In vivo and in vitro studies of GAD-antibody positive subjects with Type 2 diabetes: A distinct sub-phenotype.
The purpose of this study was to determine if immune mechanisms in GAD positive patients' contribute to the pathogenesis of a specific sub-type of Type 2 diabetes. GAD positive (n=8) and GAD negative (n=8) subjects diagnosed with Type 2 diabetes were matched for age, gender, body mass index, duration of diabetes and glycaemic control. All subjects underwent an insulin-modified frequently sampled intravenous glucose tolerance test to measure insulin sensitivity and insulin secretory function with minimal model analysis. In addition, BRIN-BD11 clonal beta-cells were supplemented with patients' sera to determine basal and alanine-stimulated insulin secretion and terminal complement complex (TCC) formation. Both groups were severely insulin resistant (0.56+/-0.17 vs. 0.99+/-0.3310(-4)min(-1)/(microUml(-1)) for GADneg and GADpos, respectively) but the GAD negative subjects had a higher basal (87+/-11 vs. 58+/-14pmoll(-1), p<0.05) and glucose-stimulated insulin secretion (DeltaAUCins 0.96+/-0.12 vs. 0.60+/-0.12pmol/(l(-1)min), p<0.05). In vivo measures of insulin secretion were negatively correlated with TCC formation, independent of antibody status. In conclusion, GAD positive subjects initially diagnosed with Type 2 diabetes are unable to compensate for insulin resistance due to more pronounced beta-cell impairment. TCC formation may be partly responsible for the insulin secretory dysfunction associated with this specific sub-type of Type 2 diabetes.
O'Gorman
Donal J
DJ
Metabolic Research Unit, Department of Endocrinology, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.
Yousif
Obada
O
Dixon
Gordon
G
McQuaid
Siobhan
S
Murphy
Elaine
E
Rahman
Yousif
Y
Gasparro
Declan
D
Pacini
Giovanni
G
Newsholme
Philip
P
Nolan
John J
JJ
D000818:Animals; D000906:Antibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007330:Insulin Antibodies / Q000097:blood; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D051381:Rats
D000906:Antibodies; D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D007330:Insulin Antibodies; D005968:Glutamate Decarboxylase