Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia

• Published in: Endocrinology (Philadelphia) Vol. 152; no. 2; pp. 394 - 404
• Main Authors: German, Jonathan P, Thaler, Joshua P, Wisse, Brent E, Oh-I, Shinsuke, Sarruf, David A, Matsen, Miles E, Fischer, Jonathan D, Taborsky, Gerald J, Schwartz, Michael W, Morton, Gregory J
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.02.2011
• Subjects: Animals; Biological and medical sciences; Blood Glucose - drug effects; Body Composition - drug effects; Brain - drug effects; Brain - metabolism; Corticosterone - blood; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes-Insulin-Glucagon-Gastrointestinal; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Glucagon - blood; Glucose Tolerance Test; Hyperglycemia - blood; Hyperglycemia - drug therapy; Insulin - pharmacology; Leptin - pharmacology; Male; Medical sciences; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Vertebrates: endocrinology; Endocrinopathy; Pancreatic hormone; Hyperglycemia; Diabetes mellitus; Leptin; Central nervous system; Adipokine; Insulin
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0890

Leptin action in the brain normalizes diabetic hyperglycemia by suppressing hepatic glucose production while increasing tissue glucose uptake despite severe insulin deficiency. The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.