Abnormal activation of glycogen synthesis in fibroblasts from NIDDM subjects. Evidence for an abnormality specific to glucose metabolism.
To determine whether the tendency for NIDDM to run in families could relate to genetically determined defects in insulin stimulation of glycogen synthesis, skin fibroblasts from subjects with a strong family history of NIDDM were studied. Fibroblasts from nondiabetic subjects without any family history of NIDDM were studied as control subjects. The cells were studied after 7-16 passages in culture. Rates of glycogen synthesis were lower in fibroblasts from NIDDM subjects both basally and with maximal insulin stimulation (0.77 +/- 0.11 vs. 0.46 +/- 0.04 pmol.well-1 x h-1 [P < 0.02] and 1.49 +/- 0.26 vs. 0.69 +/- 0.05 pmol.well-1 x h-1 +adP < 0.01]). Rates of glycogen synthesis were stimulated 1.9 +/- 0.2-fold above basal in the control cells and 1.5 +/- 0.1-fold above basal in the NIDDM cells (P < 0.02). Rates of [3H]thymidine uptake were similar in control and NIDDM fibroblasts (basal, 28.3 +/- 2.8 vs. 39.2 +/- 8.0; maximum, 50.9 +/- 7.2 vs. 69.3 +/- 16.9 dpm x 10(-3), respectively). Rates of uptake increased similarly in control and NIDDM cells by 1.8 +/- 0.1- and 1.7 +/- 0.1-fold above basal. Maximum specific fibroblast insulin binding was similar for control and NIDDM subjects (194.0 +/- 29.2 vs. 176.1 +/- 24.9 fmol 125I-labeled insulin bound/mg protein respectively). The tyrosine kinase activity of insulin receptors isolated from the control and NIDDM fibroblasts was similar (basal, 135 +/- 30 vs. 149 +/- 33; submaximal, 153 +/- 28 vs. 155 +/- 30; and maximal insulin, 191 +/- 45 vs. 213 +/- 48 dpm.mg protein-1 x min-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Wells
A M
AM
Human Metabolism Research Centre, University of Newcastle upon Tyne, United Kingdom.
Sutcliffe
I C
IC
Johnson
A B
AB
Taylor
R
R
D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis*; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D012016:Reference Values; D012867:Skin / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism
D007328:Insulin; C008147:insulin, iodo-; D006003:Glycogen; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D005947:Glucose; D013936:Thymidine