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Diet-Induced Glucose Intolerance in Mice With Decreased β-Cell ATP-Sensitive K+ Channels

  1. Maria S. Remedi12,
  2. Joseph. C. Koster1,
  3. Kamelia Markova1,
  4. Susumu Seino3,
  5. Takashi Miki3,
  6. Brian L. Patton1,
  7. Michael L. McDaniel2 and
  8. Colin G. Nichols1
  1. 1Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
  2. 2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
  3. 3Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
  1. Address correspondence and reprint requests to Dr. Colin G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: cnichols{at}cellbio.wustl.edu

Abstract

ATP-sensitive K+ channels (KATP channels) control electrical activity in β-cells and therefore are key players in excitation-secretion coupling. Partial suppression of β-cell KATP channels in transgenic (AAA) mice causes hypersecretion of insulin and enhanced glucose tolerance, whereas complete suppression of these channels in Kir6.2 knockout (KO) mice leads to hyperexcitability, but mild glucose intolerance. To test the interplay of hyperexcitability and dietary stress, we subjected AAA and KO mice to a high-fat diet. After 3 months on the diet, both AAA and KO mice converted to an undersecreting and markedly glucose-intolerant phenotype. Although Kir6.2 is expressed in multiple tissues, its primary functional consequence in both AAA and KO mice is enhanced β-cell electrical activity. The results of our study provide evidence that, when combined with dietary stress, this hyperexcitability is a causal diabetic factor. We propose an “inverse U” model for the response to enhanced β-cell excitability: the expected initial hypersecretion can progress to undersecretion and glucose-intolerance, either spontaneously or in response to dietary stress.

Footnotes

    • Accepted August 31, 2004.
    • Received August 4, 2004.
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