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

Abstract

β-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.

Reversibility of Defects in Proinsulin Processing and Islet β-Cell Failure in Obesity-Related Type 2 Diabetes

“…Islet b-cell failure is mostly progressive in type 2 diabetes, resulting in the need for serial escalations in glucoselowering therapies for many patients with this condition (1)(2)(3)(4). This failure is a consequence of impaired b-cell function and loss of b-cell mass, with varying contributions of each likely to relate to the heterogeneity in causative factors from patient to patient (1)(2)(3)(4)(5).…”

“…This failure is a consequence of impaired b-cell function and loss of b-cell mass, with varying contributions of each likely to relate to the heterogeneity in causative factors from patient to patient (1)(2)(3)(4)(5). It is a commonly held view that impaired proinsulin synthesis contributes to the b-cell dysfunction aspect of b-cell failure (1,2).…”

“…This failure is a consequence of impaired b-cell function and loss of b-cell mass, with varying contributions of each likely to relate to the heterogeneity in causative factors from patient to patient (1)(2)(3)(4)(5). It is a commonly held view that impaired proinsulin synthesis contributes to the b-cell dysfunction aspect of b-cell failure (1,2). This can be a consequence of the endoplasmic reticulum (ER) stress response that inhibits protein synthesis (including proinsulin) and/or b-cell dedifferentiation in which the expression of the essential elements required for a mature b-cell function, including the transcription of the insulin gene, are reduced or absent (1,2).…”

Hypoglycemic and Antioxidative Effects of <i>Glossogyne tenuifolia</i> on Streptozotocin-Nicotinamide-Induced Diabetic Rats

“…The disease is caused by an absolute or relative lack of insulin and/or reduced insulin activity. Type 2 diabetes mellitus (T2D) is a heterogeneous disorder characterized by a progressive decline in insulin sensitivity followed by pancreatic β-cell dysfunction [1]. It is characterized by hyperglycemia and its complications like diabetic retinopathy, diabetic nephropathy and cardio vascular diseases are the most common endocrine disorder [2].…”

Islet inflammation in type 2 diabetes

“…It has been shown that a proinflammatory milieu can lead to reduced beta cell function and survival [14][15][16]. Given the key role of beta cell impairment in the onset and progression of diabetes [17,18], it is of utmost importance to shed light on the several features linking inflammation and islet cell dysfunction. This commentary on the 'Islet inflammation in type 2 diabetes' symposium at the EASD 2015 meeting focuses on a few general issues regarding the association between inflammation and the pancreatic islets in human type 2 diabetes.…”