Aims/hypothesis The aim of this study was to obtain epidemiological data on self-monitoring of blood glucose (SMBG) in type 2 diabetes and to investigate the relationship of SMBG with disease-related ...morbidity and mortality. Methods The German multicentre Retrolective Study 'Self-monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes' (ROSSO) followed 3,268 patients from diagnosis of type 2 diabetes between 1995 and 1999 until the end of 2003. Endpoints were diabetes-related morbidity (non-fatal myocardial infarction, stroke, foot amputation, blindness or haemodialysis) and all-cause mortality. SMBG was defined as self-measurement of blood glucose for at least 1 year. Results During a mean follow-up period of 6.5 years, 1,479 patients (45.3%) began SMBG prior to an endpoint and an additional 64 patients started SMBG after a non-fatal endpoint. Interestingly, many patients used SMBG while being treated with diet or oral hypoglycaemic drugs (808 of 2,515, 32%). At baseline, the SMBG cohort had higher mean fasting blood glucose levels than the non-SMBG cohort (p<0.001), suggesting that insufficient metabolic control was one reason for initiating SMBG. This was associated with a higher rate of microvascular endpoints. However, the total rate of non-fatal events, micro- and macrovascular, was lower in the SMBG group than in the non-SMBG group (7.2 vs 10.4%, p=0.002). A similar difference was found for the rate of fatal events (2.7 vs 4.6%, p=0.004). Cox regression analysis identified SMBG as an independent predictor of morbidity and mortality, with adjusted hazard ratios of 0.68 (95% CI 0.51-0.91, p=0.009) and 0.49 (95% CI 0.31-0.78, p=0.003), respectively. A better outcome for both endpoints was also observed in the SMBG cohort when only those patients who were not receiving insulin were analysed. Conclusions/interpretation SMBG was associated with decreased diabetes-related morbidity and all-cause mortality in type 2 diabetes, and this association remained in a subgroup of patients who were not receiving insulin therapy. SMBG may be associated with a healthier lifestyle and/or better disease management.
Currently, we observe an epidemic expansion of diabetes mellitus. In subjects with Type 2 diabetes the resistance of fat, muscle and liver to insulin is the central pathophysiological event in the ...development of this disease. Genetic and environmental factors play a major role in this process, although the precise pathogenesis of insulin resistance and Type 2 diabetes is still largely unknown. However, recent studies have contributed to a deeper understanding of the molecular mechanisms underlying this process. In this review we therefore summarize the current developments in understanding the pathophysiological process of insulin resistance and Type 2 diabetes. Among the many molecules involved in the intracellular processing of the signal provided by insulin, insulin receptor substrate (IRS)‐2, the protein kinase B (PKB)‐β isoform and the forkhead transcription factor Foxo1a (FKHR) are of particular interest in this context as recent data have provided strong evidence that dysfunction of these proteins results in insulin resistance in‐vivo. Furthermore, we have now increasing evidence that the adipose tissue not only produces free fatty acids that contribute to insulin resistance, but also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. The identification of the molecular pathophysiological mechanisms of insulin resistance and Type 2 diabetes is essential for the development of novel and more effective therapies to better treat our patients with insulin resistance and Type 2 diabetes.
Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension, and cardiovascular disease. Overweight and obesity are frequently associated with ...increased plasma levels of aldosterone. Recent evidence suggests that human fat is a highly active endocrine tissue. Therefore, we tested the hypothesis that adipocyte secretory products directly stimulate adrenocortical aldosterone secretion. Secretory products from isolated human adipocytes strongly stimulated steroidogenesis in human adrenocortical cells (NCI-H295R) with a predominant effect on mineralocorticoid secretion. Aldosterone secretion increased 7-fold during 24 h of incubation. This stimulation was comparable to maximal stimulation of these cells with forskolin$(2 \times 10^{-5}\>M)$. On the molecular level, there was a 10-fold increase in the expression of steroid acute regulatory peptide mRNA. This effect was independent of adipose angiotensin II as revealed by the stimulatory effect of fat cell-conditioned medium even in the presence of the angiotensin type 1 receptor antagonist, valsartan. None of the recently defined adipocytokines accounted for the effect. Mineralocorticoid-stimulating activity was heat sensitive and could be blunted by heating fat cell-conditioned medium to 99° C. Centrifugal filtration based on molecular mass revealed at least two releasing factors: a heat sensitive fraction (molecular mass >50 kDa) representing 60% of total activity, and an inactive fraction (molecular mass <50 kDa). However, the recovery rate increased to 92% when combining these two fractions, indicating the interaction of at least two factors. In conclusion, human adipocytes secrete potent mineralocorticoid-releasing factors, suggesting a direct link between obesity and hypertension.
Context: Obesity is associated with hypersecretion of cortisol and aldosterone and a high prevalence of arterial hypertension. At the cellular level, a direct effect of adipocytes on the expression ...of the steroidogenic acute regulatory (StAR) protein, a regulator of cortisol and aldosterone synthesis, and on aldosterone and cortisol secretion has been shown. However, the molecular mechanisms mediating this effect are not known. Objective: Wnt-signaling molecules are secreted by adipocytes and regulate the activity of SF-1, a key transcription factor in adrenal steroidogenesis. Therefore, we investigated whether adipocytes stimulate adrenal steroidogenesis through the activation of Wnt-signaling. Results: Using immunohistochemistry, we detected the expression of frizzled and β-catenin in the adult human adrenal cortex. Transient transfection of a Wnt-dependent reporter-gene into adrenal NCI-H295R cells showed an induction of Wnt-mediated transcription to 308% after treatment with human fat cell-conditioned medium (FCCM). This finding was paralleled by an induction of StAR promoter activity (420%) by FCCM. The induction of StAR promoter activity by FCCM was inhibited by 49% when Wnt-signaling was blocked by the soluble Wnt-antagonist secreted Frizzled-Related-Protein-1 (sFRP-1). Overexpression of a constitutively active mutant of β-catenin induced the transcription of the StAR promoter (440%). β-Catenin and FCCM induced SF-1-mediated transcription at a SF-1-driven reporter gene (420 and 402%, respectively). Furthermore, the secretion of aldosterone and cortisol by NCI-H295R cells induced by FCCM was significantly inhibited by the Wnt-antagonist sFRP-1. Conclusion: These data indicate that the Wnt-signaling pathway is one of the mechanisms mediating the effects of fat cells on adrenal StAR transcription and aldosterone and cortisol secretion.
Regular physical activity of moderate intensity improves cardiovascular risk factors including low‐grade inflammation. However, acute vigorous exercise such as marathon running results in marked ...increases of circulating pro‐inflammatory markers. Up to now, the origin of this pro‐inflammatory boost is still debated equivocally. We analyzed the change of interleukin‐6 (IL‐6), tumor necrosis factor‐alpha (TNF‐α), and leptin from pre‐ to immediately post‐race in 15 male runners (age 43 ± 10.9 years and body mass index 24.5 ± 2.7 kg/m2) both on the protein level in the plasma and on the messenger ribonucleic acid (mRNA) level in blood mononuclear cells (BMNC).
We observed a significant increase of IL‐6 (prerace 2.08 ± 0.10 ng/L and postrace 40.14 ± 24.85 ng/L, P < 0.001) and TNF‐α (prerace 8.14 ± 1.38 ng/L and postrace 12.40 ± 3.15 ng/L, P < 0.001) and a decrease of leptin (prerace 1.64 ± 2.64 μg/L and postrace 0.80 ± 1.70 μg/L, P = 0.04) serum levels after the marathon race. Furthermore, TNF‐α, IL‐6, and leptin were expressed (mRNA level) in BMNC. However no significant differences in mRNA levels were seen before and after the run in these cells. We found an up‐regulation of TNF‐α and IL‐6 in the plasma during vigorous exercise. This increase is not attributable to BMNC. We assume a local production in, or release from, exercised tissues.
Body weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at ...diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis.
Multicentre longitudinal study carried out at diagnosis and up to 1-year follow-up.
Data on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (<5 years, n=126; >5 years <10 years, n=295; >10 years <18 years, n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c.
In individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10-18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (β 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m(2) higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (β=0.026, 95% CI=0.0097, 0.042; P=0.002).
These observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10-18 years. This should be considered in studies of β-cell function in type 1 diabetes.
To investigate whether the addition of a single bolus of insulin glulisine (glulisine), administered at either breakfast or main mealtime, in combination with basal insulin glargine (glargine) and ...oral antidiabetic drugs (OADs), provides equivalent glycaemic control in patients with type 2 diabetes, irrespective of the time of glulisine injection. A national, multicentre, randomized, open-label, parallel-group study of 393 patients with type 2 diabetes who were suboptimally controlled haemoglobin A₁c (HbA₁c) > 6.5-9.0% and fasting blood glucose (BG) less-than or equal to6.7 mmol/l on their previous glargine and OAD regimen. A single injection of glulisine was added, either at breakfast or at main mealtime, to their existing therapy. The per-protocol group (n = 316) showed improved HbA₁c (baseline vs. end-point) in the breakfast (7.4 vs. 7.0%; p < 0.0001) and main mealtime groups (7.3 vs. 6.9%; p < 0.0001). Glulisine given at breakfast was equally effective in controlling HbA₁c as glulisine given at the main mealtime adjusted HbA₁c mean difference (95% confidence interval): 0.0481% (-0.115 to 0.211); p < 0.0001 for equivalence. Overall, 30.7% of patients achieved HbA₁cless-than or equal to6.5% at end-point but slightly more patients met this target in the main mealtime group vs. the breakfast group (33.8 vs. 27.8%; p = NS). This trend continued and was more marked when considering only those patients with HbA₁c >7.0% at baseline and who reached HbA₁cless-than or equal to7.0% at end-point (44.1% overall), with 52.2 and 36.5% for main mealtime and breakfast groups, respectively (p = 0.028). Most postprandial BG values improved within each group, while the number of hypoglycaemias was low and comparable between the two treatment groups. A single bolus of glulisine, added to glargine and OADs, resulted in significantly improved HbA₁c levels, irrespective of whether glulisine was administered at breakfast or at main mealtime. These results may represent a simplified and effective approach to treatment intensification in type 2 diabetes patients.
Aims
C‐peptide secretion is currently the only available clinical biomarker to measure residual β‐cell function in type 1 diabetes. However, the natural history of C‐peptide decline after diagnosis ...can vary considerably dependent upon several variables. We investigated the shape of C‐peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose.
Methods
We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on β‐cell function was investigated in a longitudinal analysis at diagnosis and up to 5‐years follow‐up.
Results
Fasting C‐peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log‐linear with a greater decline rate in younger age groups (p < 0.0001).
Conclusions
This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of β‐cell function in the very young patients. These data can inform the design of clinical trials using C‐peptide values as an end‐point for the effect of a given treatment.
Regular physical activity of moderate intensity improves cardiovascular risk factors including low-grade inflammation. However, acute vigorous exercise such as marathon running results in marked ...increases of circulating pro-inflammatory markers. Up to now, the origin of this pro-inflammatory boost is still debated equivocally. We analyzed the change of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and leptin from pre- to immediately post-race in 15 male runners (age 43±10.9 years and body mass index 24.5±2.7kg/m2) both on the protein level in the plasma and on the messenger ribonucleic acid (mRNA) level in blood mononuclear cells (BMNC). We observed a significant increase of IL-6 (prerace 2.08±0.10ng/L and postrace 40.14±24.85ng/L, P<0.001) and TNF-alpha (prerace 8.14±1.38ng/L and postrace 12.40±3.15ng/L, P<0.001) and a decrease of leptin (prerace 1.64±2.64μg/L and postrace 0.80±1.70μg/L, P=0.04) serum levels after the marathon race. Furthermore, TNF-alpha, IL-6, and leptin were expressed (mRNA level) in BMNC. However no significant differences in mRNA levels were seen before and after the run in these cells. We found an up-regulation of TNF-alpha and IL-6 in the plasma during vigorous exercise. This increase is not attributable to BMNC. We assume a local production in, or release from, exercised tissues. PUBLICATION ABSTRACT
Aims/hypothesis Adipocytes secrete signalling molecules that elicit responses from target cells, including pancreatic beta cells. Wnt signalling molecules have recently been identified as novel ...adipocyte-derived factors. They also regulate insulin secretion in pancreatic beta cells and the cell cycle. The aim of this study was to investigate the effect of adipocyte-derived Wnt signalling molecules on insulin secretion and beta cell proliferation. Methods Human adipocytes were isolated to generate fat cell-conditioned medium (FCCM). Ins-1 cells were stimulated with FCCM and transiently transfected with reporter genes. Proliferation assays using ³Hthymidine incorporation were carried out in Ins-1 cells and primary islet cells. Insulin secretion from primary islets was assessed by radioimmunoassay. Gene expression in primary islets was assessed by Taqman PCR. Results Treatment with human FCCM increased the transcription of a T cell-specific transcription factor reporter gene (TOPFLASH) in Ins-1 cells (241%, p < 0.05). FCCM induced the proliferation of Ins-1 cells (1.8 fold, p < 0.05) and primary mouse islet cells (1.6 fold, p < 0.05). Antagonizing Wnt signalling with secreted Frizzled-related protein 1 (FRP-1) inhibited the proliferative effect induced by Wnt3a and FCCM on Ins-1 cells by 49 and 41%, respectively. In addition, FCCM led to a twofold (p < 0.05) induction of cyclin D1 promoter activity in Ins-1 cells. Furthermore, FCCM stimulated insulin secretion (204% of controls, p > 0.05) in primary mouse islets, and this stimulation was inhibited by sFRP-1. At a molecular level, canonical Wnt signalling induced glucokinase gene transcription in a peroxisome proliferator-activated receptor γ-dependent fashion, thereby defining the glucokinase gene as a novel Wnt target gene. Conclusions/interpretation Taken together, these data show that adipocyte-derived Wnt signalling molecules induce beta cell proliferation and insulin secretion in vitro, suggesting a novel mechanism linking obesity to hyperinsulinaemia.
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