An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant of GCKR That Regulates FGF21 Levels
Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, GCKR, significantly associated with circulating FGF21 levels at genome-wide significance. In the combined analysis, the common missens...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Cheung, C. Y. Y.; Tang, C. S.; Xu, A.; Lee, C.-H.; Au, K.-W.; Xu, L.; Fong, C. H. Y.; Kwok, K. H. M.; Chow, W.-S.; Woo, Y.-C.; Yuen, M. M. A.; Cherny, S. S.; Hai, J.; Cheung, B. M. Y.; Tan, K. C. B.; Lam, T.-H.; Tse, H.-F.; Sham, P.-C.; Lam, K. S. L. Tags: Genetics/Genomes/Proteomics/Metabolomics Source Type: research
Role of DNA Methylation in Type 2 Diabetes Etiology: Using Genotype as a Causal Anchor
This study uses genotypic information as a causal anchor to help decipher the likely role of DNA methylation measured in peripheral blood in the etiology of type 2 diabetes. Illumina HumanMethylation450 BeadChip data were generated on 1,018 young individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. In stage 1, 118 unique associations between published type 2 diabetes single nucleotide polymorphisms (SNPs) and genome-wide methylation (methylation quantitative trait loci [mQTLs]) were identified. In stage 2, a further 226 mQTLs were identified between 202 additional independent non–type...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Elliott, H. R.; Shihab, H. A.; Lockett, G. A.; Holloway, J. W.; McRae, A. F.; Smith, G. D.; Ring, S. M.; Gaunt, T. R.; Relton, C. L. Tags: Genetics/Genomes/Proteomics/Metabolomics Source Type: research
A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response
Insulin production by the pancreatic β-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR). We focused on Spry2—a gene implicated in human type 2 diabetes by genome-wide association studies but without a clear connection to glucose ...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Pappalardo, Z.; Gambhir Chopra, D.; Hennings, T. G.; Richards, H.; Choe, J.; Yang, K.; Baeyens, L.; Ang, K.; Chen, S.; Arkin, M.; German, M. S.; McManus, M. T.; Ku, G. M. Tags: Genetics/Genomes/Proteomics/Metabolomics Source Type: research
High-Intensity Exercise as a Dishabituating Stimulus Restores Counterregulatory Responses in Recurrently Hypoglycemic Rodents
Hypoglycemia is a major adverse effect of insulin therapy for people with type 1 diabetes (T1D). Profound defects in the normal counterregulatory response to hypoglycemia explain the frequency of hypoglycemia occurrence in T1D. Defective counterregulation results to a large extent from prior exposure to hypoglycemia per se, leading to a condition called impaired awareness of hypoglycemia (IAH), the cause of which is unknown. In the current study, we investigate the hypothesis that IAH develops through a special type of adaptive memory referred to as habituation. To test this hypothesis, we used a novel intense stimulus (hi...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: McNeilly, A. D.; Gallagher, J. R.; Huang, J. T.- J.; Ashford, M. L. J.; McCrimmon, R. J. Tags: Complications Source Type: research
RAGE-Aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy
The interaction of advanced glycation end products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy. We screened DNA aptamers directed against RAGE (RAGE-aptamers) in vitro and examined the effects on the development and progression of diabetic nephropathy in streptozotocin-induced diabetic rats. RAGE-aptamer bound to RAGE with a Kd of 5.68 nmol/L and resultantly blocked the binding of AGEs to RAGE. When diabetic rats received continuous intraperitoneal injection of RAGE-aptamer from week 7 to 11 of diabetes, the increases in renal NADPH oxidase activity, oxidative stress generation, AGE, RAGE,...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Matsui, T.; Higashimoto, Y.; Nishino, Y.; Nakamura, N.; Fukami, K.; Yamagishi, S.-i. Tags: Complications-Nephropathy-Basic and Experimental Science Source Type: research
Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPAR{alpha}
In conclusion, diabetes-induced overexpression of miR-21 in the retina is at least partly responsible for PPARα downregulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR. (Source: Diabetes)
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Chen, Q.; Qiu, F.; Zhou, K.; Matlock, H. G.; Takahashi, Y.; Rajala, R. V. S.; Yang, Y.; Moran, E.; Ma, J.-x. Tags: Complications Source Type: research
The Effect of Diabetes on Cortical Function in Stroke: Implications for Poststroke Plasticity
Diabetes may impair the capacity for neuroplasticity such that patients experience a slower and poorer recovery after stroke. The current study investigated changes in cortical function in stroke patients with diabetes to determine how this comorbidity may affect poststroke cortical plasticity and thereby functional recovery. From a cohort of 57 participants, threshold-tracking transcranial magnetic stimulation was used to assess cortical function over the ipsilateral and contralesional hemispheres in 7 patients with diabetes after an acute stroke compared with 12 stroke patients without diabetes. Cortical function was als...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Huynh, W.; Kwai, N.; Arnold, R.; Krishnan, A. V.; Lin, C. S.- Y.; Vucic, S.; Kiernan, M. C. Tags: Pathophysiology Source Type: research
Repurposed JAK1/JAK2 Inhibitor Reverses Established Autoimmune Insulitis in NOD Mice
Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and signal transducer and activator of transcription (STAT) 1 pathway in human type 1 diabetes and in mouse models, especially in β-cells. We tested the hypothesis that u...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Trivedi, P. M.; Graham, K. L.; Scott, N. A.; Jenkins, M. R.; Majaw, S.; Sutherland, R. M.; Fynch, S.; Lew, A. M.; Burns, C. J.; Krishnamurthy, B.; Brodnicki, T. C.; Mannering, S. I.; Kay, T. W.; Thomas, H. E. Tags: Immunology Immunology and Transplantation Source Type: research
Arginase-II Promotes Tumor Necrosis Factor-{alpha} Release From Pancreatic Acinar Cells Causing {beta}-Cell Apoptosis in Aging
Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L-arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II–/–) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulat...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Xiong, Y.; Yepuri, G.; Necetin, S.; Montani, J.-P.; Ming, X.-F.; Yang, Z. Tags: Islet Studies Source Type: research
{beta}-Cell Inactivation of Gpr119 Unmasks Incretin Dependence of GPR119-Mediated Glucoregulation
GPR119 was originally identified as an orphan β-cell receptor; however, subsequent studies demonstrated that GPR119 also regulates β-cell function indirectly through incretin hormone secretion. We assessed the importance of GPR119 for β-cell function in Gpr119–/– mice and in newly generated Gpr119βcell–/– mice. Gpr119–/– mice displayed normal body weight and glucose tolerance on a regular chow (RC) diet. After high-fat feeding, Gpr119–/– mice exhibited reduced fat mass, decreased levels of circulating adipokines, improved insulin sensitivity, and better gl...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Panaro, B. L.; Flock, G. B.; Campbell, J. E.; Beaudry, J. L.; Cao, X.; Drucker, D. J. Tags: Islet Studies Source Type: research
Id1 Promotes Obesity by Suppressing Brown Adipose Thermogenesis and White Adipose Browning
Obesity results from increased energy intake or defects in energy expenditure. Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. Peroxisome proliferator–activated receptor coactivator 1α (PGC1α) controls BAT-mediated thermogenesis by regulating the expression of Ucp1. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays an important role in cell proliferation and differentiation. We demonstrate a novel function of Id1 in BAT thermogenesis and programming of beige adipocytes in white adipose tissue (WAT). We foun...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Patil, M.; Sharma, B. K.; Elattar, S.; Chang, J.; Kapil, S.; Yuan, J.; Satyanarayana, A. Tags: Obesity Studies Source Type: research
Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis
Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, whereas superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone-sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (also called p85α) as a glucocorticoid receptor target gene. Here, we found that glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) m...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Kuo, T.; Chen, T.-C.; Lee, R. A.; Nguyen, N. H. T.; Broughton, A. E.; Zhang, D.; Wang, J.-C. Tags: Signal Transduction Source Type: research
MICU1 Alleviates Diabetic Cardiomyopathy Through Mitochondrial Ca2+-Dependent Antioxidant Response
Diabetic cardiomyopathy is a major cause of mortality in patients with diabetes, but specific strategies for preventing or treating diabetic cardiomyopathy have not been clarified yet. MICU1 is a key regulator of mitochondrial Ca2+ uptake, which plays important roles in regulating mitochondrial oxidative phosphorylation and redox balance. To date, however, the significance of MICU1 in diabetic hearts has not been investigated. Here, we demonstrate that MICU1 was downregulated in db/db mouse hearts, which contributes to myocardial apoptosis in diabetes. Importantly, the reconstitution of MICU1 in diabetic hearts significant...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Ji, L.; Liu, F.; Jing, Z.; Huang, Q.; Zhao, Y.; Cao, H.; Li, J.; Yin, C.; Xing, J.; Li, F. Tags: Signal Transduction Source Type: research
Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E2 Signaling and Enhances Diabetic {beta}-Cell Function
Prostaglandin E2 (PGE2) is derived from arachidonic acid, whereas PGE3 is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE3 on β-cell function, particularly in the diabetic state. In this work, we determined that PGE3 elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared with PGE2. We tested the hypothesis that enriching pancreatic islet cell membranes with EPA, thereby reducing arachidonic acid abundance, would positively impact β-cell function in the diabetic state. EPA-...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Neuman, J. C.; Schaid, M. D.; Brill, A. L.; Fenske, R. J.; Kibbe, C. R.; Fontaine, D. A.; Sdao, S. M.; Brar, H. K.; Connors, K. M.; Wienkes, H. N.; Eliceiri, K. W.; Merrins, M. J.; Davis, D. B.; Kimple, M. E. Tags: Signal Transduction Source Type: research
Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action
Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (Ag...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Shin, A. C.; Filatova, N.; Lindtner, C.; Chi, T.; Degann, S.; Oberlin, D.; Buettner, C. Tags: Metabolism Source Type: research
