Optimal Blood Glucose Control During 18 Years Preserves Peripheral Nerve Function in Patients With 30 Years’ Duration of Type 1 Diabetes

JAKOB R. LARSEN 1 2 HANS SJOHOLM PHD 0 KRISTIAN F. HANSSEN PHD 2 4 LEIV SANDVIK PHD 3 TORE J. BERG PHD 2 4 KNUT DAHL-JORGENSEN 1 2 0 Neurophysiology Department, Ulleval Univer- sity Hospital , Oslo , Norway; the 1 Pediatrics Department, Ulleval University Hospital , Oslo , Norway; the 2 Diabetes Research Center, Aker and Ulleval University Hospitals , Oslo , Norway; the 3 Center for Clinical Research, Ulleval University Hospital , Oslo , Norway. and Ullevaal Diabetes Research Center, Ullevaal University Hospital , Oslo , Norway 0407 4 Endocrinology Department, Aker University Hospital , Oslo , Norway; and the OBJECTIVE - To assess the association between 18 years of mean HbA1c and nerve conduction parameters of the lower limb in patients with type 1 diabetes of 30 years' duration. RESEARCH DESIGN AND METHODS - HbA1c has been examined prospectively since 1982 in a group of 39 patients with type 1 diabetes. Mean age at baseline was 25 years (range 18 - 40) with 12 years' disease duration. The mean age at diagnosis of diabetes was 12.5 years. Nerve function of lower limbs was assessed at baseline, after 8 years, and after 18 years. RESULTS - A total of 23 men and 16 women were studied. Mean age was 43 years. Mean HbA1c was 8.2% (range 6.6 -11.3) during 18-year follow-up. Nerve conduction velocity (NCV) and nerve action potential amplitude (NAPA) at the last examination were significantly associated with mean HbA1c (P 0. 05). From 1982 to 1999, there was a significant reduction in nerve function in patients with mean HbA1c 8.4% (highest tertile). For example, the mean NCV in the tibial nerve was reduced from 47 to 31 m/s (P 0.01). The number of nerves with NCV (P 0.01) and NAPA (P 0.01) reduced to below the reference level in each patient was also significantly associated to mean HbA1c. No significant associations were found between nerve function parameters, sex, disease duration, blood pressure, serum cholesterol, microalbuminuria, or smoking. CONCLUSIONS - The present study shows that mean HbA1c is a strong predictor of nerve function. Mean HbA1c 8.4% over 18 years was associated with near-normal nerve function. - D among the most common longiabetic polyneuropathy (DPN) is term complications of diabetes (1). Pathological electrophysiological nerve investigations in the lower limbs are a hallmark of DPN (2). Evaluating nerve conduction parameters in the lower limbs has been shown to be a reliable method of assessing the severity of DPN (3). The most common type of DPN is both a motor and sensory polyneuropathy but is primarily sensory. The natural history of DPN is still not well understood (4). Hyperglycemia is an important causal factor (59). Long-term studies of more than 10 years on the effect of chronic hyperglycemia on DPN are rare, especially in patients with intensive insulin therapy. In this prospective study of type 1 diabetic patients undergoing intensive insulin treatment, we examined nerve conduction velocity (NCV) and nerve action potential amplitude (NAPA) in the lower limbs in 1982, 1990, and 1999. The association between mean HbA1c over 18 years and nerve conduction at 18-year follow-up was studied. RESEARCH DESIGN AND METHODS A total of 39 of the patients from the Oslo study of type 1 diabetes were included in the present study. The design of the Oslo study is described in detail elsewhere (8,9). At inclusion in the present study, in 1982, the patients were between 18 and 42 years of age with disease duration between 7 and 23 years. In all patients, type 1 diabetes had been diagnosed before 30 years of age. The mean age for diagnosis of diabetes was 12.5 years, and 90% cases were diagnosed before 21 years of age. At initial inclusion into the study, the patients had either minor diabetes complications or none at all. For example, six patients had one single NCV slightly below the normal range with values between 35 and 39 m/s (mean 38). There was no evidence of alcohol abuse in any patients. A general neurological examination did not reveal any clinical signs of neuropathy. The original study included 45 patients and was designed to study the effect of intensive insulin treatment on microvascular complications. After 2 and 4 years of intensive insulin therapy with multiple insulin injections or insulin pump treatment, this therapy was shown to be superior to the traditional treatment with two injections of insulin daily in slowing down the development of microvascular late complications of diabetes (8,10). After 4 years, all patients were offered intensified insulin treatment. At the time of the present study, in 1999, the patients had been followed for 18 years. A total of 39 patients are still being followed and 2 patients have died, 1 of breast cancer and 1 of lung disease. Four patients have declined further participation. Written informed consent was obtained from all participants at baseline and at the last follow-up visit. The study protocols were approved by the regional ethics committee. Laboratory examinations HbA1c was measured prospectively by ion-exchange chromatography until 1987 and by high-performance liquid chromatography (Variant; Bio-Rad, Richmond, CA) thereafter, except for a short period with DCA 2000 (Bayer Diagnostics, Tarrytown, NY) in a few patients. The methods correlated closely (r 0.97 and 0.96, respectively), and no corrections of HbA1c values were considered necessary (reference values 4.1 6.4%). The intraassay coefficient of variation was 5% for the first method and 3% for the later methods. Lipid profiles were measured by conventional methods in the fasting state, and blood pressure was measured in the sitting position after at least 15 min of rest. Information about smoking habits and use of medication was obtained through questionnaires. Urine samples (24 h) were collected and analyzed to determine urinary excretion of albumin. Microalbuminuria was defined as urinary albumin excretion 30 mg/24 h in two of three samples, and overt nephropathy was defined as albumin excretion 300 mg/24 h in two of three samples. Height and weight were measured, and BMI was calculated as body weight (kg) divided by height squared (m2). Neurophysiologic examinations NCV and NAPA in the lower limbs were measured by experienced specialists in neurophysiology using the same methods. However, the long observation time made it necessary to change the registration equipment used for optimal registrations. The neurophysiologic studies at the last examination were performed with Key Point Equipment (Medtronic, Denmark). At the initial inclusion, Medelec MS 92 (Oxford Instruments Medical, Old Woking, U.K.) equipment was used and, after 8 years, measurements were performed with DISA Neuromatic electromyography equipment (Electronic, Skovlunde, Denmark). Standard recording sites and temperature control between 32 and 33C were ensured at all occasions. Reference values are the same for the (...truncated)