Alpha-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice.
Most patients at risk for developing type 2 diabetes are hyperinsulinemic. Hyperinsulinemia may be a response to insulin resistance, but another possible abnormality is insulin hypersecretion. BTBR mice are insulin resistant and hyperinsulinemic. When the leptin(ob) mutation is introgressed into BTBR mice, they develop severe diabetes. We compared the responsiveness of lean B6 and BTBR mouse islets to various insulin secretagogues. The transamination product of leucine, alpha-ketoisocaproate (KIC), elicited a dramatic insulin secretory response in BTBR islets. The KIC response was blocked by methyl-leucine or aminooxyacetate, inhibitors of branched-chain amino transferase. When dimethylglutamate was combined with KIC, the fractional insulin secretion was identical in islets from both mouse strains, predicting that the amine donor is rate-limiting for KIC-induced insulin secretion. Consistent with this prediction, glutamate levels were higher in BTBR than in B6 islets. The transamination product of glutamate, alpha-ketoglutarate, elicited insulin secretion equally from B6 and BTBR islets. Thus formation of alpha-ketoglutarate is a requisite step in the response of mouse islets to KIC. alpha-Ketoglutarate can be oxidized to succinate. However, succinate does not stimulate insulin secretion in mouse islets. Our data suggest that alpha-ketoglutarate may directly stimulate insulin secretion and that increased formation of alpha-ketoglutarate leads to hyperinsulinemia.
Rabaglia
Mary E
ME
Dept. of Biochemistry, Univ. of Wisconsin-Madison, Madison, WI 53706, USA.
Gray-Keller
Mark P
MP
Frey
Brian L
BL
Shortreed
Michael R
MR
Smith
Lloyd M
LM
Attie
Alan D
AD
D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D007651:Keto Acids / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism*; D020738:Leptin / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013045:Species Specificity; D000637:Transaminases / Q000378:metabolism
D007328:Insulin; D007651:Keto Acids; D007656:Ketoglutaric Acids; D020738:Leptin; D018698:Glutamic Acid; C013082:alpha-ketoisocaproic acid; D005969:Glutamate Dehydrogenase; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase