Impaired ability of glycated insulin to regulate plasma glucose and stimulate glucose transport and metabolism in mouse abdominal muscle.
Previous studies have shown that glycated insulin is secreted from pancreatic beta-cells under conditions of hyperglycaemia. This study has investigated the effects of monoglycated insulin on plasma glucose homeostasis and in vitro cellular glucose transport and metabolism by isolated abdominal muscle of mice. Monoglycated insulin was prepared under hyperglycaemic reducing conditions, purified by RP-HPLC and identified by electrospray ionisation mass spectrometry (5971.1 Da). When administered to mice at an intraperitoneal dose of 7 nmoles/kg body weight, insulin (non-glycated) decreased plasma glucose concentrations and substantially reduced the glycaemic excursion induced by conjoint intraperitoneal injection of 2 g glucose/kg body weight. In comparison, the same dose of monoglycated insulin decreased plasma glucose concentrations to a lesser extent (P < 0.05), corresponding to an approx. 20% reduction of glucose lowering potency. Using isolated abdominal muscle, insulin (10(-9)-10(-7) M) stimulated dose-dependent increases in cellular 2-deoxy-D-[1-3H]glucose uptake, D-[U-14C]glucose oxidation and glycogen production. Monoglycated insulin was approx. 20% less effective than native insulin in stimulating glucose uptake and both indices of metabolism, generally requiring 10-fold greater concentrations to achieve significant stimulatory effects. These data indicate that the impaired biological activity of glycated insulin may contribute to glucose intolerance of diabetes.
Boyd
A C
AC
School of Biomedical Sciences, University of Ulster, Coleraine, UK.
Abdel-Wahab
Y H
YH
McKillop
A M
AM
McNulty
H
H
Barnett
C R
CR
O'Harte
F P
FP
Flatt
P R
PR
D000009:Abdominal Muscles / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation; D007328:Insulin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018629:Spectrometry, Mass, Secondary Ion
D001786:Blood Glucose; D007328:Insulin; C039522:insulin, glycosylated; D005947:Glucose