[Pancreas transplantation as treatment of diabetes mellitus]

Pancreatic transplantation is able to normalize blood glucose metabolism and achieve normoglycemia in a majority of patients with insulin-dependent diabetes mellitus. Hoping that normoglycemia will favorably influence development of late complications of diabetes, an increasing number of pancreas transplantations has been performed over the last years. However, the need for immunosuppressive therapy with its problems and possible complications confines pancreatic transplantation mainly to three groups of patients: patients who undergo kidney transplantation for diabetic nephropathy, patients who have already undergone kidney transplantation for diabetic nephropathy and, rarely, patients with extreme difficulties with metabolic control. The results of pancreatic transplantation have continuously improved over the last decade, and a limited number of controlled studies is providing some evidence of a favorable effect on late complications.

Effects of diabetes mellitus on periodontal and peri-implant conditions: update on associations and risks

OBJECTIVES: To review the evidence for the association between diabetes and periodontal and peri-implant conditions and the impact of periodontal therapy in subjects with diabetes. MATERIAL AND METHODS: A search of MEDLINE-PubMed was performed up to and including December 2007. The search was limited to clinical studies published in English. Publications on animal studies were excluded. The selection criteria included all levels of available evidence. RESULTS: Evidence on the association between diabetes and periodontitis supports the concept of increased severity but not extent of periodontitis in subjects with poorly controlled diabetes. Subjects with controlled diabetes do not show an increase in extent and severity of periodontitis. Periodontitis is associated with poor glycaemic control and diabetes-related complications. It is inconclusive that periodontal therapy with or without the use of antibiotics results in improvements of glycaemic control and of markers of systemic inflammation. Evidence is lacking to indicate that implant therapy in subjects with diabetes yields long-term outcomes comparable with those of non-diabetic subjects. CONCLUSIONS: Poorly controlled diabetes may be considered a risk factor for increased severity of periodontitis. The effects of periodontal therapy on glycaemic control and systemic inflammation is not proven beyond doubt and need to be confirmed in large-scale randomized-controlled clinical trials.

Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus

Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00-1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-1.04; P = 0.095). During a median follow-up of 4.0 years (interquartile range, 2.0-6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5-year occurrence of HCC being 11.4% (95% CI, 3.0-19.8) and 5.0% (95% CI, 2.2-7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35-7.97; P = 0.009). CONCLUSION: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC.

Endothelin A-receptor blockade in experimental diabetes improves glucose balance and gastrointestinal function

Secondary complications of diabetes mellitus often involve gastrointestinal dysfunction. In the experimental Goto Kakizaki rat, a model of Type II diabetes, hyperglycaemia and reduced glucose clearance is associated with elevated plasma endothelin (ET)-1 levels and selective decreases in nitric oxide synthase in circular muscle, longitudinal muscle and neuronal elements of the gastrointestinal tract. Functionally, this is accompanied by decreased nitrergic relaxatory responses of jejunal longitudinal muscle to tetrodotoxin-sensitive electrical field stimulation. Long-term treatment with a selective ET A-type receptor antagonist, markedly reduced hyperglycaemia and restored plasma glucose clearance rates towards normal. This was associated with a restoration of N(G)-nitro-L-arginine methyl ester-sensitive relaxatory responses of jejunal longitudinal muscle to electrical field stimulation. The results indicate that beneficial effects of ETA receptor blockade on gastrointestinal function may result from an improvement in insulin sensitivity with concomitant reduction of the severity of hyperglycaemia. ETA receptor blockade may represent a new therapeutic principle for improving glucose tolerance in Type II diabetes and could be beneficial in alleviating or preventing hyperglycaemia-related secondary complications in this condition.

Impact of single nucleotide polymorphisms and of clinical risk factors on new-onset diabetes mellitus in HIV-infected individuals

Background. Metabolic complications, including cardiovascular events and diabetes mellitus (DM), are a major long-term concern in human immunodeficienc virus (HIV)-infected individuals. Recent genome-wide association studies have reliably associated multiple single nucleotide polymorphisms (SNPs) to DM in the general population. Methods. We evaluated the contribution of 22 SNPs identifie in genome-wide association studies and of longitudinally measured clinical factors to DM. We genotyped all 94 white participants in the Swiss HIV Cohort Study who developed DM from 1 January 1999 through 31 August 2009 and 550 participants without DM. Analyses were based on 6054 person-years of follow-up and 13,922 measurements of plasma glucose. Results. The contribution to DM risk explained by SNPs (14% of DM variability) was larger than the contribution to DM risk explained by current or cumulative exposure to different antiretroviral therapy combinations (3% of DM variability). Participants with the most unfavorable genetic score (representing 12% and 19% of the study population, respectively, when applying 2 different genetic scores) had incidence rate ratios for DM of 3.80 (95% confidenc interval [CI], 2.05–7.06) and 2.74 (95% CI, 1.53–4.88), respectively, compared with participants with a favorable genetic score. However, addition of genetic data to clinical risk factors that included body mass index only slightly improved DM prediction. Conclusions. In white HIV-infected persons treated with antiretroviral therapy, the DM effect of genetic variants was larger than the potential toxic effects of antiretroviral therapy. SNPs contributed significantl to DM risk, but their addition to a clinical model improved DM prediction only slightly, similar to studies in the general population.

Microalbuminuria in diabetes mellitus: efficacy of a new screening method in comparison with timed overnight urine collection

Diabetic nephropathy and end-stage renal failure are still a major cause of mortality amongst patients with diabetes mellitus (DM). In this study, we evaluated the Clinitek-Microalbumin (CM) screening test strip for the detection of microalbuminuria (MA) in a random morning spot urine in comparison with the quantitative assessment of albuminuria in the timed overnight urine collection ("gold standard"). One hundred thirty-four children, adolescents, and young adults with insulin-dependent DM Type 1 were studied at 222 outpatient visits. Because of urinary tract infection and/or haematuria, the data of 13 visits were excluded. Finally, 165 timed overnight urine were collected in the remaining 209 visits (79% sample per visit rate). Ten (6.1%) patients presented MA of > or =15 microg/min. In comparison however, 200 spot urine could be screened (96% sample/visit rate) yielding a significant increase in compliance and screening rate (P<.001, McNemar test). Furthermore, at 156 occasions, the gold standard and CM could be directly compared. The sensitivity and the specificity for CM in the spot urine (cut-off > or =30 mg albumin/l) were 0.89 [95% confidence interval (CI) 0.56-0.99] and 0.73 (CI 0.66-0.80), respectively. The positive and negative predictive value were 0.17 (CI 0.08-0.30) and 0.99 (CI 0.95-1.00), respectively. Considering CM albumin-to-creatinine ratio, the results were poorer than with the albumin concentration alone. Using CM instead of quantitative assessment of albuminuria is not cost-effective (35 US dollars versus 60 US dollars/patient/year). In conclusion, to exclude MA, the CM used in the random spot urine is reliable and easy to handle, but positive screening results of > or =30 mg albumin/l must be confirmed by analyses in the timed overnight collected urine. Although the screening compliance is improved, in terms of analysing random morning spot urine for MA, we cannot recommend CM in a paediatric diabetic outpatient setting because the specificity is far too low.

Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis

While the benefits of intensified insulin treatment in insulin-dependent (Type 1) diabetes mellitus (IDDM) are well recognized, the risks have not been comprehensively characterized. We examined the risk of severe hypoglycaemia, ketoacidosis, and death in a meta-analysis of randomized controlled trials. The MEDLINE database, reference lists, and specialist journals were searched electronically or by hand to identify relevant studies with at least 6 months of follow-up and the monitoring of glycaemia by glycosylated haemoglobin measurements. Logistic regression was used for calculation of combined odds ratios and 95% confidence intervals (95% CI). The influence of covariates was examined by including covariate-by-treatment interaction terms. Methodological study quality was assessed and sensitivity analyses were performed. Fourteen trials were identified. These contributed 16 comparisons with 1028 patients allocated to intensified and 1039 allocated to conventional treatment. A total of 846 patients suffered at least one episode of severe hypoglycaemia, 175 patients experienced ketoacidosis and 26 patients died. The combined odds ratio (95% CI) for hypoglycaemia was 2.99 (2.45-3.64), for ketoacidosis 1.74 (1.27-2.38) and for death from all causes 1.40 (0.65-3.01). The risk of severe hypoglycaemia was determined by the degree of normalization of glycaemia achieved (p=0.005 for interaction term), with the results from the Diabetes Control and Complications Trial (DCCT) in line with the other trials. Ketoacidosis risk depended on the type of intensified treatment used. Odds ratios (95% CI) were 7.20 (2.95-17.58) for exclusive use of pumps, 1.13 (0.15-8.35) for multiple daily injections and 1.28 (0.90-1.83) for trials offering a choice between the two (p = 0.004 for interaction). Mortality was significantly (p = 0.007) increased for causes potentially associated with acute complications (7 vs 0 deaths, 5 deaths attributed to ketoacidosis, and 2 sudden deaths), and non-significantly (p = 0.16) decreased for macrovascular causes (3 vs 8 deaths). We conclude that there is a substantial risk of severe adverse effects associated with intensified insulin treatment. Mortality from acute metabolic causes is increased; however, this is largely counterbalanced by a reduction in cardiovascular mortality. The excess of severe hypoglycemia in the DCCT is not exceptional. Multiple daily injection schemes may be safer than treatment with insulin pumps.

Hypovolemia contributes to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus

PURPOSE: To investigate whether body sodium content and blood volume contribute to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus. SUBJECTS AND METHODS: Exchangeable sodium, plasma and blood volumes, and catecholamine, renin, and aldosterone levels were assessed in 10 patients with Type II diabetes mellitus who had orthostatic hypotension and control groups of 40 diabetic patients without orthostatic hypotension and 40 normal subjects of similar age and sex. In subgroups, clinical tests of autonomic function and cardiovascular reactivity to norepinephrine and angiotensin II infusions were performed. RESULTS: In diabetic patients with orthostatic hypotension, mean (+/- SD) supine blood pressure was 165/98 +/- 27/12 mm Hg (P <0.05 compared with other groups) and mean upright blood pressure was 90/60 +/- 38/18 mm Hg. Compared with controls, diabetic patients with orthostatic hypotension had a 10% lower blood volume. They also had less exchangeable sodium than patients with diabetes who did not have orthostatic hypotension (P <0.01). Compared with both groups of controls, diabetic patients with orthostatic hypotension had decreased 24-hour urinary norepinephrine excretion and a reduced diastolic blood pressure response to handgrip (P <0.05). Moreover, they displayed reduced products of exchangeable sodium or blood volume and sympathetic function indexes. Cardiovascular pressor reactivity to norepinephrine was enhanced (P <0.01) and beat-to-beat variation decreased (P <0.01) in both groups of diabetic patients. Microvascular complications were more prevalent in the diabetic patients with orthostatic hypotension (90% vs 35%). CONCLUSIONS: Patients who have Type II diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension.

Revascularisation of coronary artery disease in patients with diabetes mellitus

Diabetes mellitus is becoming increasingly prevalent and magnifies the risk of cardiovascular complications. Endothelial dysfunction caused by oxidative stress is a hallmark of diabetes and is responsible for the ubiquitous manifestations of vascular disease in diabetics. Compared with non-diabetic patients, coronary artery disease is more severe and the clinical outcome impaired in diabetic patients undergoing revascularisation. Despite these limitations the benefit of revascularisation therapy is particularly pronounced in diabetics. The optimal revascularisation strategy (coronary artery bypass graft surgery versus percutaneous coronary intervention) in diabetic patients with coronary artery disease depends on clinical and anatomical considerations.

Response of interleukin-6 during euglycaemic and hyperglycaemic exercise in patients with type 1 diabetes mellitus

The aim of this randomized, single-blinded cross-over study was to investigate the response of interleukin-6 (IL-6) during moderate aerobic exercise in stable euglycaemia and hyperglycaemia in seven male patients with type 1 diabetes mellitus. IL-6 increased significantly over the entire study period in euglycaemia, but not in hyperglycaemia.

Pro-inflammatory biomarkers during experimental gingivitis in patients with type 1 diabetes mellitus: a proof-of-concept study

To compare gingival crevicular fluid (GCF) biomarker levels and microbial distribution in plaque biofilm (SP) samples for subjects with type 1 diabetes (T1DM) versus healthy subjects without diabetes during experimental gingivitis (EG).

Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus

The purpose of this study was to assess the expression profile of genes with potential role in the development of insulin resistance (adipokines, cytokines/chemokines, estrogen receptors) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placenta of pregnant women with gestational diabetes mellitus (GDM) and age-matched women with physiological pregnancy at the time of Caesarean section. qRT-PCR was used for expression analysis of the studied genes. Leptin gene expression in VAT of GDM group was significantly higher relative to control group. Gene expressions of interleukin-6 and interleukin-8 were significantly increased, whereas the expressions of genes for estrogen receptors alpha and beta were significantly reduced in SAT of GDM group relative to controls, respectively. We found no significant differences in the expression of any genes of interest (LEP, RETN, ADIPOR1, ADIPOR2, TNF-alpha, CD68, IL-6, IL-8, ER alpha, ER beta) in placentas of women with GDM relative to controls. We conclude that increased expression of leptin in visceral adipose depot together with increased expressions of proinflammatory cytokines and reduced expressions of estrogen receptors in subcutaneous fat may play a role in the etiopathogenesis of GDM.

Health risk appraisal for older people 4: case finding for hypertension, hyperlipidaemia and diabetes mellitus in older people in English general practice before the introduction of the Quality and Outcomes Framework

Early intervention can help to reduce the burden of disability in the older population, but many do not access preventive care. There is uncertainty over what factors influence case finding in older patients in general practice.

Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus

To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na(+)-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.