Effects of short-term experimental insulin resistance and family history of diabetes on pancreatic beta-cell function in nondiabetic individuals.
BACKGROUND
Normal glucose homeostasis is maintained despite reductions in insulin sensitivity by increasing insulin secretion. This ability to compensate for reduced insulin sensitivity is highly heritable, but the mechanisms for this compensation or its failure in type 2 diabetes (T2DM) are unknown.


OBJECTIVE
The objective of this study was to test whether individuals with a family history of T2DM have a fixed decrease in beta-cell mass or function that would be revealed as an impaired insulin secretory response to short-term insulin resistance.


METHODS
Glucose tolerance, insulin sensitivity (S(I)), and insulin response to i.v. glucose (AIR(G)) were compared in nondiabetic individuals with and without a family history of diabetes before and after nicotinic acid (NA) treatment.


METHODS
This study was performed at the Ambulatory General Clinical Research Center.


METHODS
Healthy, nonobese, nondiabetic individuals with or without a family history of T2DM were studied.


METHODS
Oral NA was given, with a final dose of 2 g/d, for at least 7 d.


METHODS
The main outcome measure was the disposition index (insulin sensitivity x insulin response) in response to NA.


RESULTS
Postchallenge plasma glucose levels rose during NA therapy regardless of family history. Neither group adequately increased their AIR(G) to maintain the disposition index. Family members did not differ from controls at baseline or after NA treatment for any outcome measure, but only 28 of 52 subjects experienced a 25% or greater fall in S(I) with NA treatment.


CONCLUSIONS
Short-term beta-cell compensation to NA-induced insulin resistance was incomplete and did not differ by genetic predisposition. A genetic defect controlling beta-cell growth in response to chronic insulin resistance better explains differences in the ability to compensate for insulin resistance than an inherited, fixed defect in beta-cell mass.
Rasouli
Neda
N
Medicine and Research Services, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.
Hale
Terri
T
Kahn
Steven E
SE
Spencer
Horace J
HJ
Elbein
Steven C
SC
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006801:Humans; D000960:Hypolipidemic Agents; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009525:Niacin
D001786:Blood Glucose; D000960:Hypolipidemic Agents; D007328:Insulin; D009525:Niacin; D005947:Glucose