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 Ca(2+)-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.
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 Ca(2+)-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 micedefective 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.
Authors: Natalia Gustavsson; Shun-Hui Wei; Dong Nhut Hoang; Ye Lao; Quan Zhang; George K Radda; Patrik Rorsman; Thomas C Südhof; Weiping Han Journal: J Physiol Date: 2009-01-26 Impact factor: 5.182
Authors: Natalia Gustavsson; Ye Lao; Anton Maximov; Jen-Chieh Chuang; Elena Kostromina; Joyce J Repa; Cai Li; George K Radda; Thomas C Südhof; Weiping Han Journal: Proc Natl Acad Sci U S A Date: 2008-02-28 Impact factor: 11.205
Authors: Anton Maximov; Ye Lao; Hongmei Li; Xiaocheng Chen; Josep Rizo; Jakob B Sørensen; Thomas C Südhof Journal: Proc Natl Acad Sci U S A Date: 2008-02-28 Impact factor: 11.205
Authors: Rachel A Jamison; Romana Stark; Jianying Dong; Shin Yonemitsu; Dongyan Zhang; Gerald I Shulman; Richard G Kibbey Journal: Am J Physiol Endocrinol Metab Date: 2011-08-23 Impact factor: 4.310