Delayed onset of hyperglycaemia in a mouse model with impaired glucagon secretion demonstrates that dysregulated glucagon secretion promotes hyperglycaemia and type 2 diabetes

• Published in: Diabetologia 2011-02, Vol.54 (2), p.415-422
• Main Authors: Gustavsson, N, Seah, T, Lao, Y, Radda, G. K, Südhof, T. C, Han, W
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; exocytosis; Glucagon; Glucagon - metabolism; Glucagon - secretion; Glucose; Glucose tolerance test; Glycogen - metabolism; Hepatic glucose production; Homeostasis; Human Physiology; Hyperglycemia; Hyperglycemia - blood; Hyperglycemia - genetics; Hyperglycemia - metabolism; Insulin resistance; insulin secretion; Insulin tolerance test; Internal Medicine; islets of Langerhans; Knockout mice; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Knockout; Pyruvate tolerance test; Synaptotagmins - genetics; Synaptotagmins - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1950-2

Aims/hypothesis Type 2 diabetes is caused by relative deficiency of insulin secretion and is associated with dysregulation of glucagon secretion during the late stage of diabetes development. Like insulin secretion from beta cells, glucagon secretion is dependent on calcium signals and a calcium sensing protein, synaptotagmin-7. In this study, we tested the relative contribution of dysregulated glucagon secretion and reduced insulin release in the development of hyperglycaemia and type 2 diabetes by using synaptotagmin-7 knockout (KO) mice, which exhibit glucose intolerance, reduced insulin secretion and nearly abolished Ca²⁺-stimulated glucagon secretion. Methods We fed the synaptotagmin-7 KO and control mice with a high-fat diet (HFD) for 14 weeks, and compared their body weight, glucose levels, glucose and insulin tolerance, and insulin and glucagon secretion. Results On the HFD, synaptotagmin-7 KO mice showed progressive impairment of glucose tolerance and insulin secretion, along with continued maintenance of a low glucagon level. The control mice were less affected in terms of glucose intolerance, and showed enhanced insulin secretion with a concurrent increase in glucagon levels. Unexpectedly, after 14 weeks of HFD feeding, only the control mice displayed resting hyperglycaemia, whereas in synaptotagmin-7 KO mice defective insulin secretion and reduced insulin sensitivity were not sufficient to cause hyperglycaemia in the absence of enhanced glucagon secretion. Conclusions/interpretation Our data uncover a previously overlooked role of dysregulated glucagon secretion in promoting hyperglycaemia and the ensuing diabetes, and strongly suggest maintenance of adequate regulation of glucagon secretion as an important therapeutic target in addition to the preservation of beta cell function and mass in the prevention and treatment of diabetes.