The variability in beta-cell function in placebo-treated subjects with type 2 diabetes : application of the weight-HbA1c-insulin-glucose (WHIG) model

• AIM The weight-glycosylated haemoglobin (HbA1C)-insulin-glucose (WHIG) model describes the effects of changes in weight on insulin sensitivity (IS) in newly diagnosed, obese subjects receiving placebo treatment. Thismodel was applied to a wider population of placebo-treated subjects, to investigate factors influencing the variability in IS and beta-cell function. METHODS The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3). Studies 2 and 3 consisted of nonobese subjects and subjects with advanced type 2 diabetes mellitus (T2DM). Body weight, fasting serum insulin (FSI), fasting plasma glucose (FPG) and HbA1c were used for nonlinear mixed-effects modelling (using NONMEM v7.2 software). Sources of interstudy variability (ISV) and potential covariates (age, gender, diabetes duration, ethnicity, compliance) were investigated. RESULTS An ISV for baseline parameters (body weight and beta-cell function) was required. The baseline beta-cell function was significantly lower in subjects with advanced T2DM (median difference: Study 2: 15.6%, P < 0.001; Study 3: 22.7%, P < 0.001) than in subjects with newly diagnosed T2DM (Study 1). A reduction in the estimated insulin secretory response in subjects with advanced T2DM was observed but diabetes duration was not a significant covariate. CONCLUSION The WHIG model can be used to describe the changes in weight, IS and beta-cell function in the diabetic population. IS remained relatively stable between subjects but a large ISV in beta-cell function was observed. There was a trend towards decreasing beta-cell responsiveness with diabetes duration, and further studies, incorporating subjects with a longer history of diabetes, are required.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

beta-cell function

disease progression

placebo treatment

semi-mechanistic modelling

type 2 diabetes mellitus

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