β‐cell preservation: a potential role for thiazolidinediones to improve clinical care in Type 2 diabetes

Abstract

Type 2 diabetes is caused by progressively increasing insulin resistance coupled with deteriorating beta-cell function, and there is a growing body of evidence to suggest that both of these defects precede hyperglycaemia by many years. Several studies have demonstrated the importance of maintaining beta-cell function in patients with Type 2 diabetes. This review explores parameters used to indicate beta-cell dysfunction, in Type 2 diabetes and in individuals with a predisposition to the disease. A genetic element undoubtedly underlies beta-cell dysfunction; however, a number of modifiable components are also associated with beta-cell deterioration, such as chronic hyperglycaemia and elevated free fatty acids. There is also evidence for a link between pro-inflammatory cytokines and impairment of insulin-signalling pathways in the beta-cell, and the potential role of islet amyloid deposition in beta-cell deterioration continues to be a subject for debate. The thiazolidinediones are a class of agents that have demonstrated clinical improvements in indices of beta-cell dysfunction and have the potential to improve beta-cell function. Data are accumulating to show that this therapeutic group offers a number of advantages over traditionally employed oral agents, and these data demonstrate the growing importance of thiazolidinediones in Type 2 diabetes management.

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

“…Glucotoxicity is a critical factor in the development and progression of type 2 diabetes [1,2]. Prolonged exposure of pancreatic beta cells to elevated levels of glucose is associated with inhibition of glucose-induced insulin secretion, impairment of insulin gene expression, and induction of cell death by apoptosis [3].…”

Hypoglycemic Action of Thiazolidinediones/Peroxisome Proliferator–Activated Receptor γ by Inhibition of the c-Jun NH2-Terminal Kinase Pathway

“…TZDs counteract TNF-␣-induced insulin resistance by restoring insulin receptor and IRS-1 tyrosine phosphorylation in cultured adipocytes, mice, and type 2 diabetic patients (13)(14)(15)(16)(17). TZDs also prevent progressive ␤-cell dysfunction (17,18). Several mechanisms have been proposed to account for this protective action of TZDs, including a lowering of pancreatic secretory demands (17), a direct positive effect on ␤-cells (19), or the inhibition of the production of pro-inflammatory cytokines (20).…”

Oral antidiabetic drugs: their properties and recommended use

“…These small changes in glycated haemoglobin would suggest, in the author's opinion, that metformin should still remain the treatment of choice when starting drug therapy in type 2 diabetes, but a TZD would be a preferred combination agent with metformin. The DREAM and ADOPT studies support beta-cell preservation by TZDs in type 2 diabetes with better sustained glycaemic control; 13 the PROactive and CHICAGO studies support a role for TZDs in preventing macrovascular disease, the principal killer in type 2 diabetes. NICE also highlights that there is no evidence that TZDs are of added benefit when given as triple therapy with metformin and a sulphonylurea, although both pioglitazone and rosiglitazone now have a licence for triple therapy.…”