Suppression of AMP kinase activity in skeletal muscle improves metabolic abnormalities of streptozotocin-induced insulin-deficient diabetes mellitus in mice.
Year: 2013
Type: dissertation
Abstract: Type 1 diabetes mellitus (T1DM) is caused by a consequence of pancreatic β-cell destruction leading to insulin deficiency, a defect that causes hyperglycemia, ketoacidosis, high plasma fatty acid level and cachexia.I explored the role of AMPK in skeletal muscle in those metabolic changes in streptozotocin (STZ)-induced insulin-deficient diabetes mellitus (IDDM) mice.I found that STZinduced IDDM activates AMPK and its signaling pathways in skeletal muscle.Surprisingly, inhibition of AMPK activation in skeletal muscle in STZ-induced IDDM by preferentially expressing dominant-negative AMPK (DN-AMPK), decreased plasma concentration of glucose, fatty acids, ketone bodies, and gluconeogenic hormones, although plasma insulin level remains low.Moreover, STZ-treated DN-AMPK expressing mice improved the weight loss of white adipose tissue (WAT) and skeletal muscle, and body weight loss, leading to increased survival rate.WAT in STZ-induced IDDM mice increased UCP1 (uncoupling protein 1) expression as well as decreased expression of lipogenic enzymes, but those were returned to the control levels in STZ-treated DN-AMPK expressing mice.STZ-treated DN-AMPK expressing mice recovered plasma concentration of leptin that has been known to stimulate whole body glucose and lipid metabolism in IDDM.Interleukin-6 (IL-6) is released from skeletal muscle and stimulates lipolysis in adipose tissues, and a novel myokine, irisin, induces thermogenic protein UCP1 in WAT.I found that expressions of IL-6 and irisin increased in skeletal muscle and their plasma concentrations in STZinduced IDDM mice, but those returned to the control levels in STZ-treated DN-AMPK expressing mice.Furthermore, infusion of neutral antibody for IL-6 or infusion of leptin by osmotic minipump, improved the metabolic changes in STZ-induced IDDM mice, similar to those in STZ-treated DN-AMPK expressing mice.These results thus unveil a key role for muscle AMPK in metabolic abnormalities in STZ-induced IDDM, and important role of organ networks in the metabolic regulation.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W17481905