Influence of hyperinsulinemia and insulin resistance on in vivo β-cell function: their role in human β-cell dysfunction.
OBJECTIVE
Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR).


METHODS
Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at isoglycemia (IISR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and β-cell glucose sensitivity (β-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study.


RESULTS
In NGT, IISR was related to both insulin sensitivity and antecedent insulin exposure; GISR was related to insulin exposure. IISR was positively, if weakly, related to β-GS (r= 0.16, P < 0.0001). Both IISR (-23 [39] vs. -9 [2]%, median [interquartile range], P < 0.03) and β-GS (69 [47] vs. 118 [83] pmol ⋅ min(-1) ⋅ m(-2) ⋅ mmol(-1) ⋅ L, P < 0.0001) were decreased in IGR compared with NGT. Insulin sensitivity and β-GS were the major determinants of mean OGTT glucose in both NGT and IGR, with a minor role for IISR. In a multivariate logistic model, IGR was predicted by β-GS (odds ratio 4.84 [95% CI 2.89-8.09]) and insulin sensitivity (3.06 [2.19-4.27]) but not by IISR (1.11 [0.77-1.61]).


CONCLUSIONS
Pre-exposure to physiological hyperinsulinemia stimulates insulin secretion to a degree that depends on insulin sensitivity. However, this phenomenon has limited impact on β-cell dysfunction and dysglycemia.
National Research Council Institute of Biomedical Engineering, Padova, Italy. andrea.mari@isib.cnr.it
Andrea
A
Mari
Andrea
A
Tura
Andrea
A
Natali
Christian
C
Anderwald
Beverley
B
Balkau
Nebojsa
N
Lalic
Mark
M
Walker
Ele
E
Ferrannini
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged
D001786:Blood Glucose; D007328:Insulin; D005947:Glucose