Reflections on the state of diabetes research and prospects for treatment

Abstract

Research on the etiology and treatment of diabetes has made substantial progress. As a result, several new classes of anti-diabetic drugs have been introduced in clinical practice. Nonetheless, the number of patients achieving glycemic control targets has not increased for the past 20 years. Two areas of unmet medical need are the restoration of insulin sensitivity and the reversal of pancreatic beta cell failure. In this review, we integrate research advances in transcriptional regulation of insulin action and pathophysiology of beta cell dedifferentiation with their potential impact on prospects of a durable "cure" for patients suffering from type 2 diabetes.

Keywords: Dedifferentiation; Drug target; Insulin action; Metabolic disease; New generation therapies; Selective insulin sensitizer.

Fig. 1

Comparative effectiveness and cost of metformin add-on treatments. Top-line results from the GRADE study summarizing the percentage of patients requiring addition of medications at 5 years and experiencing major cardiovascular adverse events. Medication costs are from [16]

Fig. 2

C2CD4A couples nonoxidative glycolysis with oxidative phosphorylation. Genes involved in the closed coupling of glycolysis to oxidative phosphorylation in β-cells are regulated by C2CD4A, providing a potential mechanism by which this gene product is related to diabetes susceptibility. These genes are normally suppressed (“disallowed”) to prevent β-cell monocarboxylate uptake (MCT) and conversion to pyruvate (LDH). This process is altered in diabetes, and a reduction of C2CD4A levels can lead to impaired stimulus/secretion coupling

Fig. 3

Our view of how β-cell failure develops. This diagram illustrates a schematic progression of β-cell failure and its relationship to the function of different β-cell transcription factors. Under conditions of nutrient excess or related metabolic abnormalities, FoxO1 is activated by nuclear translocation (bottom) and promotes lipid rather than glucose utilization (“metabolic inflexibility”). This activation cannot be maintained chronically, as FoxO1 degradation outruns its synthesis. When FoxO1 levels falls, the state of differentiation of the β-cell becomes impaired, and the activity of other transcription factors is also reduced. β-cells can convert to α-like cells (elevation of Arx) or progenitor-like cells (re-activation of Neurog3) [32, 43, 110]

Fig. 4

A systems approach to understand β-cell failure. The diagram illustrates the path from determining mRNA expression levels in islet cells to identifying actionable target for pharmacological treatment of β-cell failure [110]