Risk factors for coronary heart disease in diabetes mellitus.

A review of the putative risk factors associated with the development of coronary heart disease in diabetes is presented. Emphasis is given to the effect of nephropathy (persistent proteinuria) and hypertension on cardiovascular mortality in IDDM. Risk factors associated with CHD in NIDDM are also reviewed. Finally, possible reasons to explain the increased incidence of CHD associated with proteinuria in IDDM patients, including lipoprotein abnormalities, increased fibrinogen levels, increased platelet adhesiveness, and altered hemostatic variables, are discussed.

Hyperglycemia and arterial disease.

Clinical and autopsy evidence support the increased risk of atherosclerotic disease in diabetes mellitus (DM). However, mechanisms other than arterial occlusion may also contribute to clinical syndromes often assumed to be atherosclerotic in origin. There is considerable geographical variability in the frequency of arterial disease in the diabetic. Glucose intolerance short of unequivocal DM is found in some (though not all) populations to carry increased atherosclerotic risk. Morbidity and mortality data suggest that women are particularly vulnerable (as with DM). The Whitehall prospective study of cardiovascular mortality shows that risk does not rise smoothly with increasing degrees of glucose intolerance but that it doubles sharply at the 95th percentile of the 2-h post-glucose blood sugar distribution.

The WHO multinational study of vascular disease in diabetes: 2. Macrovascular disease prevalence.

14 national groups have collaborated under WHO auspices to select, from local defined populations of individuals with clinical diabetes, groups of approximately 500 within the age range 35--55 yr stratified by age, sex, and known duration of diabetes. In each center, the selected patients were submitted to a standardized study protocol, which included systematic inquiry (WHO questionnaire) for the presence of symptoms of angina pectoris, history of myocardial infarction, presence of intermittent claudication, and cigarette smoking history. Examination included standard biometry, blood pressure measurement, 12-lead (centrally Minnesota coded) electrocardiography, and central laboratory measurement of serum cholesterol and creatine. Ophthalmoscopic and urinary examinations were also included. The prevalence of arterial disease symptoms and electrocardiographic abnormalities show very large variation between countries, the lowest rates generally being found in the Oriental samples and the highest in the European. "Risk factors" for arterial disease (blood pressure, serum cholesterol, and cigarette smoking) also vary widely between diabetic groups. Although data are not yet complete, these differences appear unlikely to explain the variation in the atherosclerotic morbidity observed. Diabetic women were at least as vulnerable to arterial disease as diabetic men. A high prevalence of nonspecific abnormalities of the repolarization phase of the ECG was found, even in groups where ischemic abnormalities were rare. The origin of these is uncertain; they may represent variable local changes or possibly diabetic cardiomyopathy. This preliminary report confirms and quantifies previous indications that the impact of atherosclerotic disease on persons with diabetes varies considerably between national groups, in broad terms, running parallel with the variations in prevalence in the populations in general and suggesting that cultural and/or ethnic factors are more important determinants of atherosclerosis in diabetic individuals than is the diabetic state per se.

The WHO multinational study of vascular disease in diabetes: 3. Microvascular disease.

A preliminary comparison and analysis of microvascular disease was performed in 14 stratified samples of diabetic subjects. Microvascular disease was assessed by estimating visual disabilities, by standardized examination of the optic fundus by direct ophthalmoscopy, by estimating proteinuria, and by measuring the serum creatinine concentration. Visual impairment by questionnaire positive varied considerably between centers, probably due to cultural differences in interpretation of the questions. Physician-assessed visual disability also yielded considerable differences in frequency; however, the frequency differences were unrelated to those observed for macrovascular disease. Retinopathy--the sum of all components--was related to duration of diabetes in each participating center. The apparent frequency of proteinuria varied considerably between centers. In general, the frequency of retinopathy was related to the level of systolic blood pressure, but there was no systematic association with cigarette smoking.

The WHO multinational study of vascular disease in diabetes: 1. General description.

A general description of the multinational study under the auspices of the World Health Organization is presented. The purpose was to compare the prevalence of vascular disease in representative samples of diabetic subjects of different ethnic and cultural habitus. Standardized methods of investigation were devised. Fourteen centers participated, and the data collected so far indicate that the characteristics of the populations studied varied as to age composition, adiposity, cigarette smoking, treatment, age at diagnosis, and duration of diabetes. Thus, taking these factors into consideration and while awaiting completion of the data, conclusions must be drawn with reserve.

High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study.

OBJECTIVE: To assess the association between high but nondiabetic blood glucose levels and the risk of death from all causes, coronary heart disease (CHD), cardiovascular disease, and neoplasms. RESEARCH DESIGN AND METHODS: We studied the 20-year mortality of non-diabetic, working men, age 44-55 years, in three European cohorts known as the Whitehall Study (n = 10,025), the Paris Prospective Study (n = 6,629), and the Helsinki Policeman Study (n = 631). These men were identified by their 2-h glucose levels following an oral glucose tolerance test and by the absence of a prior diagnosis of diabetes. As the protocol for the oral glucose tolerance test and methods for measuring glucose differed between studies, mortality was analyzed according to the percentiles of the 2-h and fasting glucose distributions, using the Cox's proportional hazards model. RESULTS: Men in the upper 20% of the 2-h glucose distributions and those in the upper 2.5% for fasting glucose had a significantly higher risk of all-cause mortality in comparison with men in the lower 80% of these distributions, with age-adjusted hazard ratios of 1.6 (95% CI 1.4-1.9) and 2.0 (1.6-2.6) for the upper 2.5%. For death from cardiovascular and CHD, men in the upper 2.5% of the 2-h and fasting glucose distributions were at higher risk, with age-adjusted hazard ratios for CHD of 1.8 (1.4-2.4) and 2.7 (1.7-4.4), respectively. CONCLUSIONS: If early intervention aimed at lowering blood glucose concentrations can be shown to reduce mortality, it may be justified to lower the levels of both 2-h and fasting glucose, which define diabetes.

Plasma insulin and C-peptide after subcutaneous and intravenous administration of human insulin (recombinant DNA) and purified porcine insulin in healthy men.

We have compared the plasma profiles of C-peptide, human insulin (recombinant DNA), and purified porcine insulin of pancreatic origin (PPI) in six nondiabetic men after low-dose (4.8 U) or high-dose (9.6 U) subcutaneous injection and low-rate (1.0 U/h) or high-rate (1.7 U/h) intravenous infusion. There was no significant difference in plasma C-peptide or glucose levels when human insulin was compared with PPI at either dose level for subcutaneous injection or intravenous infusion. Thus, there was equal suppression of endogenous insulin by the two species of exogenous insulin. For low-dose subcutaneous injection there was no significant difference between plasma insulin levels of the two species at single time points or when areas were compared. For high-dose subcutaneous injection mean plasma insulin levels were higher after human insulin than after PPI (20-300 min); this serial difference reached conventional statistical significance at 50 min (P less than 0.05) and 90 min (P less than 0.01). For the area under plasma insulin profiles between 0 and 90 min after high-dose s.c. injection, human insulin was higher than PPI (P = 0.06). There was no significant difference between insulin concentrations after human insulin and PPI given by either low- or high-dose intravenous infusion, except that high-dose PPI values (55-110 min) were slightly but significantly higher after high-dose intravenous infusion. Further comparisons of the pharmacokinetics of human and other species of insulin are, therefore, justified in larger numbers of subjects and particularly in diabetic individuals.

Biosynthetic human insulin: effect in healthy men on plasma glucose and non-esterified fatty acids in comparison with highly purified pork insulin.

Biosynthetic human insulin (BHI) produced by recombinant DNA technology was administered subcutaneously and intravenously at two dose levels to two groups, each consisting of six normal men. Responses were compared with those for purified pork insulin (PPI) given by the same routes at the same dose levels to the same two groups. The glycemic response to the insulins was similar with a suggestion (seen both with intravenous and subcutaneous administration) that the glycemic depression with BHI was slightly greater at low dose and less at high dose. No significant difference between insulin types was found in the depression of non-esterified fatty acid (NEFA) concentrations, although significant differences between types with low-dose subcutaneous injection emerged during the later phases of the experiment. After termination of high-rate infusion with both insulins, NEFA concentrations rose more rapidly with some overshoot, suggesting that the rate and depth of blood glucose fall in these experiments might have triggered a brisker counterregulatory response. The small differences found between human and pork insulins, although in some cases significant, are unlikely to be of clinical importance.

The role of circulating glucose and triglyceride concentrations and their interactions with other "risk factors" as determinants of arterial disease in nine diabetic population samples from the WHO multinational study.

In 9 of the 14 national samples of diabetic patients assembled for the WHO Multinational Study of Vascular Disease in Diabetes additional laboratory data made it possible to relate manifestations of macrovascular disease to blood glucose concentrations as well as to diabetes duration and to other potential determinants. In five of the samples, serum triglyceride concentrations were also measured and were included in simple and multivariate analyses. Ischemic heart disease defined from Minnesota-coded EKGs and standardized WHO questionnaires was more strongly associated with serum triglyceride concentrations than with serum cholesterol concentrations, an association less notable in non-insulin-dependent diabetic patients. Ischemic heart disease was not related to the single fasting plasma glucose estimated for this study. Stroke and amputation were much more strongly related to the known duration of diabetes than was ischemic heart disease, and they were both related to blood glucose concentration measured at the time of study. Despite major variation in arterial disease prevalence rates between collaborating centers, risk for diabetic women appeared to equal that for diabetic men. The major variation in arterial disease prevalence between national groups could be accounted for only in part by the risk factors studied. Other factors, genetic or more likely environmental, are likely to contribute to the variation in arterial disease susceptibility and, if definable, may be potentially preventable.

Glucose tolerance and blood pressure in two population samples: their relation to diabetes mellitus and hypertension.

The relationship between blood pressure and the blood sugar concentration measured two hours after a 50 g oral glucose load has been examined in two population surveys-the Whitehall and Bedford Surveys. In the Whitehall Survey, which was conducted in men above the age of 40, there was a positive, significant correlation between blood sugar and blood pressure (systolic and diastolic) which was independent of common associations with age, body mass index (BMI) and heart rate. In the Bedford Survey, systolic blood pressures were significantly higher in newly detected diabetics and borderline diabetics, both men and women, than in normoglycaemic controls after adjustment of blood pressures for age and BMI. However, in the stratified random sample of the cooperating Bedford population, only amongst women was the blood sugar significantly and independently correlated with the systolic blood pressure. Evidence is presented and discussed that autonomic, neurohumoral factors may play some part in the pathogenesis of maturity onset diabetes.

Changes in blood pressure and body weight over ten years in men selected for glucose intolerance.

Relative changes in body weight and blood pressure over ten years of observation are reported in men recruited for a trial of therapy in relation to the natural history of glucose intolerance. Half were recommended a diet restricting carbohydrate to 120 g daily (diet group) and half were recommended to 'limit use of table sugar' (no diet). In both groups average weight and blood pressure fell over the 12 to 18 months after treatment allocation, the decline being proportionately greater for both variables in the diet group. Subsequently, average weight remained constant up to the end of the ten year study, but blood pressure levels rose, though remaining below baseline levels in the diet group. Statistical analysis of changes in blood pressure and weight between initial (pre-treatment) and third follow-up visit measurement indicated that the proportional change in blood pressure was related principally to change in weight, with little relation to initial level of blood pressure. Although a reduction in weight results in a fall in blood pressure, it does not necessarily prevent a subsequent age related increase in blood pressure.

Pet ownership, distemper antibodies and multiple sclerosis.

The incidence of cat or dog ownership was similar in 64 multiple sclerosis (MS) patients in south-east England and age- and sex-matched controls. 86% of both groups had owned a cat or dog before the date of onset of MS in the index case so that it would be difficult to detect an association between pet ownership and MS. The titres of neutralising antibody to canine distemper virus were higher in the MS patients (mean 48 +/- 68) than the controls (32 +/- 35), a significant difference (P < 0.05). This difference is not necessarily explained by a cross-reaction with measles antibody of which the titre was much higher in MS (610 +/- 560) than in the controls (320 +/- 330, P < 0.001).

Urinary albumin excretion in normal and diabetic subjects.

Using an albumin radio-immuno-assay, urinary albumin concentration and excretion rate have been measured in diabetics and control subjects overnight, after several hours ordinary activity and during two successive one hour periods of recumbency. The urine albumin concentration was relatively constant throughout each of the four collection periods. Variations in albumin excretion rate were directly related to changes in urine flow. In assessing changes in urinary albumin, concentration and urine flow should be reported as well as the calculated albumin excretion rate. In the diabetics, selected for absence of clinical proteinuria, the mean concentration of albumin did not differ significantly from that of the controls. The overnight albumin excretion rate was higher in the diabetics, but this was due to the greater volume of urine.

Low physical activity and worsening of glucose tolerance: results from a 2-year follow-up of a population sample in Malta.

The relationship between the level of habitual physical activity and glucose intolerance was examined cross-sectionally and during a 2-year follow-up among a sample of 388 subjects in Malta. At baseline, the subjects were classified into three categories of physical activity, which was inversely related to the 2-h post challenge blood glucose (P = 0.02). In a multivariate analysis, age (standardized regression coefficient 0.23; P less than 0.001), family history of diabetes (0.20; P less than 0.001), and physical activity (-0.18; P = 0.002) were the strongest predictors of the 2-h blood glucose at baseline. The age standardized 2-year risk of glucose intolerance, i.e. impaired glucose tolerance or diabetes was consistently and inversely related to the level of physical activity. Among subjects with normal glucose tolerance at baseline (n = 127) those with low physical activity had a 2.7 times higher risk of glucose intolerance during follow-up than those with high physical activity (P = 0.1), and even a 3.7-fold risk of glucose intolerance at baseline (n = 196) when both the subjects with normal and impaired glucose tolerance at baseline were considered together (P = 0.005). Similar trends were observed for the risk of diabetes. The suggested protective effect of physical activity was independent of body mass, a family history of diabetes and gender. Within the limits of this small study we conclude that physical activity may have some importance in the primary prevention of impaired glucose tolerance and, possibly, non-insulin-dependent diabetes mellitus.

Gestational diabetes: a non-entity?

Screening for gestational diabetes is commonly recommended despite the absence of a common definition of gestational diabetes. Furthermore, there is no consensus about management or treatment. Those who recommend screening do so largely on the basis of fetal morbidity, which seems to be predominantly "macrosomia"--another term without an agreed definition. The implications of macrosomia in terms of actual morbidity are also not clear. R J Jarrett reviews the history of the subject and concludes that gestational diabetes is simply impaired glucose tolerance temporally associated with pregnancy. Its main importance is as a predictor of subsequent non-insulin dependent diabetes, but it fails the major tests for a condition suitable for a screening programme.

Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microalbuminuria.

OBJECTIVE: To determine whether insulin dependent diabetics with microalbuminuria have significant abnormalities in concentrations of lipoproteins, apolipoproteins AI and B, fibrinogen, and clotting factor VII which could result in increased cardiovascular risk. DESIGN: Case-control study. SETTING: Outpatient department of a metabolic ward. PATIENTS: Group of 20 insulin dependent diabetics with urinary albumin excretion rates greater than 30 micrograms/min (microalbuminuria) and 20 individually matched insulin dependent diabetics with normal urinary albumin excretion rates (below 30 micrograms/min) matched for age, sex, and duration of diabetes. INTERVENTIONS: Fasting venous blood samples were taken for determination of concentrations of glucose, glycated haemoglobin, lipoproteins, apolipoproteins AI and B, fibrinogen, and factor VII. Height, weight, arterial pressure, and usual insulin dose were recorded, and each patient was given a dietary questionnaire to be completed at home. END POINT: Comparison of blood pressure and concentrations of lipoproteins, apolipoproteins AI and B, and fibrinogen in the diabetics with microalbuminuria and the controls. MEASUREMENTS AND MAIN RESULTS: Patients with microalbuminuria had significantly higher concentrations of low density lipoprotein cholesterol (mean 3.33 (SE 0.20) v 2.84 (0.12) mmol/l) and very low density lipoprotein cholesterol (0.30 (0.05) v 0.17 (0.03) mmol/l) than controls but significantly lower concentrations of high density lipoprotein 2 subfraction cholesterol (0.32 (0.04) v 0.54 (0.04) mmol/l). Concentrations of total triglyceride (1.11 (0.14) v 0.68 (0.08) mmol/l), very low density lipoprotein triglyceride (0.56 (0.10) v 0.30 (0.05) mmol/l), apolipoprotein B (0.88 (0.06) v 0.67 (0.03) g/l) and fibrinogen (2.2 (0.1) v 1.9 (0.1) g/l), and diastolic arterial pressure (80 (2) v 74 (2) mm Hg), were also higher in patients with microalbuminuria. CONCLUSIONS: Cardiovascular risk factors--namely, disturbances in lipoprotein and apolipoprotein concentrations, increased fibrinogen concentration, and increased arterial pressure--are already present in insulin dependent diabetics with microalbuminuria. The increased risk of coronary heart disease in patients with clinical proteinuria may result from prolonged exposure to these risk factors, which are present before any impairment of renal function.

The concomitants of raised blood sugar: studies in newly-detected hyperglycaemics: II. Urinary albumin excretion, blood pressure and their relation to blood sugar levels.

The albumin excretion rate following an oral glucose load was measured, using a sensitive radio-immunoassay method, in three groups drawn from the population of Bedford. The three groups ­ normal,borderline diabetic and diabetic ­ were classified by the level of the blood sugar 2 hours after the 50 -g glucose load. The degree of albumin excretion was positively correlated with the 2-hour blood sugar level, suggesting that hyperglycaemia may cause renal functional abnormality, which may be present at or before the time of diagnosis. In the diabetic group, only, the degree of albumin excretion was also positively correlated with the height of the blood pressure.