽

10.1097/00029330-200712020-00015 ◽

2007 ◽

Vol 120 (24) ◽

pp. 2233-2237 ◽

Cited By ~ 5

Author(s):

Gary Tin-Choi KO ◽

Peter Chun-Yip TONG ◽

Wing-Yee SO ◽

Clive S. COCKRAM ◽

Juliana Chung-Ngor CHAN

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Glucose Intolerance ◽

Pancreatic Insulin ◽

Chinese Subjects

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Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00163.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. E347-E354 ◽

Cited By ~ 32

Author(s):

Maria Sörhede Winzell ◽

Giovanni Pacini ◽

Bo Ahrén

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Insulin Secretion ◽

High Fat Diet ◽

Glucose Oxidation ◽

Dietary Supplementation ◽

Normal Diet ◽

High Fat ◽

Conjugated Linoleic Acids ◽

Insulin Resistant

Conjugated linoleic acids (CLAs) and n-3 polyunsaturated fatty acids (PUFAs) improve insulin sensitivity in insulin-resistant rodents. However, the effects of these fatty acids on insulin secretion are not known but are of importance to completely understand their influence on glucose homeostasis. We therefore examined islet function after dietary supplementation consisting of 1% CLAs in combination with 1% n-3 enriched PUFAs for 12 wk to mice on a normal diet and to insulin-resistant mice fed a high-fat diet (58% fat). In the mice fed a normal diet, CLA/PUFA supplementation resulted in insulin resistance associated with low plasma adiponectin levels and low body fat content. Intravenous and oral glucose tolerance tests revealed a marked increase in insulin secretion, which nevertheless was insufficient to counteract the insulin resistance, resulting in glucose intolerance. In freshly isolated islets from mice fed the normal diet, both basal and glucose-stimulated insulin secretion were adaptively augmented by CLA/PUFA, and at a high glucose concentration this was accompanied by elevated glucose oxidation. In contrast, in high-fat-fed mice, CLA/PUFA did not significantly affect insulin secretion, insulin resistance, or glucose tolerance. It is concluded that dietary supplementation of CLA/PUFA in mice fed the normal diet augments insulin secretion, partly because of increased islet glucose oxidation, but that this augmentation is insufficient to counterbalance the induction of insulin resistance, resulting in glucose intolerance. Furthermore, the high-fat diet partly prevents the deleterious effects of CLA/PUFA, but this dietary supplementation was not able to counteract high-fat-diet-induced insulin resistance.

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Effects of high-fat overfeeding on mitochondrial function, glucose and fat metabolism, and adipokine levels in low-birth-weight subjects

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00095.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. E43-E51 ◽

Cited By ~ 39

Author(s):

Charlotte Brøns ◽

Stine Jacobsen ◽

Natalie Hiscock ◽

Andrew White ◽

Emma Nilsson ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Birth Weight ◽

Low Birth Weight ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Normal Birth Weight ◽

High Fat ◽

Normal Birth ◽

Plasma Leptin

Low birth weight (LBW) is associated with an increased risk of insulin resistance and downregulation of oxidative phosphorylation (OXPHOS) genes when exposed to a metabolic challenge of high-fat overfeeding (HFO). To elaborate further on the differential effects of HFO in LBW subjects, we measured in vivo mitochondrial function, insulin secretion, hepatic glucose production, and plasma levels of key regulatory hormones before and after 5 days of HFO in 20 young LBW and 26 normal-birth-weight (NBW) men. The LBW subjects developed peripheral insulin resistance after HFO due to impaired endogenous glucose storage (9.42 ± 4.19 vs. 5.91 ± 4.42 mg·kg FFM−1·min−1, P = 0.01). Resting muscle phosphorcreatine and total ATP in muscle increased significantly after HFO in LBW subjects only, whereas additional measurements of mitochondrial function remained unaffected. Despite similar plasma FFA levels, LBW subjects displayed increased fat oxidation during insulin infusion compared with normal-birth-weight (NBW) subjects after HFO (0.37 ± 0.35 vs. 0.17 ± 0.33 mg·kg FFM−1·min−1, P = 0.02). In contrast to NBW subjects, the plasma leptin levels of LBW subjects did not increase, and the plasma gastric inhibitory polypeptide (GIP) as well as pancreatic polypeptide (PP) levels increased less in LBW compared with NBW subjects during HFO. In conclusion, HFO unmasks dissociation between insulin resistance and mitochondrial dysfunction in LBW subjects, suggesting that insulin resistance may be a cause, rather than an effect, of impaired muscle OXPHOS gene expression and mitochondrial dysfunction. Reduced increments in response to HFO of fasting plasma leptin, PP, and GIP levels may contribute to insulin resistance, lower satiety, and impaired insulin secretion in LBW subjects.

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FoxO1 Plays an Important Role in Regulating β-Cell Compensation for Insulin Resistance in Male Mice

Endocrinology ◽

10.1210/en.2015-1852 ◽

2016 ◽

Vol 157 (3) ◽

pp. 1055-1070 ◽

Cited By ~ 29

Author(s):

Ting Zhang ◽

Dae Hyun Kim ◽

Xiangwei Xiao ◽

Sojin Lee ◽

Zhenwei Gong ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Transgenic Mice ◽

Cell Mass ◽

Glucose Sensing ◽

Physiological Adaptation ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

And Function

Abstract β-Cell compensation is an essential mechanism by which β-cells increase insulin secretion for overcoming insulin resistance to maintain euglycemia in obesity. Failure of β-cells to compensate for insulin resistance contributes to insulin insufficiency and overt diabetes. To understand the mechanism of β-cell compensation, we characterized the role of forkhead box O1 (FoxO1) in β-cell compensation in mice under physiological and pathological conditions. FoxO1 is a key transcription factor that serves as a nutrient sensor for integrating insulin signaling to cell metabolism, growth, and proliferation. We showed that FoxO1 improved β-cell compensation via 3 distinct mechanisms by increasing β-cell mass, enhancing β-cell glucose sensing, and augmenting β-cell antioxidative function. These effects accounted for increased glucose-stimulated insulin secretion and enhanced glucose tolerance in β-cell-specific FoxO1-transgenic mice. When fed a high-fat diet, β-cell-specific FoxO1-transgenic mice were protected from developing fat-induced glucose disorder. This effect was attributable to increased β-cell mass and function. Furthermore, we showed that FoxO1 activity was up-regulated in islets, correlating with the induction of physiological β-cell compensation in high-fat-induced obese C57BL/6J mice. These data characterize FoxO1 as a pivotal factor for orchestrating physiological adaptation of β-cell mass and function to overnutrition and obesity.

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Use of metformin in pediatric type 2 diabetes

Romanian Journal of Diabetes Nutrition and Metabolic Diseases ◽

10.2478/rjdnmd-2013-0044 ◽

2013 ◽

Vol 20 (4) ◽

pp. 435-439

Author(s):

Diana Paun ◽

Alexandra Bulgar

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Environmental Factors ◽

Children And Adolescents ◽

Clinical Use ◽

Pancreatic Insulin ◽

Prevalence Of Obesity ◽

Genetic And Environmental Factors

Abstract In the last 10 years the incidence of type 2 diabetes (T2DM) in children and adolescents has increased, due to increasing prevalence of obesity in youth. Therefore, the prevalence of diabetes-related complications such as hypertension, hyperlipidemia and microalbuminuria has also increased in pediatric T2DM. The pathogenesis of T2DM in children involves genetic and environmental factors that will determine the increase of insulin resistance and decrease of beta pancreatic insulin secretion. Only metformin and insulin are approved for clinical use in children in the majority of countries. The aim of this paper is to review the benefits of the treatment with metformin in children and adolescents with T2DM.

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Increased insulin secretion fails to compensate for insulin resistance in mice with impaired glucose disposal under high-fat diet

Diabetes Research and Clinical Practice ◽

10.1016/s0168-8227(00)81988-9 ◽

2000 ◽

Vol 50 ◽

pp. 156

Author(s):

Giovanni Pacini ◽

Bo Ahrén

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

High Fat Diet ◽

Glucose Disposal ◽

High Fat

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Single-Cell Transcriptional Profiling of Mouse Islets Following Short-Term Obesogenic Dietary Intervention

Metabolites ◽

10.3390/metabo10120513 ◽

2020 ◽

Vol 10 (12) ◽

pp. 513

Author(s):

Annie R. Piñeros ◽

Hongyu Gao ◽

Wenting Wu ◽

Yunlong Liu ◽

Sarah A. Tersey ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Single Cell ◽

Cell Types ◽

Endoplasmic Reticulum Stress Response ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Cell Clusters ◽

Ductal Cells

Obesity is closely associated with adipose tissue inflammation and insulin resistance. Dysglycemia and type 2 diabetes results when islet β cells fail to maintain appropriate insulin secretion in the face of insulin resistance. To clarify the early transcriptional events leading to β-cell failure in the setting of obesity, we fed male C57BL/6J mice an obesogenic, high-fat diet (60% kcal from fat) or a control diet (10% kcal from fat) for one week, and islets from these mice (from four high-fat- and three control-fed mice) were subjected to single-cell RNA sequencing (sc-RNAseq) analysis. Islet endocrine cell types (α cells, β cells, δ cells, PP cells) and other resident cell types (macrophages, T cells) were annotated by transcript profiles and visualized using Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP) plots. UMAP analysis revealed distinct cell clusters (11 for β cells, 5 for α cells, 3 for δ cells, PP cells, ductal cells, endothelial cells), emphasizing the heterogeneity of cell populations in the islet. Collectively, the clusters containing the majority of β cells showed the fewest gene expression changes, whereas clusters harboring the minority of β cells showed the most changes. We identified that distinct β-cell clusters downregulate genes associated with the endoplasmic reticulum stress response and upregulate genes associated with insulin secretion, whereas others upregulate genes that impair insulin secretion, cell proliferation, and cell survival. Moreover, all β-cell clusters negatively regulate genes associated with immune response activation. Glucagon-producing α cells exhibited patterns similar to β cells but, again, in clusters containing the minority of α cells. Our data indicate that an early transcriptional response in islets to an obesogenic diet reflects an attempt by distinct populations of β cells to augment or impair cellular function and/or reduce inflammatory responses as possible harbingers of ensuing insulin resistance.

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