Objectives: 

It has been proposed that the islet of Langerhans develops numerous adaptations during obesity to compensate for the increased insulin requirements, however there is little information about these adaptations. We have focused our work on the functional and structural modifications that undergo pancreatic β-cells during compensatory stages that characterize pre-type 2 diabetes associated with obesity.

Materials: 

C57/Bl-6 mice of 21-days old were randomly assigned to two groups that were fed with high fat diet (60% fat) and control diet (10% fat) for twelve weeks. Dual-wavelength microfluorimetry recordings of [Ca2+]i were used to assay diet effects on calcium handling. Single-electrode voltage-clamp technique was used to study the effect of high fat diet on voltage-gated calcium channels (VGCC) and patch-clamp for ATP-sensitive potassium channels (KATP) behavior. High resolution capacitance measurements were performed in order to monitor possible effects on exocytosis and insulin vesicle dynamics.

Results: 

After twelve weeks mice fed with high fat diet exhibited a marked increase in weight, mild hyperglycemia, hyperinsulinemia and insulin resistance. Intact islets exposed to 8 and 16mM Glucose increased the [Ca2+]i by about 2-fold compared with control diet. There was a significant hypertrophy among cells belonging to high fat diet fed mice (measured as cell capacitance) but we did not found major differences regarding current density through VGCC nor open probability of KATP channels at 0, 8 and 16mM Glucose. Unlike brief depolarizations, long depolarizations led to higher exocytotic responses in beta cells from the obese animals.

Conclusions: 

We conclude that C57/Bl-6 mice fed with 60% fat diet exhibit a functional compensatory response to insulin resistance characterized by an increased insulin vesicle supply and increased calcium signals. These functional changes could explain the characteristic hyperinsulinemia of pre-diabetic patients with obesity.