Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation

Aims/hypothesis: Increased dietary fat intake is associated with obesity and insulin resistance, but studies have shown that the subsequent increase in insulin release is not appropriate for this obesity-induced insulin resistance. We therefore sought to determine whether the impaired beta cell adaptation is due to inadequate expansion of the beta cell population or to a lack of an adaptive increase in insulin release.Methods: Male mice were fed diets containing increasing amounts of fat (15, 30 or 45% of energy intake) for 1 year, after which islet morphology and secretory function were assessed.Results: Increased dietary fat intake was associated with a progressive increase in body weight (p < 0.001). Fractional beta cell area (total beta cell area/section area) was increased with increasing dietary fat (1.36 +/- 0.39, 2.46 +/- 0.40 and 4.93 +/- 1.05%, p < 0.001), due to beta cell hyperplasia, and was positively and highly correlated with body weight (r(2)=0.68, p < 0.005). In contrast, insulin release following i.p. glucose did not increase with increasing dietary fat (118 +/- 32, 108 +/- 47 and 488 +/- 200 pmol/l per mmol/l, p=0.07) and did not correlate with body weight (r(2)=0.11). When this response was examined relative to fractional beta cell area (insulin release/fractional beta cell area), it did not increase but rather tended to decrease with increasing dietary fat (157 +/- 55, 43 +/- 13 and 97 +/- 53 [pmol/l per mmol/l]/%, p=0.06) and did not correlate with body weight (r(2)=0.02).Conclusions/interpretation: Long-term fat feeding is associated with an increase in the beta cell population but an inadequate functional adaptation. Thus, a functional rather than a morphological abnormality appears to underlie dietary-fat-induced beta cell dysfunction.