Heightened Norepinephrine-Mediated Vasoconstriction in Type 2 Diabetes Robert V. Hogikyan, Andrzej T. Galecki, Jeffrey B. Halter, and Mark A. Supiano Adrenergic responsiveness (AR) appears to be increased in subjects with diabetes, but measurement of arterial AR in normotensive people with type 2 diabetes mellitus has not been previously reported. We sought to determine whether, compared with control subjects, there is increased arterial AR in type 2 diabetes meilitus and its relationship to the level of systemic sympathetic nervous system activity (SNSa). We studied 15 type 2 diabetic subjects aged 57 -+ 3 years without hypertension or clinical signs of autonomic neuropathy and 13 age-matched control subjects aged 55 ~- 2 years. We aSsessed vascular ~-AR by measuring forearm blood flow (FABF) by venous occlusion plethysmography during intrabrachial artery norepinephrine (NE) and phentolamine infusions, as well as arterial plasma NE levels and the extravascular NE releaSe rate (NE2) derived from 3H-NE kinetics, as estimates of systemic SNSa. The vasoconstricting effect of NE during intrabrachial artery NE infusion was greater in type 2 diabetes compared with control subjects (P = .02). The vasodilating effect of phentoiamine was greater in type 2 diabetics compared with control subjects (P= .05), suggesting increased endogenous arterial ~-adrenergic tone. Arterial plasma NE levels (control vtype 2, 1.8 -+ 0.10 v 1.84 +- 0.14 nmol/L, P = .86) and NE2 (control vtype 2, 11.8 ± 1.54 v 13.3 -+ 0.89 nmol/min/m 2, P = ,39) were similar in the two groups. In summary, in type 2 diabetes compared with control subjeCts, (1) the vasoconstriction response to intraarterial NE is greater, (2) plasma NE and NE2 are similar, suggesting similar levels of systemic SNSa, and (3) arterial ~-adrenergic tone is greater. We conclude that subjects with type 2 diabetes demonstrate inappropriately increased ~-AR for their level of systemic SNSa. Copyright © 1999 by W.B. Saunders Company T HE REGULATION OF vascular tone involves the coordi- nated integration of multiple systems including the sym- pathetic nervous system (SNS). In individuals with diabetes mellitus, the regulation of vascular tone may be altered and may contribute to long-term sequelae such as vascular disease, including hypertension. Also, in insulin-resistant persons with type 2 diabetes, high insulin levels have been associated with vascular disease.1 Studies of SNS function in diabetes have largely focused on type 1 diabetes patients with autonomic neuropathy. Studies of SNS activity ([SNSa] estimating the release of norepinephrine [NE] from nerve terminals) have demonstrated decreased plasma NE levels and NE spillover into the circulation, consistent with neuropathic damage to peripheral sympathetic nerves. 2,3 Vascular a-adrenergic responsiveness ([a-AR] the effector-cell response to NE) has been reported to be increased in such patients, consistent with upregulation in response to decreased SNSa. 4 The increase in vascular a-AR in diabetes could also be explained by endothelial dysfunction or resistance to the vascular effects of insulin, since both nitric oxide 5 and insulin 6 have been demonstrated to impair a-adrenergic re- From the Division of Geriatric Medicine, Department of Internal Medicine, and lnstitute of Gerontology, University of Michigan; and the Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Ann Arbor, MI. Submitted February 4, 1999; accepted June 14, 1999. Supported in part by National Institutes of Health Grants No. RR-O0042 to the University of Michigan General Clinical Research Center, AG-08808 to the Claude D. Pepper Older Americans Indepen- dence Center, and DK-20572 to the Michigan Diabetes Research and Training Center at the University of Michigan, by the Medical Research Service of the Department of Veterans Affairs, and by a grant from the John A. Hartford Foundation. Presented in part at the 55th National Meeting of the American Diabetes Association in Atlanta, GA, June 10-13, 1995. Address reprint requests to Robert V. Hogikyan, MD, GRECC (llG), VA Medical Center, 2215 Fuller Rd, Ann Arbor, M148105. Copyright © 1999 by W.B. Saunders Company 0026-0495/99/4812-0015510.00/0 sponses. Although there is some evidence that elevated SNSa may be present in individuals with elevated insulin levels, 7,s little information is available about the relationship between SNSa andAR in otherwise healthy humans with type 2 diabetes. The present study was designed to determine the relationship between SNSa and arterial NE-mediated vasoconstriction in normotensive subjects with type 2 diabetes compared with normotensive control subjects. We hypothesized that NE- mediated vasoconstriction is increased in people with type 2 diabetes. SUBJECTS AND METHODS Subjects Thirteen control subjects and 15 subjects with type 2 diabetes in otherwise good general health were recruited through newspaper advertisement and the Human Subjects Core of the Geriatrics Center at the University of Michigan. Subjects were screened before study entry by a medical history, physical examination, and laboratory tests including a complete blood cell count and routine chemistries. Diabetic subjects were classified as type 2 by their primary care providers. All had adult-onset diabetes and no history of ketoacidosis. We specifically targeted a group of subjects with limited heterogene- ity with respect to body weight and blood pressure. Subjects were excluded from participation if they exceeded 150% of their ideal body weight (Metropolitan Life Insurance Tables, 1983), had a history of hypertension or a resting seated blood pressure greater than 160 mm Hg systolic or greater than 90 mm Hg diastolic, or had evidence from either the history, physical examination, or laboratory results of other signifi- cant underlying illness. Subjects were excluded if they were taking vasoactive medications (eg, calcium-channel blocker, angiotension- converting enzyme inhibitor, [3-blocker, etc.). One of the subjects with diabetes was African-American and the remainder were Caucasian. Three subjects with type 2 diabetes were on replacement therapy for hypothyroidism with a thyrotropin level in the normal range. Two diabetic subjects were taking a diuretic for lower-extremity edema. Diabetes treatment regimens included diet alone (n = 4), a sulfonylurea (n = 6), insulin (n = 3), a sulfonylurea plus insulin (n = 1), and metformin (n = 1). With regard to the duration of diabetes, four subjects were newly diagnosed, four reported a diabetes duration of 5 years or less, three reported a diabetes duration of 10 years or less, three reported a diabetes duration greater than 10 years, and one was 1536 Metabolism, Vol 48, No 12 (December), 1999:pp 1536-1541