TY - JOUR
T1 - Selective potentiation of insulin-mediated glucose disposal in normal dogs by the sulfonylurea glipizide
AU - Putnam, W. S.
AU - Andersen, D. K.
AU - Jones, R. S.
AU - Lebovitz, H. E.
PY - 1981
Y1 - 1981
N2 - Investigative data have suggested that the extrapancreatic actions of the sulfonylureas may be paramount in their chronic antidiabetic action. The present study examines the effects of chronic sulfonylurea treatment on in vivo insulin action. Peripheral insulin levels, hepatic glucose production (Ra), and overall glucose disposal (Rd) were studied in 6 awake, normal dogs given both 0.5 and 1.0 mU/kg per min pork insulin for 2.5 h. This produces stable hyperinsulinemia from 15 to 150 min. Fasting euglycemia was held constant by the glucose clamp technique and averaged 99% basal glucose in all studies. Ra and Rd were determined from infusion of [3-3H]glucose, begun 90 min prior to insulin infusion. 10 mg of the sulfonylurea, glipizide, was given daily to the test animals for the 10 to 20 d following appropriate control studies, then was withheld for 24 h, and the dogs were restudied. Glipizide treatment did not significantly alter basal glucose turnover, Ra, mean glucose values, or mean insulin levels as determined by radioimmunoassay. Increase in Rd above basal glucose turnover in response to insulin (ΔRd) was significantly (P < 0.05) increased by glipizide treatment at both insulin dosage levels (paired analysis). At 1.0 mU/kg per min insulin, ΔRd rose from 2.6 mg/kg per min before glipizide to 6.5 mg/kg per min after glipizide treatment. At 0.5 mU/kg per min insulin, ΔRd went from 1.1 mg/kg per min before glipizide to 2.2 mg/kg per min after glipizide treatment. Glipizide treatment doubled the effects of insulin on Rd, while showing no significant effect upon insulin suppression of Ra. We conclude that a significant extrapancreatic chronic action of glipizide lies in its ability to selectively potentiate Rd.
AB - Investigative data have suggested that the extrapancreatic actions of the sulfonylureas may be paramount in their chronic antidiabetic action. The present study examines the effects of chronic sulfonylurea treatment on in vivo insulin action. Peripheral insulin levels, hepatic glucose production (Ra), and overall glucose disposal (Rd) were studied in 6 awake, normal dogs given both 0.5 and 1.0 mU/kg per min pork insulin for 2.5 h. This produces stable hyperinsulinemia from 15 to 150 min. Fasting euglycemia was held constant by the glucose clamp technique and averaged 99% basal glucose in all studies. Ra and Rd were determined from infusion of [3-3H]glucose, begun 90 min prior to insulin infusion. 10 mg of the sulfonylurea, glipizide, was given daily to the test animals for the 10 to 20 d following appropriate control studies, then was withheld for 24 h, and the dogs were restudied. Glipizide treatment did not significantly alter basal glucose turnover, Ra, mean glucose values, or mean insulin levels as determined by radioimmunoassay. Increase in Rd above basal glucose turnover in response to insulin (ΔRd) was significantly (P < 0.05) increased by glipizide treatment at both insulin dosage levels (paired analysis). At 1.0 mU/kg per min insulin, ΔRd rose from 2.6 mg/kg per min before glipizide to 6.5 mg/kg per min after glipizide treatment. At 0.5 mU/kg per min insulin, ΔRd went from 1.1 mg/kg per min before glipizide to 2.2 mg/kg per min after glipizide treatment. Glipizide treatment doubled the effects of insulin on Rd, while showing no significant effect upon insulin suppression of Ra. We conclude that a significant extrapancreatic chronic action of glipizide lies in its ability to selectively potentiate Rd.
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U2 - 10.1172/JCI110112
DO - 10.1172/JCI110112
M3 - Article
C2 - 7009650
AN - SCOPUS:0019422337
SN - 0021-9738
VL - 67
SP - 1016
EP - 1023
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -