Abstract
Type 2 diabetes mellitus is characterized by the deposition of islet amyloid polypeptide (IAPP) as amyloid in islets, a process thought to be toxic to β-cells. To determine the feasibility of targeting these aggregates therapeutically, we vaccinated transgenic (Tg) mice that overexpress human IAPP and were fed a high-fat diet to promote their diabetic phenotype. Our findings indicate that prophylactic vaccination with IAPP and its derivative IAPP7-19-TT, protects wild-type female mice, but not males, from obesity-induced early mortality, and the derivative showed a strong trend for prolonging the lifespan of Tg females but not males. Furthermore, IAPP7-19-TT-immunized Tg females cleared a glucose bolus more efficiently than controls, while IAPP-immunized Tg females showed an impaired ability to clear a glucose bolus compared to their adjuvant injected Tg controls. Interestingly, IAPP or IAPP7-19-TT treatments had no effect on glucose clearance in Tg males. Overall, these beneficial effects of IAPP targeted immunization depend on Tg status, sex, and immunogen. Hence, future studies in this field should carefully consider these variables that clearly affect the therapeutic outcome. In conclusion, IAPP targeting immunotherapy may have benefits in patients with type 2 diabetes.
Highlights
Insulin, produced by β-cells in the pancreas, has the key function of regulating blood glucose levels after food intake
Analysis of the survival curves indicated that the IAPP7-19-TT-treated Tg female mice trended strongly to survive longer than control Tg female mice (p = 0.056), with a hazard ratio of 2.5, i.e., two and a half times less likely to die than controls (Figure 1A)
Islet amyloid polypeptide is co-secreted from pancreatic β-cells with insulin and converted to amyloid deposits in type 2 diabetes [reviewed in [21]]
Summary
Insulin, produced by β-cells in the pancreas, has the key function of regulating blood glucose levels after food intake. In the early stages of type 2 diabetes, insulin production is normal or increased in absolute terms, but this is insufficient to control blood glucose levels due to reduced insulin sensitivity [1]. There may be a deficit in the ability of the pancreas to secrete insulin to closely match the temporal rise in blood glucose levels, for example, immediately following a meal, resulting in hyperglycemia. Post mortem studies indicate that between 40 and 90% of patients with type 2 diabetes show signs of amyloidosis, Immunotherapy Targeting IAPP and amyloid formation is a significant factor in the deterioration of islet function and reduction in β-cell mass [reviewed in [7]]. The process of IAPP deposition in the pancreas has been likened to amyloid-β (Aβ) deposition in the brain of Alzheimer’s disease patients
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