S. Fourlanos,
P. Narendran, L.C. Harrison, in collaboration with P.G. Colman, Department
of Diabetes & Endocrinology, Royal Melbourne Hospital; G.B. Byrnes,
Centre for Genetic Epidemiology, The University of Melbourne
Glucose homeostasis
is determined by an interrelationship between insulin secretion and
insulin action. In type 1 diabetes, an autoimmune process destroys pancreatic
beta cells leading to impaired insulin secretion. However, the contribution
of impaired insulin action (insulin resistance) to the development of
type 1 diabetes has received little attention. Therefore, we prospectively
investigated people at risk for type 1 diabetes to determine the role
of insulin resistance as a risk factor for progression to clinical disease.
First-degree
relatives of type 1 diabetes patients identified as islet antibody-positive
(pre-clinical diabetes) were followed for a median of 4 years. Insulin
secretion was measured as first phase insulin response (FPIR) to intravenous
glucose and insulin resistance was estimated by the homeostasis of model
assessment (HOMA-R). Subjects who progressed (n=43) and did not progress
(n=61) to diabetes, including 21 progressors and non-progressors matched
for age, sex, number of islet antibodies and insulin secretion, were
compared.
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Progressors had higher
insulin resistance relative to insulin secretion at baseline (Figure
1), and over follow-up to diabetes. Multivariate analysis identified
that, in addition to the recognized predictive value of islet
antibody number and level of insulin secretion, insulin resistance
relative to insulin secretion (logHOMA-R/FPIR) was independently
predictive of progression to diabetes.
Figure
1: Relationship between baseline HOMA-R and FPIR in progressors
(filled circles) and non-progressors (open circles)
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Thus, islet
antibody-positive relatives who progress most rapidly to diabetes have
a subtle disturbance of insulin-glucose homeostasis years before diagnosis,
being distinguished by greater insulin resistance for their level of
insulin secretion. Insulin resistance is potentially modifiable by diet,
physical activity and insulin-sensitizing drugs and approaches to reduce
insulin resistance might delay the development of type 1 diabetes.
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