R. C. Turner

OBJECTIVE: To evaluate baseline risk factors for coronary artery disease in patients with type 2 diabetes mellitus. DESIGN: A stepwise selection procedure, adjusting for age and sex, was used in 2693 subjects with complete data to determine which risk factors for coronary artery disease should be included in a Cox proportional hazards model. SUBJECTS: 3055 white patients (mean age 52) with recently diagnosed type 2 diabetes mellitus and without evidence of disease related to atheroma. Median duration of follow up was 7.9 years. 335 patients developed coronary artery disease within 10 years. OUTCOME MEASURES: Angina with confirmatory abnormal electrocardiogram; non-fatal and fatal myocardial infarction. RESULTS: Coronary artery disease was significantly associated with increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, and increased triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting plasma glucose concentration, and a history of smoking. The estimated hazard ratios for the upper third relative to the lower third were 2.26 (95% confidence interval 1.70 to 3.00) for low density lipoprotein cholesterol, 0.55 (0.41 to 0.73) for high density lipoprotein cholesterol, 1.52 (1.15 to 2.01) for haemoglobin A1c, and 1.82 (1.34 to 2.47) for systolic blood pressure. The estimated hazard ratio for smokers was 1.41 (1.06 to 1.88). CONCLUSION: A quintet of potentially modifiable risk factors for coronary artery disease exists in patients with type 2 diabetes mellitus. These risk factors are increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, raised blood pressure, hyperglycaemia, and smoking.

Deposition of amyloid in pancreatic islets is a common feature in human type 2 diabetic subjects but because of its insolubility and low tissue concentrations, the structure of its monomer has not been determined. We describe a peptide, of calculated molecular mass 3905 Da, that was a major protein component of amyloid-rich pancreatic extracts of three type 2 diabetic patients. After collagenase treatment, an extract containing 20-50% amyloid was solubilized by sonication into 70% formic acid and the peptide was purified by gel filtration followed by reverse-phase high-performance liquid chromatography. We term this peptide diabetes-associated peptide, as it was not detected in extracts of pancreas from any of six normal subjects. Diabetes-associated peptide contains 37 amino acids and is 46% identical to the sequences of rat and human calcitonin gene-related peptide, indicating that these peptides are related in evolution. Sequence identities with conserved residues of the insulin A chain were also seen in a 16-residue segment. On extraction, the islet amyloid is particulate and insoluble like the core particles of Alzheimer disease. Their monomers have similar molecular masses, each having a hydropathic region that can probably form beta-pleated sheets. The accumulation of amyloid, including diabetes-associated peptide, in islets may impair islet function in type 2 diabetes mellitus.

ABSTRACT A radioimmunoassay method for the measurement of plasma insulin is described relying on activated charcoal for the separation of free and bound fractions. The technique illustrates the application of theoretical precepts designed to maximise assay precision in all radioimmunoassay and other saturation assay techniques. In addition, because particular emphasis has been placed on ensuring that, as far as is possible, all incubation mixtures are similar as possible other than in hormone concentration, non-specific effects appear to have been essentially eliminated. The technique yields a mean normal fasting value of 5.3μU/ml (range 2–14 μU/ml). Its sensitivity is such that 10 μl samples of serum (or plasma) may be assayed.

Morphometric analysis of the endocrine and exocrine pancreas was done on immunoperoxidase stained post-mortem tissue from 15 Type 2 diabetic and 10 age-matched control subjects. Thirteen of the 15 Type 2 diabetic patients had islet amyloid deposits (mean, 6.5% islet area) in the corpus (body, tail and anterior part of the head) but not in the caput (the "pancreatic polypeptide rich" part of the head) whereas none was seen in control subjects. In the corpus in diabetic subjects, the pancreatic area density of B-cells was decreased by 24% (p = 0.005) and A-cells increased by 58% (p less than 0.001) compared with control subjects. The mean A/B-cell ratio increased in the corpus from 0.27 in control subjects to 0.57 in Type 2 diabetic patients. Positive immunoreactivity for the amyloid constituent peptide, Diabetes Associated Peptide, was demonstrated in islet amyloid of diabetic subjects and in B-cells of control and diabetic subjects. The increase in A-cells may contribute to the hyperglucagonaemia and hyperglycaemia of Type 2 diabetes. The impaired insulin secretion in Type 2 diabetes may be due to a decrease in B-cells and to disruption of the islet structure by amyloid. Exocrine fat was similar in the control and diabetic subjects with both groups having more in the corpus than the caput. Diabetic subjects had increased exocrine fibrosis in the corpus region (p less than 0.001), but not in the caput. Exocrine fibrosis may be secondary to disordered islet cell function.