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      Leptin acts in the brain to influence hypoglycemic counterregulation: disparate effects of acute and recurrent hypoglycemia on glucagon release

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          Abstract

          Leptin has been shown to diminish hyperglycemia via reduced glucagon secretion, although it can also enhance sympathoadrenal responses. However, whether leptin can also inhibit glucagon secretion during insulin-induced hypoglycemia or increase epinephrine during acute or recurrent hypoglycemia has not been examined. To test whether leptin acts in the brain to influence counterregulation, hyperinsulinemic hypoglycemic (∼45 mg/dl) clamps were performed on rats exposed to or not exposed to recurrent hypoglycemia (3 days, ∼40 mg/dl). Intracerebroventricular artificial cerebral spinal fluid or leptin was infused during the clamp. During acute hypoglycemia, leptin decreased glucagon responses by 51% but increased epinephrine and norepinephrine by 24 and 48%, respectively. After recurrent hypoglycemia, basal plasma leptin levels were undetectable. Subsequent brain leptin infusion during hypoglycemia paradoxically increased glucagon by 45% as well as epinephrine by 19%. In conclusion, leptin acts within the brain to diminish glucagon secretion during acute hypoglycemia but increases epinephrine, potentially limiting its detrimental effects during hypoglycemia. Exposure to recurrent hypoglycemia markedly suppresses plasma leptin, whereas exogenous brain leptin delivery enhances both glucagon and epinephrine release to subsequent hypoglycemia. These data suggest that recurrent hypoglycemia may diminish counterregulatory responses in part by reducing brain leptin action.

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          Author and article information

          Journal
          Am J Physiol Endocrinol Metab
          Am. J. Physiol. Endocrinol. Metab
          ajpendo
          ajpendo
          AJPENDO
          American Journal of Physiology - Endocrinology and Metabolism
          American Physiological Society (Bethesda, MD )
          0193-1849
          1522-1555
          27 October 2015
          15 December 2015
          15 December 2016
          : 309
          : 12
          : E960-E967
          Affiliations
          Yale University School of Medicine, Department of Internal Medicine-Section of Endocrinology, New Haven, Connecticut
          Author notes
          Address for reprint requests and other correspondence: R. Sherwin, Yale University School of Medicine, Dept. of Internal Medicine-Section of Endocrinology, 300 Cedar St., TAC S141D, New Haven, CT (e-mail: robert.sherwin@ 123456yale.edu ).
          Article
          PMC4816199 PMC4816199 4816199 E-00361-2015
          10.1152/ajpendo.00361.2015
          4816199
          26506851
          Copyright © 2015 the American Physiological Society
          Funding
          Funded by: 100000002 HHS | National Institutes of Health (NIH)
          Award ID: DK20495
          Award ID: F32DK104495
          Award ID: P30DK45735
          Funded by: 100000901 Juvenile Diabetes Research Foundation International (JDRF)
          Categories
          Call for Papers
          CNS Control of Metabolism

          hypoglycemia, glucagon, leptin, recurrent hypoglycemia

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