Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide.

Islet amyloid deposition in type 2 diabetes is associated with reduced beta-cell mass. Therefore, interventions aimed at reducing islet amyloid formation may help preserve beta-cell mass in type 2 diabetes. Rosiglitazone and metformin act by different mechanisms to improve insulin sensitivity and thereby reduce beta-cell secretory demand, resulting in decreased release of insulin and islet amyloid polypeptide (IAPP), the unique constituent of islet amyloid deposits. We hypothesized that this reduced beta-cell secretory demand would lead to reduced islet amyloid formation. Human IAPP (hIAPP) transgenic mice, a model of islet amyloid, were treated for 12 months with rosiglitazone (1.5 mg.kg(-1).day(-1), n = 19), metformin (1 g.kg(-1).day(-1), n = 18), or control (n = 17). At the end of the study, islet amyloid prevalence (percent islets containing amyloid) and severity (percent islet area occupied by amyloid), islet mass, beta-cell mass, and insulin release were determined. Islet amyloid prevalence (44 +/- 8, 13 +/- 4, and 11 +/- 3% for control, metformin-, and rosiglitazone-treated mice, respectively) and severity (9.2 +/- 3.0, 0.22 +/- 0.11, and 0.10 +/- 0.05% for control, metformin-, and rosiglitazone-treated mice, respectively) were markedly reduced with both rosiglitazone (P < 0.001 for both measures) and metformin treatment (P < 0.001 for both measures). Both treatments were associated with reduced insulin release assessed as the acute insulin response to intravenous glucose (2,189 +/- 857, 621 +/- 256, and 14 +/- 158 pmol/l for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin vs. control and P < 0.005 for rosiglitazone vs. control), consistent with reduced secretory demand. Similarly, islet mass (33.4 +/- 7.0, 16.6 +/- 3.6, and 12.2 +/- 2.1 mg for control, metformin-, and rosiglitazone-treated mice, respectively) was not different with metformin treatment (P = 0.06 vs. control) but was significantly lower with rosiglitazone treatment (P < 0.05 vs. control). When the decreased islet mass was accounted for, the islet amyloid-related decrease in beta-cell mass (percent beta-cell mass/islet mass) was ameliorated in both rosiglitazone- and metformin-treated animals (57.9 +/- 3.1, 64.7 +/- 1.4, and 66.1 +/- 1.6% for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin or rosiglitazone vs. control). In summary, rosiglitazone and metformin protect beta-cells from the deleterious effects of islet amyloid, and this effect may contribute to the ability of these treatments to alleviate the progressive loss of beta-cell mass and function in type 2 diabetes.

Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice.

Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and beta-cell dysfunction. Islet amyloid is associated with reduced beta-cell mass and function and develops in the majority of our C57BL/6J x DBA/2J (F(1)) male human islet amyloid polypeptide (hIAPP) transgenic mice after 1 yr of increased fat feeding. To determine the relative contribution of each parental strain, C57BL/6J (BL6) and DBA/2J (DBA2), to islet amyloid formation, we studied male hIAPP mice on each background strain (BL6, n = 13; and DBA2 n = 11) and C57BL/6J x DBA/2J F(1) mice (n = 17) on a 9% (wt/wt) fat diet for 1 yr. At the end of 12 mo, islet amyloid deposition was quantified from thioflavin S-stained pancreas sections. The majority of mice in all groups developed islet amyloid (BL6: 91%, F(1): 76%, DBA2: 100%). However, the prevalence (%amyloid-positive islets; BL6: 14 +/- 3%, F(1): 44 +/- 8%, DBA2: 49 +/- 9%, P < 0.05) and severity (%islet area occupied by amyloid; BL6: 0.03 +/- 0.01%, F(1): 9.2 +/- 2.9%, DBA2: 5.7 +/- 2.3%, p < or = 0.01) were significantly lower in BL6 than F(1) and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin-positive area per islet, in F(1) (r(2) = 0.75, P < 0.001) and DBA2 (r(2) = 0.87, P < 0.001) mice but not BL6 mice (r(2) = 0.07). In summary, the extent of islet amyloid formation in hIAPP transgenic mice is determined by background strain, with mice expressing DBA/2J genes (F(1) and DBA2 mice) being more susceptible to amyloid deposition that replaces beta-cell mass. These findings underscore the importance of genetic and environmental factors in studying metabolic disease.