Intraportal and splenic human islet autotransplantation combined with total pancreatectomy.
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Biomedical subjects
Publications and source records attributed to A C Burden.
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Hypertension is a major risk factor for premature death. Large outcome studies have demonstrated reduced morbidity and mortality associated with antihypertensive therapy in mixed patient populations, but data on morbidity and mortality in defined ethnic groups are lacking. Management of cardiovascular risk factors, which frequently coexist with hypertension, presents a logical management strategy in these patients. Indo-Asian patients are particularly prone to insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM), which are associated in turn with potentially atherogenic lipid profiles and poor cardiovascular outcomes. Diuretics and beta-adrenoceptor blockers exert theoretically adverse effects on lipid profiles and should be used with caution in Indo-Asian patients at risk of developing NIDDM. Hypertensive African-Caribbean patients are at increased risk of stroke and tend to suffer greater target organ damage, including renal dysfunction and cardiac hypertrophy. Hypertension in African-Caribbean patients is less sensitive to beta-adrenoceptor blockade or ACE inhibition than in white patients. Selective alpha 1-adrenoceptor antagonists and calcium channel blockers are equally effective antihypertensive agents in all races. While calcium channel blockers are metabolically neutral, alpha 1-adrenoceptor blockers promote a potentially less atherogenic lipid profile. Further study of the effects of antihypertensive treatment on morbidity and mortality in ethnic groups is required, particularly in Indo-Asian patients.
Sudden death at night is known to occur in young patients with insulin-dependent (Type 1) diabetes mellitus (IDDM) but the aetiology is uncertain. A cardiac arrhythmia has been postulated, but there has been little evidence to support this. We present the case of a 31-year-old man with IDDM of 17 years duration, who died suddenly while asleep. Over preceding months, he had had strict glycaemic control (HbA1 8.9%), normal 24 h blood pressure (mean 131 +/- 2.1/76 +/- 2.2 mmHg), no evidence of microangiopathy or endothelial dysfunction and normal standard clinical tests of autonomic function. An electrocardiogram was similarly unremarkable, with a QTc interval of 0.414 s, and an echocardiogram had demonstrated normal left ventricular mass index (96.4 g m-2). However, there was no nocturnal dip in heart rate (daytime 74 +/- 2.7, and nocturnal 68 +/- 1.6 beats min-1), and he had grossly impaired baroreflex sensitivity during Phase 4 of the valsalva manoeuvre (0.5 ms mmHg-1), with power spectral analysis studies suggesting an abnormality of parasympathetic function. The coroner's autopsy demonstrated no structural abnormalities. We hypothesize that abnormal baroreflex sensitivity could either predict a risk of or account for some of the unexplained deaths in IDDM, in that relative overactivity of the sympathetic nervous system could cause ventricular arrhythmias.
Diabetes mellitus increases the rate of atrioventricular block after a myocardial infarction; right bundle branch block is more common than expected in the diabetic outpatient population. We decided to assess whether diabetic subjects were more likely to need permanent cardiac pacemaker insertion. Data from patients in Leicestershire who had undergone permanent cardiac pacemaker insertion during a 4-year period were analysed. The capture recapture technique was used: Hospital Activity Analysis data as capture, ward admission book and case note confirmation as recapture. Diabetes coding accuracy was confirmed from the central register and from an analysis of 100 sets of case notes. The number of these patients with diabetes was then recorded. Data for the reference population was obtained using a survey of a market town in Leicestershire. There were 688 patients, most (79%) aged over 65 years. Our analysis was performed on this group. Of this age group undergoing pacemaker insertion. 11.1% was diabetic. In the same age group, 8.3% of the controls were diabetic: a relative risk of 1.34 (P < 0.01, 95% confidence interval 1.25-1.44). This relative risk is likely to be an underestimate. The aetiology of this excess risk is uncertain: it is most likely due to ischaemic heart disease, but microangiopathy or increased cholinergic sensitivity may play a role.
Impaired reactivity of the resistance vasculature may contribute to the development of diabetic microangiopathy by altering microvascular haemodynamics. This study investigates the acute effects of insulin on the contractility and relaxation properties of isolated human resistance arteries (< 300 microns internal diameter) taken from gluteal subcutaneous fat of 33 (18 male: 15 female) normotensive healthy volunteers (supine blood pressure 115.6 +/- 1.6/70.0 +/- 1.5 mm Hg [mean +/- SEM], with no family history of hypertension or diabetes mellitus. Resistance arteries were mounted in a small vessel myograph to measure isometric tension. Contractile responses to noradrenaline were reduced after incubation in 1 mU/ml of insulin for 20 min (p < 0.01; Group 1). Increasing concentrations of insulin were found to reduce the contractile response to noradrenaline in a dose-dependent manner (Group 2; 0.1 mU/ml by 8% [p < 0.01], 1 mU/ml by 17% [p < 0.02] and 10 mU/ml by 22% [p < 0.01]). Sensitivity to insulin (ED50) only decreased at the highest concentration of insulin. However, acetylcholine-induced relaxation was not altered by insulin (Group 2). Time control studies (Group 3) showed that contractile and relaxation responses over the 4-h study period were unchanged. Furthermore, the length of time the vessels were exposed to insulin did not progressively impair responses (Group 4). These findings suggest that insulin may induce abnormalities in vascular smooth muscle contractility, a factor that may contribute to or exacerbate the abnormal haemodynamics observed in the capillary microcirculation of numerous vascular beds in diabetes.
If environmental factors are important in the aetiology of insulin-dependent (Type 1) diabetes mellitus, primary schooling would be more likely to be shared by cases in an epidemic year compared with controls. We have examined a case control study, comparing primary schools attended. Cases were identified from an established register with known accurate ascertainment and compared with controls taken from a central register of all children and date of birth, sex, and race matched. Parents were asked to complete a structured questionnaire which included questions relating to the child's schooling. There were 187 cases with at least a first matched control. Thirty-two of the cases attended the same nursery or primary school as another case, 18 in the same academic year, compared with 12 controls attending the same school as another control (99% confidence interval (CI) for the difference between proportions 0.0572 - 0.107). Of these cases diagnosed in 1986, 9 attended the same school as another case. Spatial clustering occurs in Type 1 diabetes. This is further evidence of an environmental factor contributing to the genesis of the disease.
The relative risk of death by calendar date of diagnosis was investigated in a population-based incident cohort of 845 (463 males:382 females) IDDM diagnosed in Leicestershire before the age of 17 years between 1940 and 1989. The mortality status of 844 (99.9%) patients was determined as of the 31 December 1991, representing 14,346 person-years of risk. Trends in relative risk of death were investigated using Cox proportional hazards modelling for within cohort comparisons and age/sex and calendar time adjusted standardized mortality ratios (SMR) using generalized linear modelling for external comparisons. Median age at diagnosis was 10 years (range 3 months to 16 years); median duration of diabetes 15 years (range 1-51 years). Forty-four patients had died (5.2%; median age at death 31 years, range 11-51 years). A further four patients died at presentation (within 24 h) from ketoacidosis and are excluded from all analyses. Calendar date of diagnosis was found to be an important predictor of mortality. Adjusting for attained age there was evidence of a decline in relative risk of death with calendar date of diagnosis of 3.4% (95% CI, 0.005-6.9%) per annum, equivalent to a 32% fall per decade (95% CI, 5-51%), or 84% (95% CI, 21-97) from 1940 to 1989. The data are consistent with a large fall in mortality between the 1940s and 1950s representing over 50% of the total reduction in mortality between 1940 and 1991. Neither sex nor age at diagnosis were significant predictors of mortality. Over the study period 1940-89 the SMR (male and female combined) fell from 981 (541-1556) to 238 (60-953) relative to the general population. This population-based study shows that the prognosis for Type 1 (insulin-dependent) diabetes mellitus has improved markedly over the period 1940-1991.
STUDY OBJECTIVE: Analyses of causes of mortality in people with diabetes using data form death certificates mentioning diabetes provide unreliable estimates of mortality. Under-recording of diabetes as a cause on death certificates has been widely reported, ranging from 15-60%. Using a population based register on people with diabetes and linking data from another source is a viable alternative. Data from the Office of Population Censuses and Surveys (OPCS) are the most acceptable mortality data available for such an exercise, as direct comparison with other published mortality rates is then possible. DESIGN: A locally maintained population-based mortality register and all insulin-treated diabetes mellitus cases notified to the Leicestershire diabetes register (n = 4680) were linked using record linkage software developed in-house (Lynx). This software has been extensively used in a maintenance and update cycle designed to maximise accuracy and minimise duplication and false registration on the diabetes register. Deaths identified were initially coded locally to the International Classification of Diseases, 9th revision (ICD9), and later a linkage was performed to use official OPCS coding. Mortality data identified by the linkage was indirectly standardised using population data for Leicestershire for 1991. Standardised mortality ratios (SMR) were estimated, with 95% confidence intervals. Insulin dependent diabetes (IDDM) was defined as diabetes diagnosed before age 30 years with insulin therapy begun within one year of diagnosis. All other types were considered non-insulin dependent diabetes (NIDDM). Analyses were performed for the whole sample and then for the NIDDM subgroup. Results from these analyses were similar and therefore only whole group analyses are presented. MAIN RESULTS: A total of 370 deaths were identified for the period of 1990-92 inclusive - 56% were in men and 44% in women, median age (range) 71 years (12-94). Approximately 90% of deaths were subjects with NIDDM. Diabetes was mentioned on 215 (58%) death certificates. The all causes SMRs were significantly raised for men and women for all ages less than 75 years. Ischaemic heart disease (ICD9) rubrics 410-414) accounted for 146 (40%) deaths - 41% of male and 38% of female deaths. Male and female SMRs were significantly raised for the age groups 45-64, 65-74, and 75-84 years. Cerebrovascular disease (ICD9 rubrics 430-438) accounted for 39 (10%) deaths and the SMR for women the external causes of death (ICD9 rubrics E800-E999) were also significantly raised overall and in age groups 15-44 and 45-64 years. This was not true for men, although numbers of deaths in this category were small for both men (4) and women (9). CONCLUSION: Record linkage has been used successfully to link two local, population based registers. This has enabled an analysis of mortality in people with diabetes to be performed which overcomes the problems associated with using as a sample, death certificates where diabetes is mentioned. The mortality rates and SMRs estimated should more accurately reflect the true rates than would be possible using other methods. The persisting excess mortality identified for people with diabetes is of a similar magnitude and attributable to similar causes as has been reported elsewhere in population based studies.
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1. An increase in capillary blood flow and pressure has been implicated in the pathogenesis of diabetic microangiopathy. Abnormal vascular reactivity of the resistance vasculature may play a contributory role by permitting alterations in regional haemodynamics. 2. We have studied the contractile behavior of isolated resistance arteries from normotensive patients with insulin-dependent diabetes mellitus and non-diabetic matched control subjects. Contractile responses to potassium (123 mmol/l), noradrenaline (10(-8) to 3 x 10(-5) mol/l) and angiotensin II (10(-11) to 3 x 10(-8) mol/l) were recorded. Relaxation studies were performed in maximally contracted vessels using acetylcholine (10(-8) to 10(-5) mol/l) and bradykinin (10(-9) to 10(-6) mol/l) (endothelium-dependent) and sodium nitroprusside (10(-9) to 10(-5) mol/l) (endothelium-independent). 3. The maximal contractile responses to potassium (P < 0.05), noradrenaline (P < 0.01) and angiotensin II (P < 0.01) were depressed in diabetic patients. Relaxation to acetylcholine was impaired (P < 0.05), but was normal with bradykinin and sodium nitroprusside. 4. These results suggest that there may be a defect in the endothelial cell acetylcholine receptor excitation-coupling in diabetes mellitus rather than a decreased ability to synthesize and release endothelium-derived relaxing factor. Impaired contraction and endothelium-dependent relaxation of resistance arteries in diabetic patients may contribute to the development of diabetic microangiopathy by causing an increase in tissue blood flow, a rise in capillary pressure and, as a result, an increase in vascular permeability.
To assess the full effect of diabetes on survival in elderly subjects, residents of Melton Mowbray aged 65, 70, 75, 80, and 85 years were screened by glucose tolerance test and followed up for 4.5 years. Death occurred in 56 of 520 normal subjects, 9 of 44 subjects with impaired glucose tolerance, 7 of 19 newly diagnosed diabetic subjects, and 27 of 52 known diabetic subjects. Diabetic subjects were 4.5 times (95% confidence interval 2.9-7.0) more likely to die than subjects with normal glucose tolerance. Thus elderly diabetic subjects have a substantially increased risk of death compared to their normal glucose tolerant peers.
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Red cell membrane cholesterol, 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-[(4-trimethylammonium)phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH) anisotropies and basal and calmodulin-stimulated calcium pump activities were compared in 16 normolipidaemic Type 2 (non-insulin-dependent) diabetic patients and 20 normolipidaemic control subjects using the Mann-Whitney U-test. Serum cholesterol, membrane cholesterol, and membrane DPH and TMA-DPH anisotropies were similar in the two groups but both basal and calmodulin-stimulated calcium pump activities were reduced in the diabetic group: basal activity (median (inter-quartile range), mumol mg-1 h-1) 1.66 (1.18-1.97) vs 2.09 (1.90-2.50), p < 0.005 and calmodulin-stimulated activity 4.19 (3.07-5.48) vs 5.53 (4.70-6.88), p < 0.006. Although there were no correlations between glycaemic control and membrane anisotropy and between glycaemic control and calcium pump activity, the reduction in calcium pump activity is most likely due to a direct effect of diabetes on the calcium pump protein itself.
The prevalence of childhood-onset Type 1 diabetes mellitus is important for determining health care provisions. In Leicestershire 13.5% of the childhood population (0-14 years) is of South Asian origin (census 1991). This study determined the prevalence of Type 1 diabetes in Whites and South Asians in Leicestershire, using a capture/recapture method to coincide with the 1991 Census day. Children (0-14 years) with Type 1 diabetes were captured from the central diabetic register. The health visitor and consultant records were used to recapture the cases. Total ascertainment of cases was 95-100%. The prevalence of Type 1 diabetes in White children (107 cases) was 0.75/1000 children (95% CI 0.61-0.89) compared with the South Asian prevalence (18 cases) of 0.77/1000 (95% CI 0.41-1.13). The overall prevalence in White males was 0.82/1000 (0.61-1.03) compared with 0.68/1000 (0.48-0.87) in females. In South Asian males it was 0.59/1000 (0.15-1.03) compared with 0.96/1000 (0.39-1.53) in females. The prevalence of Type 1 diabetes in children of South Asian migrants to the United Kingdom cannot be said to be different from White children.
The Asian population is at greater risk from a myocardial infarction than their European counterparts. Fewer Asians are referred for coronary angiography. We studied referral rates for exercise stress testing following acute myocardial infarction in Asians and Europeans and also examined stress test outcome. A retrospective analysis was performed using hospital activity analysis data, ward admission book and stress test referral forms and reports. There were 962 acute myocardial infarctions with 90% being European. Fewer Asian patients were referred for stress testing (32.3% versus 45%, P < 0.001). Asian patients were more likely to have a positive test (42.9% versus 31.3%, P < 0.02). Fewer Asian patients completed the test (14.3% versus 31.3%, P < 0.001). Possible reasons for the decreased referral rates include communication difficulties and real or perceived poor exercise tolerance. More Asian patients should be referred for stress testing. Interpreters and information leaflets in multiple languages may help achieve this aim.
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