Bethan R Rowe

Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository.

Aims  Autoimmune disorders co‐exist in the same individuals and in families, implying a shared aetiology. The aim of this study was to compare the prevalence of the common autoimmune diseases in the parents of siblings from the Type 1 diabetes Warren repository with the general population.

Association of apolipoprotein ε2 allele with diabetic nephropathy in Caucasian subjects with IDDM

Epidemiological and family studies imply that genetic factors are important in the etiology of diabetic nephropathy in subjects with IDDM (1,2). Vascular disease is characteristic of nephropathy, and lipoproteins are important determinants of atherosclerosis. Apolipoprotein E (apoE) is a major protein constituent of lipoproteins, mediating hepatic lipoprotein uptake and reverse cholesterol transport. ApoE occurs as three isoproteins: E3 with normal function, E2 with reduced affinity, and E4 with increased affinity for the apoE receptor. These are encoded by three codominant alleles e2, E3, and e4. This polymorphism has an influence on lipid levels, the E2 isoform being associated with lower cholesterol but higher triglyceride levels compared with the E3 isoform, and the E4 isoform being associated with higher cholesterol but lower triglyceride levels (3). There is also an association with vascular disease in diabetic and nondiabetic populations (3,4). Preliminary data suggest that this triallelic polymorphism may be associated with genetic susceptibility to diabetic nephropathy (5). The aim of this study was thus to determine the role of the apoE gene polymorphism in a large cohort of IDDM patients with and without diabetic nephropathy. Four patient cohorts were examined: IDDM patients with diabetic nephropathy (nephropathy group, n = 252), IDDM patients with long duration of disease and no nephropathy (long-duration non-nephropathy group [LDNN], n = 197), a

Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM.

SummaryPremature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n=242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n=187); a geographically defined cohort of newly diagnosed diabetic patients (n=341); and IDDM patients with long duration of disease (>15 years) and no evidence of overt nephropathy (n=166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p=0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p=0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

Clinical and Neurophysiological Studies of Aldose Reductase Inhibitor Ponalrestat in Chronic Symptomatic Diabetic Peripheral Neuropathy

Increased flux through the polyol pathway mediated by the enzyme aldose reductase may be associated with the development of diabetic neuropathy. Fifty-four diabetic patients (median age 56 yr, range 25–65 yr) with chronic neuropathic symptoms were randomly allocated to placebo or aldose reductase inhibition (300 or 600 mg ponalrestat IC1128436) groups for 24 wk. Patients with vibration perception thresholds (VPTs) >35 V at the great toe or thermal difference thresholds (TTs) >10°C on the dorsum of the foot were excluded from the trial. No significant changes were observed in symptoms of pain, numbness, or paresthesia between ponalrestat and placebo groups, and there were no improvements in VPT or TT at several sites. Posterior tibial nerve conduction velocity changed from 35.3 ± 4.9 m/s at baseline to 33.4 ±4.0 m/s at 24 wk (NS) with placebo compared with 37.6 ± 5.6 vs. 37.2 ± 8.7 m/s (NS) with 300 mg ponalrestat and 34.5 ± 6.1 vs. 36.2 ± 6.8 m/s (NS) with 600 mg ponalrestat. Further studies are indicated with intervention at an earlier stage in the evolution of neuropathy and for longer periods.

Parental Origin of Diabetes-Associated HLA Types in Sibling Pairs With Type I Diabetes

Genetic susceptibility to type I diabetes is partly determined by genes located in the human leukocyte antigen (HLA) region on chromosome 6. It has been claimed that the transmission of HLA-encoded susceptibility is influenced by parental sex. Fathers are reported to transmit HLA-DR4 haplotypes more frequently to their diabetic offspring than mothers. More recently, it has been suggested that the presence of HLA-DR4 in a mother may influence susceptibility in her offspring, even when it is not inherited. We have analyzed 172 multiplex diabetic pedigrees from the U.K. and find no evidence to support an important effect of parental sex on the inheritance of HLA-encoded susceptibility. Examination of a further 110 pedigrees from the U.S. supports this finding. These results have important implications for strategies involving genetic screening for type I diabetes.

Lack of association of angiotensin II type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependent diabetes mellitus.

Several observations suggest that inherited factors are influential in the development of nephropathy in patients with insulin‐dependent diabetes mellitus (IDDM). Genetic components of the renin angiotensin system are possible candidate genes. The aim of this study was to determine the role of the hypertension associated angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism in susceptibility to nephropathy in IDDM. We examined 264 Caucasoid patients with IDDM and overt nephropathy (as defined by persistent proteinuria in the absence of other causes, hypertension and retinopathy), 136 IDDM patients with long duration of diabetes and no nephropathy (LDNN group), 200 recently diagnosed IDDM patients (Sporadic Diabetic group), and 212 non‐diabetic subjects. The AT1R gene polymorphism was assessed using the polymerase chain reaction and restriction isotyping. Genotype frequencies did not differ significantly between the sporadic diabetic group and the nephropathy group (p = 0.245), nor between the long duration non‐nephropathy group and the nephropathy group (p = 0.250). Allele frequencies were not significantly different between the three groups (p = 0.753). We conclude that there is no significant association between the hypertension associated AT1R gene polymorphism and diabetic nephropathy in patients with IDDM in the UK.

Diabetes in the UK West Indian Community: the Wolverhampton Survey

A survey was carried out to determine the prevalence of known diabetes amongst West Indians living in Wolverhampton. Two hundred and fifty‐one West Indians with diabetes were identified from a computerized register, which records all diabetic patients in the Wolverhampton area attending either the hospital diabetic clinic or general practitioner mini‐clinics, and from questionnaire data obtained through local general practitioners. An estimated 4.4% of the Wolverhampton population are of West Indian origin determined by the 1981 census, giving a prevalence of known diabetes of 2.2% compared with 1.2% in the indigenous UK white Caucasian population. Only 4% of these patients were truly insulin‐dependent but 38% were insulin‐treated, 43% were on oral hypoglycaemic agents and 19% on diet alone. Only 1.6% were diagnosed below the age of 20 years, with peak frequency of diabetes occurring in the age group 45–64 years. Thirty‐eight percent of all patients were obese, 40% were hypertensive, but only 4% had a history of angina or myocardial infarction. In UK West Indians non‐insulin‐dependent diabetes is common and is predominantly a disease of middle age, whereas insulin‐dependent diabetes is relatively uncommon.

Microalbuminuria in diabetic subjects with chronic peripheral neuropathy

Fifty-five patients with chronic peripheral neuropathy, 31 with and 24 without retinopathy, had albumin excretion rates determined on 2-h supine urine collections on three occasions by a radioimmunoassay method. Four patients with retinopathy had albustix-positive proteinuria and were excluded from subsequent analysis. Microalbuminuria was found in 20 of the 27 patients with retinopathy compared with 10 of the 24 patients with neuropathy alone. The mean albumin excretion rate (AER) was higher in neuropathic patients with retinopathy than in those patients with neuropathy alone (41.2 +/- 40.3 vs 18.8 +/- 33.2 micrograms/min, P less than 0.01). Multivariate analysis of the data was performed and this revealed a correlation coefficient of R2 = 0.33 (P less than 0.01) for AER as the dependent variable with respect to the independent variables HbA1, systolic blood pressure and known duration of diabetes. There was, however, no significant contribution separately of these individual variables to the regression equation. Microalbuminuria was significantly associated with retinopathy although almost half of the patients with neuropathy alone had microalbuminuria. The association between microalbuminuria and neuropathy even in the absence of retinopathy provides support for a microvascular element in the pathogenesis of diabetic neuropathy.