scholarly journals Obesity and Type 2 Diabetes: What Can Be Unified and What Needs to Be Individualized?

2011 ◽  
Vol 96 (6) ◽  
pp. 1654-1663 ◽  
Author(s):  
Robert H. Eckel ◽  
Steven E. Kahn ◽  
Ele Ferrannini ◽  
Allison B. Goldfine ◽  
David M. Nathan ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Clinical Care ◽  
Surgical Approaches ◽  
Future Research ◽  
Diabetes Incidence ◽  
Β Cell ◽  
Endocrine Society ◽  
Writing Group

Objective: This report examines what is known about the relationship between obesity and type 2 diabetes and how future research in these areas might be directed to benefit prevention, interventions, and overall patient care. Research Design and Methods: An international working group of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes participated in a conference held on 6–7 January 2011 and cosponsored by The Endocrine Society, the American Diabetes Association, and the European Association for the Study of Diabetes. A writing group comprising eight participants subsequently prepared this summary and recommendations. Participants reviewed and discussed published literature and their own unpublished data. Results: The writing group unanimously supported the summary and recommendations as representing the working group's majority or unanimous opinions. Conclusions: The major questions linking obesity to type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include the following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what mechanisms do obesity and insulin resistance contribute to β-cell decompensation, and if/when obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3) How does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss drugs, and/or bariatric surgery on β-cell function and glycemia? 4) What is necessary for regulatory approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance effective and cost-effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacological and surgical management.

scholarly journals Targeting β-Cell Function Early in the Course of Therapy for Type 2 Diabetes Mellitus

2010 ◽  
Vol 95 (9) ◽  
pp. 4206-4216 ◽  
Author(s):  
Jack L. Leahy ◽  
Irl B. Hirsch ◽  
Kevin A. Peterson ◽  
Doron Schneider
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Primary Care ◽  
Type 2 Diabetes Mellitus ◽  
Primary Care Physicians ◽  
Clinical Implications ◽  
Β Cell ◽  
Endocrine Society ◽  
Writing Group

Objective: This report examines current perspectives regarding likely mechanisms of β-cell failure in type 2 diabetes and their clinical implications for protecting or sparing β-cells early in the disease progression. In addition, it considers translation strategies to incorporate relevant scientific findings into educational initiatives targeting clinical practice behavior. Participants: On January 10, 2009, a working group of basic researchers, clinical endocrinologists, and primary care physicians met to consider whether current knowledge regarding pancreatic β-cell defects justifies retargeting and retiming treatment for clinical practice. Based on this meeting, a writing group comprised of four meeting participants subsequently prepared this consensus statement. The conference was convened by The Endocrine Society and funded by an unrestricted educational grant from Novo Nordisk. Evidence: Participants reviewed and discussed published literature, plus their own unpublished data. Consensus Process: The summary and recommendations were supported unanimously by the writing group as representing the consensus opinions of the working group. Conclusions: Workshop participants strongly advocated developing new systems to address common barriers to glycemic control and recommended several initial steps toward this goal. These recommendations included further studies to establish the clinical value of pharmacological therapies, continuing basic research to elucidate the nature and mechanisms of β-cell failure in type 2 diabetes mellitus, and exploring new educational approaches to promote pathophysiology-based clinical practices. The Endocrine Society has launched a new website to continue the discussion between endocrinologists and primary care physicians on β-cell pathophysiology in type 2 diabetes and its clinical implications. Join the conversation at http://www.betacellsindiabetes.org

Exploring the role of the HNF-1αG319S polymorphism in β cell failure and youth-onset type 2 diabetes: Lessons from MODY and Hnf-1α-deficient animal models

2015 ◽  
Vol 93 (5) ◽  
pp. 487-494 ◽  
Author(s):  
Michael E. Jonasson ◽  
Brandy A. Wicklow ◽  
Elizabeth A.C. Sellers ◽  
Vernon W. Dolinsky ◽  
Christine A. Doucette
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucose Sensing ◽  
Future Research ◽  
Cell Phenotype ◽  
Β Cells ◽  
Β Cell ◽  
Onset Type ◽  
The Impact

The prevalence of youth-onset type 2 diabetes (T2D) is rapidly increasing worldwide, disproportionately affecting Indigenous youth with Oji-Cree heritage from central Canada. Candidate gene screening has uncovered a novel and private polymorphism in the Oji-Cree population in the hepatocyte nuclear factor-1 alpha (HNF-1α) gene, where a highly conserved glycine residue at position 319 is changed to a serine (termed HNF-1αG319S or simply G319S). Oji-Cree youth who carry one or two copies of the “S-allele” present at diagnosis with less obesity, reduced indicators of insulin resistance, and lower plasma insulin levels at diagnosis, suggestive of a primary defect in the insulin-secreting β cells. Few studies on the impact of the HNF-1αG319S variant on β cell function have been performed to date; however, much can be learned from other clinical phenotypes of HNF-1α-deficiency, including HNF-1α mutations that cause maturity-onset diabetes of the young 3 (MODY3). In addition, evaluation of Hnf-1α-deficient murine models reveals that HNF-1α plays a central role in the regulation of insulin secretion by regulating the expression of key genes involved in β cell glucose-sensing, mitochondrial function, and the maintenance of the β cell phenotype in differentiated β cells. The overall goal of this minireview is to explore the impact of HNF-1α-deficiency on the β cell to better inform future research into the mechanisms of β cell dysfunction in Oji-Cree youth with T2D.

Liraglutide Therapy in a Prediabetic State: Rethinking the Evidence

2020 ◽  
Vol 16 (7) ◽  
pp. 699-715 ◽  
Author(s):  
Georgios S. Papaetis
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Normal Glucose Tolerance ◽  
Current Evidence ◽  
Β Cell ◽  
Prediabetic State ◽  
New Therapeutic Approaches ◽  
Normal Glucose

Background: Prediabetes is defined as a state of glucose metabolism between normal glucose tolerance and type 2 diabetes. Continuous β-cell failure and death are the reasons for the evolution from normal glucose tolerance to prediabetes and finally type 2 diabetes. Introduction: The necessity of new therapeutic approaches in order to prevent or delay the development of type 2 diabetes is obligatory. Liraglutide, a long-acting GLP-1 receptor agonist, has 97% homology for native GLP-1. Identification of the trophic and antiapoptotic properties of liraglutide in preclinical studies, together with evidence of sustained β-cell function longevity during its administration in type 2 diabetes individuals, indicated its earliest possible administration during this disease, or even before its development, so as to postpone or delay its onset. Methods: Pubmed and Google databases have been thoroughly searched and relevant studies were selected. Results: This paper explores the current evidence of liraglutide administration both in humans and animal models with prediabetes. Also, it investigates the safety profile of liraglutide treatment and its future role to postpone or delay the evolution of type 2 diabetes. Conclusion: Liralgutide remains a valuable tool in our therapeutic armamentarium for individuals who are overweight or obese and have prediabetes. Future well designed studies will give valuable information that will help clinicians to stratify individuals who will derive the most benefit from this agent, achieving targeted therapeutic strategies.

scholarly journals Serum Amylase Levels in Relation to Islet β Cell Function in Patients with Early Type 2 Diabetes

PLoS ONE ◽  
2016 ◽  
Vol 11 (9) ◽  
pp. e0162204 ◽  
Author(s):  
Lei Zhuang ◽  
Jian-bin Su ◽  
Xiu-lin Zhang ◽  
Hai-yan Huang ◽  
Li-hua Zhao ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Serum Amylase ◽  
Cell Function ◽  
Early Type ◽  
Β Cell ◽  
Β Cell Function

Let7b-5p is Upregulated in the Serum of Emirati Patients with Type 2 Diabetes and Regulates Insulin Secretion in INS-1 Cells

2020 ◽  
Author(s):  
Hayat Aljaibeji ◽  
Noha Mousaad Elemam ◽  
Abdul Khader Mohammed ◽  
Hind Hasswan ◽  
Mahammad Al Thahyabat ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Cell Function ◽  
Serum Levels ◽  
Insulin Content ◽  
Β Cell ◽  
Control Subjects ◽  
Β Cell Function

Abstract Let7b-5p is a member of the Let-7 miRNA family and one of the top expressed miRNAs in human islets that implicated in glucose homeostasis. The levels of Let7b-5p in type 2 diabetes (T2DM) patients or its role in β-cell function is still unclear. In the current study, we measured the serum levels of let7b-5p in Emirati patients with T2DM (with/without complications) and control subjects. Overexpression or silencing of let7b-5p in INS-1 (832/13) cells was performed to investigate the impact on insulin secretion, content, cell viability, apoptosis, and key functional genes. We found that serum levels of let7b-5p are significantly (p<0.05) higher in T2DM-patients or T2DM with complications compared to control subjects. Overexpression of let7b-5p increased insulin content and decreased glucose-stimulated insulin secretion, whereas silencing of let7b-5p reduced insulin content and secretion. Modulation of the expression levels of let7b-5p did not influence cell viability nor apoptosis. Analysis of mRNA and protein expression of hallmark genes in let7b-5p transfected cells revealed a marked dysregulation of Insulin, Pancreatic And Duodenal Homeobox 1 (PDX1), glucokinase (GCK), glucose transporter 2 (GLUT2), and INSR. In conclusion, an appropriate level of let7b-5p is essential to maintain β-cell function and may be regarded as a biomarker for T2DM.

scholarly journals Imeglimin Amplifies Glucose-Stimulated Insulin Release from Diabetic Islets via a Distinct Mechanism of Action

2020 ◽  
Author(s):  
Sophie Hallakou-Bozec ◽  
Micheline Kergoat ◽  
Pascale Fouqueray ◽  
Sébastien Bolze ◽  
David E. Moller
Keyword(s):  
Type 2 Diabetes ◽  
Mode Of Action ◽  
Cell Function ◽  
Drug Candidate ◽  
Β Cell ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Predominant Component ◽  
Cyclic Adp Ribose ◽  
Β Cell Function

ABSTRACTPancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that Imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool – potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+ conversion to a second messenger, cyclic ADP ribose (cADPR), via cyclic ADP ribose hydrolase (CD38) is required for Imeglimin’s effects in islets, thus representing a potential link between increased NAD+ and enhanced glucose-induced Ca2+ mobilization which - in turn - is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for Imeglimin that explains its ability to effectively restore β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes.

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