Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin

Abstract

Insulin resistance and beta-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 beta-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and beta-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and beta-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 beta-cell function.

Figures

FIG. 1

Plasma glucose during OGTT at baseline and year 1 by treatment group. Data are means ± SE. *P < 0.05 for test of difference between baseline and year 1 glucose value. Only participants who underwent OGTT testing at year 1 are included (i.e., those who did not develop diabetes at 6 months).

FIG. 2

Metabolic variables over time by treatment group. Data are means ± SE in conventional and SI units. All tests of mean changes over time between any two groups are statistically significant (P < 0.001) except in fasting glucose and fasting insulin between the lifestyle and metformin groups. The number of participants decreased over time because of the variable length of time that individuals were in the study. For example, data on fasting glucose were available for 3,065 at 1 year, 3,015 at 2 years, and 1,910 at 3 years.

FIG. 3

Diabetes hazard rates by baseline metabolic variables. Cox proportional hazards models were used to estimate the risk of developing diabetes. Estimates of the absolute risk gradient associated with a given value of a covariate using the range of covariate values (5th–95th percentiles) were used to describe the hazard rate for a participant with a covariate value equal to the group mean. The baseline values were standardized for comparability of the hazard rates among the covariates. The point on each line indicates the expected hazard rate for a subject with a metabolic variable equal to the mean value for the group as estimated in the life table analysis. In separate models using the baseline metabolic variables adjusted for baseline age, sex, and race/ethnicity, all three baseline metabolic variables significantly predicted progression to diabetes in all treatment groups (P < 0.001).

FIG. 4

Hazard rates for diabetes by metabolic variables at baseline and mean changes from baseline. In separate models using the baseline metabolic variables adjusted for baseline age, sex, race/ethnicity (left panels), all baseline metabolic variables significantly predicted progression to diabetes in all treatment groups (P = 0.016 in the metformin group for ISI and P < 0.001 for the rest of the variables) except for baseline weight and 1/fasting insulin in the metformin group. The time-dependent models using changes in the metabolic variables from baseline up to but not including the values at the time of progression to diabetes were adjusted for the baseline metabolic variable, baseline age, sex, and race/ethnicity (right panels). All changes in metabolic variables significantly predicted progression to diabetes (P = 0.007 for IGR in the placebo group and P < 0.001 for the rest of the variables). The metabolic variables changed from baseline at a significance level of 0.05 for all metabolic variables except for weight in the placebo group.

FIG. 5

Hazard rate for developing diabetes by tertiles of baseline insulin sensitivity and baseline insulin secretion. The tertiles are defined using the percentiles (33.3rd and 66.7th) of 1/fasting insulin (0.033 and 0.053), ISI (0.123 and 0.205), CIR (0.416 and 0.700), and IGR (80.0 and 136.0).

FIG. 6

Insulin secretion versus insulin sensitivity at baseline and year 1 by treatment group. Only participants who underwent OGTT testing at year 1 are included (i.e., those who had not previously been diagnosed with diabetes). Insulin secretion and sensitivity were calculated using glucose and insulin measured in conventional units (milligrams per deciliter and microunits per milliliter, respectively). β-Cell function is described by the relationship between insulin secretion (IGR and CIR) and insulin sensitivity (1/fasting insulin and ISI) at baseline and year 1 by treatment group. The curve represents the regression line of the logarithm of estimated insulin secretion as a linear function of the logarithm of estimated insulin sensitivity for all participants at baseline. The arrows that connect the estimated insulin secretion for the median insulin sensitivity at baseline and year 1 illustrate the effects of the interventions after 1 year.