beta-cell hyperexcitability: from hyperinsulinism to diabetes.
Nutrient oxidation in beta cells generates a rise in [ATP]:[ADP] ratio. This reduces K(ATP) channel activity, leading to depolarization, activation of voltage-dependent Ca(2+) channels, Ca(2+) entry and insulin secretion. Consistent with this paradigm, loss-of-function mutations in the genes (KCNJ11 and ABCC8) that encode the two subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive K(+) (K(ATP)) channel underlie hyperinsulinism in humans, a genetic disorder characterized by dysregulated insulin secretion. In mice with genetic suppression of K(ATP) channel subunit expression, partial loss of K(ATP) channel conductance also causes hypersecretion, but unexpectedly, complete loss results in an undersecreting, mildly glucose-intolerant phenotype. When challenged by a high-fat diet, normal mice and mice with reduced K(ATP) channel density respond with hypersecretion, but mice with more significant or complete loss of K(ATP) channels cross over, or progress further, to an undersecreting, diabetic phenotype. It is our contention that in mice, and perhaps in humans, there is an inverse U-shaped response to hyperexcitabilty, leading first to hypersecretion but with further exacerbation to undersecretion and diabetes. The causes of the overcompensation and diabetic susceptibility are poorly understood but may have broader implications for the progression of hyperinsulinism and type 2 diabetes in humans.
Nichols
C G
CG
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. cnichols@wustl.edu
Koster
J C
JC
Remedi
M S
MS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying