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overexpressing human amylin (unpublished).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.