The pathogenesis and pathophysiology of diabetic autonomic neuropathy is poorly understood and its treatment unsatisfactory. Autonomic dysfunction of IDDM may be different to that of NIDDM, but studies to date have been limited by significant selection bias and the instruments to evaluate symptoms and autonomic dysfunction have not been available. We will undertake a population-based study to test the hypothesis that autonomic symptoms and deficits in the neuropathy of IDDM are different to those of NIDDM, with greater involvement of the splanchnic- mesenteric bed in IDDM. In this study we will evaluate autonomic symptoms using our validated instrument, the autonomic symptom profile, in the entire cohort of 322 patients (IDDM and NIDDM;
Specific aim number 1) in the Rochester Diabetic Project (Director: Peter Dyck). This autonomic symptom profile will be combined with a laboratory profile of cardiovagal, adrenergic and sudomotor dysfunction, and by laboratory evaluation of the splanchnic-mesenteric, systemic, and cerebrovascular beds, catecholaminergic responses, and gastric transit and accommodation studies (Specific aim number 2). Mesenteric blood flow will be measured using 2-D doppler ultrasound, cerebral perfusion using transcranial doppler, beat-to-beat BP using Finapres, and heart rate from electrocardiographic monitor. Whether a patient develops symptoms of orthostatic hypotension depends on cerebral autoregulation, a process whereby cerebral perfusion remains unchanged in the face of changing systemic BP. We hypothesize that the autoregulatory slope relating the change in cerebral perfusion to that of blood pressure (BP) (deltaBFV: deltaBP), and is an index of autoregulatory adaptation, changes with duration and severity of orthostatic hypotension in diabetic autonomic neuropathy. We will evaluate cerebrovascular autoregulatory adaptation in patients with IDDM and NIDDM (Specific aim number 3). Treatment of diabetic orthostatic hypotension with alpha-agonists or fludrocortisone cause or aggravate supine hypertension. This is a particular problem in diabetics, who have increased small and large vessel atherosclerotic disease. We will evaluate if cholinesterase inhibition, by increasing ganglionic neurotransmission, will, by restoring transmission of some fibers, and amplify the efficiency of residual baroreflexes, improve orthostatic hypotension without supine hypertension (Specific aim number 4).
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| Vernino, Steven; Sandroni, Paola; Singer, Wolfgang et al. (2008) Invited Article: Autonomic ganglia: target and novel therapeutic tool. Neurology 70:1926-32 |
| Singer, Wolfgang; Sandroni, Paola; Opfer-Gehrking, Tonette L et al. (2006) Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol 63:513-8 |
| Gehrking, Jade A; Hines, Stacy M; Benrud-Larson, Lisa M et al. (2005) What is the minimum duration of head-up tilt necessary to detect orthostatic hypotension? Clin Auton Res 15:71-5 |
| Muenter Swift, N; Charkoudian, N; Dotson, R M et al. (2005) Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome. Am J Physiol Heart Circ Physiol 289:H1226-33 |
| Sandroni, Paola; Vernino, Steven; Klein, Caroline M et al. (2004) Idiopathic autonomic neuropathy: comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody. Arch Neurol 61:44-8 |
| Wang, Yanping; Schmelzer, James D; Schmeichel, Ann et al. (2004) Ischemia-reperfusion injury of peripheral nerve in experimental diabetic neuropathy. J Neurol Sci 227:101-7 |
| Low, Phillip A; Benrud-Larson, Lisa M; Sletten, David M et al. (2004) Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care 27:2942-7 |
| Vincent, Andrea M; Russell, James W; Low, Phillip et al. (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25:612-28 |
| Singer, W; Spies, J M; McArthur, J et al. (2004) Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies. Neurology 62:612-8 |
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