A Causative Role for Amylin in Diabetic Peripheral Neuropathy

Overview

Three pieces of information lead to the basis for this study: 1. Individuals with Type-2 diabetes commonly develop peripheral neuropathy. 2. Increased production of the hormone amylin occurs in individuals who have Type-2 diabetes. 3. Aggregations of amylin was found in the peripheral vasculature of rats that overexpressed human amylin. The purpose of this study is to determine whether a correlation exists between the amount of amylin present in the upper extremities of human subjects with Type-2 diabetes and the extent to which symptoms of peripheral neuropathy are expressed in those subjects. The investigators will be testing this by initially collecting blood and skin biopsy samples from subjects, followed by measuring patient sensation and pain responses to heat, cold, and pressure in the upper extremities.

Impaired blood flow through microvessels (arterioles and capillaries) leads to irreversible damage to cells within the affected watershed. In addition to hypertension and age, Type-2 diabetes (DMII) independently contributes to microvascular disease. Distinct from other diabetic complications, the impact of diabetes on neurovascular function has not clearly been shown to correlate with measures of hyperglycemia or peripheral glucose regulation. The pathophysiology underlying the association between type-2 diabetes, vascular injury and neural damage, including CNS parenchymal loss and PNS neuropathy, remains uncertain. Normally amylin, a byproduct of the synthesis of insulin by pancreatic β-cells, crosses the blood brain barrier and binds to neurons in feeding centers where it is believed to induce anorexic effects. Amylin aggregates are found in microvessels of pancreas, brain, hearts and kidneys of individuals with DMII or obesity. The investigators have demonstrated amylin aggregates in microvessels of peripheral nerves in rats overexpressing human amylin (unpublished). It is unknown whether amylin deposits are a consequence or a trigger of vascular injury, but they are clearly associated and may present a potential target for reducing diabetes-associated microvascular disease. Furthermore, their accumulation in peripheral nerve microvasculature and red blood cells (RBCs) offers possible foci for a peripheral biomarker of diabetes-induced CNS microvascular disease. Hypothesis: Patients with DMII have significant amylin deposition in the peripheral vasa nervorum and on RBCs that correlates with severity of clinical peripheral polyneuropathy and reduction of peripheral nerve conduction velocities (NCVs); these amylin measures thereby become surrogates of microvascular disease and may serve as metrics of disease severity. Aim: Obtain serum HbA1c, skin punch biopsy, RBCs, NCVs and clinical sensory examination from forty consenting adults previously diagnosed with DMII. Skin biopsy from volar forearm and red blood cell samples will be processed for amylin deposition. This pilot study will provide preliminary data to fuel a larger, potentially multi-center, clinical trial investigating the utility of peripheral amylin or RBC amylin as a quantitative biomarker of microvascular disease that would include monitoring the effect of potential therapies. Measuring serum HbA1c will allow for possible correlation to chronic extracellular glucose concentration. Based on our preliminary data from a rat model of type-2 diabetes that expresses human amylin in the pancreas, the investigators anticipate an increased amylin deposition in the skin blood vessels with the progression of type-2 diabetes as measured by sensory examination and NCVs. Although not directly measured in this study, our preliminary data from the analysis of amylin deposition in cerebral blood vessels of patients with type-2 diabetes suggest that APOE 4 carriers, at risk for developing dementia, may have an increased propensity to accumulate amylin deposits in blood vessels. Thus, the ability to easily identify and target a potential driver of microvascular disease may help prevent the devastating effects of the vascular complications of DMII, including cardiovascular disease, retinopathy, nephropathy and dementia.