Aspirin usage in a large teaching hospital diabetes clinic setting.

AIM: To document aspirin usage and the prevalence of large and small vessel complications in patients with diabetes mellitus (DM) attending the outpatient diabetes clinics of a large public hospital. METHODS: All patients attending diabetes outpatient clinics at The Royal Melbourne Hospital in Melbourne, Australia were surveyed over a 3-month period. RESULTS: Complete data were available on 629 of 632 (296 male) patients surveyed. Of the 29.3% of patients who were suffering from one or more macrovascular complication (ischaemic heart disease, cerebrovascular disease or peripheral vascular disease), 63% were currently on aspirin treatment. Of those not on aspirin, 65% had no contra-indication to aspirin treatment and a further 19% had only a relative contra-indication of either aspirin or warfarin treatment recorded. CONCLUSIONS: The published recommendations for the use of aspirin in patients with macrovascular disease were generally being followed in this clinic-based population. However, a significant proportion of patients without a contra-indication to treatment were still not receiving aspirin. The lack of clear evidence-based guidelines for aspirin use may be a factor in its under-prescription. This survey suggests clear evidence-based guidelines should be established and disseminated.

High prevalence of diabetic retinopathy and nephropathy in Polynesians of Western Samoa.

OBJECTIVE: To determine the prevalence of diabetic retinopathy and nephropathy retinopathy and nephropathy and to define associated risk factors in Polynesian Western Samoans with non-insulin-dependent diabetes mellitus (NIDDM) or impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A 1991 population-based study in Samoan adults (ages 25-74 years) included a 75-g oral glucose tolerance test, anthropometric measurements, and blood pressure recordings. Subjects with NIDDM or IGT had 45-degree stereo photographs taken (n = 263) (three standard fields of the right eye), and retinopathy was graded in comparison with Airlie House photographs. First-morning urine samples (n = 304) were also collected from these subjects and from a subsample with normal glucose tolerance. Urinary albumin concentration (UAC) was measured by radioimmunoassay: microalbuminuria was defined as UAC of 30-299 micrograms/ml; and macroalbuminuria among subjects with Proliferative diabetic retinopathy was found in 4.5% of known diabetic subjects. The prevalence of elevated UAC was 15.0% in subjects with IGT, 26.0% in newly diagnosed diabetes subjects, and 23.4% in known diabetes subjects. For all diabetic subjects (n = 162), the factors independently associated with diabetic retinopathy (logistic regression) were duration of diabetes, fasting plasma glucose, and body mass index (inversely). Duration of diabetes, serum triglyceride concentrations, and systolic blood pressure were independently associated with elevated UAC in all diabetic subjects (n = 138), and fasting plasma glucose had borderline significance. CONCLUSIONS: Diabetic retinopathy and albuminuria are common in Polynesian Western Samoans. Duration of diabetes and level of glycemia were the most important associated factors. These data underline the need for cost-effective programs for the detection and early treatment of diabetes in Western Samoa and other developing populations with high susceptibility to NIDDM.

Ponalrestat does not cause a protein binding interaction with warfarin in diabetic patients.

Ponalrestat (Statil, ICI; Prodiax, Merck Sharp and Dohme) is an aldose reductase inhibitor which is highly protein bound. Ponalrestat markedly displaced warfarin from its protein binding in vitro at a concentration of 500 micrograms ml-1, but not at a concentration of 50 or 100 micrograms ml-1. Twelve diabetic patients (six males), age range 38-65 years, in receipt of chronic stable warfarin therapy, were given ponalrestat (600 mg daily) for 2 weeks in an open trial. A matching placebo tablet was administered for 1 week before and after the active treatment period. Patients were seen ten times (four times during the ponalrestat phase), and during the ponalrestat phase, plasma samples were also taken before and at 3 h after the daily dose of ponalrestat. At none of the visits was there any significant change in prothrombin ratio (INR), plasma total or unbound warfarin concentrations, or percentage protein binding of warfarin. No clinical complications of combination treatment were detected. The maximum ponalrestat concentration observed in the patients was approximately 100 micrograms ml-1. We conclude that no significant interaction between these drugs occurs at the doses of ponalrestat studied.

Does vitreous fluorophotometry reflect severity of early diabetic retinopathy?

To determine the relationship between vitreous fluorophotometry (VF) and severity of diabetic retinopathy (DR) 13 patients with mild to moderate background DR starting continuous subcutaneous insulin infusion were followed up serially for 12 months. They were studied by colour stereo retinal photographs, which were assessed by the Wisconsin Grading System, and by VF, which was assessed by the permeability index of the retina for fluorescein. By four months the severity of DR on colour photographs had deteriorated by at least one level in at least one eye in eight patients. In four patients the DR did not deteriorate. Assessment of anatomical abnormalities by severity of DR on colour photographs correlated well with the functional abnormalities of the blood-retinal barrier(s) assessed by VF, especially for the macular field. Comparison of permeability index data in the patients developing preproliferative or proliferative features of DR (group A) with the same data in patients who did not develop such changes (group B) indicated that group A patients had more severe DR than did group B patients at entry. Grading of colour photographs showed a similar trend but with greater overlap. Considerable overlap in fluorescein permeability remained between those subjects with no visible DR and those with microaneurysms with or without haemorrhages and small hard exudates.

Quantitative magnetic resonance imaging in assessment of the blood-retinal barrier.

Application of magnetic resonance imaging (MRI) in two-dimensional quantitative assessment of blood-retinal barrier dysfunction was investigated in rabbits using a 0.1 T (4.25 MHz) resistive system. Reliable and consistent measurements of vitreous T1 were obtained repeatedly, in slices of width 5 mm and X-Y resolution of 1.2 mm. Calibration of reduction of T1 in eyes after injection of gadolinium-DTPA (Gd-DTPA) was performed, resulting in a dose-related response of relaxation rate (1/T1) to the dose of Gd-DTPA injected. Follow-up scans of injected eyes demonstrated a gradual spread of the T1 "hot-spot" as the contrast agent diffused through the vitreous. T1 rose gradually to basal levels by 72 hr. No local effect of Gd-DTPA was found by ophthalmoscopy. Xenon arc photocoagulation of rabbit retina reduced T1 from 1638 +/- 54 (n = 6, mean +/- SD) ms to 1408 +/- 118 (n = 4) msec (P less than 0.01) throughout the vitreous 5-7 hr after treatment. In treated rabbits receiving 1.0 mmol/l Gd-DTPA intravenously, T1 adjacent to lesions 90-120 min after injection was further reduced in a 63 microliter voxel to 670 +/- 50 ms (mean +/- SD, n = 5) with a minimum pixel value of 285 +/- 52 ms. It was estimated that this represented leakage into vitreous of 8.3 nmol Gd-DTPA. Plasma Gd-DTPA concentrations declined rapidly, with half-life of 20-40 min. The findings indicate that MRI is a technique with the potential for repeated quantitative three-dimensional assessment of blood-retinal barrier dysfunction.

Role of fluorescein glucuronide and its metabolism in vitreous fluorophotometry.

Rabbits were given fluorescein or fluorescein glucuronide intravenously. Fluorescein and fluorescein glucuronide concentrations in plasma and vitreous samples were measured by high-performance liquid chromatography. Vitreous fluorophotometry was performed using the Fluorotron Master to compare scans after administration of fluorescein and fluorescein glucuronide, and for comparison of in vivo fluorescence with in vitro high-performance liquid chromatography analysis. Fluorescein glucuronide was shown to enter the vitreous as early as 1 hr after injection. Fluorescein glucuronide was the dominant molecule in both vitreous and plasma of all rabbits at 6 hr. Because fluorescein glucuronide has a lower fluorescence than fluorescein, the fluorophotometer overestimates the vitreous concentration of fluorescein after its administration. Since fluorescein is metabolized rapidly to fluorescein glucuronide in man, entry of fluorescein glucuronide into the eye should be considered in measurements of blood-ocular barrier permeability by vitreous fluorophotometry.

Dissociation of insulin binding from insulin stimulation of 2-deoxyglucose transport by ruthenium red.

Ruthenium red increased specific insulin binding to isolated adipocytes 5.4 fold and 2.6 fold over binding determined in the absence and presence of Ca2+ and Mg2+. The increase in insulin binding was not accompanied by an increase in insulin sensitivity. The lack of effect of ruthenium red on insulin action argued strongly against an increase in intracellular Ca2+ as a potential messenger/transducer of insulin action and suggested that the enhancing effect of Ca2+ on insulin action was a result of increased receptor affinity.

Familial hyperinsulinemia complicated by extreme insulin resistance during pregnancy: a probable postreceptor defect.

Detailed studies of a family with hyperinsulinemia are reported. The index patient, a 30-yr-old woman with polycystic ovary syndrome, presented with gestational diabetes which was completely resistant to insulin in the presence of severe endogenous hyperinsulinemia. Sensitivity to insulin was regained after delivery. Therapy with cyproterone acetate and ethinyl estradiol for hirsutism exacerbated the hyperinsulinemia toward the levels occurring in pregnancy, with a concomitant deterioration of glucose tolerance. Five other members of her family also were found to have hyperinsulinemia together with high concentrations of circulating C-peptide. Antibodies to insulin and to insulin receptors were not detected, insulin antagonists were not increased, and insulin degradation in the circulation was normal. Insulin extracted from the patient's serum was identical to normal insulin by the criteria of Sephadex chromatography, placental membrane insulin receptor binding, and stimulation of 2-deoxyglucose uptake in isolated rat adipocytes. Although [125I]insulin binding to erythrocytes of all family members and to the patient's placental membranes was markedly reduced, binding to fibroblast cultures from the patient was normal. Insulin-stimulated glucose transport in these fibroblasts also was normal, but there was a mild (20%) reduction in the concentration of cytochalasin B-binding sites in erythrocyte ghosts. Insulin resistance in this family may be due to a partial defect distal to the insulin receptor. This is asymptomatic unless metabolic stresses (pregnancy or steroid administration) are superimposed.

A high prevalence of obesity in a diabetic population: results of a survey of food patterns in 252 patients in a 2 year period.

Dietary patterns were reviewed and correlated with the patients' clinical details in 252 patients seen at the initial visit to a diabetic clinic of a major metropolitan teaching hospital. Except in the subgroup of male patients with insulin-dependent diabetes, there was an extremely high prevalence of obesity, especially in females (70% greater 120% of standard weight; 28% greater than 150%). Traditional 'low-carbohydrate' diets were commonly found irrespective of ethnic origin, particularly in those individuals who had received previous dietary education. This study highlights the urgent need for public health education programmes in order to try to prevent the development of obesity since therapy remains unsatisfactory once it is established.

The effect of body weight and the fatty acid-oxidation inhibitor 2-tetradecylglycidic acid on pyruvate dehydrogenase complex activity in mouse heart.

The proportion of pyruvate dehydrogenase complex in the active, dephosphorylated form was decreased (compared with lean controls) in heart muscle in gold thioglucose-treated obese hyperinsulinaemic mice, and the extent of enzyme inactivation was significantly linearly correlated with both body weight and body fat content. A single oral dose (25 mg/kg body wt.) of the beta-oxidation inhibitor 2-tetradecylglycidic acid to obese animals restored pyruvate dehydrogenase complex activity to that of lean controls. It is suggested that increased fatty acid oxidation may be a major factor in mediating the phosphorylation and inactivation of pyruvate dehydrogenase complex in mouse heart muscle in obesity, and this may represent an important mechanism in the development and/or expression of insulin resistance in respect of abnormalities of cellular glucose homoeostasis in these animals.

Management of pregnancy complicated by diabetes: experience with 232 patients in a 4-year period.

Two hundred and thirty two women with diabetes complicating pregnancy were seen at a metropolitan teaching hospital during a 4-year period. Management during pregnancy in insulin dependent diabetics was directed towards strict metabolic control using conventional insulin regimens and diet. A similar programme was followed for women in whom screening revealed glucose intolerance. Control of maternal blood glucose levels, assessment of fetal maturity and modes of delivery were reviewed in an attempt to define factors which could predict optimal neonatal outcome. Patients with insulin dependent diabetes were less likely to have optimal metabolic control both during pregnancy and parturition than patients with gestational diabetes. Women with gestational, but not preexisting diabetes, demonstrated a close correlation between gestational age and parameters of fetal pulmonary maturity. A high rate of intervention to deliver infants in both groups (50%) was noted. These data indicate the need for meticulous care of women with insulin dependent diabetes during pregnancy.

Outcome of pregnancy complicated by diabetes: experience with 232 patients in a 4 year period.

The outcome of pregnancy was reviewed in 232 women with diabetes (Group 1 = 72 Insulin Dependent Diabetes; Group 2 = 9 Non Insulin Dependent Diabetes and 151 Gestational Diabetes) seen at a major metropolitan teaching hospital in the 4 yr period 1978-1981 inclusive. The perinatal mortality was 5.6% and there was a high rate of congenital malformations (5.6% major, 7.7% minor) with no difference in incidence between the 2 groups. Infants of women whose pregnancies extended beyond 37 weeks of gestation had a reduced incidence and severity of respiratory distress syndrome. Measurement of amniotic fluid lamellar body phospholipid proved accurate in predicting this complication. Neonatal hypoglycaemia correlated with poor maternal blood glucose control in the third trimester and during parturition.

Calcium-dependence of insulin receptor phosphorylation.

Phosphorylation of the insulin receptor of isolated rat adipocytes in response to insulin has been studied. Immunoprecipitation of adipocyte membrane protein demonstrated increased incorporation of 32P after exposure to insulin for 15 min, but this was dependent on the presence of physiological concentrations of Ca2+ and Mg2+. Autoradiography of solubilized immunoprecipitated membrane protein after sodium dodecyl sulphate/polyacrylamide-gel electrophoresis revealed that most of the 32P incorporation occurred in a band corresponding to Mr 95 000, which has been identified previously as the beta-subunit of the insulin receptor. 32P incorporation was inhibited by 2,4-dinitrophenol and trifluoperazine. It is suggested that insulin-receptor phosphorylation is an energy-requiring process that is Ca2+-dependent and may be modulated by calmodulin. Phosphorylation may proceed independently of glucose transport.

Spontaneous perforation of the common bile duct: report of a case.

A case is reported of spontaneous perforation of the common bile duct in a 59-year-old woman. Recurrent episodes of epigastric and right hypochondriac pain over one year culminated in the onset of obstructive jaundice. There were not signs of peritonitis, and laparotomy revealed an abscess surrounding a perforation in the common bile duct just distal to the cystic duct. A cholesterol gallstone was present at the site of perforation. A paracolon bacterium, providence alcalifaciens, was isolated from the abscess. The patient made an uncomplicated recovery after cholecystectomy and drainage of the bile duct.

Porcine calcitonin in the treatment of Paget's disease of bone: experience with 32 patients.

Thirty-two patients with osteitis deformans were treated with porcine calcitonin for 240 patient-months. Relief of pain occurred in 10 patients, while a fall in the serum alkaline phosphatase level was observed in 22 out of 24 patients whose treatment lasted for more than two weeks. Pain relief occurred predominantly in patients with pain in the lower limbs, although not all patients with lower limb pain showed improvement. Side effects, usually mild in nature, were reported by half the patients. Antiporcine calcitonin antibodies were detected in sera of six out of 14 patients. The presence of circulating antibodies seemed unrelated to the effect of therapy or to the occurrence of side effects.