J. S. Yudkin

MICROALBUMINURIA AS PREDICTOR OF VASCULAR DISEASE IN NON-DIABETIC SUBJECTS: Islington Diabetes Survey

The relation between urinary albumin excretion rate (AER) and vascular disease was studied in 187 subjects aged over 40 selected from 1084 cases attending a diabetic screening project. AER exceeded 20 micrograms/min in 3 of 13 newly diagnosed diabetic subjects (23%) and 16 of 171 non-diabetic subjects (9.4%). There was a weak relation between AER and both systolic and diastolic blood pressures. Coronary heart disease was found in 54 of 164 (32.9%) subjects with AER of 20 micrograms/min or less and in 14 of 19 (74%) with AER above this. Peripheral vascular disease was present in 16 of 165 (9.7%) subjects with AER of 20 micrograms/min or less and 8 of 18 (44%) with a high AER. Logistic regression, including diabetes, impaired glucose tolerance, systolic and diastolic blood pressures, smoking, age, sex, ethnic origin, and body mass index, demonstrated the independence of this relation between AER above 20 micrograms/min and coronary heart disease (odds ratio [OR] 6.38, 95% confidence interval 1.91-21.4) and peripheral vascular disease (OR 7.72, 2.14-27.8). After a mean of 3.6 (SD 0.19) years, 167 subjects (89.3%) were traced. There had been 9 deaths, 3 (2.0%) among 149 subjects with normal AER and 6 (33%) among 18 microalbuminuric subjects (OR 24.33, 5.40-109.7).

The relationships of concentrations of insulin, intact proinsulin and 32–33 split proinsulin with cardiovascular risk factors in Type 2 (non-insulin-dependent) diabetic subjects

SummaryStandard radioimmunoassay for insulin may substantially overestimate levels of insulin because of cross-reaction with other insulin-like molecules. We have measured concentrations of insulin, intact proinsulin and 32–33 split proinsulin using two-site monoclonal antibody based immunoradiometric assays, and of insulin by a standard radioimmunoassay (“immunoreactive insulin”) in 51 Type 2 (noninsulin-dependent) diabetic subjects in the fasting state. The relationships of these concentrations were sought with those of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride, plasminogen activator inhibitor, blood pressure, and indices of body fat distribution. Significant relationships were apparent between concentrations of “immunoreactive insulin” as measured by standard radioimmunoassay and triglyceride (rs=0.42, p<0.001), total cholesterol (rs=0.25, p=0.038), high density lipoprotein cholesterol (rs=−0.30, p=0.018) and body mass index (rs=0.30, p=0.017), but only the relationships with triglyceride (rs=0.36, p=0.006) and body mass index (rs=0.26, p=0.034) remained significant when concentrations of immunoradiometrically measured insulin were employed. Concentrations of 32—33 split proinsulin, which comprises the major insulin-like molecule in these subjects, correlated positively with triglyceride (rs=0.33, p=0.009), total cholesterol (rs=0.23, p=0.050), and plasminogen activator inhibitor (rs=0.26, p=0.049), and negatively with high density lipoprotein cholesterol (rs=−0.29, p=0.021). Concentrations of “immunoreactive insulin” and immunoradiometric assay insulin showed significant positive correlaion with both systolic (rs=0.24, p=0.044 and rs=0.29, p=0.020 respectively), and diastolic blood pressure (rs=0.48, p<0.001 and n=0.42, p=0.001 respectively), while those of intact proinsulin and 32–33 split proinsulin correlated only with diastolic blood pressure (rs=0.33, p=0.009 and rs=0.31, p=0.014 respectively). Using multiple regression analysis, and including age, sex, race and body mass index in the analyses, concentrations of intact proinsulin and 32–33 split proinsulin, but not immunoradiometric assay insulin, were significantly related to diastolic blood pressure. When all three molecules were incorporated into a single model, only 32–33 split proinsulin was related to diastolic blood pressure (F-change=6.91, [5,43 degrees of freedom]; p=0.012). Thus, high concentrations of insulin-like molecules are associated with changes in recognised cardiovascular risk factor in patients with Type 2 (non-insulin-dependent) diabetes mellitus.

PREVALENCE AND RISKS OF HYPERGLYCAEMIA AND UNDIAGNOSED DIABETES IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

Two studies were undertaken to assess the prevalence of undiagnosed diabetes mellitus in patients admitted with acute myocardial infarction (AMI), and the effect of diabetes mellitus and admission hyperglycaemia on outcome. In the retrospective study, admission levels of plasma glucose (APG) were higher (p less than 0.02) in patients dying from cardiogenic shock than in survivors, but they were not related to infarct size. In the prospective study APG was related (p less than 0.01) to concurrent levels of glycosylated haemoglobin (HbA1c), which were in turn related to outcome--the mortality rate was 23% for those with normal HbA1c (less than 7.5%), 33% for those with borderline abnormal HbA1c (7.5-8.5%), and 63% for those with clearly abnormal HbA1c (greater than 8.5%). Cardiogenic shock was commoner in the groups with higher HbA1c levels. In addition, admission hyperglycaemia was associated (p less than 0.01) with the incidence of cardiogenic shock even after correcting for the effects of HbA1c. All of the survivors from the clearly abnormal HbA1c group, but none of those from other groups, were diabetic at follow up, suggesting an overall prevalence of undiagnosed diabetes mellitus of 5.3%. The contribution of undiagnosed diabetes mellitus to total mortality following AMI seems at present to be underestimated.

Insulin Therapy in Type 2 Diabetic Subjects Suppresses Plasminogen Activator Inhibitor (PAI‐1) Activity and Proinsulin‐like Molecules Independently of Glycaemic Control

Eleven Type 2 diabetic subjects (10 male 1 female: age 56.2 ± 9.7 (SD) yr) were treated in random order either with insulin or with sulphonylureas for 8 weeks each, without attempting to alter glycaemic control between the two treatment periods. Insulin treatment was associated with suppression of endogenous insulin secretion (fasting C‐peptide levels ‐35.0 ± 24.2%; p = 0.006), and of intact proinsulin (‐43.1 ± 36.8%; p = 0.03) and 32,33 split proinsulin ‐20.1 ± 27.0%; p = 0.03). Activity of plasminogen activator inhibitor (PAI‐1), a fast acting inhibitor of fibrinolysis, decreased significantly (‐14.3% ± 27.5 %; p = 0.02) but no changes occurred in concentration of lipoproteins or apoproteins between therapies. Changes in concentrations of 32,33 split and intact proinsulin were closely and significantly related (rs = 0.83; p < 0.001) to each other but not with changes in concentrations of C‐peptide (intact proinsulin rs = ‐0.41; p = 0.11) and 32,33 split proinsulin rs = ‐0.27; (p = 0.21). Percentage changes in intact proinsulin concentrations were positively correlated with those in PAI‐1 (rs = 0.51; p = 0.05). There was, however a paradoxical negative relationship between changes in C‐peptide concentrations and those of PAI‐1 (rs = ‐0.73; p = 0.006). These preliminary observations suggest that insulin treatment in Type 2 diabetic subjects without any changes in glycaemic control is associated with a reduced activity of PAI‐1, but is without effect on any other cardiovascular risk factors. Concentrations of insulin precursor molecules may play a role in determining fibrinolytic activity.

Unexplained variability of glycated haemoglobin in non-diabetic subjects not related to glycaemia.

SummaryWe have studied levels of glycated haemoglobin in a sample of 223 people aged over 40 years without known diabetes mellitus screened in a community study. Each had a glucose tolerance test and glycated haemoglobin measured by four methods — agar gel electrophoresis with and without removal of Schiff base, affinity chromatography and isoelectric focusing. The correlation coefficients between 2 h blood glucose and levels of glycated haemoglobin were between 0.43 and 0.64. This poor correlation was not explained on the basis of assay or biological variability of either 2 h blood glucose or glycated haemoglobin. Multiple regression analysis showed that other assays of glycated haemoglobin contributed to the variance of any single glycated haemoglobin value by 0.1%–52.9% (median 12.8%) compared to the variance of 18.6%–41.4% (median 30.8%) explained by 2 h blood glucose alone, suggesting that in a non-diabetic population, the degree of glucose intolerance may explain only one third of the variance of glycated haemoglobin levels, but other factors operate to produce consistent changes in levels of glycated haemoglobin. Investigation of 42 subjects with consistently high (20 subjects) or low (22 subjects) levels of glycated haemoglobin relative to their 2 h blood glucose level showed no difference in age, gender, body mass index, haemoglobin levels or smoking, although 50% of low glycators had impaired glucose tolerance. Neither ambient bloodglucose levels, as estimated on two five-point blood-glucose profiles, nor dietary intake of carbohydrate, starch, sugars, fibre or alcohol, explained the difference between high and low glycators. The determinants of the consistent interindividual differences in levels of glycated haemoglobin in nondiabetic subjects remain to be determined.

A comparison of the relationships of the glucose tolerance test and the glycated haemoglobin assay with diabetic vascular disease in the community. The Islington Diabetes Survey.

We have compared the relationships of fasting and 2 h blood-glucose during a 75 g oral glucose tolerance test, and those of an affinity chromatography assay of glycated haemoglobin, with the presence of vascular complications of diabetes mellitus in 223 subjects without known diabetes aged over 40 years selected from a community screening study population. The subjects included 15 (6.9%) with newly diagnosed diabetes and 52 (24.1%) with impaired glucose tolerance. Employing receiver operating characteristic analysis, the tests were similar in their relationship with three cases of retinopathy, 19 of microalbuminuria and six of peripheral neuropathy. The prevalence of coronary heart disease, defined as angina, myocardial infarction, or electrocardiographic changes of ischaemia, increased linearly across all four quartiles of both 2 h blood glucose and glycated haemoglobin concentration, but using logistic regression analysis, 2 h blood glucose was a better predictor of coronary heart disease than glycated haemoglobin. Receiver operating characteristic analysis also showed that 2 h blood glucose generally performed better than any of four assays of glycated haemoglobin in classifying those subjects with coronary heart disease.

Hyperglycaemia following acute myocardial infarction: the contribution of undiagnosed diabetes.

We studied 397 patients admitted to hospital with acute myocardial infarction (AMI) to validate an admission level of haemoglobin Alc (HbAlc) diagnostic for previously unknown diabetes mellitus by assessing glucose tolerance after 3 months. In 38% of survivors clearly abnormal HbAlc level (>7.8) was 100% sensitive and 99% specific for diabetes with fasting hyperglycaemia, although the sensitivity fell to 67% when three diabetic subjects without fasting hyperglycaemia were included. Admission hyperglycaemia (plasma glucose ≥11 mmol/l) was present in 20% of patients with AMI, of whom only one in five had levels of HbA1c indicating prior diabetes. Glycosylated haemoglobin is a more sensitive and specific test for diabetes in patients with AMI than admission hyperglycaemia. Undiagnosed diabetes was found in 4.3% of subjects with AMI who contributed 9.6% of hospital mortality.

Glucose Intolerance and Hypertension in North London: The Islington Diabetes Survey

In a general practice‐based screening survey, 1040 (63.3%) of a randomly selected sample of 1644 people over the age of 40 years were examined for diabetes mellitus (DM) and hypertension (HT). Glucose intolerance was assessed by a single 2 h post‐load blood glucose estimation and HT (diastolic blood pressure ≥95mmHg by a single blood pressure reading) or being on anti‐hypertensive treatment.

Hyperglycaemia, Diabetes and Myocardial Infarction

As many as one-quarter of all patients admitted to hospital after acute myocardial infarction (AMI) may have an elevated blood glucose concentration. Moreover hyperglycaemia in this context is associated with a poor prognosis. In this article we examine the prevalence of hyperglycaemia and the determinants of blood glucose level on patients with AM1 to assess whether the relationship between hyperglycaemia and poor outcome might be causative, and thereby potentially amenable to intervention.

Increased mean platelet volume after acute myocardial infarction relates to diabetes and to cardiac failure.

Mean platelet volume, platelet count and an estimate of platelet volume distribution were studied following acute myocardial infarction in 59 diabetics and 88 non-diabetics and were compared with values in 100 non-diabetic and 50 diabetic non-infarct subjects. In the non-diabetics mean platelet volume and platelet distribution width were similar in the non-infarcted patients and in the infarcted patients without severe cardiac failure. All diabetics with myocardial infarction had larger mean platelet volumes and platelet distribution width than the diabetic non-infarct controls. All myocardial infarction patients with severe cardiac failure had larger platelet volumes than patients with mild or no failure. Increased mean platelet volume may reflect either increased platelet activation or increased numbers of large, hyperaggregable platelets. Abnormalities of platelet function may contribute to the relatively poor prognosis of myocardial infarction in patients with diabetes.