Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes

X. Fan, Y. Ding, S. Brown, L. Zhou, M. Shaw, M. C. Vella, H. Cheng, E. C. Mcnay, R. S. Sherwin, Rory McCrimmon

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    34 Citations (Scopus)

    Abstract

    Fan X, Ding Y, Brown S, Zhou L, Shaw M, Vella MC, Cheng H, McNay EC, Sherwin RS, McCrimmon RJ. Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes. Am J Physiol Regul Integr Comp Physiol 296: R1702-R1708, 2009. First published April 8, 2009; doi:10.1152/ajpregu.90600.2008.-In nondiabetic rodents, AMP-activated protein kinase (AMPK) plays a role in the glucose-sensing mechanism used by the ventromedial hypothalamus (VMH), a key brain region involved in the detection of hypoglycemia. However, AMPK is regulated by both hyper- and hypoglycemia, so whether AMPK plays a similar role in type 1 diabetes (T1DM) is unknown. To address this issue, we used four groups of chronically catheterized male diabetic BB rats, a rodent model of autoimmune T1DM with established insulin-requiring diabetes (40 +/- 4 pmol/l basal c-peptide). Two groups were subjected to 3 days of recurrent hypoglycemia (RH), while the other two groups were kept hyperglycemic [chronic hyperglycemia (CH)]. All groups subsequently underwent hyperinsulinemic hypoglycemic clamp studies on day 4 in conjunction with VMH microinjection with either saline (control) or AICAR (5-aminoimidazole-4-carboxamide) to activate AMPK. Compared with controls, local VMH application of AICAR during hypoglycemia amplified both glucagon [means +/- SE, area under the curve over time (AUC/t) 144 +/- 43 vs. 50 +/- 11 ng.l(-1).min(-1); P < 0.05] and epinephrine [4.27 +/- 0.96 vs. 1.06 +/- 0.26 nmol.l(-1).min(-1); P < 0.05] responses in RH-BB rats, and amplified the glucagon [151 +/- 22 vs. 85 +/- 22 ng.l(-1).min(-1); P < 0.05] response in CH-BB rats. We conclude that VMH AMPK also plays a role in glucose-sensing during hypoglycemia in a rodent model of T1DM. Moreover, our data suggest that it may be possible to partially restore the hypoglycemia-specific glucagon secretory defect characteristic of T1DM through manipulation of VMH AMPK.

    Original languageEnglish
    Pages (from-to)R1702-R1708
    Number of pages7
    JournalAmerican Journal of Physiology - Regulatory, Integrative and Comparative Physiology (AJP - Regulatory, Integrative and Comparative Physiology)
    Volume296
    Issue number6
    DOIs
    Publication statusPublished - 2009

    Keywords

    • epinephrine
    • glucagon
    • ventromedial hypothalamus
    • adeno-associated viral vector
    • INSULIN-INDUCED HYPOGLYCEMIA
    • SWITCH-OFF HYPOTHESIS
    • ALPHA-CELL FUNCTION
    • VENTROMEDIAL HYPOTHALAMUS
    • GLUCAGON-SECRETION
    • BETA-CELL
    • FOOD-INTAKE
    • AUTONOMIC MEDIATION
    • HORMONE RESPONSES
    • KEY ROLE

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