Autonomic neuropathy in nondiabetic offspring of type 2 diabetic subjects is associated with urinary albumin excretion rate and 24-h ambulatory blood pressure: the Fredericia Study.

The aim of this study was to examine the impact of parental type 2 diabetes on the autonomic nervous system and to determine whether autonomic neuropathy is present and associated with changes in 24-h ambulatory blood pressure (AMBP) and urinary albumin excretion rate (UAER) in nondiabetic subjects with parental type 2 diabetes. We examined 223 nondiabetic offspring of type 2 diabetic subjects and a control group of 258 offspring of nondiabetic subjects. The autonomic nervous system was assessed by three cardiovascular reflex tests, 24-h AMBP was measured with an oscillometric recorder (90207; Spacelabs, Redmond, WA), and UAER was determined through three overnight urine samples. The subjects with parental type 2 diabetes had significantly lower heart rate variation in all three bedside tests (P < 0.01) than subjects without parental diabetes. The prevalence of autonomic neuropathy in the nondiabetic offspring with parental type 2 diabetes (6.7%) was significantly (P < 0.01) higher compared with the control group (1.6%). Autonomic neuropathy was associated with a higher fasting insulin level (P < 0.05), higher UAER (P < 0.001), higher 24-h mean AMBP (P < 0.01), and reduced diurnal blood pressure variation (P < 0.001) after adjustment for age, sex, and BMI. In conclusion, parental type 2 diabetes was found to be associated with alterations in the autonomic nervous system in nondiabetic subjects. The presence of autonomic neuropathy in subjects with parental type 2 diabetes was associated with higher UAER, fasting insulin level, and 24-h AMBP and a reduced diurnal blood pressure variation. This study indicates that parental type 2 diabetes has an impact on the cardiac autonomic function in nondiabetic subjects.

Correlations between fasting plasma C-peptide, glucagon-stimulated plasma C-peptide, and urinary C-peptide in insulin-treated diabetics.

This study correlated fasting plasma C-peptide (CP), plasma CP 6 min after stimulation with 1 mg glucagon i.v., and the mean of three 24-h urinary excretions of C-peptide (UCP)/creatinine in 132 insulin-treated diabetics. Patients were divided into three groups: group 1, stimulated CP less than 0.06 nM (n = 51); group 2, stimulated CP 0.06-0.60 nM (n = 48); and group 3, stimulated CP greater than 0.60 nM (n = 33). In all patients fasting CP was closely correlated to stimulated CP (r = .988, P less than .001), whereas the correlations between UCP and both fasting CP (r = .904, P less than .001) and stimulated CP r = .902, P less than .001) were slightly less pronounced. The associations between UCP and both fasting CP (r = .716, P less than .001) and stimulated CP (r = .731, P less than .001) were modest in group 2, and even more so in group 3 (r = .557, P less than .001 and r = .641, P less than .001, respectively). In conclusion, fasting CP is closely correlated to glucagon-stimulated CP in insulin-treated diabetics and can probably be used equally well in the assessment of beta-cell function. The associations between UCP and both fasting and glucagon-stimulated CP are less pronounced, especially in patients with well-preserved beta-cell function.

Reproducibility of beta-cell function estimates in non-insulin-dependent diabetes mellitus.

We evaluated the reproducibility of different estimates of endogenous insulin secretion in 30 patients with non-insulin-dependent diabetes mellitus (NIDDM). Fasting blood glucose concentration was similar on the 2 days of study. The coefficients of variation of fasting plasma C-peptide, plasma C-peptide 6 min after the injection of 1 mg i.v. glucagon, and the increment in plasma C-peptide after glucagon were 16.0, 14.8 and 24.1%, respectively. The coefficients of variation of the corresponding plasma insulin values were 19.2, 24.8, and 34.8%, respectively. The coefficient of variation of 24-h urinary C-peptide excretion was 22.1%. Because fasting plasma C-peptide correlated closely with plasma C-peptide 6 min after glucagon (test 1: r = .70, P less than .01; test 2: r = .76, P less than .01), it seems that these two values can be used equally well as assessment of beta-cell function in NIDDM. In conclusion, fasting plasma insulin, fasting plasma C-peptide, and plasma C-peptide 6 min after glucagon stimulation showed a similar and acceptable degree of reproducibility. Plasma insulin 6 min after glucagon and increments in plasma insulin and C-peptide, as well as urinary C-peptide, seem to be less reproducible.

Normal blood pressure and preserved diurnal variation in offspring of type 2 diabetic patients characterized by features of the metabolic syndrome: the Fredericia Study.

OBJECTIVE: To examine whether an elevated blood pressure (BP) level and an impaired reduction in nocturnal BP are already present in nondiabetic first-degree relatives of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We examined 253 offspring of type 2 diabetic patients using ambulatory BP monitoring and compared the BP level and profile with 275 offspring of nondiabetic subjects. Anthropometric measures and cholesterol, fasting blood glucose, and insulin levels were also compared between groups. RESULTS: No significant differences in BP level (P > 0.05) or diurnal BP profile were evident between the nondiabetic glucose-tolerant offspring of type 2 diabetic subjects and the offspring of nondiabetic subjects. BMI (P < 0.05 and P < 0.01, male vs. female), waist-to-hip ratio (P < 0.05), fasting blood glucose (P < 0.01), C-peptide (P < 0.05 and P < 0.01, male vs. female), insulin resistance index (P < 0.05 and P < 0.01, male vs. female), triglycerides (P < 0.05), apolipoprotein B (apoB) (P < 0.01 and P < 0.05, male vs. female), and apoA1/apoB (P < 0.01) were significantly higher in the nondiabetic offspring of type 2 diabetic subjects than in the offspring of nondiabetic subjects. CONCLUSIONS: This study shows a preserved diurnal BP profile and a normal BP level in the nondiabetic glucose-tolerant offspring of type 2 diabetic subjects compared with the offspring of nondiabetic subjects, although the offspring of diabetic patients are characterized by features of the metabolic syndrome.

Prevalence of fasting hyperglycemia and known non-insulin-dependent diabetes mellitus classified by plasma C-peptide: Fredericia survey of subjects 60-74 yr old.

A Danish population of 5699 individuals (60-74 yr old) was screened by fasting blood glucose (FBG) and interviewed about known diabetes. The distribution of FBG in individuals not known to have diabetes showed no sex difference or significant variation with age. Fasting hyperglycemia (FH), defined as FBG greater than or equal to mM in subjects without a history of diabetes, was found in 1.7% of men and women. Known diabetes (KD) had a prevalence of 3.9 and 5.0% in men and women, respectively. The prevalence rates of FH and KD increased significantly with age. In the two subgroups, plasma C-peptide was measured after overnight fasting and subsequently 6 min after an intravenous injection of glucagon. Based on the distribution of the C-peptide concentrations in non-insulin-treated KD subjects, lower limits for non-insulin-dependent diabetes mellitus (NIDDM) of 0.30 pmol/ml for fasting C-peptide and 0.60 pmol/ml for stimulated C-peptide were arbitrarily chosen. According to these cutoff points, only 38.5% of KD subjects treated with insulin had insulin-dependent diabetes mellitus, corresponding to 9.3% of all KD subjects. After exclusion of these patients, the prevalence of recognized NIDDM was 3.5% in men and 4.5% in women. All FH subjects except one had C-peptide values in the NIDDM interval. A close agreement between fasting and glucagon-stimulated C-peptide was seen. In epidemiological studies with an expected high prevalence of NIDDM, we propose to use fasting C-peptide for classification of patients with insulin-treated diabetes.

Concentration-response relationship in imipramine treatment of diabetic neuropathy symptoms.

A single-blind imipramine dose titration study was conducted in 15 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by use of visual analog scales. Imipramine doses were individually adjusted until doses yielded plasma concentrations of imipramine plus desipramine that were well above 400 nmol/L or until all neuropathy symptoms had vanished. In all except one patient, there was marked relief of symptoms. In the responding patients (n = 14), much of the effect occurred at plasma levels of imipramine plus desipramine below 100 nmol/L, but a considerable interindividual variation was observed. Concentrations above 400 to 500 nmol/L were required to ensure maximal effect in all patients, and we did not find any indication of a decreased effect at high drug levels. The dose-dependent kinetics of imipramine was confirmed, and dose increments should therefore be carried out in small steps and preferably with monitoring of drug levels.

Predischarge maximal exercise test identifies risk for cardiac death in patients with acute myocardial infarction.

A maximal exercise test was performed in 54 patients with acute myocardial infarction (AMI) before discharge and in 49 age-matched control subjects. The long-term prognosis was assessed after an average follow-up of 7.6 years in AMI patients and 5.8 years in control subjects. The maximal work capacity and systolic blood pressure increase in AMI patients was 59% that of control subjects (p less than 0.001). Seventeen AMI patients had significant ST-segment shifts, 13 with ST depression and 4 with ST elevation. In AMI patients experiencing a cardiac death during follow-up the maximal work capacity and systolic blood pressure increase were significantly lower than in survivors and those who died from noncardiac reasons (p less than 0.01; p less than 0.05), with no difference between these groups in the number of patients with ST-segment shifts. The average maximal work capacity of control subjects was 143 watts. A maximal work capacity half this (less than or equal to 72 watts) predicted long-term mortality in AMI patients (p less than 0.001). In addition a low increase in systolic blood pressure (less than 30 mm Hg) also predicted long-term mortality (p less than 0.005), whereas ST shifts were of no significant value. In this study maximal work capacity turned out to be the best single exercise variable for identifying groups of AMI patients with very low and relative high risk of cardiac death. When all 3 exercise variables were combined, the predischarge maximal exercise test was of great value in identifying AMI patients at low risk for cardiac death (predictive value of a negative test: 95%).

The ExacTech blood glucose testing system.

The ExacTech system, a new device for home measurement of blood glucose was tested in the laboratory, in the out-patient clinic, and by diabetic patients. The system is based on an electrochemical principle, and consists of specially impregnated strips and a small, pencil-shaped meter. (1) Six meters were tested in the laboratory at blood glucose concentrations of 4, 10 and 20 mmol/l. Low coefficients of variation were found at 10 and 20 mmol/l, but those at 4 mmol/l were rather high (approximately 10%). Analysis of variances showed no difference in the between and the within variation of the meters. (2) The blood glucose concentrations of 50 consecutive out-patients were determined by the ExacTech system and a standard laboratory method. Correlation analysis showed an r value of 0.95 (P less than 0.001). (3) The results obtained by 13 patients repeating the correlation experiment were in agreement with the second part of the study. The ExacTech system is very simple to operate by the patients, and can be recommended for home monitoring of blood glucose.

Over-mortality as related to age and gender in patients with established non-insulin-dependent diabetes mellitus.

In 1981-1982, 5699 persons representing 92.9% of the total population aged 60-74 years living in Fredericia, Denmark, were interviewed about a possible history of diabetes and had a fasting blood glucose measured. A total of 236 gave a positive history of diabetes; 88 had one fasting blood glucose of 7 mmol/L or more. For each of these probands, an age- and gender-matched control person with normal fasting blood glucose and no history of diabetes was selected randomly. Of the 236, 91.5% had NIDDM as judged by glucagon-stimulated C-peptide tests. At the end of December 1995, the participants were traced through the National Register and their status (alive or dead) was determined. The date of death was confirmed. The median observation time from screening and inclusion in the study till death or the end of the observation period in December 1995 was 12.81 years, the maximum was 14.91, and the 25th and 75th percentile values were 6.36 and 13.94 years, respectively. At the end of 1995, 165 (74.4%) of 228 persons with known diabetes at the time of ascertainment had died opposed to 90 (40.4%) of the 223 nondiabetic control persons. The difference is statistically highly significant (p < 0.00001, log-rank test). Within the first 5 years of observation, 42.9% of diabetic men died and only 22.5% of non-diabetic men. This percentage of deaths in diabetic men was found already in the 60-64 year age interval (46.2%). The mortality rate for the non-diabetic population seems to increase later. After 13 years of observation, 74 (81.3%) of 91 men with known diabetes had died, in the age-matched control men, 50 (56.2%) of 89 (p = 0.00006). Ninety-one (66.4%) of 137 diabetic women had died: 40 (29.9%) of 134 control women (p < 0.00001). The difference between mortality in diabetic men and women, and between nondiabetic men and women is highly significant (p = 0.00285 and 0.00001, respectively). The over-mortality of established diabetic persons decreases with age. In the age group 60-74 years, the over-mortality is about 2.5 without gender difference.

Microalbuminuria in non-insulin-dependent diabetes.

According to international consensus, microalbuminuria is defined as an elevated urinary albumin excretion rate (UAER) of 20-200 micrograms/min, which is below the proteinuric range. Nephropathy is a major complication in IDDM, seen in about 30% of patients after many years of diabetes. Increasing microalbuminuria is an excellent marker of subsequent nephropathy in these patients. End-stage diabetic nephropathy is also important in NIDDM, but in most Western countries this serious complication eventually develops in only 5 to 10% of cases, whereas the majority of patients die before this from cardiovascular disease. In completely healthy individuals there is no clear correlation between age and UAER, at least up to about 70 years of age. The mean excretion rate is around 5 micrograms/min, with a considerable range, but excretion only rarely exceeds 15 micrograms/min. In population studies among middle-aged and elderly individuals, higher values are seen. In newly diagnosed NIDDM about 40% of patients show an excretion rate above 15-20 micrograms/min. There is a significant but not precise correlation between albumin excretion rate and glycemic control, and usually UAER is reduced by standard antidiabetic treatment. In a considerable number of patients, high values cannot be reduced. In the course of NIDDM about 20-30% of patients show microalbuminuria. In patients with known diabetes, microalbuminuria is related not only to subsequent diabetic proteinuria, but even more strongly to early death, mainly from cardiovascular disease. Even slight microalbuminuria (15-40 mg/l in early morning urines) is clearly associated with increased mortality. In subjects with newly detected elevated blood glucose (by screening) microalbuminuria also predicts early mortality. The mechanisms are not established, but several arteriosclerosis-related risk factors are seen more frequently in patients with microalbuminuria, e.g. lipid abnormalities, elevated systolic blood pressure (BP), hemostatic measures, as well other markers of cardiovascular disease. Usually there is a significant but not precise correlation between BP and UAER in groups of patients throughout the course of diabetes. New studies document that also in the elderly background population microalbuminuria is a significant risk factor for early death, maybe even stronger than the established risk markers, which thus may be confounded with the presence of microalbuminuria.

Microalbuminuria as predictor of increased mortality in elderly people.

OBJECTIVE: Correlation of the urinary albumin excretion rate and the risk of death among elderly subjects. DESIGN: 216 Subjects aged 60-74 whose urinary albumin excretion rate had been determined were followed up 62-83 months later. SETTING: Municipality of Fredericia, Denmark. SUBJECTS: 223 People who had been selected as control subjects for diabetics found during a systematic screening for diabetes of all people aged 60-74 living in the municipality of Fredericia, Denmark. Of these subjects, 216 had an extensive clinical and biochemical examination within a few weeks of selection. MAIN OUTCOME MEASURE: Death. RESULTS: The median urinary albumin excretion rate was 7.52 micrograms/min. Eight of those with a rate below the median died compared with 23 with a rate equal to or greater than the median (p = 0.0078). The median albumin excretion rate in the 31 who died was 15.00 micrograms/min. Cardiovascular disease was the most common cause of death in both groups. A multivariate regression analysis of survival data was performed using the proportional hazards model. Besides albumin excretion rate, male sex, serum creatinine concentration, and hypertension were found to be of prognostic value. CONCLUSIONS: The association between the albumin excretion rate and mortality that has been described in recent years in patients with diabetes mellitus may be present in elderly people in general, even when other known risk factors are taken into account.

[Active treatment of uremia in the study county of Vejle. Epidemiology 1979-1994 and future perspectives]. / Aktiv uraemibehandling i Vejle Amt. Epidemiologi 1979-1994 og fremtidsperspektiver.

We studied 275 renal replacement therapy (RRT) patients in a Danish county (population 329,000) from January 1st 1979 to June 30th 1994. Incidence, prevalence and age of new patients increased. The fraction of patients with diabetic nephropathy also increased. Patient survival remained constant (five-year survival 62% for patients observed for more than 90 days). The total number of new patients entering haemodialysis and peritoneal dialysis seemed to be reaching a constant level, that could be calculated using a logistic function. The fraction of patients leaving therapy remained constant over the years and was higher for peritoneal dialysis than for haemodialysis (32 vs. 20% per year). The future prevalence can be estimated by combining these two last findings.

[Self-monitoring of blood glucose and understanding of the disease in patients with insulin-treated diabetes. Correlation with metabolic regulation]. / Selvmonitorering af blodglukose og sygdomsforståelse hos patienter med insulinbehandlet diabetes. Sammenhaeng med metabolisk regulation.

A questionnaire investigation was undertaken to register the extent to which 212 insulin-treated diabetic patients undertook home measurements of blood glucose and the consequences which they drew from these measurements. This was compared with the metabolic regulation estimated by HbA1c. The average HbA1c-value was 8.0%. Only 13% had HbA1c-values within the reference range for non-diabetic persons. 85% of the patients undertook self-monitoring of blood glucose. In 47.6% insulin was administered once or twice daily, 42.5% were treated with multiple injections and 9.9% employed insulin pumps. Regardless or the form of treatment, good metabolic control was associated with numerous daily measurements of blood glucose whereas no independent connection was found between the form of treatment and the level of regulation. The best regulated patients altered the dosage of insulin with low blood glucose values and planned reduced activity. No connection was observed between the form of treatment, level of regulation or whether the patients undertook self-monitoring and the number of hospital contacts on account of hypoglycaemia or hyperglycaemia. Metabolic regulation was not satisfactory despite self monitoring of blood glucose and good understanding of the disease.