Increased Proinsulin Levels and Decreased Acute Insulin Response Independently Predict the Incidence of Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study

Abstract

Previous studies have indicated that ␤-cell dysfunction predicts the development of diabetes, although it is unknown whether the use of combinations of insulin secretory measures further improves prediction. The Insulin Resistance Atherosclerosis Study is a prospective, multicenter, epidemiological study of the relationship between insulin sensitivity and the risk of diabetes and cardiovascular disease. At baseline, fasting concentrations of insulin, intact proinsulin (PI), and split PI were measured, and acute insulin response (AIR) was determined during a frequently sampled intravenous glucose tolerance test (FSIGTT). Subjects who were nondiabetic at baseline (n ‫؍‬ 903) were reexamined after 5 years of follow-up; 148 had developed diabetes. In separate logistic regression models adjusted for age, sex, clinic, and ethnicity, 1 SD differences in measures of ␤-cell dysfunction were associated with diabetes incidence (AIR: odds ratio [OR] 0.37, 95% CI 0.27-0.52; intact PI: OR 1.90, 95% CI 1.57-2.30; split PI: OR 1.94, 95% CI 1.63-2.31). After additional adjustment for BMI, impaired glucose tolerance, and insulin sensitivity, these measures continued to be significantly associated with risk of diabetes (all P < 0.0001). Furthermore, in models that included both PI and AIR, each was an independent predictor, and individuals who had combined low AIR and high PI experienced the highest diabetes risk. In conclusion, both low AIR and high PI independently predicted diabetes in a well-characterized multiethnic population. Although fasting PI is simpler to assess, determining AIR from an FSIGTT may further improve prediction. If pharmacological agents to prevent diabetes are proved to be efficacious in ongoing clinical trials, then it may be beneficial to perform FSIGTTs to identify better (for intensive intervention) prediabetic subjects who would ultimately require lifelong pharmacological therapy.

Characterisation of subjects with early abnormalities of glucose tolerance in the Stockholm Diabetes Prevention Programme: the impact of sex and type 2 diabetes heredity

“…Interestingly, the HOMA analysis showed that subjects with IFG have more pronounced impairments of beta cell function than subjects with IGT. We also observed increased PI levels in males with IFG as compared to IGT, which may indicate more pronounced impaired beta cell responsiveness in IFG [19]. However, an influence of insulin resistance in this context cannot be ruled out [20].…”

Identification of Subjects with Insulin Resistance and β-Cell Dysfunction Using Alternative Definitions of the Metabolic Syndrome

“…Although the magnitudes of the associations were weaker than those for S i , there were a number of notable ethnic differences, including a stronger association of NCEP-MetS with low AIR and low DI among blacks. This observation is significant in light of the well-documented prospective association between ␤-cell dysfunction and risk of diabetes, an association that is independent of directly measured insulin sensitivity (45,46). The biological mechanism underlying the association between MetS and ␤-cell dysfunction may be related to the fact that a number of MetS components, including elevated abdominal obesity and triglyceride concentration and reduced HDL levels, are strongly correlated with elevated circulating concentrations of free fatty acids (47), chronic elevations of which are known to be associated with lipotoxic damage to the pancreatic ␤-cells (48).…”

Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study

“…It was recently reported that the proinsulin : insulin ratio and the acute insulin response were independent predictors of type 2 diabetes. Individuals with a combination of a low acute insulin response and a high proinsulin : insulin ratio were at the highest risk of developing type 2 diabetes [39]. Furthermore, in a recent Swedish study proinsulin predicted cardiovascular death and morbidity over a period of 27 years, independently of other major cardiovascular risk factors [40].…”