Role of Insulin Secretion and Sensitivity in the Evolution of Type 2 Diabetes in the Diabetes Prevention Program

Abstract

Insulin resistance and ␤-cell dysfunction, two factors central to the pathogenesis of type 2 diabetes, were studied in relation to the development of diabetes in a group of participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP) at baseline and after specific interventions designed to prevent diabetes. Participants were randomly assigned to placebo (n ‫؍‬ 1,082), metformin (850 mg twice a day) (n ‫؍‬ 1,073), or intensive lifestyle intervention (n ‫؍‬ 1,079). The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio ‫؍‬ 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity) and with baseline insulin secretion (hazard rate ratio ‫؍‬ 0.57-0.76 per SD). Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio ‫؍‬ 0.46 -0.95 per SD increase and 0.29 -0.79 per SD increase, respectively). In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables. The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of ␤-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and ␤-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and ␤-cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups. In conclusion, higher insulin secretion and sensitivity at baseline and improvements in response to treatment were associated with lower diabetes risk in the DPP. The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of ␤-cell function.

Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants

“…This improvement in insulin sensitivity was associated with reduction of the risk of the development of diabetes overall and in each treatment arm (16). This is concordant with other diabetes prevention randomized controlled trials showing that improvement in insulin sensitivity induced by lifestyle intervention is a strong predictor of risk reduction in individuals with diabetes (17).…”

Cardiometabolic Risk in Chinese Women with Prior Gestational Diabetes: A 15-Year Follow-Up Study

“…We could not find the same prediction with β-cell functions represented by HOMA-BCF and the insulinogenic indices. Although it has been well accepted that the interplay between insulin resistance and decrease in β-cell capacity predates the occurrence of frank DM [35,36,37,38,39,40,41,42], Tabák et al [43] have recently demonstrated that β-cell function might not decline until 2 years prior to the occurrence of DM. Their finding also suggests that insulin sensitivity could start to decline as long as 13 years prior to the occurrence of DM while the trajectory of β-cell function could follow a rise between 3 and 4 years and decline 2 years prior to DM [43].…”

H. pylori seroprevalence and risk of diabetes: An ancillary case–control study nested in the diabetes prevention program

“…Several studies have reported on the association between H. pylori infection and insulin resistance with mixed results 15,16,21,38 but none have reported the association between H. pylori and composite beta-cell function as measured by disposition index-like measure from OGTT, which is a measure of pancreatic beta cell function that captures both insulin secretion and insulin sensitivity 23 . A low disposition index-like measure from OGTT indicates an impaired pancreatic beta cell function and is a validated predictor of diabetes risk 39,40 .…”

“…A composite beta-cell function (disposition index-like measure from OGTT) was estimated by the product of the corrected insulin response (CIR) and insulin-sensitivity index (ISI), as previously used in the DPP 23 . Corrected insulin response was calculated as follows: (100 × insulin at 30 minutes) ÷ (glucose at 30 minutes × [glucose at 30 minutes – 70 mg/dL]).…”