Sazan Rasul

Fetuin-A and angiopoietins in obesity and type 2 diabetes mellitus.

Although type 2 diabetes mellitus (DM) is a chronic metabolic disorder with multiple etiologies, obesity has been constantly linked with insulin resistance and manifestation of type 2 DM. In addition, obesity is associated with hypertension, dyslipidemia, and fatty liver disease and is regarded as a subclinical inflammatory condition characterized by release of pro-inflammatory mediators such as cytokines from adipose tissue. Both, type 2 DM and obesity are considered as major risks for developing micro- and macrovascular diseases. Recent studies showed that impaired circulating levels of fetuin-A, which is involved in propagating insulin resistance as well as circulating levels of angiopoietins, which are growth factors promoting angiogenesis, were observed in patients with obesity, metabolic syndrome, and type 2 DM. However, independent of type 2 DM and obesity, defective regulation of fetuin-A and angiopoietin are playing a critical role in predisposing to coronary and peripheral vascular diseases. Therefore, mechanisms linking type 2 DM and obesity with fetuin-A and angiopoietins seem to be complex and are in need of further exploration. In this review, we aimed to present a summary concerning associations of type 2 diabetes, obesity, and vascular diseases with circulating levels of angiopoietins and fetuin-A. Furthermore, we aimed to focus on roles of fetuin-A and angiopoietins and to highlight the most plausible mechanisms that might explain their associations with type 2 DM and obesity.

Circulating angiopoietin-2 and soluble Tie-2 in type 2 diabetes mellitus: a cross-sectional study

BackgroundType 2 diabetes is associated with increased levels of Angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2), but its impact on vascular disease is still unknown. This study aimed to further explore the associations of Ang-2 and sTie-2 with metabolic control and diabetic complications.MethodsIn a cross-sectional designed study, levels of Ang-2 and sTie-2 as well as their relationships to cardiometabolic parameters were determined in 80 type 2 diabetic subjects (age 65 ± 7 years, female 47.4%).ResultsAfter controlling for age and BMI, Ang-2 levels were associated with levels of sTie-2, diastolic blood pressure, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), creatinine, glomerular filtration rate (GFR), and gamma-glutamyl transferase (GGT) (all p < 0.02). Presence of diabetic macrovascular complications, polyneuropathy and insulin therapy were associated with higher Ang-2 levels (p < 0.05). Conversely, sTie-2 levels were associated with glycated hemoglobin (HbA1c), fasting plasma glucose and insulin, HOMA-IR, triglyceride, and liver function parameters (all p < 0.03). Multiple linear regression analysis showed that Ang-2 remained significantly associated only with levels of GGT (p < 0.04), whereas sTie-2 remained significantly associated with HbA1c, insulin levels, and HOMA-IR (p < 0.03). No differences in Ang-2 and sTie-2 levels were observed with regard to gender of participants.ConclusionsAng-2 is independently associated with levels of GGT while sTie-2 is independently associated with levels of HbA1c, plasma insulin and HOMA-IR in type 2 diabetic subjects. Therefore we suggest that the associations of Ang-2 and sTie-2 with type 2 diabetes are based on different patho-physiological mechanisms.

Plasma neuropeptide Y levels differ in distinct diabetic conditions

Neuropeptide Y (NPY) is an important hormone in appetite regulation. Although the contribution of NPY to metabolic disease has been previously demonstrated, there are only a few reports addressing NPY plasma levels under distinct diabetic conditions. In this study we evaluated NPY plasma levels in diabetes mellitus type 2 (DM2) patients with (n=34) and without (n=34) diabetic polyneuropathy (PNP) and compared these with age and gender matched healthy controls (n=34). We also analyzed NPY plasma levels in gestational diabetes mellitus (GDM) patients with age and pregnancy-week matched controls with normal glucose tolerance (NGT). NPY concentration was determined using a commercially available radioimmunoassay kit. In addition, metabolic parameters of DM2 and GDM patients were recorded. One-way ANOVA tests with appropriate post hoc corrections showed elevated levels of NPY in DM2 patients with and without PNP when compared with those of healthy controls (122.32±40.86 and 117.33±29.92 vs. 84.65±52.17 pmol/L; p<0.001, p<0.005, respectively). No significant difference was observed between diabetic patients with and without PNP. The NPY levels were similar in the GDM group and in pregnant women with NGT (74.87±14.36 vs. 84.82±51.13 pmol/L, respectively). Notably, the NPY concentration correlated positively with insulin levels in DM2 patients (R=0.35, p<0.01). Our data suggest a potential involvement of circulating NPY in DM2 pathology.

Diabetic polyneuropathy relates to bone metabolism and markers of bone turnover in elderly patients with type 2 diabetes: greater effects in male patients.

BACKGROUND There is evidence that diabetic polyneuropathy (PNP) is associated with reduced bone mineral density (BMD) in type 1 diabetes but little is known about the impact of diabetic PNP on bone metabolism in type 2 diabetes. OBJECTIVES The aim of this study was to evaluate differences in bone metabolism by measuring markers of bone turnover and BMD in men and postmenopausal women with type 2 diabetes and diabetic PNP compared with those without PNP. Gender differences were analyzed for both groups of patients. METHODS One hundred twenty patients with type 2 diabetes, 68 without PNP (43 men, 25 women, mean age 62 [8] years) and 52 with PNP (28 men, 24 women, mean age 64 [8] years) were studied. Clinical parameters with bone turnover biomarkers such as osteocalcin, bone alkaline phosphatase, procollagen type 1 amino-terminal propeptide, and carboxy-terminal telopeptide of type 1 collagen were measured in all patients. Dual energy x-ray absorptiometry to evaluate BMD was performed in a subgroup of patients. RESULTS After controlling for age, body mass index, duration of diabetes, smoking, glycosylated hemoglobin, homeostasis model assessment index for insulin resistance, serum C-reactive protein, creatinine, calcium, gamma-glutamyltransferase, parathyroid and sex hormones levels, presence of micro/macrovascular complications, statin- as well as diabetes-related therapies, levels of carboxy-terminal telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide were significantly higher among patients with PNP when compared with patients without PNP (P = 0.01 and P = 0.03, respectively). Differences in bone biomarkers were more pronounced among men with diabetes. BMD did not differ significantly between patients with and without PNP, independent of gender. CONCLUSIONS Male patients with PNP exhibit a higher rate of bone turnover than men without PNP. High rate of bone turnover increases the susceptibility for developing osteoporosis. Prevention of diabetic PNP might also reduce the incidence of osteoporosis and fractures in patients with type 2 diabetes.

Levels of fetuin‐A relate to the levels of bone turnover biomarkers in male and female patients with type 2 diabetes

Objective  To evaluate the relationship of plasma fetuin‐A levels with markers of bone turnover in male and female type 2 diabetic subjects.

Relations of adiponectin to levels of metabolic parameters and sexual hormones in elderly type 2 diabetic patients.

BACKGROUND Despite the effective role of adiponectin levels in the predisposition to type 2 diabetes mellitus, the potential impact of adiponectin in manifest type 2 diabetes is less studied. OBJECTIVES This study aimed to determine gender-specific differences regarding the relationship between adiponectin levels and metabolic parameters as well as sex hormones in elderly type 2 diabetics. METHODS Sixty-two elderly type 2 diabetic men (mean age 60 [9] years) and 38 postmenopausal type 2 diabetic women (mean age 64 [9] years) were evaluated in a cross-sectional study. Glycemic control, lipids, sex hormones, adiponectin, and anthropometric parameters were measured in all participants. RESULTS Serum adiponectin was higher in women than in men (P < 0.006). After controlling for age and body mass index, adiponectin concentrations showed a positive correlation with sex hormone-binding globulin and high-density lipoprotein levels (P < 0.001) and a negative correlation with glycated hemoglobin, homeostasis model assessment index for insulin resistance, glucose, C-peptide, and triglyceride levels (P < 0.05) in all patients. In men, adiponectin significantly correlated with serum levels of testosterone (r = 0.420; P < 0.002). In women, negative correlations were observed between adiponectin levels and the fatty liver index (r = -0.492; P < 0.006) and γ-glutamyltransferase (r = -0.432; P < 0.01). CONCLUSIONS High serum adiponectin is a feature of better metabolic control and lipid profile, whereas low adiponectin levels are associated with fatty liver disease in women and low testosterone levels in men with type 2 diabetes.

The Microtubule-Associated Protein Tau and Its Relevance for Pancreatic Beta Cells

Structural and biochemical alterations of the microtubule-associated protein tau (MAPT) are associated with degenerative disorders referred to as tauopathies. We have previously shown that MAPT is present in human islets of Langerhans, human insulinomas, and pancreatic beta-cell line models, with biophysical similarities to the pathological MAPT in the brain. Here, we further studied MAPT in pancreatic endocrine tissue to better understand the mechanisms that lead to functional dysregulation of pancreatic beta cells. We found upregulation of MAPT protein expression in human insulinomas when compared to human pancreatic islets of Langerhans and an imbalance between MAPT isoforms in insulinomas tissue. We cloned one 3-repeat domain MAPT and transduced this into a beta-cell derived rodent cell line Rin-5F. Proliferation experiments showed higher growth rates and metabolic activities of cells overexpressing MAPT protein. We observed that a MAPT overexpressing cell line demonstrates altered insulin transcription, translation, and insulin secretion rates. We found the relative insulin secretion rates were significantly decreased in a MAPT overexpressing cell line and these findings could be confirmed using partial MAPT knock-down cell lines. Our findings support that MAPT may play an important role in insulin granule trafficking and indicate the importance of balanced MAPT phosphorylation and dephosphorylation for adequate insulin release.

Association between osteogenesis and inflammation during the progression of calcified plaque as evaluated by combined 18F-NaF and 18F-FDG PET/CT

18F-FDG is the most widely validated PET tracer for the evaluation of atherosclerotic inflammation. Recently, 18F-NaF has also been considered a potential novel biomarker of osteogenesis in atherosclerosis. We aimed to analyze the association between inflammation and osteogenesis at different stages of atherosclerosis, as well as the interrelationship between these 2 processes during disease progression. Methods: Thirty-four myeloma patients underwent 18F-NaF and 18F-FDG PET/CT examinations. Lesions were divided into 3 groups (noncalcified, mildly calcified, and severely calcified lesions) on the basis of calcium density as measured in Hounsfield units by CT. Tissue-to-background ratios were determined from PET for both tracers. The association between inflammation and osteogenesis during atherosclerosis progression was evaluated in 19 patients who had at least 2 examinations with both tracers. Results: There were significant correlations between the maximum tissue-to-background ratios of the 2 tracers (Spearman r = 0.5 [P < 0.01]; Pearson r = 0.4 [P < 0.01]) in the 221 lesions at baseline. The highest uptake of both tracers was observed in noncalcified lesions, but without any correlation between the tracers (Pearson r = 0.06; P = 0.76). Compared with noncalcified plaques, mildly calcified plaques showed concordant significantly lower accumulation, with good correlation between the tracers (Pearson r = 0.7; P < 0.01). In addition, enhanced osteogenesis-derived 18F-NaF uptake and regressive inflammation-derived 18F-FDG uptake were observed in severely calcified lesions (Pearson r = 0.4; P < 0.01). During follow-up, increased calcium density and increased mean 18F-NaF uptake were observed, whereas mean 18F-FDG uptake decreased. Most noncalcified (86%) and mildly calcified (81%) lesions and 47% of severely calcified lesions had concordant development of both vascular inflammation and osteogenesis. Conclusion: The combination of 18F-NaF PET imaging and 18F-FDG PET imaging promotes an understanding of the mechanism of plaque progression, thereby providing new insights into plaque stabilization.

Similarities in trabecular hypertrophy with site-specific differences in cortical morphology between men and women with type 2 diabetes mellitus

The goal of our study was to investigate interactions between sex and type 2 diabetes mellitus (T2DM) with regard to morphology of the peripheral skeleton. We recruited 85 subjects (mean age, 57±11.4 years): women with and without T2DM (n = 17; n = 16); and men with and without T2DM (n = 26; n = 26). All patients underwent high-resolution, peripheral, quantitative, computed tomography (HR-pQCT) imaging of the ultradistal radius (UR) and tibia (UT). Local bone geometry, bone mineral density (BMD), and bone microarchitecture were obtained by quantitative analysis of HR-pQCT images. To reduce the amount of data and avoid multi-collinearity, we performed a factor-analysis of HR-pQCT parameters. Based on factor weight, trabecular BMD, trabecular number, cortical thickness, cortical BMD, and total area were chosen for post-hoc analyses. At the radius and tibia, diabetic men and women exhibited trabecular hypertrophy, with a significant positive main effect of T2DM on trabecular number. At the radius, cortical thickness was higher in diabetic subjects (+20.1%, p = 0.003). Interestingly, there was a statistical trend that suggested attenuation of tibial cortical hypertrophy in diabetic men (cortical thickness, pinteraction = 0.052). Moreover, we found an expected sexual dichotomy, with higher trabecular BMD, Tb.N, cortical BMD, Ct.Th, and total area in men than in women (p≤ 0.003) at both measurement sites. Our results suggest that skeletal hypertrophy associated with T2DM is present in men and women, but appears attenuated at the tibial cortex in men.

[18F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery

PurposeMedullary thyroid carcinoma (MTC) is characterized by a high rate of metastasis. In this study we evaluated the ability of [18F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection.MethodsA group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region-based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse.ResultsPrimary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P < 0.05). Only DOPA PET/ceCT cN1b status remained significant in the multivariate analysis (P = 0.016, relative risk 4.02).ConclusionThis study revealed that DOPA PET/ceCT has high sensitivity in the detection of primary MTC and superior sensitivity in the detection of LN metastases compared to ultrasonography. DOPA PET/ceCT identification of N1b status predicts postoperative tumour persistence. Thus, implementation of a DOPA-guided LN dissection might improve surgical success.