Cardiovascular Effects of Incretin-Based Therapies: Integrating Mechanisms With Cardiovascular Outcome Trials
As the worldwide prevalence of diabetes and obesity continues to rise, so does the risk of debilitating cardiovascular complications. Given the significant association between diabetes and cardiovascular risk, the actions of glucose-lowering therapies within the cardiovascular system must be clearly defined. Incretin hormones, including GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide), are gut hormones secreted in response to nutrient intake that maintain glycemic control by regulating insulin and glucagon release. GLP-1 receptor agonists (GLP-1Ras) and dipeptidyl peptidase 4 inhibitor...
Source: Diabetes - January 11, 2022 Category: Endocrinology Source Type: research
Issues and Events
(Source: Diabetes)
Source: Diabetes - January 11, 2022 Category: Endocrinology Source Type: research
Aging Leukocytes and the Inflammatory Microenvironment of the Adipose Tissue
Age-related immunosenescence, defined as an increase in inflammaging and the decline of the immune system, leads to tissue dysfunction and increased risk for metabolic disease. The elderly population is expanding, leading to a heightened need for therapeutics to improve health span. With age, many alterations of the immune system are observed, including shifts in the tissue-resident immune cells, increased expression of inflammatory factors, and the accumulation of senescent cells, all of which are responsible for a chronic inflammatory loop. Adipose tissue and the immune cell activation within are of particular interest f...
Source: Diabetes - December 17, 2021 Category: Endocrinology Source Type: research
The Women ’s Leadership Gap in Diabetes: A Call for Equity and Excellence. Diabetes 2021;70:1623–1633
Recently, a series of articles on women ’s leadership in diabetes, which reflects the gender disparity in academic medicine, was published inDiabetes (1–3), centered around the article by Dunne et al. (1). The underrepresentation of female talent in the field of clinical medicine has been a longstanding and well-established issue. Women in academia are disproportionately disadvantaged in terms of first author and senior author publications, representation on editorial boards of journals, and leadership roles within academic societies (4). Different strategies that enable leadership development and remove barriers have ...
Source: Diabetes - December 17, 2021 Category: Endocrinology Source Type: research
Issues and Events
(Source: Diabetes)
Source: Diabetes - December 17, 2021 Category: Endocrinology Source Type: research
Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders
In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes an d emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations. (Source: Diabetes)
Source: Diabetes - December 3, 2021 Category: Endocrinology Source Type: research
Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy
The dynamic regulation of autophagy in β-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In β-cells, mechanistic target of rapamycin complex 1 (mTORC1) is inhibited while fasting and is rapidly stimulated during refeeding by a single amino acid, leucine, and glucose. Stimulation of mTORC1 by nutrien ts inhibited the autophagy initiator ULK1 and the transcription factor TFEB, thereby preventing autophagy when β-cells were continuously exposed to nutrients. Inhibition of mTORC1 byRaptor knockout mimicked the effects of fasting and stimulated autophagy while inhibiting insulin secretion...
Source: Diabetes - December 3, 2021 Category: Endocrinology Source Type: research
Recessive Genome-Wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes
Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 case subjects and 279,507 control subjects from 7 European-ancestry cohorts, including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including fiv...
Source: Diabetes - December 3, 2021 Category: Endocrinology Source Type: research
The Role of TRAP γ/SSR3 in Preproinsulin Translocation Into the Endoplasmic Reticulum
In the endoplasmic reticulum (ER), the translocation-associated protein complex (TRAP), also called signal sequence receptor (SSR), includes four integral membrane proteins TRAP α/SSR1, TRAPβ/SSR2, and TRAPδ/SSR4 with the bulk of their extramembranous portions primarily in the ER lumen, whereas the extramembranous portion of TRAPγ/SSR3 is primarily cytosolic. Individually diminished expression of either TRAPα/SSR1, TRAPβ/SSR2, or TRAPδ/SSR4 mRNA is known in each case to lower TRAPα/SSR1 protein levels, leading to impaired proinsulin biosynthesis, whereas forced expression of TRAPα/SSR1 at least partially suppresse...
Source: Diabetes - December 2, 2021 Category: Endocrinology Source Type: research
Adipose Tissue Inflammation Is Not Related to Adipose Insulin Resistance in Humans
The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and...
Source: Diabetes - December 2, 2021 Category: Endocrinology Source Type: research
SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants With Type 1 Diabetes
Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium —glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin...
Source: Diabetes - December 2, 2021 Category: Endocrinology Source Type: research
Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes
Life-threatening hypoglycemia is a limiting factor in the management of type 1 diabetes. People with diabetes are prone to develop hypoglycemia because they lose physiological mechanisms that prevent plasma glucose levels from falling. Among these so-called counterregulatory responses, secretion of glucagon from pancreatic α-cells is preeminent. Glucagon, a hormone secreted in response to a lowering in glucose concentration, counteracts a further drop in glycemia by promoting gluconeogenesis and glycogenolysis in target tissues. In diabetes, however, α-cells do not respond appropriately to changes in glycemia and, t hus,...
Source: Diabetes - December 2, 2021 Category: Endocrinology Source Type: research
Issues and Events
(Source: Diabetes)
Source: Diabetes - December 2, 2021 Category: Endocrinology Source Type: research
MG53 E3 Ligase –Dead Mutant Protects Diabetic Hearts From Acute Ischemic/Reperfusion Injury and Ameliorates Diet-Induced Cardiometabolic Damage
Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading causes of death, highlighting a major unmet medical need. Over the past decade, mitsugumin 53 (MG53), also called TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity, which mediates metabolic disorders. Here, we show that an E3 ligase –dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic adverse effects. When administered in normal animals, both the recombinant human wild-type...
Source: Diabetes - November 29, 2021 Category: Endocrinology Source Type: research
GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity
In this study, we assessed the roles of GRP75, other than as a component, in insulin action in both in vitro and in vivo models with insulin resistance. We found that GRP75 was downregulated in mice fed a high-fat diet (HFD) and that induction ofGrp75 in mice could prevent HFD-induced obesity and insulin resistance. Mechanistically, GRP75 influenced insulin sensitivity by regulating mitochondrial function through its modulation of mitochondrial-supercomplex turnover rather than mitochondria-associated membrane communication: GRP75 was negatively associated with respiratory chain complex activity and was essential for mitoc...
Source: Diabetes - November 22, 2021 Category: Endocrinology Source Type: research
