Showing papers in "Diabetic Medicine in 2000"

Radicals and oxidative stress in diabetes.

Abstract: Recent evidence is reviewed indicating increased oxidative damage in Type 1 and Type 2 diabetes mellitus as well as deficits in antioxidant defence enzymes and vitamins. Mechanisms are considered whereby hyperglycaemia can increase oxidative stress, and change the redox potential of glutathione and whereby reactive oxygen species can cause hyperglycaemia. It is argued that oxygen, antioxidant defences, and cellular redox status should now be regarded as central players in diabetes and the metabolic syndrome.

Socio-economic status, obesity and prevalence of Type 1 and Type 2 diabetes mellitus.

Abstract: Summary Aims The influence of socio-economic status on the prevalence of Type 1 and Type 2 diabetes mellitus, and on obesity, was explored using routinely collected healthcare data for the population of Tayside, Scotland. Methods Among 366 849 Tayside residents, 792 and 5474 patients with Type 1 and Type 2 diabetes, respectively, were identified from a diabetes register. The Carstairs Score was used as a proxy for socio-economic status. This is a material deprivation measure derived from the UK census, using postcode data for four key variables. Odds ratios for diabetes prevalence, adjusted for age, were determined for each of six deprivation categories (1 – least deprived, 6/7 – most deprived). The mean body mass index (BMI) in each group was also determined, and the effect of deprivation category explored by analysis of covariance, adjusting for age and sex. Results The prevalence of Type 2 diabetes, but not Type 1 diabetes, varied by deprivation. People in deprivation category 6 and 7 were 1.6-times (95% confidence interval 1.4–1.8) more likely to have Type 2 diabetes than those least deprived. There was no relationship between deprivation and BMI in Type 1 diabetes (P = 0.36), but there was an increase in BMI with increasing deprivation in Type 2 diabetes (P < 0.001; test of linearity P < 0.001). Conclusions The study confirms the relationship between deprivation and the prevalence of Type 2 diabetes. There are more obese, diabetic patients in deprived areas. They require more targeted resources and more primary prevention.

Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmö, Sweden.

Abstract: Aims To assess whether there is an association between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects free from symptomatic cardiovascular disease. Methods A cross-sectional population-based study in Malmo, Sweden, of 4816 (40% men) subjects, born 1926–1945. The prevalence of insulin resistance was established by the homeostasis model assessment (HOMA) and defined as values above the 75th percentile. Criteria issued by the European Group for the Study of Insulin Resistance (EGIR) were used for the definition of the insulin resistance syndrome. Common carotid artery intima-media thickness (IMT) and carotid stenosis (> 15%) were measured by B-mode ultrasonography. Results Age and sex-adjusted common carotid IMT among subjects with the insulin resistance syndrome (12.7%) and controls was 0.812 mm, respectively, 0.778 mm (P < 0.001). The prevalence of stenosis in the two groups was 22.9 and 19.2% (P = 0.040). Insulin resistance per se was after adjustment for age and sex associated with increased IMT (0.780 mm vs. 0.754 mm, P < 0.001). This association disappeared, however, when other factors included in the insulin resistance syndrome were taken into account. Conclusions Fasting serum insulin covaries with a number of factors and conditions known to influence the development of atherosclerosis. It is concluded that the association between insulin resistance, as assessed by the HOMA method in non-diabetic subjects, and atherosclerosis is explained by its covariance with established risk factors for cardiovascular disease of which hypertension seems to be the most significant.

Beneficial effects of C‐peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus

Abstract: Summary Aims Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy. Methods Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months. Results Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 μg/min (basal) to 34 μg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 ± 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05). Conclusion These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

Type 2 diabetes mellitus in UK children--an emerging problem.

Abstract: SUMMARY Aims Type 2 diabetes mellitus has never previously been described in UK children, although an increasing incidence in childhood is recognized in international studies. The prevalence of obesity in UK children is increasing and is a recognized risk factor for the development of diabetes. The aim of this study was to identify and characterize children with Type 2 diabetes in the West Midlands and Leicester. Methods Children were identified by contacting paediatricians responsible for diabetes in five hospitals. Details were collected on demographics, mode of presentation, investigations and treatment on a standard proforma. Results Eight girls were identified with Type 2 diabetes, aged 9–16 years and who were of Pakistani, Indian or Arabic origin. They were all overweight (percentage weight for height 141–209%) and had a family history of diabetes in at least two generations. They presented insidiously with hyperglycaemia and glycosuria without ketosis and five were asymptomatic. Islet cell antibodies measured in seven patients were negative. Four had acanthosis nigricans which is a cutaneous marker of insulin resistance and the other four had high plasma levels of insulin and/or C peptide. These patients are distinct from those with maturity-onset diabetes of the young (MODY). All were initially managed with dietary measures, seven have been treated with oral anti-diabetic agents of whom two have subsequently required insulin. Conclusions These are the first UK case reports of Type 2 diabetes in children. Paediatricians need to be aware of the risk of Type 2 diabetes developing in childhood in high-risk ethnic groups, particularly in association with obesity and a positive family history.

Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients

Abstract: AIMS: This study was designed to test the efficacy and safety of low-dose rosiglitazone, a potent, insulin-sensitizing thiazolidinedione, in combination with sulphonylurea in Type 2 diabetic patients. METHODS: For the intention-to-treat analysis, 574 patients (59% male, mean age 61 years) were available, randomized to receive 26 weeks of twice-daily placebo (n = 192), rosiglitazone 1 mg (n = 199) or rosiglitazone 2 mg (n = 183) in addition to existing sulphonylurea treatment with gliclazide (47.6% of patients), glibenclamide (41.8%) or glipizide (9.4%) (two patients were taking carbutamide or glimepiride). Change in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), fructosamine, insulin, C-peptide, albumin, and lipids were measured, and safety was evaluated. RESULTS: Mean baseline HbA1c was 9.2% and FPG was 11.4 mmol/l. Rosiglitazone at doses of 1 and 2 mg b.d. plus sulphonylurea produced significant decreases, compared with sulphonylurea plus placebo, in HbA1c (-0.59% and -1.03%, respectively; both P<0.0001) and FPG (1.35 mmol/l and 2.44 mmol/l, respectively; both P<0.0001). Both HDL-cholesterol and LDL-cholesterol increased and potentially beneficial decreases in non-esterified fatty acids and gamma glutamyl transpeptidase levels were seen in both rosiglitazone groups. The overall incidence of adverse experiences was similar in all three treatment groups, with no significant cardiac events, hypoglycaemia or hepatotoxicity. CONCLUSIONS: Overall, the combination of rosiglitazone and a sulphonylurea was safe, well tolerated and effective in patients with Type 2 diabetes.

Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes.

Abstract: SUMMARY Introduction Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1α gene are the commonest cause of MODY. Individual patients with HNF-1α mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1α mutations that show marked hypersensitivity to sulphonylureas. Case reports In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. Conclusions HNF-1α MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1α MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control. Keywords genetics, HNF-1α, MODY, pharmacogenetics, sulphonylurea sensitivity

Effectiveness of screening and monitoring tests for diabetic retinopathy : a systematic review

Abstract: SUMMARY Aims To determine which screening and monitoring tests for diabetic retinopathy are most effective and under what circumstances. Methods A systematic review of the English language literature, published from 1983 to April 1999. Results Available studies are generally limited in their ability to answer the important questions on the effectiveness of tests for early detection of diabetic retinopathy. No randomized controlled trials were identified although primary studies exist for two screening tests: ophthalmoscopy, either direct or indirect, and retinal photography, using either mydriasis or non-mydriasis. Retinal photography under mydriasis appears to be the most effective test, with the majority reporting levels of sensitivity in excess of 80%. However effectiveness is compromised when photographs are ungradable. Ophthalmoscopy can also reach acceptable standards of sensitivity and specificity. Conclusion Based on an assessment of available cohort studies, the most effective strategy for testing is the use of mydriatic retinal photography with the additional use of ophthalmoscopy for cases where photographs are ungradable. This does not exclude the use of ophthalmoscopy alone for opportunistic case finding but there is evidence of considerable variation in effectiveness of this test.

Prevalence of symptoms of depression and anxiety in a diabetes clinic population.

Abstract: Aims To investigate the use of a short questionnaire to measure psychological symptoms in a busy clinic setting, and to examine the prevalence of these symptoms in adults with diabetes. The perceived need for psychological treatment services was also measured. Methods Adults (> 18 years) with either Type 1 or Type 2 diabetes were invited to complete a short demographic form and the Hospital Anxiety and Depression Scale (HADS) whilst waiting for their routine diabetes outpatients appointment. Complication status was measured via patients' medical records. Glycaemic control (HbA1c) was also recorded. Results A high response rate (96%) was achieved. Prevalence rates of psychological symptoms were high (overall 28% of study participants reported moderate–severe levels of depression or anxiety or both). Men were somewhat more likely to report moderate–severe depressive symptoms, whereas women reported more moderate–severe anxiety. A significant association between depression and poor glycaemic control was observed in the men, but not in the women. Regression analysis demonstrated that the interaction between sex and glycaemic control, HbA1c and sex were all significantly associated with depression and anxiety (R2 = 0.16 and 0.19, respectively). One-third of subjects reported that at the moment they would be interested in receiving counselling or psychotherapy if it was currently available at the diabetes clinic. Conclusions This study has shown that the HADS is an appropriate questionnaire to use in a clinic setting in adults with diabetes. There may be a stronger association between glycaemic control and psychological symptomatology in men than in women. There remains a significant proportion of individuals with diabetes who require psychological support, which, if available, might help improve glycaemic control and thus overall wellbeing.

Insulin aspart vs. human insulin in the management of long-term blood glucose control in Type 1 diabetes mellitus: a randomized controlled trial

Abstract: SUMMARY Aims To compare the efficacy of insulin aspart, a rapid-acting insulin analogue, with that of unmodified human insulin on long-term blood glucose control in Type 1 diabetes mellitus. Methods Prospective, multi-centre, randomized, open-labelled, parallel-group trial lasting 6 months in 88 centres in eight European countries and including 1070 adult subjects with Type 1 diabetes. Study patients were randomized 2:1 to insulin aspart or unmodified human insulin before main meals, with NPH-insulin as basal insulin. Main outcome measures were blood glucose control as assessed by HbA1c, eight-point self-monitored blood glucose profiles, insulin dose, quality of life, hypoglycaemia, and adverse events. Results After 6 months, insulin aspart was superior to human insulin with respect to HbA1c with a baseline-adjusted difference in HbA1c of 0.12 (95% confidence interval 0.03–0.22) %Hb, P < 0.02. Eight-point blood glucose profiles showed lower post-prandial glucose levels (mean baseline-adjusted −0.6 to −1.2 mmol/l, P < 0.01) after all main meals, but higher pre-prandial glucose levels before breakfast and dinner (0.7–0.8 mmol/l, P < 0.01) with insulin aspart. Satisfaction with treatment was significantly better in patients treated with insulin aspart (WHO Diabetes Treatment Satisfaction Questionnaire (DTSQ) baseline-adjusted difference 2.3 (1.2–3.3) points, P < 0.001). The relative risk of experiencing a major hypoglycaemic episode with insulin aspart compared to human insulin was 0.83 (0.59–1.18, NS). Major night hypoglycaemic events requiring parenteral treatment were less with insulin aspart (1.3 vs. 3.4% of patients, P < 0.05), as were late post-prandial (4–6 h) events (1.8 vs. 5.0% of patients, P < 0.005). Conclusions These results show small but useful advantage for the rapid-acting insulin analogue insulin aspart as a tool to improve long-term blood glucose control, hypoglycaemia, and quality of life, in people with Type 1 diabetes mellitus.

Perinatal mortality in Type 2 diabetes mellitus.

Abstract: Summary Aims In many parts of the world the number of pregnancies in women with Type 2 diabetes mellitus (DM) now exceeds that in women with Type 1 DM, but there are few data published on perinatal mortality in Type 2 DM. This study reports observational data on perinatal mortality in Type 2 DM from a population with a high background rate of this disorder. Methods Over a 12-year period (1985–1997) at the Diabetes Clinic at National Women’s Hospital, Auckland, there were 434 pregnancies in women with Type 2 DM (256 known and 178 diagnosed with gestational diabetes mellitus (GDM), but confirmed to have Type 2 DM early post-partum), 160 pregnancies in women with Type 1 DM and 932 in women with GDM. Perinatal mortality was classified as either intermediate fetal death (20–28 weeks’ gestation), late fetal death (28 weeks’ gestation to term) or early neonatal death (up to 1 month post-partum). Results The perinatal mortality in Type 2 DM was 46.1/1000, significantly higher than the rates for the general population (12.5), Type 1 DM (12.5) and GDM (8.9) (P < 0.0001). Congenital malformations accounted for only 10% of the perinatal mortality. There was a seven-fold increase in the rate of late fetal death and 2.5-fold increase in the rates of intermediate fetal and late neonatal death. Subjects with Type 2 DM were significantly older and more obese than subjects with Type 1 DM, and presented later to the diabetes service. Conclusions Perinatal mortality in Type 2 DM is significantly increased, mainly owing to an excess of late fetal death. Maternal factors such as obesity may be important contributors to the high perinatal mortality. Women diagnosed with GDM who have unrecognized Type 2 DM are also at high risk, but perinatal mortality is low in women with milder degrees of glucose intolerance in pregnancy.

Oral hypoglycaemic agents in 118 diabetic pregnancies.

Abstract: SUMMARY Aims To assess maternal and neonatal complications in pregnancies of diabetic women treated with oral hypoglycaemic agents during pregnancy. Methods A cohort study including all consecutively registered, orally treated pregnant diabetic patients set in a diabetic obstetrical service at a university hospital: 50 women treated with metformin, 68 women treated with sulphonylurea during pregnancy and a reference group of 42 diabetic women treated with insulin during pregnancy. Results The prevalence of pre-eclampsia was significantly increased in the group of women treated with metformin compared to women treated with sulphonylurea or insulin (32 vs. 7 vs. 10%, P < 0.001). No difference in neonatal morbidity was observed between the orally treated and insulin-treated group; no cases of severe hypoglycaemia or jaundice were seen in the orally treated groups. However, in the group of women treated with metformin in the third trimester, the perinatal mortality was significantly increased compared to women not treated with metformin (11.6 vs. 1.3%, P < 0.02). Conclusion Treatment with metformin during pregnancy was associated with increased prevalence of pre-eclampsia and a high perinatal mortality.

Self-monitoring in Type 2 Diabetes Mellitus: A Meta-Analysis

Abstract: Aims Self-monitoring of blood or urine glucose is widely used by subjects with Type 2 diabetes mellitus. This study evaluated the effectiveness of the technique at improving blood glucose control through a systematic review and meta-analysis. Methods Randomized controlled trials were identified that compared the effects of blood or urine glucose monitoring with no self-monitoring, or blood glucose self-monitoring with urine glucose self-monitoring, on glycated haemoglobin as primary outcome in Type 2 diabetes. Results Eight reports were identified. These were rated for quality and data were abstracted. The mean (SD) quality score was 15.0 (1.69) on a scale ranging from 0 to 28. No study had sufficient power to detect differences in glycated haemoglobin (GHb) of less than 0.5%. One study was excluded because it was a cluster randomized trial of a complex intervention and one because fructosamine was used as the outcome measure. A meta-analysis was performed using data from four studies that compared blood or urine monitoring with no regular monitoring. The estimated reduction in GHb from monitoring was -0.25% (95% confidence interval -0.61 to 0.10%). Three studies that compared blood glucose monitoring with urine glucose monitoring were also combined. The estimated reduction in GHb from monitoring blood glucose rather than urine glucose was -0.03% (-0.52 to 0.47%). Conclusions The results do not provide evidence for clinical effectiveness of an item of care with appreciable costs. Further work is needed to evaluate self-monitoring so that resources for diabetes care can be used more efficiently.

Non-dipping circadian blood pressure and renal impairment are associated with increased mortality in diabetes mellitus.

Abstract: Summary Aims To assess the relevance of circadian blood pressure variation to future morbidity and mortality in patients with diabetes mellitus. Methods A retrospective descriptive 4 year follow-up study of data collected after ambulatory blood pressure monitoring in a clinic setting. Results Seventy-five patients (46 male; 29 female) of whom 41% had Type 1 diabetes and 59% Type 2 were followed up for a median of 42 months (11–56). The median creatinine for the whole group at baseline was 101 (56–501) μmol/l. The median circadian blood pressures for the total study population were 147 (110–194)/87 (66–109) mmHg during daytime and 132 (86–190)/77 (50–122) mmHg during night-time. Half of the patients exhibited a fall in night-time pressures to 10% lower than daytime pressures (dippers). Dippers were younger, 47 (32–75) years, than non-dippers, 57 (35–79) years, P = 0.03. Over time, dippers had a lower mortality than non-dippers, with 8% deaths in the cohort of dippers, 26% deaths in the cohort of non-dippers, P = 0.04. Cox regression analysis revealed significant contributions from age, duration of diabetes and baseline renal function to subsequent mortality in non-dippers. Analysing current degree of renal impairment and original dipper status together revealed that, of those patients whose creatinine remained normal, 7% of patients whose blood pressure dipped had subsequently died and 10% of non-dipping patients had died; of those patients whose creatinine unequivocally rose, 10% of dipping patients had died and 42% of non-dipping patients had died, P = 0.03 Conclusions Loss of circadian variation in blood pressure is associated with an increased mortality rate, regardless of diabetes type. The combination of non-dipping and subsequent renal impairment leads to the highest mortality rate. The study suggests a role for ambulatory blood pressure monitoring in day-to-day clinical practice to select patients with nephropathy who are at greatest risk, in an effort to alter outcome.

Automated detection of microaneurysms in digital red-free photographs: a diabetic retinopathy screening tool.

Abstract: Aims To develop a technique to detect microaneurysms automatically in 50 degrees digital red-free fundus photographs and evaluate its performance as a tool for screening diabetic patients for retinopathy,Methods Candidate microaneurysms are extracted, after the image has been modified to remove variations In background intensity, by algorithms that enhance small round features. Each microaneurysm candidate is then classified according to its intensity and size by the application of a sec of rules derived from a training set of 102 images.Results When 3783 individual images were analysed and the results compared with the opinion of a clinical research fellow examining the same images, the program achieved a sensitivity of 81% and a specificity of 93% for the detection of images containing microaneurysms, Nine hundred and twenty-five sets of 4 images per patient were then analysed and the total number of microaneurysms detected compared with the overall patient retinopathy grade derived by the clinician examining the same images. In this context, intended to mimic a screening situation, the program achieved a sensitivity of 85% and a specificity of 76% for the detection of patients with (any) retinopathy (positive predictive value 0.71, negative predictive value 0,88),Conclusions An automated technique was developed to detect retinopathy in digital red-free fundus images that can form part of a diabetic retinopathy screening programme. It is believed that it can perform a useful role in this context identifying images worthy of closer inspection or eliminating 50% or more of the screening population who have no retinopathy.

Universal vs. risk factor‐based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome

Abstract: Summary Aims Gestational diabetes mellitus (GDM) is associated with adverse maternal and fetal outcome. Screening for GDM is therefore recommended but the best screening method remains controversial. This prospective, randomized study compared a risk factor-based screening programme with a universally based one. Methods Subjects were randomized at booking to one of two groups: the risk factor group had a 3-h 100-g oral glucose tolerance test (OGTT) at 32 weeks if any risk factor for GDM was present; the universal group had a 50-g glucose challenge test performed and if their plasma glucose at 1 h was ≥ 7.8 mmol/l, a formal 3-h 100-g OGTT was then performed. Results Universal screening detected a prevalence of GDM of 2.7%, significantly more than the 1.45% detected in the risk factor screened group (P < 0.03). Universal screening facilitated earlier diagnosis than risk factor screening – mean gestation 30 ± 2.6 weeks vs. 33 ± 3.7 weeks (P < 0.05). A higher rate of spontaneous vaginal delivery at term, and lower rates of macrosomia, Caesarean section, prematurity, pre-eclampsia and admission to neonatal intensive care unit were observed in the universally screened, early diagnosis group. Conclusions Universal screening for GDM is superior to risk factor based screening – detecting more cases, facilitating early diagnosis and is associated with improved pregnancy outcome.

Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with Type 1 diabetes mellitus with microalbuminuria and overt nephropathy.

Abstract: SUMMARY Aims Elevated urinary albumin excretion is associated with macrovascular atherosclerotic complications in Type 1 diabetes mellitus. Adhesion molecules mediate leucocyte adhesion to the endothelium early in the atherosclerotic process. The present study tests the hypothesis that microalbuminuria and diabetic nephropathy are associated with elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1, soluble intercellular adhesion molecule (sICAM)-1, and soluble E-selectin (sE-selectin) aiming to illustrate factors of potential pathogenetic relevance for the excess cardiovascular disease in diabetic patients with renal complications. Methods Soluble adhesion molecule concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in healthy controls (n = 16) and in 59 Type 1 diabetic patients: group 1 – patients with normoalbuminuria (n = 16); group 2 – patients with microalbuminuria (n = 15); group 3 – patients with macroalbuminuria and normal serum creatinine (n = 15), group 4 – patients with macroalbuminuria and moderately elevated serum creatinine (n = 13). Results Plasma concentrations of sVCAM-1 and sICAM-1 were similar in healthy controls and normoalbuminuric Type 1 diabetic patients, but the concentrations were increased by the presence of microalbuminuria and overt nephropathy (P < 0.001 and P < 0.0001, anova). Concentrations of sE-selectin did not differ between diabetic patients and controls. Conclusions Plasma concentration of sICAM-1 is elevated in Type 1 diabetic patients with microalbuminuria and the concentrations of sICAM-1 as well as sVCAM-1 are elevated in patients with macroalbuminuria and normal s-creatinine. The elevated plasma concentrations of these soluble adhesion molecule concentrations in patients with renal complication can be of pathogenetic importance for the development of atherosclerosis and plasma soluble adhesion molecule concentrations may provide additional information on cardiovascular risk.

The prevalence of multiple diabetes-related complications.

Abstract: Aims To determine the prevalence of the complications of diabetes and the interrelationship between them within a United Kingdom district health authority population. Methods Data extracted from a general practice diabetes audit were combined with data for patients with diabetes derived from a patient index constructed using record linkage techniques. Results A total of 10 709 patients were identified as having diabetes (prevalence 2.47%). Coronary heart disease was present in 25.2%, cerebrovascular disease in 9.6%, complications of the ‘diabetic foot’ in 18.1%, retinopathy in 16.5% and nephropathy in 2.0%. Over a half of the patients (52.1%) had none of the studied complications, 30.2% had one, 12.7% had two, 4.1% had three, 0.8% had four and 0.1% had all five. All complications were related to both age and duration of diabetes but duration was particularly apparent for the microvascular complications (retinopathy and nephropathy). Macrovascular complications in the Type 2 diabetic population appear advanced in onset compared with Type 1. Conclusions Multiple complications are apparent in almost one fifth of patients with diabetes. Macrovascular morbidity in Type 2 diabetes of early onset indicates that a targeted approach to treatment may prove most beneficial in both patient and health service terms.

The Charcot foot.

Abstract: Aims To review the clinical manifestations of the Charcot foot in diabetes mellitus, with particular reference to theories concerning aetiology. Methods Systematic review of the published literature, searching for the keywords ‘Charcot’, ‘foot and diabetes’ and ‘neuropathy’ on Medline, as well as by examination of the references in recent published reviews. Conclusions The Charcot foot of diabetes mellitus is a common problem, and yet is not widely recognized by non-specialists. The failure of professionals to identify the condition in its early phases is probably largely responsible for the gross deformity which follows continued weight-bearing. The condition is confined to those with severe peripheral neuropathy. It is thought to result from three factors: motor neuropathy leading to the development of abnormal forces within the foot, subsequent disorganization of the foot as a result of associated osteopenia and progressive destruction from continued weight-bearing, enabled by reduced pain sensation. The cause of the osteopenia is not known, but it is associated with increased bone blood flow, which may be mainly the result of loss of sympathetic innervation. The importance of increased limb blood flow in the pathogenesis of the Charcot foot has been recognized for over a century. Paradoxically, the increased flow is associated with evidence of macrovascular disease, in that the prevalence of vascular calcification of pedal vessels approaches 90%. After an interval of many months, the condition tends to evolve: the increased blood flow lessens, the osteopenia is reduced and the disorganized bones become sclerotic. This tendency for the condition to evolve remains unexplained, since it would not be expected if the condition was caused solely by progressive denervation. As a result, it is suggested that another factor may be involved in the pathogenesis of the Charcot foot: an abnormal vasomotor reflex, analogous to reflex sympathetic dystrophy, occurring against a background of severe peripheral neuropathy. The resolution of the condition occurs because it is the reflex component of the hyperaemia which proves self-limiting.

The prevalence of diabetes, association with cardiovascular risk factors and implications of diagnostic criteria (ADA 1997 and WHO 1998) in a 1996 community‐based population study in Hong Kong Chinese

Abstract: Aims While the American Diabetes Association (ADA) 1997 diagnostic criteria advocate the use of fasting plasma glucose only, the World Health Organization (WHO) criteria retain the use of the standard oral glucose tolerance test (OGTT). The present study evaluated the relative merit of the respective diagnostic criteria in Chinese. Methods Data collected for the Hong Kong Cardiovascular Risk Factor Prevalence Study was analysed. This was a representative population-based study, conducted from 1995 to 1996 among 2,900 Chinese subjects aged 25-74 years using a 75-g OGTT. Results The prevalence of diabetes (known plus unknown) was 6.2% (95% confidence interval 5.3-7.1%), 9.2% (8.1-10.3%), and 9.8% (8.7-10.9%) based on ADA 1997, WHO 1985 and WHO 1998 criteria, respectively, with a very high prevalence in older subjects. The 2,451 subjects classified as normal under ADA 1997 criteria were heterogenous: 15.3% had impaired glucose tolerance; 2.1% had diabetes under WHO 1998 criteria. These latter two smaller groups had cardiovascular risk profiles comparable to that found among the impaired fasting glucose subjects (under ADA), but worse than that among the concordant normal glucose tolerance subjects. Conclusions The ADA criteria underestimate both diabetes prevalence and cardiovascular risk in this population. Hence fasting glucose alone is an inadequate approach and OGTT should be retained to identify at-risk individuals in both clinical diagnosis and epidemiological studies.

Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with Type 1 diabetes mellitus: relation to glycaemic control and microvascular complications.

Abstract: SUMMARY Aims To evaluate serum levels of vascular endothelial growth factor (VEGF) in a large group of children, adolescents and young adults with Type 1 diabetes mellitus to investigate whether increased VEGF concentrations are associated with long-term glycaemic control and microvascular complications. Methods The study involved 196 patients with Type 1 diabetes mellitus (age range 2–24 years, onset of diabetes before the age of 12 years, duration of disease longer than 2 years), without clinical and laboratory signs of microvascular complications; they were divided into three groups (group 1 –n = 37, age 12 years). Fifty-three adolescents and young adults (age 16.1–29.7) with different grades of diabetic retinopathy and microalbuminuria were also selected (group 4). A total of 223 healthy controls were matched for age and sex with each group of patients with diabetes mellitus. Results VEGF serum levels were significantly increased in pre-school and pre-pubertal children with diabetes as well as in pubertal patients compared to controls. VEGF concentrations were markedly increased in adolescents and young adults with microvascular complications compared with both healthy controls and diabetic patients without retinopathy or nephropathy. Multivariate analysis showed that elevation of VEGF in serum was an independent correlate of complications. One-year mean HbA1c values were significantly correlated with VEGF concentrations (r = 0.372; P 10%), long-term (2 years) improvement of glycaemic control (aiming at HbA1c < 7%) resulted in a significant reduction of VEGF levels. Conclusions VEGF serum concentrations are increased in prepubertal and pubertal children with diabetes. Glycaemic control influences VEGF serum levels. Severity of microvascular complications is associated with marked increase of VEGF concentrations in the serum of these patients.

The Child Health Questionnaire in children with diabetes: cross-sectional survey of parent and adolescent-reported functional health status.

Abstract: SUMMARY Aims To study parent and adolescent-reported physical, psychosocial and family wellbeing in children aged 5–18 years with diabetes Methods Subjects: 5–18-year-olds attending a diabetes clinic at a tertiary children's hospital Measures: (1) Child Health Questionnaire (CHQ) PF-50, a functional heath status measure for children aged 5–18 years (parents); (2) CHQ CF-80, a similar self-report measure (adolescents aged 12–18 years); (3) 11 study-designed questions related to diabetes-specific concerns (parents); (4) global ratings of physical and psychosocial health (clinicians); (5) HbA1c level (all subjects) CHQ data were compared with Australian normative data collected six months earlier Results Reports were obtained from 128 parents and 71 adolescents (90 and 92% response) The CHQ demonstrated good psychometric properties in this sample of children with diabetes Parents reported children with diabetes to have generally poorer health than children in the normative sample, especially on psychosocial and parent/family scales Psychosocial health was markedly lower in 5–11-year-olds with HbA1c > 88%, but not in 12–18-year-olds Presence of diabetes-related symptoms and concerns correlated with lower physical and psychosocial functioning Parents and clinicians concurred in their ratings of health for 12–18-year-olds but not 5–11-year-olds Adolescents reported their own health similarly to adolescents in the normative sample Conclusions Parents report children aged 5–18 years with diabetes to have poorer health than children in the normative sample across all domains Clinicians may underrate the impact of diabetes for younger children, with possible therapeutic implications In providing an overall description of health, instruments like the CHQ may add another dimension to the care of children with diabetes and can feasibly be used within clinical settings

Autoantibodies to glutamic acid decarboxylase in diabetic patients from a multi‐ethnic Australian community: the Fremantle Diabetes Study

Abstract: SUMMARY Aims To investigate ethnic/racial differences in the prevalence of serum antibodies to glutamic acid decarboxylase (GADA) and ICA512/IA-2 in diabetic patients from a large, urban community. Methods A cross-sectional sample of 1381 diabetic patients aged 11–98 years, representing 61% of those identified in a postcode-defined population base of 120 097 people were studied. Diabetes was classified on clinical grounds. Serum GADA and anti-ICA512/IA-2 were measured by radioimmuno-precipitation assay. Results Anglo-Celts formed 62% of the sample, southern Europeans 18%, other Europeans 8% and Asians 3%. GADA prevalence in Type 1 and Type 2 diabetes mellitus was 46.0% and 4.2%, respectively, amongst Anglo-Celts and 22.2% and 1.7% in southern Europeans. The prevalence of anti-ICA512/IA-2 in Type 1 diabetes was 17.4% and, in a sample of 233 patients with Type 2 diabetes, 0.8%. GADA-positive Type 2 patients had a lower body mass index and greater glycosylated haemoglobin, and were more likely to be taking insulin, than GADA-negative Type 2 diabetic subjects (P < 0.05), consistent with the phentoype of latent autoimmune diabetes of adults (LADA). In both Type 1 and Type 2 diabetes, there was a strong inverse association between GADA and serum triglycerides (P < 0.001). Conclusions The relatively low GADA prevalence in Anglo-Celt patients with Type 1 diabetes is a feature of this community-based study and suggests that GADA levels do fall with time, given the older age of the sample and a relatively long period between diagnosis and sampling. Southern Europeans had an even lower GADA prevalence, regardless of diabetes type. Variations in GADA frequency in diabetic patients of differing European ethnicity has implications for clinical management and healthcare planning.

Early social mixing and childhood Type 1 diabetes mellitus: a case-control study in Yorkshire, UK.

Abstract: Summary Aims Evidence from animal models shows an increased risk of Type 1 diabetes mellitus associated with the absence of early life exposure to pathogens. To test this ‘hygiene hypothesis’, patterns of social mixing and infections in the first year of life and the risk of developing autoimmune diabetes in childhood were examined. Methods Personal interviews were conducted with the mothers of 220 children with Type 1 diabetes (0–15 years) and 433 age/sex matched controls from a population-based case control study in Yorkshire, UK. Social mixing including attendance at daycare, and infections occurring under 1 year of age were measures of exposure. Adjusted odds ratios (OR) were derived using conditional logistic regression. Results Frequency of attendance at daycare during the 1st year of life was inversely associated with childhood diabetes (OR 0.71, 95% confidence interval 0.51–1.00, P = 0.05), a finding not explained by mother's age, level of education or maternal diabetes. Increasing numbers of children in the daycare setting and numbers of sessions attended were significantly associated with increasing protection from diabetes. The strongest effect was observed in children with diabetes diagnosed aged 0–4 years. Conclusions Social mixing through attendance at daycare in early infancy appears to confer protection against the development of childhood diabetes. This may be mediated through exposure to infectious agent(s) as a significant dose–response effect was evident with increasing numbers of child ‘contacts’. These findings suggest early infectious exposure may play a role in the development of immunoregulatory mechanisms which protect against diabetes and further work is warranted.

Post‐challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima‐media thickness: the RIAD Study

Abstract: SUMMARY Aims Only scarce information exists on the distribution and atherosclerosis risk in different types of hyperglycaemia at diabetes detection. This study aimed to analyse the occurrence of isolated fasting (IFH), isolated post-challenge (IPH) and combined hyperglycaemia (FH/PH) among subjects detected to have diabetes and the association of these types of hyperglycaemia with cardiovascular risk factors and carotid intima-media thickness (IMT). Methods A total of 785 middle-aged subjects of the Risk Factors in Impaired Glucose Tolerance (IGT) for Atherosclerosis and Diabetes (RIAD) study underwent a 75-g oral glucose tolerance test and examination of various atherosclerosis risk factors. IMT was measured by B-mode ultrasound. Results One hundred and nineteen (15.2%) asymptomatic diabetic subjects were detected: of these, 35.3% with IFH, 26% with IPH and 38.7% with FH/PH. The level of risk factors was higher in diabetic vs. non-diabetic subjects. HbA1c and cardiovascular risk factors were in the same range for IFH and IPH except for active plasminogen activator inhibitor (PAI)-1 which was significantly higher in IFH. A higher risk burden was found in the FH/PH group vs. both IFH and IPH. IMT was as follows: non-diabetic subjects 0.85 ± 0.18 mm, IFH 0.91 ± 0.20 mm, IPH 0.94 ± 0.18 mm, FH/PH 0.98 ± 0.17 mm (P < 0.05 vs. non-diabetes). 2 h post-challenge glucose (2hPG) correlated more closely (r = 0.23, P < 0.001) to IMT than fasting plasma glucose (FPG) (r = 0.14, P = 0.004). The importance of 2hPG was confirmed by the direct comparison of FPG and 2hPG in a three dimensional analysis. A significant increase of IMT was only observed in the subgroups with abnormal post-challenge hyperglycaemia for both combinations with normal FPG and IFG. FPG category did not significantly add to IMT in either group of post-challenge hyperglycaemia. Regression analysis in the whole sample revealed 2hPG but not FPG as a significant determinant of IMT. Further significant risk factors were age, male sex, total cholesterol, HDL-cholesterol and hypertension. Conclusions The RIAD study population at high risk for Type 2 diabetes mellitus, post-challenge hyperglycaemia was found to relate more strongly than fasting hyperglycaemia with carotid IMT.

Rosiglitazone taken once daily provides effective glycaemic control in patients with Type 2 diabetes mellitus

Abstract: Aims To evaluate the clinical efficacy and safety of rosiglitazone as a once daily treatment for Type 2 diabetes mellitus (DM). Methods Three hundred and sixty-nine patients with Type 2 DM (mean age 63 years; mean body mass index (BMI) 29.4 kg/m2) were enrolled in a double-blind, parallel group, placebo-controlled, dose-ranging study. Patients were randomly assigned to receive placebo or rosiglitazone at doses of 4, 8, or 12 mg daily for 8 weeks. Results At 8 weeks, fasting plasma glucose (FPG) decreased significantly in the rosiglitazone 4 mg, 8 mg, and 12 mg groups (−0.9, −2.0 and −1.7 mmol/l; P = 0.0003, < 0.0001, and < 0.0001, respectively) compared with placebo (+0.4 mmol/l). The improvements in FPG were dose ordered for 4 and 8 mg/day. The 12 mg/day dose produced no additional improvement. There were small decreases in haemoglobin and haematocrit in the rosiglitazone treatment groups. The overall incidence of adverse experiences was similar in all treatment groups, including placebo with no evidence of hypoglycaemia or hepatotoxicity. Conclusions Rosiglitazone improves glycaemic control when given once daily to treat Type 2 diabetes mellitus and is well tolerated at doses up to and including 12 mg.

Low birthweight and metabolic abnormalities in twins with increased susceptibility to Type 2 diabetes mellitus.

Abstract: Aims To evaluate the role of environmental intra-uterine factors in determining the birthweights of twins with increased susceptibility to diabetes and discordant for abnormal responses to the oral glucose tolerance test (OGTT) and verify the possible association of within-pair birthweight differences and metabolic abnormalities in adult life. Methods Forty-six monozygotic (MZ) and 32 dizygotic (DZ) twins were enrolled; 13 MZ twins were discordant for impaired glucose tolerance (IGT) and/or hyperinsulinaemia compared to their co-twins. Results The 13 MZ discordant twins showed significantly lower birthweights than their normal co-twins (P or = 0.450 kg) to the two lower tertiles ( Conclusions These data suggest a causative role for environmental intrauterine factors on the determination of birthweight and support the hypothesis that within-pair birthweight difference, rather than an absolute low birthweight, is responsible for the metabolic abnormalities in the adult life.

Maternal and perinatal outcomes in 143 Danish women with gestational diabetes mellitus and 143 controls with a similar risk profile.

Abstract: Aims To assess maternal and fetal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM) compared to non-diabetic pregnancies with an otherwise similar risk profile and to study the association between different anti-diabetic treatments and fetal outcomes. Methods The records of 143 consecutive GDM pregnancies and 143 non-diabetic controls matched on the basis of age, parity and pre-pregnancy body mass index (BMI) were studied. The GDM patients were treated with diet, tolbutamide and insulin. Data were collected from medical records and birth records. Results Despite treatment, the GDM group had a statistically significant higher frequency of maternal hypertension (20% vs. 11%), induction of labour (61% vs. 24%), Caesarean section (33% vs. 21%), macrosomia (14% vs. 6%), neonatal hypoglycaemia (24% vs. 0) and admission to a neonatal unit (46% vs. 12%). The risk of complications was similar in the different treatment groups. However, in the tolbutamide-treated group, one case of long-standing severe hypoglycaemia in a premature neonate occurred. Conclusions Pregnancies complicated by GDM are associated with a higher frequency of adverse maternal and fetal outcomes. The outcomes seem to be unaffected by treatment modality. However, because of the potential risk of hypoglycaemia in some neonates, tolbutamide treatment cannot be recommended in pregnancy.

Is mild gestational hyperglycaemia associated with maternal and neonatal complications? The Diagest Study.

Abstract: Summary Aims To evaluate the maternal and neonatal complications rates of mild gestational hyperglycaemia (MGH) compared to a control group in France. Methods A systematic screening by a 50-g glucose challenge test was offered to all women between 24 and 28 weeks of gestation in 15 maternity units. If the 50-g glucose challenge test was ≥ 7.2 mmol/l, a 100-g 3-h oral glucose tolerance test (OGTT) was performed. MGH (n = 131) was defined by one abnormal value on the 3-h OGTT (Carpenter and Coustan criteria). The control group (n = 108) was defined by a 50-g glucose challenge test below 7.2 mmol/l. Women with MGH received no treatment or specific advice during the pregnancy. Large for gestational age (LGA) was defined by a birth weight of at least the 90th percentile on French standard growth curves. Results Women with MGH were older than the controls (28.8 (5.8) vs. 27.0 (5.2); P 27, maternal age > 35, multiparity and educational level), there was a persistent relationship between LGA and MGH (odds ratio 2.50; 95% confidence interval (1.16–5.40); P < 0.05). MGH was more frequently associated with adverse maternal and fetal outcome than in the controls (53.4% vs. 28.7%; P < 0.01). Conclusions This study suggested that the increased rate of adverse maternal and fetal outcome, especially LGA, was associated with untreated mild gestational hyperglycaemia women compared to a control group. This link to lower degrees of hyperglycaemia during pregnancy is independent of confounding factors.

Glucagon-like peptide (GLP)-1 and leptin concentrations in obese patients with Type 2 diabetes mellitus.

Abstract: SUMMARY Aims To assess differences in circulating leptin and glucagon-like peptide (GLP)-1 concentrations before and after an oral glucose load, in euglycaemic and isoinsulinaemic conditions, between obese patients with and without Type 2 diabetes mellitus. Methods Ten male obese (body mass index (BMI) > 30 kg/m2) patients with Type 2 diabetes and 20 matched non-diabetic subjects were studied. Leptin, GLP-1(7–36)amide and GLP-1(7–37) concentrations were measured 0, 30, 60, and 90 min after a 50-g oral glucose load administered 90 min after the beginning of a euglycaemic hyperinsulinaemic clamp. Results GLP-1(7–36)amide concentrations before the glucose load were significantly lower in diabetic patients than in controls (median (quartiles): 50.5 (44.7–53.2) vs. 128.7(100–172.5) pg/ml; P < 0.01), while no difference was observed in baseline GLP-1(7–37). In non-diabetic subjects, GLP-1(7–36)amide and GLP-1(7–37) concentrations increased significantly after the oral glucose load, while no glucose-induced increase in GLP-1 concentration was observed in diabetic patients. GLP-1(7–36)amide at 30, 60, and 90 min, and GLP-1(7–37) at 30 min, of the glucose challenge, were significantly lower in diabetic patients. Leptin concentrations were not significantly different in diabetic patients when compared to non-diabetic subjects, and they did not change after the oral glucose load. Discussion Leptin concentrations are not significantly modified in obese Type 2 diabetic patients. GLP-1(7–36)amide baseline concentrations are reduced in Type 2 diabetes; moreover, diabetic subjects show an impaired response of GLP-1 to oral glucose in euglycaemic, isoinsulinaemic conditions. This impairment, which is not the result of differences in glycaemia or insulinaemia during assessment, could contribute to the pathogenesis of hyperglycaemia in Type 2 diabetes mellitus.