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The presence of immunoreactive insulin in saliva and its relationship to plasma immunoreactive insulin was investigated in healthy subjects, newly diagnosed non-obese Type 2 (non-insulin-dependent) diabetic patients and obese non-diabetic subjects, basally and after an oral glucose tolerance test. The mean ± SEM fasting values of plasma and salivary immunoreactive insulin were significantly higher in diabetic patients and obese non-diabetic subjects than in normal volunteers ( p<0.05). During the glucose challenge, the increase of salivary insulin was related with that of plasma in the three groups of subjects, with a time lag in normal and obese subjects. In normal volunteers, plasma and salivary peak values were respectively 49.5 ± 13.4 μU/ml ( p<0.05 vs obese subjects) at 60 min and 12.0±3.3μU/min ( p<0.05 vs obese subjects) at 120 min; in diabetic patients, the values were 51.7 ± 5.6 μU/ml ( p<0.05 vs obese subjects) and 14.6±4.1 μU/min at 120 min; in obese subjects, the peak value for plasma insulin was 111.5±40.1 μU/ml at 90 min and for salivary insulin 15.6 ± 5.1 μU/min at 120 min. A positive linear relationship was shown between plasma and salivary insulin during the oral glucose tolerance test. The identity of salivary insulin was assessed by reversed-phase HPLC. We conclude that salivary immunoreactive insulin can be found in Type 2 diabetic patients and in obese non-diabetic subjects, as well as normal volunteers, that plasma and salivary insulin are related after a glucose load, and that differences exist in salivary insulin secretion patterns among the three groups of subjects. [ABSTRACT FROM AUTHOR]

Several studies have shown an association between blood pressure and nephropathy, but few have been large enough to examine whether, or how, this relation is influenced by retinopathy. We have therefore examined the independent relations of blood pressure to urinary albumin excretion and retinopathy in a cross-sectional observational study of over 3000 insulin-dependent diabetic patients (the EURODIAB IDDM Complications Study). The relation of blood pressure to urinary albumin excretion differed strikingly between patients with (46%) and without (54%) retinopathy. In those with retinopathy, mean urinary albumin excretion rate was normal (<20 Μg/min) below median diastolic pressure (75 mm Hg) and increased steeply ( p<0.001) with blood pressure above this level. However, in patients without retinopathy, mean albumin excretion rate was normal across the range of diastolic pressure. This finding could not be explained by differences in glycaemic control or duration of diabetes between patients with and without retinopathy. These data identify a subgroup of patients whose high risk of nephropathy may reflect abnormal renal vulnerability to mildly raised blood pressure. Retinopathy is a close correlate of this vulnerability. Detection of even mild retinopathy, together with raised blood pressure, may be important in assessing nephropathy risk. [ABSTRACT FROM AUTHOR]

Arterial hypertension and poor glycaemic control are central to the development of microalbuminuria in insulin-dependent diabetes mellitus (IDDM). Recent consensus has established sensitive criteria for their detection and treatment, although the proportion of patients who may benefit is unclear. Between 1988 and 1990, we measured urinary albumin to creatinine concentration ratio (A/C) in 3,636 adult out-patients with IDDM of more than 3 years duration, serum creatinine under 133 Μmol/l and who were not undergoing antihypertensive treatment. A/C indicating microalbuminuria (≥2.38/ 2.96 mg/mmol, male/female) was found in 620 of 3,451 patients without proteinuria, and associated with hypertension (blood pressure ≥140 and/or 90 mm Hg; p=0.0016; rate: 39.6%), independent of diabetes duration ( p=0.0082) and male gender ( p=0.0350; relative risk=1.16; 95% confidence interval: 1.01-1.32). Hypertension was less common among those with normal A/C (27.5%, p<0.0001) but was positively related with diabetes duration. Of the 1,015 patients with A/C>2.0 mg/mmol 529 were reexamined. Glycated haemoglobin levels exceeded 3 SD above the mean of normal in 84.3% of the 198 microalbuminuric patients (AER=20-200 Μg/min), but were comparably poor (79.2%) in normoalbuminuria. Duration of diabetes was inversely related to glycated haemoglobin only in microalbuminuria (0.05< p<0.1). Intervention to lower blood pressure remains mainly restricted to those patients with long-term diabetes and slower development of kidney disease. Near-normalisation of glycaemia remains the priority for the majority of patients with microalbuminuria. [ABSTRACT FROM AUTHOR]

The geriatric nutritional risk index (GNRI) is a nutrition-related risk assessment tool and has been used in various clinical settings. The relationship between body mass index (BMI) and the associated risk of diabetic retinopathy (DR) remains inconclusive. We aimed to evaluate the association between GNRI and DR in patients with type 2 diabetes. We included a total of 1359 patients with type 2 diabetes who followed up in our diabetes clinic and underwent fundus photographic examinations from August 2006 to February 2014. DR was assessed by retinal ophthalmologists using comprehensive ophthalmologic examinations. Patients were divided into tertiles according to their GNRI category. Patients in a lower GNRI tertile tended to have a higher proportion of nonproliferative DR (NPDR) and proliferative DR (PDR) compared with those in the other tertiles. The risk of PDR was higher in patients included in GNRI tertile 1 (Odds ratio (OR) 2.252, 95% Confidence Interval (CI) 1.080–4.823, P = 0.033) and GNRI tertile 2 (OR 2.602, 95% CI 1.323–5.336, P = 0.007) compared with those in GNRI tertile 3. In patients with lower GNRIs, the prevalence of DR was higher than in those with higher GNRIs. When GNRI was compared with BMI using the area under the curve, overall accuracy was high in GNRI. The risk of PDR was high in patients with low GNRI and there is an inverse association between GNRI scores and prevalence of DR. GNRI might be a useful tool to predict DR in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Increased vascular permeability is an early sign of vascular damage and can be measured with the transcapillary escape rate of albumin (TERalb). Although TERalb has a multi-exponential kinetic model, most published TERalb data are based on mono-exponential kinetic models with variation in blood sampling schemes. Aim of this posthoc study was to evaluate the influence of variation in blood sampling schemes and the impact of mono- or bi-exponential analyses on the calculation of TERalb. Study participants were part of a cross-over intervention study protocol, investigating effects of sodium loading on blood pressure, endothelial surface layer and microcirculation. Multiple blood samples were drawn between 3 and 60 min after injection of radioactive iodide labeled human serum albumin (rHSA). Results: In total 27 male participants with 54 measurements were included. For all participants the maximum serum radioactivity was reached within 20 min, while 85% of the participants had their maximum serum activity within 10 min. The TERalb calculated with the subsequently chosen T20–60 min reference scheme (6.19 ± 0.49%/h) was significantly lower compared to the TERalb of the T3–60 min, T5–60 min, and Tmax – 60 min schemes. There was no significant difference between the T20–60 min reference scheme and the T10–60 min and T15–60 min schemes. Bi-exponential kinetic modeling did not result in significant different observations compared to the mono-exponential kinetic analysis. Conclusions: As there is variation in the timing of the maximum serum radioactivity of rHSA, blood sampling schemes starting before 10 min after administration of rHSA will result in a significant overestimation of TERalb. In addition, variation in kinetic modeling did not result in significant changes in TERalb. Therefore, we emphasize the need to standardize TERalb and for practical and logistical reasons advocate the use of a mono-exponential model with blood sampling starting 20 min after rHSA administration. [ABSTRACT FROM AUTHOR]

A dietary protein intake (DPI) of between 0.6 and 0.8 g protein per kilogram body weight per day (g/kg/day) is frequently recommended for adults with moderate-to-advanced chronic kidney disease (CKD). However, evidence on whether patients with diabetic kidney disease (DKD) actually benefit from a DPI of ≤ 0.8 g/kg/day and from a low-protein diet (LPD) at CKD stages 1–3 has not been consistent. We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Knowledge, as well as the bibliographies of articles identified in the search, for eligible randomized controlled trials that had investigated the effects of LPD (prescribed DPI < 0.8 g/kg/day) versus control diet on the progression of DKD. Nine trials that included 506 participants and follow-up periods varying from 4.5 to 60 months were included in the subsequent systematic review and meta-analysis. The data showed that patients with DKD who consumed < 0.8 g protein/kg/day had a significantly reduced decline in glomerular filtration rate (GFR) (mean difference [MD] 22.31 mL/min/1.73 m2, 95% confidence interval [CI] 17.19, 27.42; P < 0.01) and a significant decrease in proteinuria (standard mean difference [SMD] − 2.26 units, 95% CI − 2.99, − 1.52; P < 0.001) versus those on the control diet. The benefits of LPD to patients with DKD at CKD stages 1–3 were a markedly decreased proteinuria (SMD − 0.96 units, 95% CI − 1.81, − 0.11; P = 0.03) and slight but significant decreases in glycated hemoglobin (− 0.42%) and cholesterol levels (− 0.22 mmol/L). Our meta-analysis indicated that a DPI of < 0.8 g/kg/day was strongly associated with a slow decline in GFR and decreased proteinuria in the patients with DKD. Patients with CKD stages CKD 1–3 benefited from LPD in terms of a marked decrease of proteinuria and slight but significant improvements in lipid and glucose control. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe patient characteristics and clinical outcome among patients with diabetic foot ulcers under treatment of a multidisciplinary outpatient clinic in multiethnic Suriname, a developing country in South America. Retrospectively, all diabetes patients (> 18 years) with foot ulcers starting their treatment at the outpatient clinic between November 2013 and October 2014 were included and followed for at least 12 weeks. To assess differences in clinical outcome between subgroups, chi-square and incorporating time-related data, the log-rank test were used. One hundred patients were included (lost to follow-up, n = 20). Half of patients were males (n = 40). Mean age was 57.8 years. Nephropathy, peripheral arterial disease, and neuropathy were present in 90.9, 41.7, and 90.3%, respectively. Thirty-five percent of wounds healed within 12 weeks (median at 50 days, 13 visits). Sixty-eight percent of wounds were infected. No major but four minor amputations were carried out. Looking at subgroups, infection and ethnicity (African vs. Asian descent), but not gender or age, increased risk for delayed healing (p < 0.001 and p = 0.049, log-rank test). It seems of high priority to increase awareness and search for accurate preventive strategies for diabetic foot, and related wounds and infections, with special attention for ethnic disparities, in Suriname. [ABSTRACT FROM AUTHOR]

The prothrombotic state in type 1 diabetes mellitus (T1DM) has been reported as a plausible cause of vascular complications. Rotational thromboelastometry (ROTEM) assay enables the global assessment of coagulation status. This study aimed to assess hypercoagulability in children with T1DM using ROTEM. A total of 43 T1DM children (20 females and 23 males) aged 2-18 years and age- and sex-matched 30 healthy control subjects were enrolled in the study group. ROTEM assays [intrinsic TEM (INTEM) and extrinsic TEM (EXTEM)] were used to measure and analyze coagulation time (CT), clot formation time, maximum clot firmness (MCF). Glycated hemoglobin levels (HbA1c), diabetic complications, platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and dimerized plasmin fragment D (D-dimer) were determined in the study group. The mean duration of T1DM diagnosis was 3.15 ± 2.49 years, and the mean HbA1c level was 8.94 ± 1.88% (74.29 ± 20.59 mmol/mol). None of the patients had macrovascular complications. Nephropathy was present in five patients. In the T1DM group, EXTEM-CT [80.00 (66.75−108.50)] was significantly lower, and EXTEM-MCF [65.00 (64.00−70.00)] and INTEM-MCF [65.00 (62.00−68.00)] were significantly higher than in the controls ( p < 0.001, p = 0.026, and p = 0.004, respectively). However, the duration of T1DM and the degree of metabolic control had no influence on these parameters. Platelet count, PT, aPTT, fibrinogen and D-dimer levels were comparable between the diabetic patients and the control group. There were statistically significant correlations between fibrinogen level and INTEM-MCF and EXTEM-MCF ( p < 0.001, p = 0.002 and r = 0.545, r = 0.454, respectively) This study shows that decreased levels of CT and increased levels of MCF suggest hypercoagulability in patients with T1DM. Further studies are needed to confirm our findings on a larger number of diabetic patients. [ABSTRACT FROM AUTHOR]

Introduction: Patients with diabetes type 1 (DM1) struggle daily to achieve good glucose control. The last decade has seen a rush of research groups working towards an artificial pancreas (AP) through the application of a double subcutaneous approach, i.e., subcutaneous (SC) continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion. Few have focused on the fundamental limitations of this approach, especially regarding outcome measures beyond time in range. Methods: Based on insulin physiology, the limitations of CGM, SC insulin absorption, meal challenge, and physical activity in DM1 patients, we discuss the limitations of the double SC approach. Finally, we discuss safety measures and the achievements reported in some recent AP studies that have utilized the double SC approach. Results: Most studies show that a double SC AP increases the time in range compared to a sensor-augmented insulin pump and shortens the time in hypoglycemia. Despite these achievements, the proportion of time spent in hyperglycemia is still roughly 20-40%, and hypoglycemia is still present 1-4% of the time. The main factors limiting further progress are the latency of SC CGM (at least 5-10 min) and the slow pharmacokinetics of SC-delivered fast-acting insulin. The maximum blood insulin level is reached after 45 min and the maximum glucose-lowering effect is observed after 1.5-2 h, while the glucose-lowering effect lasts for at least 5 h. Conclusions: Although using a double SC AP leads to significant improvements in glucose control, the SC approach has severe limitations that hamper further progress towards a robust AP. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Foot ulcers in people with diabetes are a common and serious global health issue. Dressings form a key part of ulcer treatment. Existing systematic reviews are limited by the lack of head-to-head comparisons of alternative dressings in a field where there are several different dressing options. We aimed to determine the relative effects of alternative wound dressings on the healing of diabetic foot ulcers. Methods: This study was a systematic review involving Bayesian mixed treatment comparison. We included randomised controlled trials evaluating the effects on diabetic foot ulcer healing of one or more wound dressings. There were no restrictions based on language or publication status. Results: Fifteen eligible studies, evaluating nine dressing types, were included. Ten direct treatment comparisons were made. Whilst there was increased healing associated with hydrogel and foam dressings compared with basic wound contact materials, these findings were based on data from small studies at unclear or high risk of bias. The mixed treatment comparison suggested that hydrocolloid-matrix dressings were associated with higher odds of ulcer healing than all other dressing types; there was a high degree of uncertainty around these estimates, which were deemed to be of very low quality. Conclusions/interpretation: These findings summarise all available trial evidence regarding the use of dressings to heal diabetic foot ulcers. More expensive dressings may offer no advantages in terms of healing than cheaper basic dressings. In addition, evidence pointing to a difference in favour of 'advanced' dressing types over basic wound contact materials is of low or very low quality. [ABSTRACT FROM AUTHOR]

There is scanty information on the role of genetic factors, especially those relating to haptoglobin (Hp) phenotypes in the expression of complications among diabetes mellitus patients in Ghana. In this study, we investigated whether there is any association between Hp phenotypes and diabetic complications and to determine if association of the Hp phenotypes with diabetic complications in Ghanaian diabetics differ from those in Caucasians. A total of 398 participants were randomly recruited into the study. These comprised diabetic patients numbering 290 attending a diabetes Clinic in Ghana and 108 non-diabetic controls from the same community. Analyses of the results indicate that most of the diabetics with complications were of the Hp 2-2 (35%) and Hp 2-1 (23.9%) phenotypes. Fewer diabetics were found to be of the Hp 2-1 M phenotype. The controls were mostly of Hp 1-1 and Hp 2-1 M phenotypes. The odds ratio of having complications in a diabetic with an Hp 2-2 phenotype was 18.27 times greater than that for Hp 0-0. Hp 2-2 phenotype with its poor antioxidant activity may therefore be a useful predictor for the propensity of an individual to develop diabetes complications. [ABSTRACT FROM AUTHOR]

Hydroxymethylfurfural (HMF), a well-known heterocyclic Maillard reaction product, has often been studied for its potential toxic, mutagenic, and carcinogenic effects. Recent clinical studies, however, have strongly suggested that HMF might have exciting antitumor potential. We report on the development and validation of a bioanalytical assay for HMF that could be suitable as a basis for pharmacokinetic models in cancer patients. Two strategies were tested, i.e., direct and indirect methodologies. A direct isocratic LC determination at 283 nm was designed. Two indirect attempts involved derivatization coupled to HPLC-UV. It was possible to resolve the stereoisomers of the HMF derivative, and factors influencing their equilibrium ratio are discussed. HMF was extracted from the biomatrix by solid-phase extraction using different cartridges. A comparative study was made of the implemented methods as well as the extraction protocols. Both indirect assays proved to be more sensitive and were used to assess HMF quantitatively in human plasma. However, the newly introduced derivatization conditions led to the highest sensitivity with a LOD (S/N ratio = 3) of at least 2 pmol analyte on column. The assay selectivity was satisfactory in pre- and post-dose real samples. The mean recoveries of the assays were 79% and 89%, with acceptable accuracies and reproducibilities. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Hyperfibrinogenaemia and albuminuria are cardiovascular risk factors, often coexisting in diabetic and non-diabetic people. Albuminuria in turn is associated with a compensatory albumin overproduction in non-diabetic patients. It is not known whether the presence of albuminuria in patients with type 2 diabetes mellitus is associated with greater albumin and fibrinogen production rates than in normoalbuminuric patients. Subjects, materials, and methods: Using leucine isotope methods, we measured fractional and absolute synthesis rates (FSR, ASR) of albumin and fibrinogen in post-absorptive type 2 diabetic patients with either normal (n=11) or increased (n=10) urinary albumin excretion. Results: In albuminuric patients, albumin FSR (16.2±1.5%/day) and ASR (20.5±1.9 g/day) were greater (p<0.02 and p<0.05, respectively) than in normoalbuminuric patients (FSR=11.5±1.1%/day; ASR=15.7±1.2 g/day). Fibrinogen FSR was similar between patients with normal and increased albumin excretion, but concentration, the circulating pool and ASR of fibrinogen were 40 to 50% greater (p<0.035) in patients with albuminuria. Albuminuria was positively correlated with albumin ASR, with fibrinogen concentration, the fibrinogen pool and ASR, whereas albumin synthesis was inversely correlated with calculated oncotic pressure. Conclusions/interpretation: Synthesis of albumin and fibrinogen is upregulated in type 2 diabetic patients with increased urinary albumin excretion. Albuminuria is associated with enhanced fibrinogen and albumin synthesis. [ABSTRACT FROM AUTHOR]

The oxidative behaviour of the antidiabetic agent glibenclamide on a bare carbon paste electrode (CPE) and a Sephadex-modified carbon paste electrode (SMCPE) was explored by cyclic and differential pulse voltammetry (DPV). The analysis procedure consisted of an open circuit accumulation step in stirred sample solution of Britton-Robinson buffer (0.04 mol L-1, pH 2.0). This was followed by medium exchange to a clean solution of Britton-Robinson buffer (0.04 mol L-1, pH 5.0), and subsequently an anodic potential scan was effected to obtain the voltammetric peak. The glibenclamide oxidation peak current obtained by DPV was proportional to the concentration of the glibenclamide in the range of 1.0×10-9 mol L-1 to 5.0×10-8 mol L-1 for 180 s accumulation time, with a detection limit of 4.0×10-10 mol L-1. A method was developed for the determination of glibenclamide in formulation and spiked human serum. Moreover, the proposed procedure was used to estimate the serum concentrations after oral administration of a 5 mg tablet of glibenclamide to three diabetic subjects. [ABSTRACT FROM AUTHOR]

Easy observation of the fundus oculi makes retinopathy the most frequently reported chronic complication of diabetes and, consequently, the one we know best in terms of epidemiology and natural history. Achieving near-normal levels of blood glucose and blood pressure provides empirical though powerful tools for clinicians to delay the onset and progression of diabetic retinopathy. Even when these measures have failed and retinopathy becomes sight-threatening, laser photocoagulation has proven remarkably effective. Nonetheless, retinopathy remains a leading cause of blindness and there is little evidence that diabetes-related visual loss is decreasing in industrialized countries. This may result from the mixed blessing of prolonged survival of patients who had become diabetic when metabolic control was pursued less fastidiously than today. Screening for sight-threatening retinopathy is the most cost-effective medical procedure known and should help optimise the use of diagnostic and therapeutic resources, but its widest deployment still meets with inertia and lack of interest within most health care systems. Improving clinical skills and technology, however, allow us to take a more optimistic look at the future, as pathogenesis-targeted forms of treatment are being developed and tested through appropriately powered clinical trials. [ABSTRACT FROM AUTHOR]

Charcot neuroarthropathy has been recognised for over 130 years and yet it remains a major cause of morbidity for patients with diabetes mellitus and a continuing challenge for physicians. It is rare but it seems to be increasing in prevalence and this provides hope that with larger studies it will soon be possible to clarify the natural history and optimal treatment regimens. The underlying cause is thought to be trauma in a neuropathic foot that leads to a complex series of pathological processes culminating in bone and joint destruction and subsequent deformity. The acute reaction is often misdiagnosed and many patients present late with established deformity. Even when the diagnosis is considered at an early stage there are no definitive criteria or tests to confirm charcot neuroarthropathy and a high index of suspicion is necessary in any diabetic patient with a swollen warm foot in the presence of somatic or autonomic neuropathy. Treatment has traditionally involved the use of various methods to avoid weight bearing but recent work has begun to suggest that bisphosphonates might be able to arrest the acute process. In the long term, treatment involves a multidisciplinary approach aimed at providing appropriate footwear to reduce plantar pressures and avoid foot ulceration; in some circumstances this involves surgical correction of deformities before adequate footwear can be supplied. Further studies of the emerging treatments for Charcot neuroarthropathy are needed to provide long-term outcome data on morbidity and deformity. [ABSTRACT FROM AUTHOR]

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation endproducts, amyloid β peptide and the family of β sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered. [ABSTRACT FROM AUTHOR]

The peripheral benzodiazepine receptor (PBR) has been implicated in growth control of various tumour models. Although colorectal cancers were found to overexpress PBR, the functional role of PBR in colorectal cancer growth has not been addressed to date. Using primary cell cultures of human colorectal cancers and the human colorectal carcinoma cell lines HT29, LS174T, and Colo320 DM we studied the involvement of PBR in the growth control and apoptosis of colorectal cancers. Both mRNA and protein expression of PBR were detected by RT-PCR and flow cytometry. Using confocal laser scanning microscopy and immunohistochemistry the PBR was localized in the mitochondria. The specific PBR ligands FGIN-1-27, PK 11195, or Ro5-4864 inhibited cell proliferation dose-dependently. FGIN-1-27 decreased the mitochondrial membrane potential, which indicates an early event in apoptosis. Furthermore, FGIN-1-27, PK 11195 or Ro5-4864 increased caspase-3 activity. In addition to their apoptosis-inducing effects, PBR ligands induced cell cycle arrest in the G[SUB1]/G[SUB0]-phase.) Thus, our data demonstrate a functional involvement of PBR in colorectal cancer growth and qualify the PBR as a possible target for innovative therapeutic approaches in colorectal cancer. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. Methods: Risk factors for renal failure were examined in 3558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Results: In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2559 with Type II (non-insulin-dependent) diabetes mellitus, the average follow-up was 8.4 years ( ± 2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG abnormalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. Conclusion/interpretation: We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type II diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure. [Diabetologia (2001) 44 [Suppl 2]: S 46–S 53] [ABSTRACT FROM AUTHOR]

BACKGROUND: Tumor necrosis factor α (TNFα), a cytokine produced at inflammatory sites and in adipose tissue, is known primarily for its detrimental effects on insulin action. There is evidence to suggest that TNFα may also influence β-cell function. Leptin is another adipose tissue-derived hormone that might also act on β-cells. OBJECTIVE: We explored the independent and combined effects of TNFα and leptin upon basal and glucose-stimulated insulin transcription and secretion in the HIT-T15 pancreatic β cell line. METHODS: Cells were cultured for 40 h in the presence of near-normal basal (7 mM) or high (16.7 mM) glucose and treated with either TNFα (1, 10 and 50 ng/ml) or leptin (10, 50 and 100 ng/ml) or both together. Insulin concentrations were measured by radioimmunoassay. Insulin mRNA levels were evaluated by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method, after normalization with β-actin mRNA. RESULTS: TNFα significantly suppressed basal and glucose-stimulated insulin secretion and proinsulin mRNA transcription in a dose-dependent manner, an effect that was more powerful in the presence of high glucose. Leptin also inhibited dosedependent insulin mRNA and protein at both glucose concentrations, but did not appear to further potentiate the suppressive effects of TNFα. CONCLUSION: TNFα suppresses both basal and glucose-stimulated insulin transcription and secretion in HIT-T15 cells, an effect that is enhanced significantly by high glucose. Leptin also independently inhibits basal and glucose-stimulated insulin secretion and transcription but does not modify TNFα effects. These effects might contribute to the abnormalities of glucose metabolism that characterize conditions of increased TNFα and/or leptin production. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Previous studies have demonstrated that leptin inhibits glucose-stimulated insulin secretion from isolated islets, although a lack of leptin effect on insulin secretion has also been reported. The effect of long term in vivo leptin treatment of insulin secretion has, however, not been established. Therefore, in the present study, we have evaluated the effect of long term in vivo treatment of leptin on glucose-induced insulin secretion in ob/ob mice. METHODS: After 7 days' treatment of leptin (1001 µg daily s.c.), insulin release was measured in isolated islets by batch incubation followed by radioimmunoassay. Glucose utilization and oxidation were measured by measuring the formation of ³H[sub 2]O and [sup 14]CO[sub 2] from [5-³H] and [U-[sup 14]C] glucose, respectively. Glucose-6-phosphatase activity was measured by measuring the conversion of [sup 14]C-glucose-6-P to [sup 14]C-glucose. In addition, immunohistochemistry of pancreatic specimens was undertaken for study of expression of insulin, GLUT-2 and hormone-sensitive lipase (HSL). RESULTS: Leptin treatment significantly improved insulin secretion both at 5.5 mM (by 15%; P < 0.05) and 16.7 mM (by 85%; P < 0.001) glucose, compared to vehicle-treated controls. Furthermore, whereas leptin treatment did not affect islet insulin or DNA contents, a significant decrease in islet triglyceride content and glucose-6-phosphatase activity was observed. Moreover, the immunocytochemical data revealed an increased immunostaining for insulin, GLUT-2 and hormone-sensitive lipase (HSL) in islets from leptin-treated ob/ob mice. CONCLUSION: The results suggest that long-term leptin treatment of ob/ob mice improves glucose-stimulated insulin secretion in parallel with reduced glucose-6-phosphatase activity, increased HSL and decreased triglyceride levels in islets. These perturbations may explain the improvement of glucose-stimulated insulin secretion induced by leptin. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The rate of glucose disposal was determined in 10 black and 10 white obese nondiabetic urban women from South Africa to assess insulin resistance. DESIGN AND METHODS: Euglycemic hyperinsulinemic clamp and body composition analysis. RESULTS: Age, body mass index (BMI), anthropometric measurements and body composition were similar in both groups of women. A five-level computed tomography (CT) scan showed a similar mean subcutaneous fat mass in both groups of women (black obese women 555±9.0 vs white obese women 532±6.0 cm2), but less visceral fat in black obese women (90±3.0 vs 121±3.1 cm2; P<0.05). Black obese women had higher fasting free fatty acid (997±69 vs 678±93 μmol/l; P<0.05) and lactate concentrations (1462±94 vs 1038±39 μmol/l; P<0.05), but lower fasting insulin levels (87±12 vs 155±9 pmol/l; P<0.001). Black obese women also had a more favorable HDL: total cholesterol ratio (30.5% vs 23.0%; P<0.04). The mean glucose disposal rate (M) and disposal expressed as glucose sensitivity index (M/I) were reduced in the black obese women vs white obese women (M: 7.1±0.8 vs 13.7±1.0 mmol/kg·min-1×100; P<0.01, and M/I: 0.12±0.01 vs 0.24±0.02 mmol/kg·min-1/pmol/l×1000; P<0.01). Only black obese women showed a significant decrease in C-peptide levels during the clamp (2.9±0.22 vs 1.2±0.12 nmol/l; P<0.001). During the euglycemic period, the black obese women had higher lactate levels at all time points, but only the white obese women had increased lactate levels (918±66 to 1300±53 μmol/l; P<0.05). CONCLUSION: Black obese women demonstrate a higher degree of insulin resistance, despite less visceral fat and a higher HDL: total-cholesterol ratio. In addition, endogenous β-cell secretory function in black obese women appears to be more sensitive to the suppressive effect of exogenous... [ABSTRACT FROM AUTHOR]

Aims/hypothesis. To identify factors associated with early development of and late protection from microvascular complications in subjects with Type I (insulin-dependent) diabetes mellitus.¶Methods. The frequency of microvascular complications and their relation to risk factors were studied in 300 Type I diabetic subjects with short duration of disease ( ≤ 5 years) compared with 1062 subjects with long duration ( ≥ 14 years). Microvascular disease was defined as the presence of either retinopathy (assessed from centrally-graded retinal photographs) or urinary albumin excretion rate of more than 20 μg/min.¶Resu1ts. The prevalence of microvascular disease was 25 % in the short duration group. In the long duration group 18 % had no evidence of microvascular complications. In the short duration group factors associated with early development of complications were cigarette smoking and a family history of hypertension. Subjects free of microvascular complications in spite of long duration of diabetes had better glycaemic control, lower blood pressure, better lipid profile and lower von Willebrand factor levels.¶Conclusion/interpretation. At the early stages of Type I diabetes, cigarette smoking and genetic susceptibility to hypertension are important risk factors for microvascular complications. At a later stage, additional risk factors are poorer glycaemic control, higher blood pressure, and an unfavourable lipid profile possibly associated with endothelial dysfunction. Many of these factors are amenable to long-term intervention which should be started as soon as possible in the course of the disease. [Diabetologia (2000) 43: 348–355] [ABSTRACT FROM AUTHOR]

Aims/hypothesis. We measured insulin clearance rates in children and young adults with Type I (insulin-dependent) diabetes mellitus to establish their relation with insulin sensitivity and with factors such as growth hormone secretion and body mass index.¶Methods. We studied 46 subjects [mean (range) age 14.4 (9.8–24.6) years), body mass index 21.1 (15.8–29.6)Kgm2] using an overnight (1800–0800 hours) variable rate insulin infusion euglycaemic clamp protocol (5 mmol/l). Plasma free insulin concentrations during steady-state euglycaemia were used as an index of insulin sensitivity and insulin clearance determined as a ratio of insulin infusion rate to plasma free insulin.¶Results. During steady-state euglycaemia (0500–0730 hours), insulin sensitivity [mean (SEM) plasma insulin 0.020 (0.002) mU/l] and insulin clearance rates [19.1 (1.8) ml · kg–1· min] varied with age non-linearly and in a reciprocal fashion to each other (cubic regression F = 4.09, p = 0.01; F = 3.55, p = 0.02, respectively). Insulin sensitivity was negatively related to BMI (r = –0.37, p = 0.011) and mean overnight growth hormone concentrations (r = –0.40, p = 0.007). Insulin clearance was only related to growth hormone concentrations (r = –0.37, p = 0.014). These relations were still evident after stepwise multiple regression analysis (potential determinants: C peptide, sex, age, puberty stage, HbA1 c, duration of diabetes): insulin sensitivity r = 0.55, p < 0.001; insulin clearance r = 0.37, p < 0.02.¶Conclusions/interpretation. Insulin clearance rates vary with age in young subjects with Type I diabetes and are highest during mid-adolescence when insulin sensitivity is at its lowest. Both insulin sensitivity and insulin clearance are related to circulating growth hormone concentrations. [Diabetologia (2000) 43: 61–68] [ABSTRACT FROM AUTHOR]

The prevalence of QT interval prolongation is higher in people with diabetes and its complications. Sudden death has been reported as a common cause of death in insulin-dependent diabetic patients affected by autonomic neuropathy. It has been postulated that QT prolongation predisposes to cardiac arrhythmias and sudden death. In this analysis the prevalence of QT interval prolongation and its relation with diabetic complications were evaluated in the EURODIAB IDDM Complications Study (3250 insulin-dependent diabetic patients attending 31 centres in 16 European countries). Five consecutive RR and QT intervals were measured with a ruler on the V5 lead of the resting ECG tracing and the QT interval corrected for the previous cardiac cycle length was calculated according to the Bazett's formula. The prevalence of an abnormally prolonged corrected QT was 16 % in the whole population, 11 % in males and 21 % in females ( p < 0.001). The mean corrected QT was 0.412 s in males and 0.422 s in females ( p < 0.001). Corrected QT duration was independently associated with age, HbA1 c and blood pressure. Corrected QT was also correlated with ischaemic heart disease and nephropathy but this relation appeared to be stronger in males than in females. Male patients with neuropathy or impaired heart rate variability or both showed a higher mean adjusted corrected QT compared with male patients without this complication. The relation between corrected QT prolongation and autonomic neuropathy was not observed among females. In conclusion we have shown that corrected QT in insulin-dependent diabetic female patients is longer than in male patients, even in the absence of diabetic complications known to increase the risk of corrected QT prolongation. [Diabetologia (1999) 42: 68–75] [ABSTRACT FROM AUTHOR]

The role of blood pressure elevation in the incidence and progression of diabetic retinopathy is not clearly established and results have been conflicting. Blood pressure and urinary albumin excretion (UAE) are closely related. In order to evaluate the independent relationship between retinopathy and blood pressure elevation, precise information on UAE is essential, as confounding by renal disease (incipient or overt), cannot otherwise be excluded.The aim of the present study was to evaluate the association between diabetic retinopathy and 24-h ambulatory blood pressure (AMBP) in a group of well-characterized normoalbuminuric IDDM patients. In 65 normoalbuminuric (UAE < 20 μg/min) IDDM patients we performed 24-h AMBP (Spacelabs 90 207) with readings at 20-min intervals. Fundus photographs were graded independently by two experienced ophthalmologists. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA1 c was determined by HPLC. Tobacco use and level of physical activity were assessed by questionnaire. Fifteen patients had no detectable retinal changes [grade 1], 35 had grade 2 retinopathy; and 15 had more advanced retinopathy [grade 3–6] . Diastolic night blood pressure was significantly higher in patients with diabetic retinopathy compared to patients without retinopathy (68 ± 8 mmHg [grade 3–6] and 65 ± 6 mmHg [grade 2], compared to 61 ± 4 mmHg [grade 1], p = 0.02). Diurnal blood pressure variation was significantly blunted in the patients with retinopathy as indicated by a higher night/day ratio of diastolic blood pressure (84.6 % ± 4 [grade 3–6], and 81.2 % ± 6 [grade 2] compared to 79.1 % ± 4 [grade 1], p = 0.01). Heart rate tended to be higher in patients in group 2 and 3–6 compared to patients without retinopathy with p values of 0.07 and 0.11 for day-time and 24 h values, respectively. Mean HbA1 c increased significantly with increasing levels of retinopathy ( p < 0.01). Patients were similar regarding sex, age, tobacco use, and level of physical activity. Notably, UAE was almost identical in the three groups (5.0 × /÷1.7 [grade 1], 3.9 × /÷1.8 [grade 2], and 5.1 × /÷1.6 μg/min [grade 3–6]). In conclusion, night blood pressure is higher and circadian blood pressure variation blunted in patients with retinopathy compared to patients without retinopathy despite strict normoalbuminuria and similar UAE levels in the groups compared. Our data suggest that the association between blood pressure and diabetic retinopathy is present also when coexisting renal disease is excluded. Disturbed diurnal variation of blood pressure is a pathophysiological feature related to the development of both retinopathy and nephropathy in IDDM patients. [Diabetologia (1998) 41: 105–110] [ABSTRACT FROM AUTHOR]

The offspring of mothers with diabetes mellitus during pregnancy are presumed to develop altered glucose homeostasis. We analysed metabolic parameters at birth and glucose tolerance and insulin secretion during oral glucose tolerance tests at 1–9 years of age in 129 children born to mothers with pregestational insulin-dependent diabetes (IDDM) and 69 infants of gestational diabetic mothers. Newborns of IDDM mothers displayed higher insulin ( p < 0.001), glucose ( p < 0.05), and insulin/glucose ratios ( p < 0.002) than newborns of gestational diabetic mothers. During childhood, frequencies of impaired glucose tolerance (IGT) rose in infants of IDDM mothers from 9.4 % at 1–4 years to 17.4 % at 5–9 years of age, while in children of gestational diabetic mothers an increase from 11.1 % up to 20.0 % was observed. Offspring of gestational diabetic mothers displayed higher stimulated blood glucose ( p < 0.025) than infants of IDDM mothers, while children of IDDM mothers showed higher stimulated insulin ( p < 0.025), accompanied by increased fasting and stimulated insulin/glucose ratios ( p < 0.05 and p < 0.02, respectively). Stimulated insulin in childhood was positively correlated to insulin at birth ( p < 0.05). Furthermore, insulin/glucose ratio in childhood showed a positive correlation to insulin ( p < 0.01) and insulin/glucose ratio at birth ( p < 0.005). In conclusion, a pathogenetic role of fetal and neonatal hyperinsulinism for the development of IGT in both groups of infants of diabetic mothers is suggested, in particular for early induction of insulin resistance in the offspring of mothers with pregestational IDDM. [Diabetologia (1997) 40: 1097–1100] [ABSTRACT FROM AUTHOR]

Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB10301, DQA1*0501 and DQB10201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 ( p > 0.05) and DQB10201/0302 ( p < 0.01). The findings of the present study suggest that DQB10201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB10301-DQA1*0501-DQB10201/DRB1*0401 -DQA103-DQB1*0302) are at greater risk of developing severe retinopathy. [Diabetologia (1996) 39: 1313-1317] [ABSTRACT FROM AUTHOR]

The article presents abstracts of studies of lipid intervention studies, reported at the 36th annual meeting of the European Association for the Study of Diabetes in Jerusalem, from September 17 to 21, 2000. They include "Atorvastatin, simvastatin and vessel permeability: An effect independent of LDL-lowering" and "Atorvastatin improves microvessel wall permeability in patients with primary hypercholesterolemia".

The article presents abstracts of studies of tumor necrosis factor (TNF)alpha, leptin and obesity, reported at the 36th annual meeting of the European Association for the Study of Diabetes in Jerusalem, from September 17 to 21, 2000. They include "A physiological model of circulating leptin concentration in humans: Effects of gender, menopause, hormone replacement therapy, and smoking" and "Relationships between leptin and satiety in humans: Influence of dietary macronutrient composition".