A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus
Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic β-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer regi...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Roman, T. S.; Cannon, M. E.; Vadlamudi, S.; Buchkovich, M. L.; Wolford, B. N.; Welch, R. P.; Morken, M. A.; Kwon, G. J.; Varshney, A.; Kursawe, R.; Wu, Y.; Jackson, A. U.; National Institutes of Health Intramural Sequencing Center (NISC) Comparative Seque Tags: Genetics/Genomes/Proteomics/Metabolomics Source Type: research
Recovery of Corneal Sensitivity and Increase in Nerve Density and Wound Healing in Diabetic Mice After PEDF Plus DHA Treatment
Diabetic keratopathy decreases corneal sensation and tear secretion and delays wound healing after injury. In the current study, we tested the effect of treatment with pigment epithelium-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) on corneal nerve regeneration in a mouse model of diabetes with or without corneal injury. The study was performed in streptozotocin-induced diabetic mice (C57BL/6). Ten weeks after streptozotocin injection, diabetic mice showed significant decreases of corneal sensitivity, tear production, and epithelial subbasal nerve density when compared with age-matched normal mice. ...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: He, J.; Pham, T. L.; Kakazu, A.; Bazan, H. E. P. Tags: Integrated Physiology-Central Nervous System Regulation of Metabolism Pharmacology and Therapeutics Source Type: research
Functional and Structural Findings of Neurodegeneration in Early Stages of Diabetic Retinopathy: Cross-sectional Analyses of Baseline Data of the EUROCONDOR Project
This cross-sectional study evaluated the relationship between 1) functional and structural measurements of neurodegeneration in the initial stages of diabetic retinopathy (DR) and 2) the presence of neurodegeneration and early microvascular impairment. We analyzed baseline data of 449 patients with type 2 diabetes enrolled in the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) study (NCT01726075). Functional studies by multifocal electroretinography (mfERG) evaluated neurodysfunction, and structural measurements using spectral domain optical coherence tomography (SD-OCT) evaluated neurodege...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Santos, A. R.; Ribeiro, L.; Bandello, F.; Lattanzio, R.; Egan, C.; Frydkjaer-Olsen, U.; Garcia-Arumi, J.; Gibson, J.; Grauslund, J.; Harding, S. P.; Lang, G. E.; Massin, P.; Midena, E.; Scanlon, P.; Aldington, S. J.; Simao, S.; Schwartz, C.; Ponsati, B.; Tags: Complications-Retinopathy Source Type: research
Inhibition of Renal Sodium-Glucose Cotransport With Empagliflozin Lowers Fasting Plasma Glucose and Improves {beta}-Cell Function in Subjects With Impaired Fasting Glucose
The objective of this study was to examine the effect of renal sodium–glucose cotransporter inhibition with empagliflozin on the fasting plasma glucose (FPG) concentration and β-cell function in subjects with impaired fasting glucose (IFG). Eight subjects with normal fasting glucose (NFG) and eight subjects with IFG received empagliflozin (25 mg/day) for 2 weeks. FPG concentration and β-cell function was measured with a nine-step hyperglycemic clamp before and 48 h and 14 days after the start of empagliflozin. Empagliflozin caused 50 ± 4 and 45 ± 4 g glucosuria on day 2 in subjects with IFG an...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Abdul-Ghani, M.; Al Jobori, H.; Daniele, G.; Adams, J.; Cersosimo, E.; Triplitt, C.; DeFronzo, R. A. Tags: Epidemiology-Diabetes Complications Source Type: research
Acute Hypoglycemia in Healthy Humans Impairs Insulin-Stimulated Glucose Uptake and Glycogen Synthase in Skeletal Muscle: A Randomized Clinical Study
Hypoglycemia is the leading limiting factor in glycemic management of insulin-treated diabetes. Skeletal muscle is the predominant site of insulin-mediated glucose disposal. Our study used a crossover design to test to what extent insulin-induced hypoglycemia affects glucose uptake in skeletal muscle and whether hypoglycemia counterregulation modulates insulin and catecholamine signaling and glycogen synthase activity in skeletal muscle. Nine healthy volunteers were examined on three randomized study days: 1) hyperinsulinemic hypoglycemia (bolus insulin), 2) hyperinsulinemic euglycemia (bolus insulin and glucose infusion),...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Voss, T. S.; Vendelbo, M. H.; Kampmann, U.; Hingst, J. R.; Wojtaszewski, J. F. P.; Svart, M. V.; Moller, N.; Jessen, N. Tags: Complications-Hypoglycemia Source Type: research
Impact of Glycemic Variability on Chromatin Remodeling, Oxidative Stress, and Endothelial Dysfunction in Patients With Type 2 Diabetes and With Target HbA1c Levels
This study investigated whether epigenetic regulation of the adaptor protein p66Shc, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA1c >7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbA1c of ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F2α (8-isoPGF2α), and epigenetic regulation of p66Shc were assessed at baseline and follow-up. C...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Costantino, S.; Paneni, F.; Battista, R.; Castello, L.; Capretti, G.; Chiandotto, S.; Tanese, L.; Russo, G.; Pitocco, D.; Lanza, G. A.; Volpe, M.; Lüscher, T. F.; Cosentino, F. Tags: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes Pathophysiology Source Type: research
The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes
Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-B (NF-B)–mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine the function of MLL1 in wound healing. Mll1f/fLyz2Cre+ mice display delayed wound healing and decreased wound mac...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Kimball, A. S.; Joshi, A.; Carson, W. F.; Boniakowski, A. E.; Schaller, M.; Allen, R.; Bermick, J.; Davis, F. M.; Henke, P. K.; Burant, C. F.; Kunkel, S. L.; Gallagher, K. A. Tags: Immunology Immunology and Transplantation Source Type: research
MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic {beta}-Cells
We report here that MCL-1 downregulation is associated with cytokine-mediated killing of human β-cells, a process partially prevented by MCL-1 overexpression. By generating a β-cell–specific Mcl-1 knockout mouse strain (βMcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. β-Cells from βMcl-1KO mice were, however, more susceptible to cytokine-induced apoptosis. Moreover, βMcl-1KO mice displayed higher hyperglycemia and lower pancreatic insulin content after multiple low-dose streptozotocin treatment. We found that the kinase GSK3β,...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Meyerovich, K.; Violato, N. M.; Fukaya, M.; Dirix, V.; Pachera, N.; Marselli, L.; Marchetti, P.; Strasser, A.; Eizirik, D. L.; Cardozo, A. K. Tags: Islet Biology-Apoptosis Islet Studies Source Type: research
Age-Dependent Decline in the Coordinated [Ca2+] and Insulin Secretory Dynamics in Human Pancreatic Islets
Aging is associated with increased risk for type 2 diabetes, resulting from reduced insulin sensitivity and secretion. Reduced insulin secretion can result from reduced proliferative capacity and reduced islet function. Mechanisms underlying altered β-cell function in aging are poorly understood in mouse and human islets, and the impact of aging on intraislet communication has not been characterized. Here, we examine how β-cell [Ca2+] and electrical communication are impacted during aging in mouse and human islets. Islets from human donors and from mice were studied using [Ca2+] imaging, static and perifusion ins...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Westacott, M. J.; Farnsworth, N. L.; St. Clair, J. R.; Poffenberger, G.; Heintz, A.; Ludin, N. W.; Hart, N. J.; Powers, A. C.; Benninger, R. K. P. Tags: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism Islet Studies Source Type: research
Ablation of Neuropilin 1 in Myeloid Cells Exacerbates High-Fat Diet-Induced Insulin Resistance Through Nlrp3 Inflammasome In Vivo
Neuropilin 1 (Nrp1), a coreceptor for class 3 semaphorins and growth factors, is highly expressed in vascular cells and myeloid cells, including macrophages. Unlike well-characterized proangiogenic functions of endothelial cell Nrp1, the contributions of macrophage Nrp1 within the context of metabolic dysfunction remain to be established. The aim of this study was to determine the contributions of macrophage Nrp1 in high-fat diet (HFD)-instigated insulin resistance in vivo. Insulin sensitivity and Nlrp3 inflammasome activation were monitored in wild-type (WT) and myeloid cell-specific Nrp1 knockout (Nrp1myel-KO) mice fed a...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Dai, X.; Okon, I.; Liu, Z.; Bedarida, T.; Wang, Q.; Ramprasath, T.; Zhang, M.; Song, P.; Zou, M.-H. Tags: Obesity-Animal Obesity Studies Source Type: research
Starch Digestion-Related Amylase Genetic Variant Affects 2-Year Changes in Adiposity in Response to Weight-Loss Diets: The POUNDS Lost Trial
In conclusion, the genetic variant determining starch metabolism influences the response to weight-loss dietary intervention. Overweight and obese individuals carrying the AMY1-AMY2 rs11185098 genotype associated with higher amylase activity may have greater loss of adiposity during low-calorie diet interventions. (Source: Diabetes)
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Heianza, Y.; Sun, D.; Wang, T.; Huang, T.; Bray, G. A.; Sacks, F. M.; Qi, L. Tags: Nutrition-Clinical Obesity Studies Source Type: research
Hypothalamic Inflammation in Human Obesity Is Mediated by Environmental and Genetic Factors
In conclusion, obesity in humans is associated with HI and disturbances in the gut-brain axis, which are influenced by both environmental and genetic factors. (Source: Diabetes)
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Kreutzer, C.; Peters, S.; Schulte, D. M.; Fangmann, D.; Türk, K.; Wolff, S.; van Eimeren, T.; Ahrens, M.; Beckmann, J.; Schafmayer, C.; Becker, T.; Kerby, T.; Rohr, A.; Riedel, C.; Heinsen, F.-A.; Degenhardt, F.; Franke, A.; Rosenstiel, P.; Zubek, Tags: Obesity-Human Obesity Studies Source Type: research
The Effect of Ingested Glucose Dose on the Suppression of Endogenous Glucose Production in Humans
Insulin clamp studies have shown that the suppressive actions of insulin on endogenous glucose production (EGP) are markedly more sensitive than for stimulating glucose disposal (Rd). However, clamp conditions do not adequately mimic postprandial physiological responses. Here, using the variable infusion dual-tracer approach, we used a threefold range of ingested glucose doses (25, 50, and 75 g) to investigate how physiological changes in plasma insulin influence EGP in healthy subjects. Remarkably, the glucose responses were similar for all doses tested, yet there was a dose-dependent increase in insulin secretion and pla...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Kowalski, G. M.; Moore, S. M.; Hamley, S.; Selathurai, A.; Bruce, C. R. Tags: Integrated Physiology-Liver Metabolism Source Type: research
Rab8a Deficiency in Skeletal Muscle Causes Hyperlipidemia and Hepatosteatosis by Impairing Muscle Lipid Uptake and Storage
Skeletal muscle absorbs long-chain fatty acids (LCFAs) that are either oxidized in mitochondria or temporarily stored as triglycerides in lipid droplets (LDs). So far, it is still not fully understood how lipid uptake and storage are regulated in muscle and whether these are important for whole-body lipid homeostasis. Here we show that the small GTPase Rab8a regulates lipid uptake and storage in skeletal muscle. Muscle-specific Rab8a deletion caused hyperlipidemia and exacerbated hepatosteatosis induced by a high-fat diet. Mechanistically, Rab8a deficiency decreased LCFA entry into skeletal muscle and inhibited LD fusion i...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Chen, Q.; Rong, P.; Xu, D.; Zhu, S.; Chen, L.; Xie, B.; Du, Q.; Quan, C.; Sheng, Y.; Zhao, T.-J.; Li, P.; Wang, H. Y.; Chen, S. Tags: Integrated Physiology-Muscle Metabolism Source Type: research
Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues
We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine-N-oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulin...
Source: Diabetes - August 22, 2017 Category: Endocrinology Authors: Coutinho, E. A.; Okamoto, S.; Ishikawa, A. W.; Yokota, S.; Wada, N.; Hirabayashi, T.; Saito, K.; Sato, T.; Takagi, K.; Wang, C.-C.; Kobayashi, K.; Ogawa, Y.; Shioda, S.; Yoshimura, Y.; Minokoshi, Y. Tags: Integrated Physiology-Central Nervous System Regulation of Metabolism Source Type: research
