Patients' attitudes towards screening for diabetes and other medical conditions in the dental setting.

AIM: To determine the attitudes of patients attending routine appointments at primary care dental clinics and general dental practices towards the possibility of chair-side screening for medical conditions, including diabetes, in the dental setting. METHODS: A brief, anonymous, self-administered questionnaire distributed to adult patients (≥18 years) attending 2 primary care dental clinics and 16 general dental practices in South-West England. RESULTS: One hundred and ninety-seven completed questionnaires were received from patients at primary care dental clinics and 429 from general dental practice patients. Overall, 87% of respondents thought that it was important or very important that dentists screened patients for medical conditions such as diabetes; 79% were very willing to let a dental team member carry out screening. The majority indicated willingness to be screened for various medical conditions during a visit to the dentist, with significantly higher proportions of respondents in the primary care clinics indicating willingness (hypertension: 83% vs 74%; heart disease: 77% vs 66%; diabetes 82% vs 72% [all p <0.02]). Nearly two thirds of primary care clinic respondents and over half of general practice patients indicated that they would be willing to discuss test results with the dental team. Overall, 61% had never knowingly been screened or tested for diabetes; 20% reported that they had been tested within the previous 12 months. CONCLUSION: The majority of respondents supported the concept of medical screening in a dental setting and were willing both to have screening tests and discuss their results with the dental team. Patient acceptance is paramount for successful implementation of such screening programmes.

Genetic association analyses of non-synonymous single nucleotide polymorphisms in diabetic nephropathy.

AIMS/HYPOTHESIS: Diabetic nephropathy, characterised by persistent proteinuria, hypertension and progressive kidney failure, affects a subset of susceptible individuals with diabetes. It is also a leading cause of end-stage renal disease (ESRD). Non-synonymous (ns) single nucleotide polymorphisms (SNPs) have been reported to contribute to genetic susceptibility in both monogenic disorders and common complex diseases. The objective of this study was to investigate whether nsSNPs are involved in susceptibility to diabetic nephropathy using a case-control design. METHODS: White type 1 diabetic patients with (cases) and without (controls) nephropathy from eight centres in the UK and Ireland were genotyped for a selected subset of nsSNPs using Illumina's GoldenGate BeadArray assay. A chi (2) test for trend, stratified by centre, was used to assess differences in genotype distribution between cases and controls. Genomic control was used to adjust for possible inflation of test statistics, and the False Discovery Rate method was used to account for multiple testing. RESULTS: We assessed 1,111 nsSNPs for association with diabetic nephropathy in 1,711 individuals with type 1 diabetes (894 cases, 817 controls). A number of SNPs demonstrated a significant difference in genotype distribution between groups before but not after correction for multiple testing. Furthermore, neither subgroup analysis (diabetic nephropathy with ESRD or diabetic nephropathy without ESRD) nor stratification by duration of diabetes revealed any significant differences between groups. CONCLUSIONS/INTERPRETATION: The nsSNPs investigated in this study do not appear to contribute significantly to the development of diabetic nephropathy in patients with type 1 diabetes.

Maternal glucose levels influence birthweight and 'catch-up' and 'catch-down' growth in a large contemporary cohort.

AIM: To explore the effects of maternal glucose on birthweight, infant and childhood growth in non-diabetic pregnant women using routinely collected data. METHODS: Routinely collected data were extracted retrospectively from two clinical databases. These data comprised measurements of maternal random plasma glucose, infant birthweight, infant and child weight and height at 6-8 weeks, 24-36 weeks and 96-120 weeks in 6263 cases. After data cleaning, 4681 were analysed. RESULTS: When the data were analysed in thirds, a positive association between birthweight standard deviation scores (SDS), weight SDS and height SDS with maternal random plasma glucose (RPG) was observed. Regression analysis of birthweight SDS and RPG was significant (P < 0.001). Babies were approximately 48 g heavier at birth for each 1 mmol/l increase of mother's RPG. Infants who showed 'catch-up' growth (as shown by change in weight SDS) at 2 years were born to mothers with lower glucose levels than infants who showed 'catch-down' growth (P < 0.001). CONCLUSIONS: Random maternal glucose concentrations (taken at 28 weeks' gestation) in the normal range are positively related to birthweight. Glucose concentrations also predict greater weight and length in infancy. Despite this, babies born to mothers with higher glucose concentrations within the normal range show significant 'catch-down' growth in infancy as shown by a fall in weight SDS.

Is neighbourhood deprivation a risk factor for gestational diabetes mellitus?

AIMS: To assess the relationship between neighbourhood deprivation and the rate of gestational diabetes mellitus (GDM) using routinely collected data from a clinical information system, in Plymouth, UK. METHODS: Between 1 January 1996 and 31 December 1997, 3933 women residing within the Plymouth Primary Care Trust (PCT) were screened for GDM using indices of neighbourhood deprivation and prevalence of GDM. Areas (n = 43) were classified according to the Townsend index, measuring material deprivation. Pregnant women with and without GDM were compared. RESULTS: The prevalence of GDM was 1.7%[95%, confidence interval (CI) 1.20, 2.11]. The prevalence of GDM ranged from 1.05% (95% CI 0.60, 1.70) in the most deprived to 2.10% (95%, CI 1.34, 3.13), in the least deprived neighbourhood. Crude rates decreased by 50%[relative prevalence (RP) (95% CI) 0.50 (0.27, 0.94); P = 0.06] amongst those living in the most-deprived compared with those living in the least-deprived areas. Using a stepwise binary logistic regression model, older age at delivery significantly increased the risk of developing GDM. [RP (95%, CI) 1.09, (1.04, 1.13)]. Townsend deprivation score had no significant independent association with GDM when other covariates were considered. CONCLUSION: These data suggest that the neighbourhood context in which women live has no impact on the risk of GDM. Diabet.

Short-term effects of severe dietary carbohydrate-restriction advice in Type 2 diabetes--a randomized controlled trial.

OBJECTIVE: This study sought to examine the effects of a 3-month programme of dietary advice to restrict carbohydrate intake compared with reduced-portion, low-fat advice in obese subjects with poorly controlled Type 2 diabetes. RESEARCH DESIGN AND METHODS: One hundred and two patients with Type 2 diabetes were recruited across three centres and randomly allocated to receive group education and individual dietary advice. Weight, glycaemic control, lipids and blood pressure were assessed at baseline and 3 months. Dietary quality was assessed at the end of study. RESULTS: Weight loss was greater in the low-carbohydrate (LC) group (-3.55 +/- 0.63, mean +/- sem) vs. -0.92 +/- 0.40 kg, P = 0.001) and cholesterol : high-density lipoprotein (HDL) ratio improved (-0.48 +/- 0.11 vs. -0.10 +/- 0.10, P = 0.01). However, relative saturated fat intake was greater (13.9 +/- 0.71 vs. 11.0 +/- 0.47% of dietary intake, P < 0.001), although absolute intakes were moderate. CONCLUSIONS: Carbohydrate restriction was an effective method of achieving short-term weight loss compared with standard advice, but this was at the expense of an increase in relative saturated fat intake.

A novel polymorphism in the 5' flanking region of the glucose transporter (GLUT1) gene is strongly associated with diabetic nephropathy in patients with Type 1 diabetes mellitus.

Glucose transporter 1 (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. Recent studies have suggested that polymorphisms in the GLUT1 gene are associated with susceptibility to diabetic nephropathy (DN) in patients with diabetes mellitus. In this study, a novel polymorphism (A-2841T) in the 5' flanking region of GLUT1 was examined in 288 patients with Type 1 diabetes mellitus (T1DM) and 101 normal controls. The polymorphisms were amplified and the fragment digested with the enzyme HpyCH4V. There was a highly significant increase in the frequency of the TT-2841 genotype in patients with nephropathy (n=131) compared with those with either no microvascular complications after a 20-year duration of diabetes (uncomplicated; n=72; 54.5% vs. 2.7%, chi=79.4, P<.000001). There was no difference between the uncomplicated group and those who only had retinopathy (n=50; 2.7% vs. 4.0%, respectively). The frequency in recently diagnosed patients was 17.1% and only 2.0% in normal controls. In contrast, the AA genotype was found in 13.6% of the nephropaths, 76.3% of uncomplicated, 48.0% of retinopaths, and 65% of normal controls. These results confirm previous reports of an association between the GLUT1 gene and susceptibility to DN but not retinopathy. The localisation of this polymorphism suggests that it may be involved in the expression of the gene.

Weight differences in Plymouth toddlers compared to the British Growth Reference Population.

Routinely collected weight measurements from 4665 Plymouth children born 1996-97 were compared with the British Growth Reference Charts (BGRC). The children were 0.33 SDS heavier on average than the reference population at 24-30 months, an actual excess of 460 g.

Space-time clustering of childhood Type 1 diabetes in Devon and Cornwall, England.

AIMS: Several studies on space-time clustering have been reported in childhood diabetes, but the findings are conflicting. The present study was undertaken to examine whether such clustering could be detected at either birth or the time of diagnosis in the far South-west of England. METHODS: A cohort of 518 children aged 0-15 years and diagnosed with Type 1 diabetes from 1975 to 1996 contained in the population-based Cornwall and Plymouth Children's Diabetes Register (CPCDR) were included in the analyses. The case ascertainment for this register is estimated to be 94.4% complete. Mantel's modification of Knox's method was employed. A method based on K-function was also used, for the first time, to investigate the space-time clustering of diabetes. RESULTS: Significant space-time clustering at diagnosis was found by the Knox's test in the following combinations of critical cut-off thresholds: 25, 35 and 50 km and 90, 270 and 360 days (all P < 0.05), with the highest significance found at 35 km and 360 days (P = 0.0011). K-function analysis also confirmed the overall clustering (P = 0.013). CONCLUSIONS: There is strong evidence of space-time clustering in the onset of childhood Type 1 diabetes in Devon and Cornwall, England. These results lend some support to the hypothesis that viral infections and some unknown localized environmental factors play a role in the development of childhood Type 1 diabetes.

NFkappaB polymorphisms and susceptibility to type 1 diabetes.

Nuclear factor kappa B (NFkappaB) is an important transcription factor that is involved in the response to oxidative stress and inflammation. Recent studies suggest that it may be involved in the development of diabetic microvascular complications. A highly polymorphic (CA) dinucleotide repeat microsatellite has been identified in the regulatory region of the NFkappaB gene. The aim of this study was to investigate whether this polymorphic region was associated with susceptibility to type 1 diabetes, or its late complications. Genomic DNA was extracted from the peripheral blood of 217 patients with type 1 diabetes mellitus (T1DM) and 111 normal healthy controls. In our population 18 alleles (A1-A18) were identified. There was a highly significant decrease in the frequency of allele 146 bp (A14) in type 1 diabetes (0.03) compared with the normal controls (0.28) (chi(2) = 79.8, Pc = 0.00001). In contrast, the frequency of the allele 138 bp (A10) was significantly increased in patients with type 1 diabetes (0.17) compared with the normal controls (0.02) (chi(2) = 32.8, P < 0.00000). These results demonstrate that the NFkappaB gene may play a role in the susceptibility to type 1 diabetes: individuals with the A10 allele may be more likely to develop diabetes compared with the A14 allele.

Drinking water composition and childhood-onset Type 1 diabetes mellitus in Devon and Cornwall, England.

AIMS: Previous studies have reported inconsistent results on the association between some compositions (e.g. nitrate) in domestic water and the risk of childhood-onset Type 1 diabetes mellitus. This study aimed to examine the relationship between nitrate, zinc and magnesium in drinking water and the risk of childhood-onset Type 1 diabetes mellitus. METHODS: The study covers the Cornwall and the former Plymouth Health Authority Regions in the far south-west of England. Five hundred and seventeen children, aged 0-15 years, diagnosed with Type 1 diabetes mellitus between 1975 and 1996, were identified for inclusion in the study. Domestic water data (nitrate, Zn, Mg, Cu, Al, Ca, Fe and Mn) between 1993 and 1997 were provided by South-west Water Plc, UK, for each of the 40 Water Supply Zones in which the subjects had been resident at the time of diagnosis. The standardized incidence ratio (SIR) of the disease was calculated for each Water Supply Zone using the UK 1991 census population data. The relationship between the SIR of the disease and the water quality indicators in thirds (three strata of low, medium and high concentrations) was examined by chi2 test for trend and Poisson regression analysis. RESULTS: The initial analyses by chi2 test for trend on the relation of SIRs and drinking water compositions suggested that copper, magnesium and nitrate might have some protective effects, but Poisson regression analyses showed that only zinc and magnesium were significant factors. The data suggest that the incidence rate of childhood diabetes is significantly lower when the concentrations of zinc and magnesium in the domestic drinking water are in the range 22.27-27.00 microg/l (incidence rate ratio (IRR), 0.76; 95% CI, 0.59-0.97) and greater than 2.61 mg/l (IRR, 0.72; 95% CI, 0.58-0.91), respectively. CONCLUSIONS: Our findings suggest evidence of a possible association between zinc and magnesium in the domestic drinking water and childhood diabetes in the far south-west of England. However, these possible protective effects of zinc and magnesium in domestic drinking water warrant further confirmation.

Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy.

BACKGROUND: Despite good metabolic control, many patients with type 1 diabetes still develop nephropathy, implicating a role for genetic factors. Recent studies examining the regulatory region of the aldose reductase (ALR2) gene, the rate-limiting enzyme of the polyol pathway, support its role as a candidate gene for nephropathy. Here we report the quantitation of ALR2, together with sorbitol dehydrogenase mRNA in the peripheral blood mononuclear cells (PBMCs) of type 1 diabetic patients with (N = 29) and without nephropathy (N = 11) following stimulation with high levels of D-glucose. METHODS: PBMCs from patients and normal controls were cultured for five days with phytohemagglutinin in either normoglycemia (11 mmol/L D-glucose) or supplemented with 10 mmol/L D-glucose (moderate hyperglyemia) or 20 mmol/L D-glucose (hyperglycemia). The RNA was extracted and analyzed by ribonuclease protection assay. RESULTS: ALR2 mRNA levels were significantly elevated with increasing D-glucose concentration (normal to hyperglycemic) in those patients with nephropathy (P < 0.0001). In marked contrast, in those without nephropathy and in the normal healthy controls, there was no change in mRNA expression. Furthermore, those patients with nephropathy and the Z-2/X susceptibility genotype had the greatest increase in ALR2 mRNA compared with those with low-risk genotypes (P < 0.007). CONCLUSION: These results show that patients with nephropathy exhibit marked disturbances in the expression of the enzyme components of the polyol pathway. Ultimately this leads to tissue damage and ischemia.

Polymorphisms of the glucose transporter (GLUT1) gene are associated with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with type 1 diabetes mellitus. Recent studies suggest that genetic factors, including polymorphisms in the flanking region of the aldose reductase gene (5'ALR2), play an important role in the pathogenesis of nephropathy. Glucose transporter (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. The aim was to investigate the frequency of a polymorphism within the GLUT1 gene in 186 Caucasoid patients with type 1 diabetes and 104 normal controls. METHODS: Amplimers flanking the Xba-I polymorphic site in the second intron were employed to amplify DNA from subjects. The amplified DNA was restricted with endonuclease Xba-I, separated by gel electrophoresis, and visualized. In the absence of an Xba-I site, a fragment of 1.1 kilobase was seen, whereas fragments of 0.9 and 0.2 were generated if the Xba-I site was present. RESULTS: There was a highly significant increase in the frequency of the 1.1 allele in those patients with nephropathy (N = 70) compared with those with no proteinuria or retinopathy after 20 years of diabetes (uncomplicated N = 44, 61.4 vs. 40.9%, respectively, P < 0.001). The 1.1/1.1 genotype was also significantly increased in the nephropathy group compared with the uncomplicated group of patients (37.1 vs. 13.6%, respectively, P < 0.01). The frequency of the 1.1/1.1 genotype was similar in 30 patients with retinopathy but not nephropathy when compared with the uncomplicated group of patients (13.6 vs. 16.7%). Furthermore, only 8 out of 49 patients with DN had the Z+2 5'ALR2 DN "protective" allele and the 0.9 GLUT1 allele in contrast to 21 out of 39 uncomplicated patients (P < 0.0002). CONCLUSION: These results suggest that the GLUT1 gene together with the aldose reductase gene are associated with susceptibility to DN in patients with type 1 diabetes.

A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus.

Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of the insulin-producing islet beta cells. It is likely that several genetic and environmental factors contribute to this process. There is increasing evidence showing that polymorphisms in cytokine genes may play an important role in modifying the immune response. Interleukin-6 (IL-6) is a cytokine that has been implicated in a number of immune-mediated diseases. Further, there is a polymorphism at position -174 (G(-174)C) of the promoter region of the IL-6 gene that may alter the expression of the gene. In this study, the G(-174)C polymorphism was investigated in 257 Caucasoid patients with type 1 diabetes, 53 two-parent-proband trios, and 120 normal, healthy controls. DNA was amplified using amplimers that flank the G(-174)C site, and the products were digested with the restriction endonuclease NlaIII to detect the G or the C allele. The homozygous G,G(-174) genotype was increased in the patients compared with the normal controls (50.6% vs. 33.3%, p < 0.002), with a decrease in the C,C genotype in the patients compared with the controls (12.5% vs. 24.2%, respectively, p < 0.004). In the 53 trios studied, the G allele was transmitted in 29 of 53 informative meioses. There was no association with age at onset of diabetes or the presence of diabetic complications. In conclusion, these results suggest that the IL-6 gene may contribute to the genetic susceptibility to type 1 diabetes.

The HLA-E locus is associated with age at onset and susceptibility to type 1 diabetes mellitus.

Previous studies have suggested that the human leukocyte antigen (HLA) class I region may be involved in determining the age at onset and clinical severity of type 1 diabetes. We have investigated the frequency of polymorphisms of the nonclassical HLA class I gene, HLA-E, in 199 British Caucasian patients with type 1 diabetes and 82 healthy controls. A highly significant increase in the frequency of the HLA-E 0101 genotype was found in the patients compared to controls (chi(2) = 15.3, p < 0.00009). The frequency of the HLA-E 0101 genotype was increased in those patients diagnosed after 10 years of age, while the frequency of the 0101, 0103 genotype was significantly increased in those subjects diagnosed before 10 years of age (chi(2) = 26.0 p < 0.000003 and chi(2) = 13.0 p < 0.0003, respectively). No obvious interaction between the HLA-E locus and the class II DQB1*0201, 0302, and 0501 susceptibility alleles was found. This is the first report of an association between the HLA-E locus and susceptibility to an autoimmune disease.