The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror

Abstract

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (K_ATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

Keywords: Langerhans’ islets; glucagon; hyperglycaemia; hypoglycaemia; type 2 diabetes.

Figure 1

Intrinsic model of glucagon secretion mediated by ATP-sensitive potassium channels (K_ATP). In conditions of systemic hypoglycaemia (1–6 mmol/L) ATP/ADP ratio in α cells decreases, allowing the opening of K_ATP and subsequent reduction of membrane potential, which allow the activation of voltage-gated sodium channels (Na_v). The increase of intracellular sodium generates a short action potential, given to a rapid inactivation of Na_v when membrane potential exceeds −60 mV. This short action potential is enough to allow the opening of T type Ca²⁺ channels, and subsequently the opening of Na_v, and finally the activation L type Ca²⁺ channels, which generate a positive membrane action potential, allowing the opening of type P/Q Ca²⁺ channels (main Ca²⁺ channel), and thereby generating optimal intracellular calcium levels for glucagon vesicles exocytosis. Finally, this increase in membrane potential would culminate in activation of voltage-gated potassium channels (VGK), and subsequent cellular repolarization.

Figure 2

Paracrine regulation of glucagon secretion. (a) Insulin signalling in α cell regulates glucagon secretion. It has been proposed that sequential phosphatidylinositol 3-kinase (PI3K) and phosphodiesterase-3B (PDE3B) activation drive a fall in AMP-c concentration and a reduced ATP binding capacity K_ATP, blocking glucagon secretion. (b) The insulin receptor-coding gene deletion in α cell drives to hyperglycaemia and hyperglucagonemia via ATP accumulation. (c) GABA and serotonin from β cells inhibit glucagon secretion. GABA-A receptors under non-pathologic conditions trigger α cell hyperpolarization with VGCA closure and rapamycin target kinase in mammalian cells (mTOR) inactivation, one of the primary regulators of α cell proliferation. Serotonin via 5-HT1F membrane receptor activation leads to cAMP reduction, inhibiting, therefore, glucagon release. (d) Consequently, any impairment on their secretion could be linked to an increase in α cell mass and hyperglucagonemia in diabetes. (e) β cells glucose-mediated depolarization cause coupled- δ-cells depolarization, activating somatostatin secretion, subsequent α cell hyper-polarization, and inhibition of glucagon release by somatostatin receptor 2 (STTR2) activation.

Figure 3

Autocrine regulation of glucagon secretion. In the α cell, GRs activation increases glucagon gene transcription via cAMP response element-binding (CREB). Glutamate is also present in α cell vesicles. It acts as a glucagon-secretion enhancer acting by ionotropic glutamate receptors (iGluR) stimulation or by binding other proteins like α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and kainate receptors in the α cell membrane. Activation of iGluR drives to α cell depolarisation, activation of VGCA, and subsequent the fusion of glucagon-containing vesicles with cell membranes.