Molecular Pathways Underlying the Pathogenesis of Pancreatic α-Cell Dysfunction

The pancreatic islets are richly innervated by parasympathetic, sympathetic and sensory nerves. Several different neurotransmitters are stored within the terminals of these nerves, both the classical neurotransmitters, acetylcholine and noradrenaline, and several neuropeptides. The neuropeptides, vasoactive intestinal polypeptide, pituitary adenlyate cyclase activating polypeptide and gastrin releasing peptide are constituents of the parasympathetic nerves, whereas the neuropeptides galanin and neuropeptide Y are localised to sympathetic nerve terminals. Furthermore, the neuropeptide calcitonin gene-related peptide is localised to sensory nerves and cholecystokinin is also an islet neuropeptide, although the nature of the cholecystokinin nerves is not established. Stimulation of the autonomic nerves and treatment with neurotransmitters affect islet hormone secretion. Thus, insulin secretion is stimulated by parasympathetic nerves or their neurotransmitters and inhibited by sympathetic nerves or their neurotransmitters. The islet autonomic nerves seem to be of physiological importance in mediating the cephalic phase of insulin secretion, in synchronising the islets to function as a unit allowing oscillations of islet hormone secretion, and in optimising islet hormone secretion during metabolic stress, e.g. hypoglycaemia and neuroglycopenia. The autonomic nerves could also be involved in the islet adaptation to insulin resistance with possible implication for the development of glucose intolerance and Type II (non-insulin-dependent) diabetes mellitus. It is concluded that islet innervation, through the contribution of all branches of the autonomic nerves and several different neurotransmitters is of importance both for the physiology and pathophysiology of the islets.

As a counterregulatory hormone for insulin, glucagon plays a critical role in maintaining glucose homeostasis in vivo in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Compared with healthy subjects, diabetic patients and animals have abnormal secretion of not only insulin but also glucagon. Hyperglucagonemia and altered insulin-to-glucagon ratios play important roles in initiating and maintaining pathological hyperglycemic states. Not surprisingly, glucagon and glucagon receptor have been pursued extensively in recent years as potential targets for the therapeutic treatment of diabetes.

In the presence of obesity, beta-cell mass needs to be increased to compensate for the accompanying demands and maintain euglycemia. However, in Korea, the majority of type 2 diabetic patients are nonobese. We determined the absolute masses, relative volumes, and ratio of alpha- and beta-cell in the pancreas and islets in normal and diabetic Korean subjects to correlate these findings with the clinical characteristics. Whole pancreases procured from organ donors were divided into 24 parts (control 1, n = 9). Tissue was also obtained by surgical resection after 35 partial pancreatectomies: in 25 diabetic patients, 10 age- and body mass index (BMI)-matched patients of benign or malignant pancreatic tumor without diabetes mellitus (DM) (control 2). Morphometric quantifications were performed. In control 1, the relative volume of beta-cells was 2.1 +/- 0.9%, and the total beta-cell mass was 1.3 +/- 0.3 g. The relative volume of beta-cells was found to be variable (control 1, 2.1 +/- 0.9%; control 2, 1.9 +/- 0.7%; DM, 1.4 +/- 1.0%; P 6415 micro m(2); P < 0.05) in control 1 and diabetic patients. The relative volume of beta-cell was found to be correlated with BMI in diabetic patients and normal organ donors. Moreover, decreased beta-cell but increased alpha-cell proportion in the islets suggests for a selective beta-cell loss in the pathogenesis of Korean type 2 diabetes.