Diabetes mellitus and the β cell: the last ten years

Abstract

Diabetes is a major global problem. During the past decade, the genetic basis of various monogenic forms of the disease, and their underlying molecular mechanisms, have been elucidated. Many genes that increase type 2 diabetes (T2DM) risk have also been identified, but how they do so remains enigmatic. Nevertheless, defective insulin secretion emerges as the main culprit in both monogenic and polygenic diabetes, with environmental and lifestyle factors, via obesity, accounting for the current dramatic increase in T2DM. There also have been significant advances in therapy, particularly for some monogenic disorders. We review here what ails the β cell and how its function may be restored.

Figure 1. Stimulus-secretion coupling in human beta-cells.

A. Glucose is taken up via the glucose transporter Glut1 and phosphorylated by glucokinase (GCK). Further metabolism, especially in the mitochondria (Mitoch) results in generation of ATP at the expense of ADP. This leads to K_ATP-channel closure. Sulphonylureas (SU) inhibit the channel by direct binding, by-passing metabolism. The increased membrane resistance (R_m↑) resulting from K_ATP-channel closure allows small background inward currents, such as those associated with spontaneous opening of T-type Ca²⁺-channels to depolarize the β-cell (Ψ↓). This leads to regenerative activation of voltage-gated L-type and P/Q-type Ca²⁺-channels and Na⁺-channels, which produces action potential firing. The associated Ca²⁺-influx triggers exocytosis of insulin granules (SG). Incretins such as GLP-1 potentiate exocytosis by both protein kinase A (PKA)-dependent and Epac2-dependent mechanisms. Plus signs indicate stimulation, and minus signs inhibition, of the indicated process(es). PM, plasmalemma. B. Ca²⁺-channel clustering and extent of [Ca²⁺]_i domains before and after long-term FFA exposure. SG, Secretory granules.

Figure 2. Impaired glucose-induced insulin secretion cannot be accounted for by reduced insulin content.

(A) Insulin content in islets from non-diabetic (ND) and age- and BMI-matched T2DM organ donors). (B) Insulin secretion, normalized to islet insulin content, evoked by 1mM and 20mM glucose in ND and T2DM islets. Mean±s.e.m. (C) Stimulation index (insulin secretion at 20mM glucose divided by that at 1mM) in ND and T2DM islets *p<0.05 versus 1mM glucose; †p<0.05 vs. ND islets. From: Walker et al. (2011)

Figure 3. Diet affects diabetes incidence.

New cases of diabetes diagnosed in Norway during the years 1925-1955 (expressed as a percentage of the population). Diabetes incidence is higher in individuals >60 years (i.e. with T2DM) than those <30 years (most of whom will have T1DM). While the incidence of T1DM remains unchanged, T2DM decreases by 85% during the 1940-45 German occupation. From Westlund (1966).