Glucose sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat. A new genetic model of NIDDM.
In the Goto-Kakizaki rat, a new genetic model of NIDDM, insulin response to glucose is selectively impaired. To elucidate the mechanism of this abnormality, we studied the properties of ATP-sensitive K+ channels, the inhibition of which is a key step of insulin secretion induced by fuel substrates, using the patch-clamp technique. The glucose-sensitivity of KATP channels was considerably reduced in GK rats. However, the inhibitory effects of ATP on channel activity and unitary conductance were not significantly different between control and GK rats. Thus, it appears that the impaired insulinotropic action of glucose in beta-cells of GK rats is attributable to insufficient closure of the KATP channels, probably because of deficient ATP production by impaired glucose metabolism. KATP-channel activities in both control and diabetic beta-cells were found to be equally suppressed by glyceraldehyde and 2-ketoisocaproate. These results strongly suggest that the step responsible for the metabolic dysfunction of diabetic beta-cells is located within the glycolytic pathway before glyceraldehyde-3-phosphate or in the glycerol phosphate shuttle.
Tsuura
Y
Y
Department of Metabolism and Clinical Nutrition, Kyoto University Faculty of Medicine, Japan.
Ishida
H
H
Okamoto
Y
Y
Kato
S
S
Sakamoto
K
K
Horie
M
M
Ikeda
H
H
Okada
Y
Y
Seino
Y
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005941:Glucokinase / Q000032:analysis; D005947:Glucose / Q000494:pharmacology*; D005985:Glyceraldehyde / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D007651:Keto Acids / Q000494:pharmacology; D008297:Male; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D007328:Insulin; D007651:Keto Acids; D015221:Potassium Channels; D005985:Glyceraldehyde; C013082:alpha-ketoisocaproic acid; D000255:Adenosine Triphosphate; D005941:Glucokinase; D005947:Glucose