Showing papers in "Diabetic Medicine in 2004"

Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes.

Abstract: Gestational diabetes (GDM) is defined as carbohydrate intolerance that begins or is first recognized during pregnancy. Although it is a well-known cause of pregnancy complications, its epidemiology has not been studied systematically. Our aim was to review the recent data on the epidemiology of GDM, and to describe the close relationship of GDM to prediabetic states, in addition to the risk of future deterioration in insulin resistance and development of overt Type 2 diabetes. We found that differences in screening programmes and diagnostic criteria make it difficult to compare frequencies of GDM among various populations. Nevertheless, ethnicity has been proven to be an independent risk factor for GDM, which varies in prevalence in direct proportion to the prevalence of Type 2 diabetes in a given population or ethnic group. There are several identifiable predisposing factors for GDM, and in the absence of risk factors, the incidence of GDM is low. Therefore, some authors suggest that selective screening may be cost-effective. Importantly, women with an early diagnosis of GDM, in the first half of pregnancy, represent a high-risk subgroup, with an increased incidence of obstetric complications, recurrent GDM in subsequent pregnancies, and future development of Type 2 diabetes. Other factors that place women with GDM at increased risk of Type 2 diabetes are obesity and need for insulin for glycaemic control. Furthermore, hypertensive disorders in pregnancy and afterwards may be more prevalent in women with GDM. We conclude that the epidemiological data suggest an association between several high-risk prediabetic states, GDM, and Type 2 diabetes. Insulin resistance is suggested as a pathogenic linkage. It is possible that improving insulin sensitivity with diet, exercise and drugs such as metformin may reduce the risk of diabetes in individuals at high risk, such as women with polycystic ovary syndrome, impaired glucose tolerance, and a history of GDM. Large controlled studies are needed to clarify this issue and to develop appropriate diabetic prevention strategies that address the potentially modifiable risk factors.

Treatment of symptomatic diabetic polyneuropathy with the antioxidant α‐lipoic acid: a meta‐analysis

Abstract: Aims To determine the efficacy and safety of 600 mg of α-lipoic acid given intravenously over 3 weeks in diabetic patients with symptomatic polyneuropathy. Methods We searched the database of VIATRIS GmbH, Frankfurt, Germany, for clinical trials of α-lipoic acid according to the following prerequisites: randomized, double-masked, placebo-controlled, parallel-group trial using α-lipoic acid infusions of 600 mg i.v. per day for 3 weeks, except for weekends, in diabetic patients with positive sensory symptoms of polyneuropathy which were scored by the Total Symptom Score (TSS) in the feet on a daily basis. Four trials (ALADIN I, ALADIN III, SYDNEY, NATHAN II) comprised n = 1258 patients (α-lipoic acid n = 716; placebo n = 542) met these eligibility criteria and were included in a meta-analysis based on the intention-to-treat principle. Primary analysis involved a comparison of the differences in TSS from baseline to the end of i.v. Treatment between the groups treated with α-lipoic acid or placebo. Secondary analyses included daily changes in TSS, responder rates (≥ 50% improvement in TSS), individual TSS components, Neuropathy Impairment Score (NIS), NIS of the lower limbs (NIS-LL), individual NIS-LL components, and the rates of adverse events. Results After 3 weeks the relative difference in favour of α-lipoic acid vs. placebo was 24.1% (13.5, 33.4) (geometric mean with 95% confidence interval) for TSS and 16.0% (5.7, 25.2) for NIS-LL. The responder rates were 52.7% in patients treated with α-lipoic acid and 36.9% in those on placebo (P < 0.05). On a daily basis there was a continuous increase in the magnitude of TSS improvement in favour of α-lipoic acid vs. placebo which was noted first after 8 days of treatment. Among the individual components of the TSS, pain, burning, and numbness decreased in favour of α-lipoic acid compared with placebo, while among the NIS-LL components pin-prick and touch-pressure sensation as well as ankle reflexes were improved in favour of α-lipoic acid after 3 weeks. The rates of adverse events did not differ between the groups. Conclusions The results of this meta-analysis provide evidence that treatment with α-lipoic acid (600 mg/day i.v.) over 3 weeks is safe and significantly improves both positive neuropathic symptoms and neuropathic deficits to a clinically meaningful degree in diabetic patients with symptomatic polyneuropathy. Diabet. Med. 21, 114–121 (2004)

Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes

Abstract: Aims A cross-sectional study has been performed in order to estimate the prevalence, severity, and current treatment of chronic painful peripheral neuropathy (CPPN) in people with diabetes in the community. Methods Using a structured questionnaire and examination we have assessed these factors in a community sample of people with diabetes (n = 350) and compared them with 344 age- and sex-matched people without diabetes from the same locality. Results The prevalence of CPPN was estimated to be 16.2%[95% confidence interval (CI): 6.8–16%] in people with diabetes compared with 4.9% (95% CI: 2.6–7.2%) in the control sample (P < 0.0001). Diabetic subjects with and without CPPN did not differ in age, sex, type and duration of diabetes, body mass index, smoking status and glycaemic control. However, CPPN diabetic subjects had significantly higher Visual Analogue Scale (VAS) scores for pain over the preceding 24 h [median (interquartile range) 3.5 (1.5–6.7) cm vs. 0.7 (0–3.9) cm, P < 0.0001]. Also, the total McGill Pain Questionnaire Score (a measure of pain quality and severity) was 18 (13–31.5) vs. 10 (4–16) (P < 0.0001). Of patients with diabetes and CPPN, 12.5% (7/56) had never reported their symptoms to their treating physician and 39.3% (22/56) had never received any treatment for their painful symptoms. Conclusions CPPN is common, often severe but frequently unreported and inadequately treated.

Automated detection of diabetic retinopathy in digital retinal images: a tool for diabetic retinopathy screening.

Abstract: Aims To develop a system to detect automatically features of diabetic retinopathy in colour digital retinal images and to evaluate its potential in diabetic retinopathy screening. Methods Macular centred 45° colour retinal images from 1273 patients in an inner city diabetic retinopathy screening programme. A system was used involving pre-processing to standardize colour and enhance contrast, segmentation to reveal possible lesions and classification of lesions using an artificial neural network. The system was trained using a subset of images from 500 patients and evaluated by comparing its performance with a human grader on a test set of images from 773 patients. Results Maximum sensitivity for detection of any retinopathy on a per patient basis was 95.1%, accompanied by specificity of 46.3%. Specificity could be increased as far as 78.9% but was accompanied by a fall in sensitivity to 70.8%. At a setting with 94.8% sensitivity and 52.8% specificity, no cases of sight-threatening retinopathy were missed (retinopathy warranting immediate ophthalmology referral or re-examination sooner than 1 year by National Institute for Clinical Excellence criteria). If the system was implemented at 94.8% sensitivity setting over half the images with no retinopathy would be correctly identified, reducing the need for a human grader to examine images in 1/3 of patients. Conclusion This system could be used when screening for diabetic retinopathy. At 94.8% sensitivity setting the number of normal images requiring examination by a human grader could be halved.

The Metabolic Syndrome is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study

Abstract: Aims To evaluate the cardiovascular risk associated with the presence of the Metabolic Syndrome in Type 2 diabetic subjects. Methods Subjects with the Metabolic Syndrome, defined by WHO criteria, were identified in a large sample of non-insulin-treated Type 2 diabetic patients examined within the Verona Diabetes Complications Study (n = 946). At baseline and after a mean of 4.5 years follow-up, cardiovascular disease (CVD) was assessed by medical history, physical examination, electrocardiogram (ECG) and echo-duplex of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were scrutinized in order to identify CVD deaths. In statistical analyses, CVD was considered as an aggregate end-point, including fatal and non-fatal coronary, cerebrovascular and peripheral vascular disease as well as ischaemic ECG abnormalities and vascular lesions at the echo-duplex. Results The proportion of subjects with the Metabolic Syndrome was very high (92.3%). At the baseline, 31.7% of subjects were coded positive for CVD, which was more prevalent in subjects with the Metabolic Syndrome (32.9 vs. 17.8%, P = 0.005). Among subjects free of CVD at the baseline (n = 559), CVD events during the follow-up were significantly increased in patients with the Metabolic Syndrome as compared with those without it (19.9% vs. 3.9%, P < 0.001). Multiple logistic regression analysis showed that, along with sex, age, smoking and HbA1c, the presence of the Metabolic Syndrome independently predicted prevalent (OR 2.01, P = 0.045) and incident CVD (OR 4.89, P = 0.031). Conclusions In Type 2 diabetes, the presence of the Metabolic Syndrome is associated with an almost 5-fold increase in CVD risk.

Diabetes control and complications: the role of glycated haemoglobin, 25 years on

Abstract: The long-term complications of diabetes have major consequences for individual subjects and growing healthcare delivery and cost implications for society. Evidence for the benefits of good glycaemic control, as monitored by glycated haemoglobin measurements, has been developed in the 25 years since they were introduced to the point where HbA(1c) assays play central roles in patient management, clinical guidance and audit, and clinical trial design. In this review this evidence is examined and three classes of uncertainty identified that diminish confidence in the effectiveness of these roles for HbA(1c). 1 Analytical variability between different methods for HbA(1c) has restricted the application of clinical targets and this problem has recently been addressed by reference method standardization. There are two approaches to this which result in different HbA(1c) values and this discrepancy needs to be resolved. 2 Biological variability in HbA(1c) values between individuals also restricts its predictive role when applied to populations. The correlations between HbA(1c) measurements and various components of glycaemia (overall, fasting, postprandial) are still uncertain and differences in protein glycation and de-glycation are greater between subjects than often thought. The influence of variability in erythrocyte life span is an area where research is needed, especially in diabetic subjects. 3 Clinical variability is the most important and complex area of uncertainty. A predictive link between HbA(1c) and clinical outcomes is not as clear-cut as often stated. The correlation with the development of microvascular disease is well established in Type 1 diabetes, but in Type 2 subjects (90% of those with diabetes) the evidence that HbA(1c) monitoring is of value in predicting or preventing macrovascular disease is not strong, although it is the major cause of morbidity and early death in this group. It is recommended that, as a matter of urgency, these issues be examined, particularly within the context of self-care in diabetes.

Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial

Abstract: AIMS The autoimmune-mediated destruction of pancreatic beta-cells in Type 1 diabetes mellitus renders patients deficient in two glucoregulatory peptide hormones, insulin and amylin. With insulin replacement alone, most patients do not achieve glycaemic goals. We aimed to determine the long-term efficacy and safety of adjunctive therapy with pramlintide, a synthetic human amylin analogue, in patients with Type 1 diabetes. METHODS In a double-blind, placebo-controlled, parallel-group, multicentre study, 651 patients with Type 1 diabetes (age 41 +/- 13 years, HbA(1c) 8.9 +/- 1.0%, mean +/- sd) were randomized to mealtime injections of placebo or varying doses of pramlintide, in addition to their insulin therapy, for 52 weeks. RESULTS Addition of pramlintide [60 microg three times daily (TID) or four times daily (QID)] to insulin led to significant reductions in HbA(1c) from baseline to Week 52 of 0.29% (P < 0.011) and 0.34% (P < 0.001), respectively, compared with a 0.04% reduction in placebo group. Three times the proportion of pramlintide- than placebo-treated patients achieved an HbA(1c) of < 7%. The greater reduction in HbA(1c) with pramlintide was achieved without an increase in concomitant insulin use and was accompanied by a significant reduction in body weight from baseline to Week 52 of 0.4 kg in the 60 microg TID (P < 0.027) or QID (P < 0.040) pramlintide treatment groups, compared with a 0.8-kg gain in body weight in the placebo group. The most common adverse event in pramlintide-treated patients was transient, mild-to-moderate nausea. CONCLUSIONS These results show that mealtime amylin replacement with pramlintide, as an adjunct to insulin therapy, improves long-term glycaemic and weight control in patients with Type 1 diabetes.

Diabetic foot ulcer and multidrug-resistant organisms: risk factors and impact.

Abstract: Aims The primary objective was to characterize factors allowing the colonization of diabetic foot wounds by multidrug-resistant organisms (MDRO), and the secondary objective was to evaluate the influence of MDRO colonization/infection on wound healing. Methods In 180 patients admitted to a specialized diabetic foot unit, microbiological specimens were taken on admission. Potential risk factors for MDRO-positive specimens were examined using univariate and multivariate analyses. Prospective follow-up data from 75 patients were used to evaluate the influence of MDRO colonization/infection on time to healing. Results Eighteen per cent of admission specimens were positive for MDRO. MDRO-positive status was not associated with patient characteristics (age, sex, type of diabetes, complications of diabetes), wound duration, or wound type (neuropathic or ischaemic). In the multivariate analysis, the only factors significantly associated with positive MDRO status on admission were a history of previous hospitalization for the same wound (21/32 compared with 48/148; P = 0.0008) or the presence of osteomyelitis (22/32 compared with 71/148; P = 0.025). In the longitudinal study of 75 wounds, MDRO-positive status on admission or during follow-up (6 months at least or until healing, mean 9 ± 7 months) was not associated with time to healing (P = 0.71). Conclusion MDROs are often present in severe diabetic foot wounds. About one-third of patients with a history of previous hospitalization for the same wound, and 25% of patients with osteomyelitis, had MDRO-positive specimens. This suggests that hygiene measures, or isolation precautions in the case of admission of patients presenting with these characteristics, should be aggressively implemented to prevent cross-transmission. Positive MDRO status is not associated with a longer time to healing.

Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in Type 2 diabetes.

Abstract: Aims To investigate the association of features of the metabolic syndrome with the prevalence of chronic complications. Methods A cross-sectional study was conducted with 548 patients with Type 2 diabetes mellitus (DM). Metabolic syndrome was diagnosed in the presence of at least two of the following: hypertension, dyslipidaemia, obesity, and microalbuminuria. Results Patients with the metabolic syndrome (85%) had a higher prevalence of peripheral vascular disease (PVD) (35% vs. 18%), retinopathy (44% vs. 20%), distal sensory neuropathy (DSN) (44% vs. 24%), micro- and macroalbuminuria (38% vs. 28%) and coronary artery disease (CAD) (53% vs. 36%). The more metabolic syndrome features (none/one, two, three or four), the higher the proportion of diabetes complications: PVD 18%, 31%, 37% and 38%; stroke 1.0%, 4.5%, 5.9% and 11.3%; retinopathy 20%, 38%, 42% and 64%; DSN 24%, 32%, 49% and 57%; micro- and macroalbuminuria 28%, 36% and 41%; and CAD 36%, 44%, 52% and 60% (P < 0.05). Conclusions The metabolic syndrome and the aggregation of its components were significantly associated with macro- and microvascular complications in Type 2 DM patients.

Diabetes mellitus as a risk factor for primary open-angle glaucoma: a meta-analysis.

Abstract: Aim The association of diabetes mellitus with primary open-angle glaucoma has been controversial. The study aimed to examine the strength of this association through a detailed meta-analysis of studies published in peer-reviewed journals. Methods A comprehensive search for articles published through 2002 was performed and data were abstracted. Prior to meta-analysis, all studies were evaluated for publication bias and heterogeneity. Pooled odds ratio (OR) was calculated using the random and the fixed-effects model. Results Twelve studies published between 1987 and 2001 were included (five case-control studies and seven cross-sectional studies). Significant heterogeneity among the studies was detected (P = 0.023). No evidence of publication bias was found (P = 0.37). The association of diabetes mellitus with primary open-angle glaucoma was statistically significant assuming either a random effects [OR = 1.50, 95% confidence interval (CI) 1.16, 1.93], or a fixed-effects model (OR = 1.27, 95% CI 1.10, 1.45). Conclusions Our meta-analysis results suggest that diabetic patients are at significantly increased risk of developing primary open-angle glaucoma. Clinicians should be aware of this possibility.

Clinical inertia in the management of Type 2 diabetes metabolic risk factors

Abstract: Aims Delays in the initiation and intensification of medical therapy may be one reason patients with diabetes do not reach evidence-based goals for metabolic control. We assessed intensification of medical therapy over time, comparing the management of hyperglycaemia, hypertension, and hyperlipidaemia. Methods Prospective cohort study of 598 adults with Type 2 diabetes receiving primary care in an academic medical centre from May 1997 to April 1999. We assessed whether patients failing to achieve standard treatment goals for haemoglobin A1c (HbA1c), systolic blood pressure (SBP), or low density lipoprotein (LDL) cholesterol when last measured during 12 months (Year 1, 5/97–4/98) had increases in their corresponding medical regimen during the following 12 months (Year 2, 5/98–4/99). Results Among untreated patients in Year 1, seven of 12 (58%) of those above goal for HbA1c were initiated on medical therapy in Year 2, compared with 16 of 48 (34%) above SBP goal (P = 0.02) and 26 of 115 (23%) above LDL cholesterol goal (P = 0.02). Among patients on therapy and above goal, 124 of 244 (51%) patients with elevated HbA1c had their regimen increased in Year 2, compared with 85 of 282 (30%) with elevated SBP (P < 0.001) and 22 of 79 (30%) with elevated LDL cholesterol (P < 0.001). From Year 1 to Year 2 there was a decline in the overall proportion of patients above goal for LDL cholesterol (from 58% to 45%, P = 0.002) but not for HbA1c or blood pressure. Conclusions Greater initiation and intensification of pharmaceutical therapy, particularly for elevated blood pressure or cholesterol, may represent a specific opportunity to improve metabolic control in Type 2 diabetes. Diabet. Med. 21, 150–155 (2004)

Type 2 diabetes mellitus: a disease of the innate immune system? An update

Abstract: A few years ago a hypothesis was proposed suggesting that elements of the innate immune system, such as acute phase reactants, contribute to the development of Type 2 diabetes mellitus. Acute phase reactants such as C-reactive protein and sialic acid may thus predict risk of developing Type 2 diabetes mellitus, as well as being markers of diabetes microvascular and macrovascular complications. This article discusses these issues.

Prognostic value of admission plasma glucose and HbA1c in acute myocardial infarction

Abstract: OBJECTIVE: Stress hyperglycaemia increases the risk of mortality after acute myocardial infarction in diabetic and in non-diabetic patients. We aimed to determine the contribution of admission plasma glucose and HbA(1c) on post-acute myocardial infarction prognosis. PATIENTS AND METHODS: Admission plasma glucose and HbA(1c) were simultaneously measured in all patients consecutively hospitalized for acute myocardial infarction. Patient survival was measured on 5 and 28 days after admission. Patients were defined as having 'previously diagnosed diabetes' (personal history of diabetes defined using ADA 1997 criteria), 'no diabetes', those without previously diagnosed diabetes and HbA(1c) below 6.5%, or 'possible diabetes', i.e. those without previously diagnosed diabetes and HbA(1c) above 6.5%. RESULTS: Of the 146 patients included, four had died by day 5 and 14 by day 28. Admission plasma glucose was higher in patients who had died by day 28 (11.7 +/- 5.8 vs. 8.0 +/- 3.3 mmol/l, P = 0.002), whereas HbA(1c) was not (6.4 +/- 1.9 vs. 6.1 +/- 0.8%, NS). Admission plasma glucose was significantly higher in those who had died by day 28 after adjustment on HbA(1c). A multivariate analysis, including sex, age and heart failure prior to acute myocardial infarction, showed that admission plasma glucose concentration was an independent predictor of survival after acute myocardial infarction. Twenty-seven of the patients had previously diagnosed diabetes and 119 had no history of diabetes. Eleven were found to have possible diabetes. Admission plasma glucose was significantly higher in previously diagnosed diabetes (11.1 +/- 5.6) than in the other groups: 7.7 +/- 2.9 in non-diabetes, 8.2 +/- 2.1 in possible diabetes (P < 0.0001). The relationship between HbA(1c)-adjusted admission plasma glucose and mortality after acute myocardial infarction was also found in the non-diabetes group. CONCLUSIONS: Admission plasma glucose, even after adjustment on HbA(1c), is a prognostic factor associated with mortality after acute myocardial infarction. Acute rather than the chronic pre-existing glycometabolic state accounts for the prognosis after acute myocardial infarction.

WHO and ATPIII proposals for the definition of the metabolic syndrome in patients with Type 2 diabetes.

Abstract: Aims Different criteria have been proposed by the World Health Organization (WHO) and by the Third Report of the National Cholesterol Education Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATPIII) for the diagnosis of the metabolic syndrome. Its identification is of particular importance for coronary risk assessment. Methods The prevalence of the metabolic syndrome was determined according to the two different proposals in 1569 consecutive subjects with Type 2 diabetes. Results By the WHO proposal, 81% of cases (95% confidence interval, 79–83) were labelled as metabolic syndrome. Microalbuminuria had the highest specificity (99%) and visceral obesity the highest sensitivity (93%). Seventy-eight per cent of patients (95% CI, 76–80) fulfilled the ATPIII criteria for metabolic syndrome, low HDL-cholesterol having the highest specificity (95%), elevated blood pressure having the highest sensitivity. According to both proposals, 1113 patients were positive; 183 were concordantly negative, indicative of a fairly good agreement (k statistics, 0.464). Subjects only positive for the WHO proposal were more frequently males, had a lower BMI and a higher arterial pressure. Only subjects identified by the ATPIII proposal had a significantly higher prevalence of previously detected coronary heart disease. Conclusions Minimum criteria for the metabolic syndrome are met in most patients with Type 2 diabetes. Correct identification of the syndrome is important for an integrated approach to reduce the high costs and the associated disabilities. The ATPIII proposal more clearly identifies the burden of coronary heart disease associated with the metabolic syndrome.

What does postprandial hyperglycaemia mean

Abstract: Aims The potential importance of postprandial glucose (PPG) control in the development of complications in Type 2 diabetes is much debated. The recent American Diabetes Association (ADA) consensus statement discussed the role of postprandial hyperglycaemia in the pathogenesis of diabetic complications and concluded that the relationship between PPG excursions and the well-established risk factors for cardiovascular disease (CVD) should be further examined. Using the ADA statement as a starting point and including the more recent American College of Endocrinology guidelines on glycaemic control, a panel of experts in diabetes met to review the role of PPG within the context of the overall metabolic syndrome, in the development of complications in Type 2 diabetes. Results Post-prandial hyperglycaemia is a risk indicator for micro- and macrovascular complications, not only in patients with Type 2 diabetes but also in those with impaired glucose tolerance. In addition, the metabolic syndrome confers an increased risk of CVD morbidity and mortality. The debate focused on the relative contributions of postprandial hyperglycaemia, the metabolic syndrome and, in particular, raised triglyceride levels in the postprandial state, to the development of cardiovascular complications of diabetes. Conclusions The panel recommended that in the prevention and management of microvascular complications of Type 2 diabetes, targeting both chronic and acute glucose fluctuations is necessary. Lowering the macrovascular risk also requires control of (postprandial) triglyceride levels and other components of the metabolic syndrome.

Swab cultures accurately identify bacterial pathogens in diabetic foot wounds not involving bone.

Abstract: Aims Current clinical practice assumes swab cultures from wounds are unreliable. However, this assumption is based upon data culled only from wounds in which osteomyelitis and/or gangrene were present. This study aimed to re-evaluate the accuracy of swab cultures vs. deep tissue cultures in diabetic wounds of varying depth and severity. Methods A total of 60 infected diabetic foot wounds were cultured. Two specimens were taken from each wound: superficial swab before debridement and deep tissue specimen towards the end of surgical debridement. Results In 37 wounds (62%), the micro-organisms isolated from the swab specimen and those isolated from the deep tissue specimen were identical. In another 12 wounds (20%), the swab culture contained all micro-organisms isolated from the deep tissue culture, but also contained additional micro-organisms. Analysis according to the depth of the wound, demonstrated that swabs identified all micro-organisms isolated from the deep tissue specimens in 36/40 wounds (90%) that did not extend to bone as opposed to 13/20 wounds (65%) that extended to bone. Conclusions Swab cultures are valuable in identifying pathogens in diabetic foot wounds when bone is not involved. When surgical debridement is contraindicated or delayed, swab cultures can be used to select appropriate antibiotic therapy.

The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study.

Abstract: OBJECTIVE The effect of spironolactone, cilazapril and their combination on albuminuria was examined in a randomized prospective study in female patients with diabetes and hypertension. PATIENTS AND METHODS Sixty female diabetic patients aged 45-70 years with blood pressure (BP) 140-180/90-110 mmHg, serum creatinine (sCr) < or = 160 micro mol/l, HbA(1c) < or = 10%, and albuminuria were treated by atenolol 12.5-75 mg/d and hydrochlorothiazide 6.25-25 mg/d. Titration-to-target helped to reach BP values < or = 135/85 mmHg in 46 patients after 12 weeks. These patients were randomized to spironolactone 100 mg/d or cilazapril 5 mg/d for 24 weeks. Then both groups received spironolactone 50 mg/d and cilazapril 2.5 mg/d for 24 weeks. BP was stabilized by tapering the dose of the initial agents. Urinary albumin/creatinine ratio (ACR), BP, K(+). sCr and HbA(1c) were assessed at baseline and at weeks 12, 16, 36 and 60. RESULTS The average BP at week 12 was 128 +/- 4/81 +/- 3 mmHg and remained constant, in both groups, throughout the study. ACR declined on spironolactone from a median value (range) of 452 (124-1571) to 216 (64-875) mg/g (P = 0.001), and on cilazapril to 302 (90-975) mg/g (P = 0.001). The difference between spironolactone and cilazapril was significant (P = 0.002). Combined treatment resulted in a further modest decline in ACR. Serum creatinine was unaltered by spironolactone and rose slightly (121 to 126 micro mol/l, P = 0.02) on cilazapril. CONCLUSION At the doses tested, spironolactone was superior to cilazapril in reducing albuminuria. Combined administration was more effective than either drug alone. These effects were independent of BP values. Hyperkalaemia was the main side-effect.

Schizophrenia, the metabolic syndrome and diabetes

Abstract: The prevalence of diabetes is increased in patients with schizophrenia. Although many reasons, including hereditary and lifestyle factors, contribute to this association, recently there has been heightened interest in the subject because of the link between the use of the newer atypical anti-psychotic drugs and the development of diabetes. These drugs cause significant weight gain and this may be one of the mechanisms by which they increase incident diabetes. The increased prevalence of diabetes among people with schizophrenia has implications for the delivery of care by psychiatrists, diabetologists and primary care.

New and experimental approaches to treatment of diabetic foot ulcers: a comprehensive review of emerging treatment strategies

Abstract: Diabetic foot ulcers occur in up to 15% of all diabetic patients and are a leading cause of nontraumatic amputation worldwide. Neuropathy, abnormal foot biomechanics, peripheral vascular disease and external trauma are the major contributors to the development of a foot ulcer in the diabetic patient. Therapy today includes repeated debridement, offloading, and dressings, for lower grade ulcers, and broad spectrum antibiotics and occasionally limited or complete amputation for higher grades, requiring a team effort of health care workers from various specialties. The large population affected by diabetic foot ulcers and the high rates of failure ending with amputation even with the best therapeutic regimens, have resulted in the development of new therapies and are the focus of this review. These include new off loading techniques, dressings from various materials, methods to promote wound closure using artificial skin grafts, different growth factors or wound bed modulators and methods of debridement. These new techniques are promising but still mostly unproven and traditional approaches cannot be replaced. New and generally more expensive therapies should be seen as adding to traditional approaches.

Validation of a system of foot ulcer classification in diabetes mellitus

Abstract: Objective The lack of a simple, robust classification of diabetic foot ulcers has critically hampered research into optimum patterns of care. We have therefore attempted validation of the previously published S(AD) SAD system, which is based on grading of ulcer features using simple clinical methods. Research design and methods This was a prospective study in which 300 people with ulcers newly referred to a hospital-based multidisciplinary clinic between 1 January 2000 and 1 July 2002 were classified at the time of their first assessment. If a patient had more than one episode, the last to occur was selected as the index ulcer. If two or more ulcers were registered simultaneously, the one which was regarded as the more significant was chosen. Ulcers were categorized according to area, depth, sepsis, ischaemia and neuropathy. All patients were followed for at least 6 months, or until death if earlier. Outcome criteria used were healed and unhealed (unhealed persisting, unhealed at amputation or death) and were cross-tabulated with different baseline variables. Results Ulcers healed in 209 of the 300 patients (69.7%), while 30.0 (10%) had been resolved by amputation (eight major; 22 minor) and 32 (10.7%) by death. Twenty-nine (9.7%) persisted unhealed. There were significant differences in outcome according to area (χ2 = 25.9, P < 0.001), depth (χ2 = 33.8, P < 0.001), sepsis (χ2 = 13.5, P = 0.004) and arteriopathy (χ2 = 33.7, P < 0.001), but not to denervation (χ2 = 5.1, P = 0.16). The strength of these associations was confirmed using Somers d: area (rs = −0.24, P < 0.001), depth (rs = −0.32, P < 0.001), sepsis (rs = −0.15, P < 0.01), arteriopathy (rs = −0.30, P < 0.001), denervation (rs = −0.10, P = 0.08). Logistic regression analysis using area, depth, sepsis and arteriopathy as independent variables, and those which contributed significantly to the model were area (P = 0.01), depth (P < 0.001) and arteriopathy (P < 0.001). Conclusions These data demonstrate that simple clinical methods can be used to categorize features of individual ulcers, and that area, depth and arteriopathy contribute independently to a model to predict outcome. A system of classification such as this is an essential requirement for the categorization of populations with similar features and similar prognosis, which may then be used as the basis for prospective research into optimal wound management.

C-reactive protein, its role in inflammation, Type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones.

Abstract: Increased concentrations of the marker of inflammation, C-reactive protein (CRP), are associated with insulin resistance, Type 2 diabetes and the development of cardiovascular disease. In particular, inflammation is closely associated with endothelial dysfunction and is recognized as one of the cardiovascular risk factors clustering in the Insulin Resistance Syndrome or Metabolic Syndrome. The exact mechanisms linking insulin resistance and inflammation remain unclear. However, the close association between insulin resistance and inflammation in atherogenesis suggests that therapies that address both parameters may have benefits in reducing diabetes-related macrovascular complications. The thiazolidinedione class of oral anti-diabetic agents are powerful insulin sensitizers that also have anti-inflammatory properties. Treatment with these agents has a range of anti-atherogenic effects, including reduced levels of CRP, plasminogen activator inhibitor-1 (PAI-1), TNF-alpha and reactive oxygen species. Additionally, the insulin-sensitizing effect of thiazolidinediones improves other factors of the Insulin Resistance Syndrome, including dyslipidaemia and hypertension. Outcome studies are underway to determine if the effects of improving insulin sensitivity and reducing inflammation will translate into clinical benefits and reduce the cardiovascular morbidity and mortality associated with insulin resistance and Type 2 diabetes.

Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin.

Abstract: BACKGROUND Glargine is a long-acting insulin analogue potentially more suitable than NPH insulin in intensive treatment of Type 1 diabetes mellitus (T1 DM), but no study has proven superiority. The aim of this study was to test superiority of glargine on long-term blood glucose (BG) as well as on responses to hypoglycaemia vs. NPH. METHODS One hundred and twenty-one patients with T1 DM on intensive therapy on four times/day NPH and lispro insulin at each meal, were randomized to either continuation of NPH four times/day (n = 60), or once daily glargine at dinner-time (n = 61) for 1 year. Lispro insulin at meal-time was continued in both groups. In 11 patients from each group, responses to stepped hyperinsulinaemic-hypoglycaemia were measured before and after 1 year's treatment. RESULTS Mean daily BG was lower with glargine [7.6 +/- 0.11 mmol/l (137 +/- 2 mg/dl)] vs. NPH [8.1 +/- 0.22 mmol/l (146 +/- 4 mg/dl)] (P < 0.05). HbA(1c) at 4 months did not change with NPH, but decreased with glargine (from 7.1 +/- 0.1 to 6.7 +/- 0.1%), and remained lower than NPH at 12 months (6.6 +/- 0.1%, P < 0.05 vs. NPH). Frequency of mild hypoglycaemia [self-assisted episodes, blood glucose < or = 4.0 mmol/l (72 mg/dl)] was lower with glargine vs. NPH (7.2 +/- 0.5 and 13.2 +/- 0.6 episodes/patient-month, P < 0.05). After 1 year, NPH treatment resulted in no change of responses to hypoglycaemia, whereas with glargine plasma glucose, thresholds and maximal responses of plasma adrenaline and symptoms to hypoglycaemia improved (P < 0.05). CONCLUSIONS The simpler glargine regimen decreases the percentage of HbA(1c) and frequency of hypoglycaemia and improves responses to hypoglycaemia more than NPH. Thus, glargine appears more suitable than NPH as basal insulin for intensive treatment of T1 DM.

An increase in insulin sensitivity and basal beta-cell function in diabetic subjects treated with pioglitazone in a placebo-controlled randomized study.

Abstract: Aims To investigate the effect of treatment with pioglitazone on beta-cell function and insulin sensitivity in Type 2 diabetes. Methods Thirty subjects with diet-controlled Type 2 diabetes were randomized to 3 months treatment with pioglitazone (n = 19) or placebo (n = 11). All subjects underwent basal sampling for homeostatic model assessment (HOMA), followed by an intravenous glucose tolerance test and hyperglycaemic clamp, followed by an euglycaemic hyperinsulinaemic clamp; at baseline and after treatment. Results All results are expressed as mean (sem). Pioglitazone increased basal insulin sensitivity by 24.7% (7.8) HOMA-%S vs. 2.1% (5.9) in the placebo group (P = 0.02). Stimulated insulin sensitivity, M/I, increased in the pioglitazone group compared with placebo: +15.1 (2.8) l kg−1 min−1 vs. +3.2 (2.9) l kg−1 min−1, respectively (P = 0.009). Pioglitazone increased adiponectin by 39.3 (6.3), ng/ml compared with a decrease of 0.8 (1.3) ng/ml with placebo (P = 0.00004). HOMA-%B increased with pioglitazone, +11.5% (4.8) vs. −2.0% (4.8) with placebo (P = 0.049), but there was no change in stimulated beta-cell function as determined by hyperglycaemic clamps. There was a significant reduction in the proinsulin/insulin ratio in the pioglitazone group, −0.057 (0.02) compared with placebo, +0.004 (0.02) (P = 0.03). There was a significant reduction in HbA1c of 0.6% (0.1) in the pioglitazone group compared with placebo (P = 0.003). There was no significant weight gain associated with pioglitazone therapy: +0.7 (sem 0.6) kg vs. +1.1 (sem 0.5) kg in placebo group (P = NS). Conclusions Basal beta-cell function and insulin sensitivity improved following pioglitazone therapy. The improvement in proinsulin to insulin ratio suggests that beta-cells are under less stress.

Association of simple anthropometric measures of obesity with visceral fat and the metabolic syndrome in male Caucasian and Indo-Asian subjects.

Abstract: Aims The aims of this study were first, to investigate the relationship between simple anthropometric measures of obesity with visceral fat as assessed by a single slice magnetic resonance imaging (MRI)-scan in patients attending a hospital clinic. Second, to determine which anthropometric measure best relates to the adverse metabolic profile of the metabolic syndrome. Methods Forty-one male subjects [body mass index (BMI): 30.2+5.8 kg/m(2), age: 50.3+13.6 years] were studied by MRI-scan to measure visceral fat at L4/L5 level and to investigate its relationship with simple anthropometric measures. Second, we studied 83 male subjects to determine which anthropometric measure best predicts the metabolic complications (using the ATPIII criteria) of obesity in the setting of a hospital clinic. Results Waist circumference was the best anthropometric measurement that correlated with MRI-visceral fat mass assessed at L4/L5 in 41 subjects who had an MRI scan (P=0.0001, r(2)=0.36, beta=0.56) amongst variables which also included age, BMI, sagittal diameter, diabetes and ethnicity. Stepwise multiple regression analysis showed sagittal diameter (P=0.001, r(2)=0.4, beta=0.406), age (P=0.003, beta=0.271) and waist circumference (P=0.012, beta=0.297) were the best predictors of the adverse metabolic profile of the metabolic syndrome in all 83 male subjects amongst BMI, waist-hip ratio (WHR), ethnicity and diabetes-related factors. Conclusions Waist circumference is a simple anthropometric parameter that best correlates with single slice MRI-scan, but sagittal diameter (measured using abdominal calipers) better predicts the adverse metabolic profile of the metabolic syndrome. Although there is considerable variation in abdominal fat topography between ethnic groups, and also within populations, sagittal diameter assessment is a technique that is simple and best predicts the metabolic syndrome.

Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome.

Abstract: Aims Was metformin during pregnancy in women with polycystic ovary syndrome (PCOS) associated with pre-eclampsia, and was it safe for mother and neonate? Methods In the current study, pre-eclampsia and other pregnancy outcomes were prospectively studied in 90 women with PCOS who conceived on metformin 1.5–2.55 g/day, and had ≥ 1 live birth (97 pregnancies, 100 live births) compared with 252 healthy women (not known to have PCOS) with ≥ 1 live birth, consecutively delivered in a community obstetrics practice. Results Women with PCOS were older than controls (33 ± 5 vs. 29 ± 6 years, P 35 years old at conception (23 vs. 13%, P = 0.028), much heavier (93 ± 23 vs. 72 ± 18 kg, P < 0.0001, BMI 33.8 ± 7.8 kg/m2 vs. 25.6 ± 5.9, P < 0.0001), and more likely to be Caucasian (97 vs. 90%, P = 0.05), but there were similar numbers with preconception Type 2 diabetes mellitus [2/90 (2.2%) vs. 1/252 (0.4%), P = 0.17]. Pre-eclampsia in PCOS (5/97 pregnancies, 5.2%), did not differ (P = 0.5) from controls (9/252, 3.6%), nor did it differ (P = 1.0) in PCOS vs. control primigravidas [2/45 (4.4%) vs. 4/91 (4.4%)]. Development of gestational diabetes in PCOS did not differ from controls [9/95 pregnancies (9.5%) vs. 40/251 (15.9%), P = 0.12]. Of the 100 live births to 90 women with PCOS, there were no major birth defects. Mean ± sd birth weight of the 80 live births ≥ 37 weeks gestation in women with PCOS (3414 ± 486 g) did not differ from controls’ 206 live births ≥ 37 weeks (3481 ± 555 g), P = 0.34, nor did the percentage of ≥ 37 week gestation neonates ≥ 4000 g (12.5 vs. 17.5%, P = 0.3) or ≥ 4500 g (1.3 vs. 2.9%, P = 0.7). Conclusions Metformin is not associated with pre-eclampsia in pregnancy in women with PCOS, and appears to be safe for mother and fetus.

Coxsackie B virus serology and Type 1 diabetes mellitus: a systematic review of published case-control studies.

Abstract: Background Enteroviruses, in particular Coxsackie B4, have been implicated in the aetiology of Type 1 diabetes mellitus, but the epidemiological evidence has not been systematically evaluated. Methods Systematic review of evidence from published controlled studies of the relationship between Coxsackie B virus serology and incident or prevalent Type 1 diabetes mellitus. Studies were identified through a Medline search (1966 to 2002), supplemented by references from identified papers and hand search of relevant journals. All studies (full papers, abstracts or letters) with data adequate for calculation of unadjusted odds ratios (with 95% confidence intervals) for Type 1 diabetes mellitus in relation to Coxsackie B virus serology were included. Results The review included 26 case-control studies; no cohort study met the inclusion criteria. Odds ratios for Type 1 diabetes mellitus in serology-positive vs. serology-negative subjects ranged from 0.2 to 22.3. For Coxsackie B (any serotype) 7/13 studies had point estimates significantly greater than 1.0 (P < 0.05). For Coxsackie B3, Coxsackie B4 and Coxsackie B5-specific assays, 1/11, 6/17 and 1/11 studies, respectively, had point estimates significantly greater than 1.0. Summary odds ratios were not calculated because of doubts about the validity of individual study estimates, heterogeneity between studies, and the possibility of publication bias. Conclusions The results of these studies are inconsistent and do not provide convincing evidence for or against an association between Coxsackie B virus infection and Type 1 diabetes mellitus. Better designed studies using effective assays are needed to resolve this important issue.

Conventional measures underestimate glycaemia in cystic fibrosis patients.

Abstract: Aims Diabetes mellitus is an increasingly important complication of cystic fibrosis (CF). The association with increased morbidity of cystic fibrosis-related diabetes (CFRD) has emphasized the need for accurate monitoring of glycaemia in all CF patients. The diagnosis has relied on conventional thresholds in an oral glucose tolerance test (OGTT) derived from epidemiological studies in non-CF subjects. However, it has not been established if these values are equivalent in CF and non-CF populations. Methods We compared glycaemia in 21 non-diabetic CF subjects with 21-age and BMI-matched non-CF controls using HbA1c, OGTT and a subcutaneous continuous glucose monitoring system (CGMS) that measures interstitial glucose levels. Results All conventional measures of glycaemia were similar in the two groups: HbA1c mean CF vs. controls (5.5 vs. 5.3%P = 0.4), fasting glucose (4.8 vs. 4.7 mmol/l P = 0.7) and 2-h glucose (5.8 vs. 5.7 mmol/l P = 0.8). However, these conventional measures did not accurately reflect glycaemia 30-, 60- and 90-min. Glucose values and area under the curve in OGTT were all higher in CF subjects than controls (P = 0.01–0.0001). Mean CGMS value [5.9 (0.8) vs. 5.1 (0.5) mmol/l, P = 0.004], and the proportion of subjects with peak CGMS values > 11.1 mmol/l (33 vs. 5%P = 0.00001) were also higher in CF subjects than controls. These results remained significantly different when only subjects with normal glucose tolerance in the two groups were studied. Conclusions We have shown that overall glycaemia, as shown by both the response during an OGTT and CGMS, is higher in CF subjects who have similar HbA1c, fasting and 2-h glucose values. These results question whether it is appropriate to use the diagnostic thresholds and OGTT time points derived from the non-CF population for a diagnosis of diabetes in patients with cystic fibrosis.

Evaluation of delivery of enhanced diabetes care to patients of South Asian ethnicity: the United Kingdom Asian Diabetes Study (UKADS).

Abstract: Aims We tested the hypothesis that enhanced care for diabetes, tailored to the needs of the South Asian community with Type 2 diabetes, would improve risk factors for diabetic vascular complications and ultimately reduce morbidity and mortality. Patients and methods The study was a cluster randomized controlled trial (RCT) with general practice the unit of randomization. Six West Midlands general practices with a high proportion of South Asian patients were randomized to 'enhanced care' using Asian link workers and extra community diabetes specialist nurse sessions (intervention) or continued standard practice care (control). Results Of 401 patients recruited to the study, 361 (90%), comprising 178 from Coventry and 183 from Birmingham were eligible and included in the analyses. The mean age at baseline (standard deviation, SD) was 58.9 (11.7 years) with median (interquartile range; IQR) duration of diabetes 6.5 (3-11) years. At one year follow-up there was a significant difference in reduction of systolic (4.6 mmHg, P=0.035) and diastolic blood pressure (3.4 mmHg, P=0.003) and total cholesterol (0.4 mmol/l, P=0.005), comparing the intervention and control groups. After adjusting for baseline measurement and age, only differential reduction in diastolic blood pressure remained significant. There was no significant change in HbA(1c) and no difference between the groups. Conclusions Using link workers and extra community diabetes specialist nurse input together with treatment protocols in primary care might prove a useful strategy in working towards NSF targets for diabetes management. In this study, small reductions in blood pressure and cholesterol were achieved. Improvement in glycaemic control may require longer and possibly different strategies. Further research is required to evaluate fully the effectiveness, including the costs and longer term sustainability of culturally sensitive initiatives.

The post-prandial state in Type 2 diabetes and endothelial dysfunction: effects of insulin aspart.

Abstract: Objective Recently, much attention has been focused on the possibility that the post-prandial state may be a cardiovascular risk factor in diabetes. The aim of the present study was to evaluate whether the post-prandial state is associated with endothelial dysfunction in patients with diabetes and to explore the effect on this aspect of managing post-prandial hyperglycaemia by insulin aspart. Research design and methods Twenty-three patients with Type 2 diabetes and 10 normal controls were recruited. In the diabetic patients two different tests were performed in each subject: a standard meal preceded by subcutaneous injection of soluble insulin (0.15 U/kg body weight) or of short-acting insulin aspart (0.15 U/kg body weight). These tests were designed to achieve different levels of post-prandial hyperglycaemia. Controls received a single standard meal test. Immediately before, and 1, 2, 4 and 6 h after each meal, blood glucose, triglycerides, free fatty acids and flow-mediated vasodilation were measured. Results Compared with regular insulin, insulin aspart significantly reduced the area under the curve for post-prandial hyperglycaemia (58.3 ± 17.6 vs. 68.1 ± 17.7; P < 0.04), and preserved flow-mediated vasodilation, which was decreased in the post-prandial state (39.4 ± 2.9 vs. 34.1 ± 2.2; P < 0.01). Triglyceride and free fatty acid levels were not differentially affected by the treatment. In normal controls the meal did not affect flow-mediated vasodilation. Conclusion This study shows that the post-prandial state is accompanied by endothelial dysfunction in Type 2 diabetic patients and that insulin aspart improved endothelial function. Diabet. Med. 21, 171–175 (2004)

Regional differences in risk factors and clinical presentation of diabetic foot lesions.

Abstract: Background Problems associated with the diabetic foot are worldwide. However, there may be regional variation among risk factors and clinical presentation. Prospective comparative data concerning this topic are rare. Aim To determine differences in underlying risk factors and clinical presentation of foot problems among people with diabetes in different regions. Patients and methods Six hundred and thirteen consecutive patients with diabetic foot lesions from three centres [Soest-Germany (GER), Dar-es-Salaam, Tanzania (TAN) and Chennai, India (IND)] were included during the period June 1998 through December 1999. Diabetes-related data, risk-factor profiles, and lesion-related data were collected for each patient. Due to varying proportions of recurrent lesions among the centres, only data from patients with newly presenting diabetic foot lesion were analysed. Results Of the 613 patients sampled, 368 (60%) were treated for newly presenting diabetic foot lesion. In all three centres, patients were predominately male and had Type 2 diabetes. The average diabetes duration until the onset of the initial foot lesion was 14 years in GER and 12 years in IND, but only 5 years in TAN. The corresponding patient ages were 71, 56 and 51 years. Neuropathy was common to patients in all three centres. Peripheral vascular disease (PVD) was a frequent risk factor in GER (48%). In TAN and IND it was far less common (12 and 13%), probably due to younger patient populations, shorter diabetes duration and lower proportions of smokers. Inadequate footwear was the most common cause of foot lesions in GER (19%), while lack of footwear, irregular foot care and burns were the primary precipitating factors among patients in TAN and IND. Conclusion Similarities in different regions of the world among people with diabetes suffering newly presenting foot lesions include a predominance of males and patients with Type 2 diabetes, as well as a high frequency of diabetic neuropathy. However, differences concerning age, diabetes duration, peripheral vascular disease, and precipitating factors contributing to injury are also observed.