32-LB: Early Selective Loss of CGRP Sensory Innervation to Cutaneous Arterioles May Be an Early Prediabetic Feature Developing prior to the Onset of Overt Type 2 Diabetes (T2D) in Rhesus Monkeys and Humans Instead of Being a Consequence

Abstract

Vasculopathy complications of T2D cause limited tissue perfusion, ulcers, and often amputation. Mechanisms underlying T2D vasculopathy remain ambiguous. Compare to normal controls, multi-molecular immunofluorescence of glabrous hand and foot skin biopsies from 12T2D monkeys and 35 humans revealed a consistent depletion of CGRP containing sensory innervation (CGRPsens) that normally mediates local vasodilatation of cutaneous resistance arterioles. By contrast, arteriole vasoconstricting noradrenergic sympathetic innervation (NAsymp) remained largely intact. Thus, a vasoconstrictive imbalance could potentially impede arteriole blood flow contributing to hypertension and reduced capillary perfusion. Further analyses of monkeys indicated that this neurovascular pathology may begin during prediabetic metabolic syndrome. Surprisingly, the NAsymp and a separate set of CGRPsens to precapillary arterioles and capillaries initially remained intact in the T2D monkeys and humans and may even be increasing. This may be a maladaptive response to dilate and increase capillary perfusion to compensate for a reduced arteriole supply. As such, dilatation of the capillaries may increase their blood volume, but inadvertently reduce the rate of blood flow resulting in anoxia. In advanced T2D, a de novo superficial shunt pathology appears and capillaries begin to deteriorate. In contrast to this neurovascular pathology occurring early or before overt T2D onset, we and others have non-painful and painful T2D neuropathies involving other types of tactile sensory innervation typically occur after T2D hyperglycemia is well established. Thus, the early stage neurovascular pathology may be a direct contributor to the onset of 2TD instead of being a consequence of TD2 hyperglycemia, and may be a potential target for early detection and pre-emptive treatment. Disclosure F. Rice: None. G. Houk: None. B.C. Hansen: None. X. Tigno: None. P. Albrecht: None.