Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state.
OBJECTIVE
To evaluate insulin sensitivity and insulin secretion in prediabetic and diabetic subjects with mutations in MODY1 (HNF-4 alpha) and MODY3 (HNF-1 alpha) genes, in subjects with GAD antibodies, latent autoimmune diabetes in adults and in subjects with the common form of Type II (non-insulin-dependent) diabetes mellitus.


METHODS
Insulin secretion was measured as the incremental 30-min insulin (I30) and insulin glucose ratio (I:G30) during OGTT whereas insulin sensitivity was measured as the insulin sensitivity index during OGTT in 131 carriers of MODY mutations [NGT = 38, IFG/IGT = 21, diabetes mellitus (DM) = 72], in 293 subjects with GADA (NGT = 47, IFG/IGT = 29, DM = 217) and in 2961 subjects with a family history of the common form of Type II diabetes but without MODY mutations or GADA (NGT = 1360, IFG/IGT = 857, DM = 744). A subgroup of the subjects underwent a euglycaemic clamp (n = 210) and intravenous glucose tolerance test (n = 337) for the estimation of insulin sensitivity and first-phase insulin secretion.


RESULTS
Non-diabetic subjects with MODY mutations had pronounced impaired insulin secretion (I30, I:G30) compared with the two other groups (p = 0.005). Normal or non-diabetic glucose tolerance was maintained by enhanced insulin sensitivity compared with the other two groups (p < 0.05 and p < 0.005). In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes. The 2-h glucose values inversely correlated with insulin sensitivity in subjects with GADA (r = -0.447, p < 0.001) and subjects from Type II diabetic families (r = -0.426, p < 0.001), whereas no such relation was observed in subjects with MODY mutations (r = 0.151, p = NS). There were no statistically significant differences in insulin secretion or insulin sensitivity between subjects with GADA or subjects with a family history of Type II diabetes, either at the NGT or the IFG/IGT stage.


CONCLUSIONS
Glucose-tolerant carriers of MODY mutations are characterised by a severe impairment in insulin secretion. Enhanced insulin sensitivity is the most likely explanation for the normal glucose tolerance. Whereas subjects with positive GADA or Type II diabetes have impaired insulin sensitivity with increasing glucose concentrations, MODY mutation carriers seem to be protected from the effect of glucose toxicity.
Tripathy
D
D
Wallenberg Laboratory, Department of Endocrinology, Lund University, Sweden.
Carlsson
A L
AL
Lehto
M
M
Isomaa
B
B
Tuomi
T
T
Groop
L
L
D000328:Adult; D017668:Age of Onset; D001323:Autoantibodies / Q000097:blood; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure; D001824:Body Constitution; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D005387:Finland; D006580:Genetic Carrier Screening; D005941:Glucokinase / Q000235:genetics; D018149:Glucose Intolerance / Q000097:blood / Q000503:physiopathology; D005951:Glucose Tolerance Test; D005968:Glutamate Decarboxylase / Q000276:immunology; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011236:Prediabetic State / Q000097:blood / Q000503:physiopathology*; D013548:Sweden; D014157:Transcription Factors / Q000235:genetics
D001323:Autoantibodies; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; C403128:MLX protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta; D005941:Glucokinase; D005968:Glutamate Decarboxylase