β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment

Abstract

OBJECTIVEThis article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.RESEARCH DESIGN AND METHODSA group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.RESULTSThe writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.CONCLUSIONSβ-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

“…While the relative contribution and temporal appearance of these events vary across different patients and populations, these 2 abnormalities usually exist concomitantly in the majority of patients (4). Therefore, an ideal antidiabetic therapeutic would involve strategies to enhance both insulin sensitivity and β cell function.…”

“…An impaired insulin response to glucose has long been documented in T2DM subjects (15)(16)(17)(18)(19), and evidence indicates that β cell dysfunction involves a decline in both β cell responsiveness to insulin secretagogues and overall β cell mass (4,20). Ex vivo glucosestimulated insulin secretion (GSIS) is diminished in primary islets from T2DM patients compared with normal subjects (20), indicating that there is an islet-autonomous defect in GSIS in T2DM.…”

Principle of Management of Type 2 Diabetes: From Clinical, Public Health and Research Perspectives

“…Beta-cell failure is central to the ultimate development and progression of type 2 diabetes and it antedates and predicts diabetes onset and progression [40]. Subjects with normal glucose tolerance with 2-hour plasma glucose 120-139 mg/dL may have already lost 50% of beta-cell function, whereas subjects with impaired glucose tolerance with 2-hour plasma glucose 180-199 mg/dL have lost up to 80% of beta-cell function.…”

“…Thus, when the diagnosis of diabetes is made, the patient may have already lost 80% of their beta-cell function [41,42]. The available clinical studies with appropriate protocols, however, indicate that existing therapy may not reverse or arrest progression of beta-cell dysfunction in type 2 diabetes [40]. Weight loss reduces insulin resistance and beta-cell workload and physical activity increases insulin utilization and also helps to reduce beta-cell workload and bodyweight.…”

Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

“…Therefore, elucidating the molecular mechanisms underlying pancreatic β-cell dysfunction is a key to understanding the pathology of diabetes [3,4]. Sequestosome 1 (SQSTM1, referred to hereafter as p62) is a multifunctional scaffold protein that can interact with several signaling pathways through its functional subdomains, including the Phox and Bem1 (PB1) domain, zinc-finger domain, TNF receptor-associated factor 6 (TRAF6)-binding domain, and Kelch-like ECHassociated protein 1 (Keap1) interacting region (KIR) [5][6][7].…”