Figure 5. K_ATP channels and dysregulation of glucagon secretion in diabetes.

A, relative change in glucagon secretion measured in islets from healthy donors (n = 40) and donors diagnosed with T2D (n = 10) in response to an elevation of glucose from 1 to 20 mm. Responses in T2D islets fell into two groups; one with normal regulation (n = 5) and one with inverted regulation (n = 5). B, glucagon secretion in islets from two healthy organ donors at 1 and 6 mm glucose in the absence and presence of 2 μm diazoxide. C, net change of plasma glucagon measured in healthy individuals and in patients with T1D 4 h after administration of the SU glimepiride (4 mg, orally). Data from Cooperberg & Cryer (2009) (redrawn). D, relationship between total whole‐cell K channel conductance (G) and glucagon secretion (continuous curve) in T2D patients with normal K_ATP channel regulation (i) and with small (ii), moderate (iii) or large (iv) increases in K_ATP channel activity. The arrows indicate the changes in glucagon secretion produced by an elevation of glucose from 1 to 6 mm. The bar graphs (Inset) show the predicted effects of increasing glucose with variable degrees of basal K_ATP channel hyperactivity. E, schematic illustrating the effects of SU or an SSTR antagonist. The α‐cell is initially repolarized (top trace) because resting whole‐cell K⁺ conductance in excess of background (ΔG) is increased from the optimal 0.1 nS to 0.2 nS (see Fig. 2). This increase may result from either an increase in K_ATP (grey; due to a metabolic defect in the α‐cells) and/or GIRK (red; due to increased somatostatin release from δ‐cells) channel activity. Inhibition of K_ATP channels with SU (middle) or GIRK channels with an SSTR antagonist reduces ΔG to the 0.1 nS, which is optimal for α‐cell electrical activity and glucagon secretion.