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

Abstract

ATP-sensitive K؉ channels (K ATP channels) control electrical activity in ␤-cells and therefore are key players in excitation-secretion coupling. Partial suppression of ␤-cell K ATP 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 ␤-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 ␤-cell excitability: the expected initial hypersecretion can progress to undersecretion and glucose-intolerance, either spontaneously or in response to dietary stress. Diabetes 53:3159 -3167, 2004

Hyperinsulinism in mice with heterozygous loss of KATP channels

“…Beta cell hyperexcitability and secretory phenotype: an 'inverse-U' model We have thus further proposed [18], and the data here support, an inverse-U model [40] for the general beta cell response to hyperexcitability generated by alterations of K + (or other) conductances (Fig. 7).…”

“…in K ATP KO animals [12][13][14]) or in response to altered stimulatory conditions (e.g. high-fat diet [18]), a secondary loss of secretory capacity leads to relative hypoinsulinaemia and glucose intolerance. Graded degrees of hyperexcitability will lead to graded enhancements of insulin secretion until, above some threshold, beta cells are driven to insulin secretory failure.…”

“…Mice were anaesthetised with 2-bromo-2-chloro-1,1,1-trifluoroethane in an anaesthetising chamber and killed by cervical dislocation. Pancreata were cannulated and injected with Hank's balanced salt solution (Sigma, St Louis, MO, USA) containing collagenase (Type XI [Sigma]) (0.3 mg/ml, pH 7.4) [18]. Briefly, pancreata were digested for 5 min at 37°C, hand shaken and washed three times in cold Hank's solution [18].…”

“…Pancreata were cannulated and injected with Hank's balanced salt solution (Sigma, St Louis, MO, USA) containing collagenase (Type XI [Sigma]) (0.3 mg/ml, pH 7.4) [18]. Briefly, pancreata were digested for 5 min at 37°C, hand shaken and washed three times in cold Hank's solution [18]. Islets were manually isolated under a dissecting microscope, and maintained overnight in CMRL medium (Gibco BRL) containing 5.6 mmol/l glucose in a humidified 37°C incubator.…”

“…Thus, genetic abolition of beta cell K ATP channels in mice fails to recapitulate some features of CHI, whereas a transgenic model of reduced K ATP does reiterate a hyperinsulinaemic phenotype throughout life. We have therefore proposed that, while complete absence may cause insulin secretory failure as in Kir6.2 and SUR1 knockout (KO) mice [12,13,17,18], partial loss of beta cell K ATP channel activity in vivo, as observed in dominant-negative Kir6. 2[AAA] mice, causes insulin hypersecretion.…”