Mouse with inducible and reversible T1D for studying metabolic memory
The broad long term objective is to provide a unique type 1 diabetes model that can be used by the complications research community to study the molecular mechanisms underlying hyperglycemic memory. The Diabetes Control and Complications Trial (DCCT) showed that in people with short-duration type 1 diabetes, intensive glycemic control dramatically reduced the occurrence and severity of diabetic microvascular complications. The post-DCCT HbA1c values for the intensive and normal control groups soon became statistically identical and remained so during the years of follow-up in the ongoing Epidemiology of Diabetes Interventions and Complications Study (EDIC). Surprisingly, the effects of a 6.5-year difference in HbA1c during the DCCT on the rate of incidence of retinopathy and nephropathy have persisted. This phenomenon has been called “metabolic” or “hyperglycemic memory”. We urgently need to discover the molecular and cellular basis of hyperglycemic memory, so that we can design ways to prevent or reverse it. The research plan is to characterize the time course of doxycycline-dependent type 1 diabetes induction, reversal, and effect of duration on re-inducibility of diabetes in double transgenic mice expressing Kir 6.2 with the V59M gain-of-function mutation under the control of the tetracycline operator (tetO), and rat insulin promoter 2-driven rtTA. The inducible and reversible diabetes phenotype will be evaluated after 1, 3, and 5 months of diabetes, in each of these groups after 1 month of normal glucose metabolism, and in each of these groups after 1 month of normal glucose followed by 1 month of re-induced diabetes. Non-induced age-matched double transgenic and doxycycline exposed age-matched non-double transgenic littermates will be used as controls. Complete metabolic profiles of mice will be obtained for all the experimental groups. The effect of Kir6.2V59M-mediated diabetes induction and reversal on islet number, morphology, and insulin content will be evaluated by immunohistochemistry followed by morphometric analysis for all the experimental groups.

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