Novel approaches to restore beta cell function in prediabetes and type 2 diabetes

Abstract

The World Health Organization estimates that diabetes prevalence has risen from 108 million in 1980 to 422 million in 2014, with type 2 diabetes accounting for more than 90% of these cases. Furthermore, the prevalence of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) is more than 40% in some countries and is associated with a global rise in obesity. Therefore it is imperative that we develop new approaches to reduce the development of prediabetes and progression to type 2 diabetes. In this review, we explore the gains made over the past decade by focused efforts to improve insulin secretion by the beta cell or insulin sensitivity of target tissues. We also describe multitasking candidates, which could improve both beta cell dysfunction and peripheral insulin sensitivity. Moreover, we highlight provocative findings indicating that additional glucose regulatory tissues, such as the brain, may be key therapeutic targets. Taken together, the promise of these new multi-faceted approaches reinforces the importance of understanding and tackling type 2 diabetes pathogenesis from a multi-tissue perspective.

Keywords: Beta cell dysfunction; Insulin resistance; Insulin secretion; Obesity; Prediabetes; Review; Type 2 diabetes.

Fig. 1

Relationship between beta cell insulin release and peripheral insulin sensitivity in determining states of glycaemic control. Individuals are classified as having normal glucose tolerance, prediabetes or type 2 diabetes based on the evaluation of fasting plasma glucose levels and/or 2 h plasma glucose values after a 75 g OGTT, or HbA_1c measurement. With emerging peripheral insulin resistance, beta cells compensate by releasing more insulin (as depicted); (a) in individuals who are not at risk of developing abnormalities of glucose tolerance, the beta cells continue to release more insulin in response to prolonged insulin resistance, and potentially beta cell mass also increases, thereby maintaining normoglycaemia over time. (b) In individuals who are at increased risk of developing diabetes because of genetic or epigenetic susceptibility, beta cells are unable to adequately compensate for emerging peripheral insulin resistance because insulin release is insufficient for the degree of insulin resistance, and mild hyperglycaemia (prediabetes) develops. Over time, the progressive nature of the beta cell defect results in ongoing loss of secretory function and a further decline in beta cell mass such that severe hyperglycaemia (type 2 diabetes) develops. Gluc, glucose; Ins, insulin. This figure is available as part of a downloadable slide set

Fig. 2

Beta cell function, peripheral insulin sensitivity and points of entry for therapeutic targeting. In the islet beta cell (blue), glucose enters via the GLUT1/2 glucose transporter. Its intracellular metabolism increases the ATP/ADP ratio, triggering closure of K_ATP channels, stimulating plasma membrane depolarisation (Ψ) and opening of the voltage-dependent calcium channels, thereby permitting entry of extracellular Ca²⁺ into the cell. The net increase in intracellular Ca²⁺ facilitates SNARE complex-regulated GSIS. GLP-1 binds to the GLP-1 receptor, and increases cAMP and amplifies GSIS. Sulfonylureas stimulate insulin release by binding to and closing (thus activating) K_ATP/SUR channels. In the skeletal muscle cell (pink), circulating insulin binds to the insulin receptor to trigger canonical insulin signalling through IRS-PI3K. This leads to F-actin remodelling to provide tracks upon which GLUT4 vesicles travel to SNARE proteins at the plasma membrane for subsequent docking and fusion to facilitate glucose uptake. Factors that multitask in both beta cell- and muscle-specific processes and act positively include STX4, PAK1, BMP7 and osteocalcin, while TXNIP exerts negative actions. Dashed lines indicate pathways that are as yet unclear. GLP-1R, GLP-1 receptor; IR, insulin receptor; SNARE, SNAP (soluble NSF [N-ethylmaleimide-sensitive factor] attachment protein) receptor; VDCC, voltage-dependent calcium channel. This figure is available as part of a downloadable slide set