Normal Glucose Tolerance Subjects Research Articles

Reduced muscle expression heterogeneity by categorising diabetic subjects resulted in improved statistical significance for trascriptome comparison

The information gained through studies investigating muscle gene expression profiles (GEPs) for diabetes biomarkers identification, has resulted in the general belief that muscle transcriptome is relatively unaltered while the subject gradually progresses from a healthy to a diabetic condition. In this study, we focused on identifying the diabetes subgroup based on the subject's muscle gene expression profile to reduce the expression heterogeneity and regain statistical significance in transcriptome comparison. Given the muscle GEPs of type-II diabetic (T2D) and normal glucose tolerant (NGT) subjects, the R-package WGCNA was used to identify a set of correlated genes termed a module. The Random Forest classifier trained over expression profiles of genes belonging to respective modules was used to classify subjects into subgroups. The study was able to categorize early-stage diabetic (ESD) and advance stage diabetic (ASD) subjects based on muscle gene expression profiles. The ASD subjects differed significantly from ESD subjects with respect to diabetes-related clinical traits. Comparison between ASD and NGT subjects showed significant up-regulation of muscle atrophy marker atrogin-1 along with the FOXO signaling pathway. The expression of PDK4, an important inhibitor of glycolytic flux was up-regulated whereas, glucose oxidation biomarkers, HK2 and LDHB were down-regulated in ASD subjects. The result obtained from this study highlights muscle-associated gene expression changes that could be used to categorize diabetic subjects into biologically relevant subgroups.

1499-P: Adipocyte Development from Mesenchymal Progenitor Cells Differ between Subjects with Normal Glucose Tolerance or Type 2 Diabetes

Subcutaneous adipose tissue protects from T2D by sequestering lipids and preventing lipotoxicity and insulin resistance. Adipose depots are maintained throughout the lifetime by the formation of new adipocytes from mesenchymal progenitor cells that reside within the tissue. In previous studies, we have found that mesenchymal progenitor cells from human adipose tissue can be expanded with little loss of multipotency by culturing tissue explants in 3-dimensional hydrogels under pro-angiogenic conditions. Mesenchymal progenitor cells obtained in this manner can be induced to differentiate into multiple adipocyte subtypes, including beige adipocytes characterized by their induction of UCP1 upon cAMP elevation. Using this approach, we explored whether mesenchymal progenitor cells from the subcutaneous abdominal (ABD) and gluteal (GLU) depots of subjects with normal glucose tolerance (NGT) or T2D would differ in their capacity to differentiate into adipocyte subtypes. Results from n=12 subjects (6 with NGT and 6 with T2D) revealed no significant differences between depots or glycemic states in the number of mesenchymal progenitor cells that can be expanded, in their proliferative rate upon subsequent passaging, or in their capacity to differentiate into either white or beige adipocytes. However, we found that cells from either the ABD or GLUT depot from NGT subjects displayed substantial spontaneous adipocyte differentiation even without adipogenic induction, but cells from subjects with T2D did not. This difference was highly significant, and potentially reflects a diminished capacity of mesenchymal progenitor cells to maintain subcutaneous adipose depots in-vivo in subjects with T2D. Further transcriptomic and epigenomic analyses of expanded progenitor cells, currently underway, has the potential to reveal cellular mechanisms of impaired spontaneous adipocyte differentiation in subjects with Type 2 Diabetes. Disclosure S.Corvera: None. T.A.Desouza: None. R.N.Ziegler: None. N.Rosano: None. M.J.Thompson: None.

Soluble TNFR1 Levels in Type 2 Diabetes and its Association with Stages of Proteinuria.

Early identification of at-risk individuals for diabetic nephropathy would help in preventing or delaying end-stage renal failure. We measured the levels of circulating soluble tumor necrosis factor receptor 1 (sTNFR1) in various stages of proteinuria (MAC) to determine the association of this marker with diabetic nephropathy. The study was performed on 160 subjects, and a case-control methodology was employed. Type 2 diabetic subjects were recruited based on albuminuria and were grouped as (1) normoalbuminuria (NA); (2) microalbuminuria (MIC); (3) MAC; (4) normal glucose tolerance (NGT) subjects who served as healthy controls. sTNFR1 levels were measured by quantitative enzyme-linked immunosorbent assay (ELISA). Soluble tumor necrosis factor receptor 1 (sTNFR1) levels were highest in the MAC group, followed by the microMAC group. The sTNFR1 levels were not statistically different between the NGT and NA groups. On regression models, sTNFR1 was associated with MIC [odds ratio (OR)- 6.491, 95% confidence interval (CI)-1.868-22.55] and MAC (OR per standard deviation-15.28; 95% CI-3.76-62.15; p < 0.001) even after controlling for all the possible confounding factors. Receiver operator curve (ROC) analysis revealed sTNFR1 cut-point of 1832 pg/mL had a C-statistic of 0.685 to discriminate MI from NA with 52% sensitivity. Whereas the sTNFR1 cut-point of 2050 pg/mL with a C-statistic of 0.8177 had 77% sensitivity for identifying MAC. Soluble tumor necrosis factor receptor 1 (sTNFR1) is significantly associated with MIC and MAC group in type 2 diabetes, and this suggests a potential early diagnostic biomarker role of sTNFR1 for MAC among Asian Indians.

One-hour post-load glucose and subclinical left atrial myocardial dysfunction in hypertensive patients.

Recently, studies demonstrated that normal glucose-tolerant subjects (NGT) with one-hour post load plasma glucose value >155 mg/dl during oral glucose tolerance test (OGTT) (NGT≥155) present an impaired cardio-metabolic profile, with subclinical myocardial damage. Atrial morphological and functional alterations, closely related to diastolic dysfunction, are important predictors of atrial fibrillation (AF), cardiovascular (CV) events, and mortality in the entire population as well as in diabetic patients. The aim of our study was to evaluate subclinical atrial myocardial damage, assessed with speckle tracking echocardiography, in NGT≥155 mg/dl patients, comparing to NGT<155 mg/dl subjects, impaired glucose tolerant (IGT) individuals and patients with newly diagnosed type 2 diabetes (T2DM). We enrolled 229 Caucasian patients. All subjects underwent anthropometrical and hemodynamic parameters evaluation, OGTT, advanced Color-Doppler echocardiography with evaluation of main atrial and ventricular parameters. As expected, from first to the fourth group there was a worsening of the metabolic profile as attested by fasting, one-hour and two-hour post load plasma glucose levels, during OGTT. Moreover, from NGT<155 to T2DM group there was an impairment in reservoir and pump atrial function (PALS and PACS, respectively) (p<0.0001). Present data demonstrated for the first time that NGT≥155 subjects present subclinical atrial dysfunction. These results may be clinically relevant because they highlight how atrial myopathy occurs early in pre-diabetes stage regardless of fibrotic and morphological alterations of the ventricular myocardium.

Effect of sarcopenia, osteoporosis, and osteosarcopenia on spine fracture in American adults with prediabetes.

This study aimed to investigate the effect of sarcopenia, osteoporosis, and osteosarcopenia on spine fracture in patients with prediabetes. We collected and analyzed the data from the U.S. National Health and Nutrition Examination Surveys during the period from 2009 to 2018. Bone mineral density and the skeletal muscle mass index (SMI) were measured with dual-energy X-ray absorptiometry (DXA). The diagnosis of spine fracture was based on DXA and history. People with prediabetes were more likely to develop sarcopenia than normal glucose tolerance subjects (OR 1.33, 95% CI 1.07-1.66), while there was no significant increase of osteoporosis in prediabetes (OR 0.91, 95% CI 0.78-1.05). The SMI was independently associated with osteoporosis in prediabetes adults (OR 0.65, 95% CI 0.50-0.85). Both sarcopenia and osteoporosis were positively associated with spine fracture in prediabetes (OR 4.44, 95% CI 1.76-11.21, and OR 2.90, 95% CI 1.85-4.56, respectively). The risk of spine fracture was substantially higher in the presence of osteosarcopenia (OR 6.63; 95% CI, 1.34-32.94) than in the presence of sarcopenia or osteoporosis alone in prediabetes. In adults with prediabetes, both sarcopenia and osteoporosis are risk factors for spine fracture, and the combination of sarcopenia and osteoporosis further increases the prevalence of spine fracture.

A comparison of daily glucose fluctuation among GCK-MODY and type 2 diabetes using continuous glucose monitoring technology.

Glucokinase variant-induced maturity-onset diabetes of the young (GCK-MODY) exhibits the unique clinical features of mild fasting hyperglycaemia. However, formal studies of its glucose excursion pattern in daily life in comparison with those with or without other types of diabetes are lacking. We conducted a case-control study including 25 patients with GCK-MODY, 25 A1c-matched, drug naive patients with type 2 diabetes (T2DM) and 25 age-, BMI- and sex-matched subjects with normal glucose tolerance (NGT). All the subjects wore flash glucose monitoring (FGM) sensors for 2 weeks, and glucose readings were masked. Glucose excursion was significantly lower in the GCK-MODY than that in A1c-matched T2DM during the daytime, but was similar during the nighttime. The daytime coefficient of variation [CV] driven by postprandial glucose could separate GCK-MODY from well-controlled T2DM, but the nighttime CV could not. In discriminating between GCK-MODY and T2DM, the area under the curve (AUC) of the CV was 0.875. However, in GCK-MODY and NGT subjects, the CVs were similar at 24h, whereas the other four excursion parameters were significantly higher in GCK-MODY than those in NGT subjects. FGM confirmed the stability and mildness of hyperglycemia in GCK-MODY patients. Postprandial regulation is a key driver of the difference in excursion between GCK-MODY and T2DM.

Resistin G-A haplotype at SNP-420/-358 is associated with the latent sarcopenic obesity index in the toon genome study.

Resistin, which induces insulin resistance, is mainly expressed in monocytes/macrophages in humans. We reported previously that serum resistin was highest in the G-A haplotype defined by resistin single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and - 358 (rs3219175). As sarcopenic obesity is associated with insulin resistance, we aimed to examine whether serum resistin and its haplotypes were associated with sarcopenic obesity at a latent stage. We cross-sectionally analyzed 567 community-dwelling Japanese participants attending annual medical check-ups in which the sarcopenic obesity index was evaluated. The age- and gender-matched normal glucose tolerance subjects with G-A homozygotes and those with C-G homozygotes were examined via RNA-sequencing and pathway analysis (each n=3), and RT-PCR (each n=8). In multivariate logistic regression analyses, the fourth quartile (Q4) of serum resistin and G-A homozygotes were both associated with the latent sarcopenic obesity index defined by a visceral fat area of ≥ 100 cm2 and grip strength Q1 after adjustment for age and gender, with or without other confounding factors. RNA sequencing and pathway analysis showed that tumor necrosis factor (TNF) was involved in the top five pathways in the whole blood cells of G-A homozygotes compared with C-G homozygotes. RT-PCR revealed that TNF mRNA was higher in G-A homozygotes than in C-G homozygotes. The G-A haplotype was associated with the latent sarcopenic obesity index defined by grip strength in the Japanese cohort, could be mediated by TNF-α.

Chronic physiologic hyperglycemia impairs insulin-mediated suppression of plasma glucagon concentration in healthy humans

Background and aimsHyperglucagonemia is a characteristic feature of type 2 diabetes mellitus (T2DM). We examined the effect of chronic (48–72 h) physiologic increase (+50 mg/dl) in plasma glucose concentration on suppression of plasma glucagon concentration by insulin and by hyperglycemia in normal glucose tolerance (NGT) individuals. Materials and methodsStudy One: 16 NGT subjects received OGTT and 3-step hyperinsulinemic (10, 20, 40 mU/m2·min) euglycemic clamp before and after 48 hour glucose infusion to increase plasma glucose by ~50 mg/dl. Study Two: 20 NGT subjects received OGTT and 2-step hyperglycemic (+125 and + 300 mg/dl) clamp before and after 72 hour glucose infusion. Plasma insulin, C-peptide and glucagon concentrations were measured during OGTT, euglycemic hyperinsulinemic and hyperglycemic clamps. Ratio of plasma glucagon/insulin was used as an index of insulin-mediated suppression of glucagon secretion. ResultsDuring all 3 insulin clamp steps (Study 1), plasma glucagon concentration was increased compared to baseline study, and plasma glucagon/insulin ratio was significantly reduced by 24 % (p < 0.05). The rate of insulin-stimulated glucose disposal was inversely correlated with plasma glucagon/insulin ratio (r = −0.44, p < 0.05) and with glucagon AUC (r = −0.48, p < 0.05). During the 2-step hyperglycemic clamp (Study 2) plasma glucagon was similar before and after 72 h of glucose infusion; however, glucagon/insulin ratio was significantly reduced (p < 0.05). Incremental area under plasma insulin curve during the first (r = −0.74, p < 0.001) and second (r = −0.85, p < 0.001) hyperglycemic clamp steps was strongly and inversely correlated with plasma glucagon/insulin ratio. ConclusionSustained (48–72 h) physiologic hyperglycemia (+50 mg/dl) caused whole body insulin resistance and impaired insulin-mediated suppression of glucagon secretion, suggesting a role for glucotoxicity in development of hyperglucagonemia in T2DM.

Inflammatory Cell Infiltration Into Islets Without PD-L1 Expression Is Associated With the Development of Immune Checkpoint Inhibitor-Related Type 1 Diabetes in Genetically Susceptible Patients.

Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from 3 cases with ICI-related T1D, and their histopathological data were compared those from 3 patients who had received ICI therapy but did not develop T1D (non-T1D) and 7 normal glucose-tolerant subjects as controls. All ICI-related T1D patients had susceptible HLA haplotypes. In ICI-related T1D, the β-cell area decreased and the α-cell area increased compared to non-T1D and controls. The number of CD3- positive cells around islets increased in ICI-related T1D and non-T1D compared with controls, while the number of CD68-positive cells around islets increased in ICI-related T1D compared with non-T1D and controls. The expression ratios of PD-L1 on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while PD- L1 expression was observed in most cells of pancreatic islets in controls. This study, therefore, indicates that ICI therapy itself could reduce PD-L1 expression on islets in all subjects, which may be related to β cell vulnerability. In addition, we showed that absence of PD-L1 expression on β cells, genetic susceptibility and infiltration of macrophages as well as T lymphocytes around islets might be responsible for T1D onset.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation

PurposeFruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities.MethodsThe present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose–response relation.ResultsDuring a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949–0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766–0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957–4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368–0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762–1.023]).ConclusionThese findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

Decreased Urine N6-methyladenosine level is closely associated with the presence of diabetic nephropathy in type 2 diabetes mellitus.

BackgroundTo investigate the dynamic changes of urine N6-methyladenosine (m6A) levels in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) and evaluate the clinical significance.MethodsFirst, the levels of urine m6A were examined and compared among 62 patients with T2DM, 70 patients with DN, and 52 age- and gender-matched normal glucose tolerant subjects (NGT) by using a MethyIFIashTM Urine m6A Quantification Kit. Subsequently, we compared the concentrations of urine m6A between different stages of DN. Moreover, statistical analysis was performed to evaluate the association of urine m6A with DN.ResultsThe levels of m6A were significantly decreased in patients with DN [(16.10 ± 6.48) ng/ml], compared with NGT [(23.12 ± 7.52) ng/ml, P < 0.0001] and patients with T2DM [(20.39 ± 7.16) ng/ml, P < 0.0001]. Moreover, the concentrations of urine m6A were obviously reduced with the deterioration of DN. Pearson rank correlation and regression analyses revealed that m6A was significantly associated with DN (P < 0.05). The areas under the receiver operator characteristics curve (AUC) were 0.783 (95% CI, 0.699 – 0.867, P < 0.0001) for the DN and NGT groups, and 0.737 (95% CI, 0.639 – 0.835, P < 0.0001) for the macroalbuminuria and normoalbuminuria groups, and the optimal cutoff value for m6A to distinguish the DN from NGT and the macroalbuminuria from normoalbuminuria cases was 0.4687 (diagnostic sensitivity, 71%; diagnostic specificity, 76%) and 0.4494 (diagnostic sensitivity, 79%; diagnostic specificity, 66%), respectively.ConclusionsThe levels of urine m6A are significantly decreased in patients with DN and change with the deterioration of DN, which could serve as a prospective biomarker for the diagnosis of DN.

360-OR: Hyperglucagonemia Reduces De Novo Lipogenesis and Increases Gluconeogenesis in Healthy Subjects

Although the effect of glucagon on glucose metabolism has been well characterized, its effect on lipid metabolism, particularly lipolysis and de novo lipogenesis, in humans in vivo has been poorly studied with controversial results. We examined the effect of short-term hyperglucagonemia on de novo lipogenesis (DNL) and endogenous glucose production (EGP) in 8 healthy normal glucose tolerant subjects (5M/3F, age=35±5, BMI= 24±1) who received a 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min) infusion with measurement of EGP (3-3H-glucose) on the following morning 6-AM. Subjects received deuterated water (D2O, 5g/kg fat free mass) at PM on the night prior to study. 8 weeks later subjects returned for a repeat study with 12-hour infusion of normal saline. DNL was quantified by measuring the incorporation of deuterated water into circulating triglycerides. Gluconeogenic rate was measured as (EGP) x (plasma C5/C2 glucose ratio) (EGP) x (plasma C5/C2 glucose ratio) . Plasma esterified and non-esterified FFA levels were measured with gas chromatography mass spectrometry (GC-MS) . Plasma glucagon increased from 57±3 to 219±21 pg/ml within one hour and remained elevated throughout the study. DNL was significantly decreased (1.64 ± 0.58% vs. 3.± 0.98%, p&amp;lt;0.05) after glucagon versus saline infusion. Both plasma palmitate (0.73 ± 0.vs. 0.67 ± 0.mmol/L) and total FFA (1.35 ± 0.vs. 1.21 ±0.mmol/L) concentrations were elevated after glucagon infusion (p&amp;lt;0.05) . EGP increased following glucagon infusion (2.13 ± 0.14 vs. 1.97± 0.11mg/kg/min, p =0.006) . The increase in EGP was primarily due to increased gluconeogenesis (1.48 ± 0.14 vs. 1.27 ± 0.11, p=0.02) , while the rate of glycogenolysis did not change (0.65± 0.14 vs. 0.70± 0.11, p=ns) . Conclusion: Short-term (12-hour) physiologic hyperglucagonemia in healthy subjects reduces hepatic de novo lipogenesis, stimulates adipose tissue lipolysis, and increases hepatic glucose production by increasing gluconeogenesis. Disclosure X.Chen: None. F.Carli: None. S.Pezzica: None. G.Mocciaro: None. D.Ciociaro: None. A.Gastaldelli: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk Global Business Services, Consultant; Boehringer Ingelheim International GmbH, Inventiva Pharma, Other Relationship; Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc., Speaker's Bureau; Novo Nordisk. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc., Speaker's Bureau; AstraZeneca. D.Tripathy: None. Funding EFSD Albert Renold Travel Fellowship; FAVHR

Impaired glucose tolerance is associated with enhanced postprandial pancreatic polypeptide secretion

BackgroundThe purpose of this study is to compare serum pancreatic polypeptide (PP), insulin, C‐peptide, and glucagon in different glucose tolerance stages; analyze the influencing factors of PP secretion; and further explore the role of PP in the pathogenesis of diabetes mellitus.MethodsData were collected from 100 subjects from hospital. According to the results of oral glucose tolerance test (OGTT), the subjects were divided into a normal glucose tolerance (NGT) group, an impaired glucose regulation (IGR) group, and a newly diagnosed type 2 diabetes mellitus (T2DM) group. PP and the related parameters were measured, and the area under the curve (AUC) 120 min after OGTT was calculated. AUCpp (AUC of PP) was used as the dependent variable and the potentially influencing factors were used as the independent variable for multiple linear regression analysis.ResultsPostprandial 60 min PP in the IGR group was higher than those in the NGT group (2973.80 [±547.49] pg·h/mL vs 2663.55 [±594.89] pg·h/mL, p < 0.05). AUCpp was significantly higher in the IGR group (428.76 pg·h/mL, 95% confidence interval [CI] [41.06 –816.46], p = 0.031) and newly diagnosed T2DM group (404.35 pg·h/mL, 95% CI [5.37–803.33], p = 0.047) than in the NGT group. AUCpp was negatively correlated with body mass index (BMI) (r = −0.235, p = 0.038) and positively correlated with postprandial 60 min blood glucose (r = 0.370, p = 0.001) and AUCbg (AUC of blood glucose) (r = 0.323, p = 0.007). Multiple linear regression analysis indicated that there was a linear correlation between BMI, AUCbg, and AUCpp (p = 0.004, p = 0.001), and the regression equation was calculated as: AUCpp = 6592.272 + 86.275 × AUCbg‐95.291 × BMI (R2 = 12.7%, p < 0.05).ConclusionsCompared with NGT subjects, IGR and T2DM patients have an enhanced postprandial PP secretion. In T2DMs, the secretion of PP is mainly affected by BMI and blood glucose.

To Evaluate the Association of Serum Adiponectin with Fasting and Postprandial Plasma Glucose and Fasting Lipids in Control, IGT and T2DM Subjects

Background: Association of adiponectin with insulin resistance occurs early in obesity development; however it remains unclear if this association is of further importance in prediabetes and early stages of type 2 diabetes and remains the same through all glucose intolerance development stages. The present study was undertaken to evaluate the association of dysglycemia and dyslipidemia with adiponectin in prediabetic subjects as well as in T2DM subjects. Objective: The objective of our study was to evaluate adiponectin level in subjects with pre-diabetes and to compare it with the levels in newly diagnosed type 2 diabetes and healthy (normal glucose tolerance) subjects. Method: It was an observational analytic study with a group compare design. The study was conducted in the Biomedical Research Group and Department of Biochemistry &amp; Cell Biology of the Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka. This study was done during the period of July 2012 to June 2013. Results: Bivariate Spearman’s correlation analyses were performed for adiponectin with clinical, anthropometrical and other biochemical variables in the Control, IGT and T2DM groups. Postprandial glucose (p=0.023) and age (p=0.011) had a positive correlation with adiponectin in control subjects. A negative correlation was observed between adiponectin and BMI in IGT subjects (p=0.004). A positive correlation with adiponectin and serum HDL (p=0.03) and a negative correlation with serum LDL (p=0.03) were found in T2DM subjects. Conclusion: From our study we can conclude that, BMI has a negative association with adiponectin in IGT subjects. Serum LDL has a negative association and HDL has a positive association with adiponectin in IGT and T2DM subjects.

Association of Serum Adiponectin with Dysglycemia and Dyslipidemia in Impaired Glucose Tolerance and Type 2 Diabetes Mellitus

Background: The association of low adiponectin concentration and type 2 diabetes is well studied but the association of adiponectin with prediabetes is still unresolved. Data from Bangladeshi population shows that both insulin secretory defect and insulin resistance are present in T2DM subjects, but the secretory defects seem to have a predominant role. In a search for the downward factors regulating the basic defects attention has also been focused to inflammatory markers and adipocytokines. Adiponectin is one of the major targets for such studies and few studies have already been conducted on the association of adiponectin with prediabetes in our population. Objective: The objective of our study was to evaluate adiponectin level in subjects with pre-diabetes and to compare it with the levels in newly diagnosed type 2 diabetes and healthy (normal glucose tolerance) subjects. Method: It was an observational analytic study with a group compare design. The study was conducted in the Biomedical Research Group and Department of Biochemistry &amp; Cell Biology of the Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka. This study was done during the period of July 2012 to June 2013. Results: IGT and Controls subjects were age and BMI matched. Mean (±SD) age of Control, IGT and T2DM subjects were 38.75±8.40, 42.71±7.65 and 44.61±7.00 years respectively. Age of T2DM subjects were higher compared to controls (p=0.022). Mean (SD) BMI of the Control, IGT and T2DM subjects were 20.53±2.43, 20.89±2.22 and 21.14±2.23 respectively. Conclusion: From our study we can conclude that, type 2 DM subjects have lower adiponectin level compared to controls. Prediabetic subjects do not have lower adiponectin level, but they have a lower adiponectin- glucose ratio compared to controls.

Comprehensive analysis of circulating miRNA expression profiles in insulin resistance and type 2 diabetes in Qatari population

Insulin resistance (IR) is type 2 diabetes’ hallmark. MiRNAs regulate many target genes that makes them attractive candidates for regulating insulin production, secretion and action. Therefore, we anticipate a change in the circulatory profile of miRNAs in IR subjects compared to normal glucose tolerance subjects. In the present study, we sought to identify the circulating miRNAs associated with IR as biomarkers in Qatari population. The circulating miRNA profile was assessed in a pilot study of healthy volunteers (n = 22) whose insulin sensitivity was quantitated by euglycemic hyperinsulemic clamp. Moreover, in the validation phase (n = 40) subjects were added including lean and obese T2D. MiR-186 showed a consistent significant increase in insulin resistance subjects compared to NGT in the discovery and validation phase analysis. In addition, intergroup comparison of circulating miRNA pinpointed 2 miRNAs: MiR-122 increased substantially in obese T2D subjects, with diagnostic value to predict obesity in T2D subjects, and let-7b increased significantly in lean T2D subjects. Our results suggest that circulating miRNAs serve as biomarkers for IR, T2D and obesity in Qatari population. Further functional studies are warranted to better identify the targets of these miRNAs and understand the underlying molecular and cellular mechanisms.

Serum levels of novel anti-inflammatory cytokine Interleukin-38 in diabetes patients infected with latent tuberculosis (DM-LTB-3)

IL-38 is a recently discovered, novel anti-inflammatory cytokine, which belongs to the IL-1β family. The role played by this cytokine in diabetes-tuberculosis nexus is not known. Serum levels of IL-38, TNF-α, IL-6, and IL-1β in Normal Glucose Tolerance (NGT) and chronic Diabetes (DM) subjects, both with and without latent tuberculosis (LTB) (n = 256) were quantified by ELISA. While, serum levels of IL-38 were significantly reduced, the levels of TNF-α, IL-6, and IL-1β were not altered, in LTB infected diabetes patients. While no significant secretion of IL-38 was detected in the quantiferon supernatant, secretion of TNF-α, IL-6, and IL-1β was significantly reduced in LTB infected diabetes patients. The decreased systemic levels of IL-38 and reduced in vitro secretion of other pro-inflammatory cytokines might represent a crucial pathway associated with diabetes-tuberculosis nexus.

Clinical significance of high mobility group box 1/toll-like receptor 4 in obese diabetic patients.

High mobility group box 1 (HMGB1) is an alarmin that may link to obesity and type 2 diabetes mellitus (T2DM). The present study analyzed the correlation between HMGB1/ Toll-like receptor 4 (TLR4) and certain biochemical parameters in obese (OB) diabetic patients. 40 normal glucose tolerant subjects (NGT) and 40 patients with newly diagnosed T2DM were enrolled. All patients were further divided into non-obese NGT (NGT-NOB), obese NGT (NGT-OB), non-obese T2DM (T2DM-NOB) and obese T2DM (T2DM-OB) groups according to body mass index (BMI).The levels of HMGB1 in serum were quantified using ELISA, whereas the mRNA expression levels of TLR4 in peripheral blood mononuclear cells were assessed using reverse transcription-quantitative PCR. The results suggested that the levels of HMGB1 and TLR4 were higher in NGT-OB and T2DM-NOB groups compared with those in NGT-NOB group. Similarly, the levels of these two markers were higher in T2DM-OB group compared with those in NGT-OB group. Correlation analysis indicated that the levels of HMGB1 and TLR4 were positively correlated with triglyceride (TG), fasting plasma glucose (FPG) levels and BMI, whereas a negative correlation between HMGB1 and high density lipoprotein (HDL) was noted. Linear regression analysis suggested that HMGB1 was associated with FPG and TG levels, whereas TLR4 was strongly associated with TG levels and BMI. The results demonstrated that the expression levels of HMGB1 and TLR4 in patients with T2DM or obesity were increased, which were associated with glycolipid metabolism disorders. Therefore, the HMGB1/TLR4 may serve a role in inflammatory process associated with obesity and T2DM.

Glucose metabolic disorder in Klinefelter syndrome: a retrospective analysis in a single Chinese hospital and literature review

BackgroundWe aimed to investigate the clinical characteristics and islet β-cell function in patients with Klinefelter syndrome (KS) and hyperglycemia.MethodsThis is a retrospective study. In total, 22 patients diagnosed with KS were identified from the electronic medical record system, including 9 patients with hyperglycemia (total patients with hyperglycemia, THG-KS group) and 5 hyperglycemic KS patients with oral glucose tolerance test (OGTT) results (HG-KS group). An additional 5 subjects with hyperglycemia and 5 normal glucose tolerance (NGT) subjects matched based on body mass index were included as the HG group and NGT group, respectively. Data from clinical and laboratory examinations were collected. We further performed a literature review of KS and hyperglycemia.ResultsWe found that KS patients developed abnormal glucose metabolism earlier in life than those without KS, and the median age was 17 years, ranging from 10 years to 19 years. Six of 17 (35.3%) patients were diagnosed with diabetes mellitus and 3 of 17 (17.6%) patients were diagnosed with prediabetes. Among 10 patients with both fasting blood glucose and insulin results recorded, there were 8 out of 17 (47.1%) KS patients had insulin resistance. The prevalence of hypertension and dyslipidemia was higher in patients with hyperglycemia and KS than in patients with NGT KS. Compared with the HG group, insulin sensitivity levels were lower in HG-KS group, whereas homeostasis model assessment of β-cell function levels (p = 0.047) were significantly, indicating higher insulin secretion levels in the HG-KS group.ConclusionsKS patients develop hyperglycemia earlier in life than those without KS and show lower insulin sensitivity and higher insulin secretion. These patients also have a higher prevalence of other metabolic diseases and may have different frequencies of developing KS-related symptoms.

Classic Type 1 Diabetes Mellitus and Fulminant Type 1 Diabetes Mellitus: Similarity and Discrepancy of Immunological Characteristics and Cytokine Profile.

PurposeWe aimed to explore the immunological characteristics and cytokine profile of the initial stage of type 1 diabetes.Patients and MethodsIn total, 123 age- and sex-matched subjects with newly diagnosed classic type 1 diabetes mellitus (T1ADM), fulminant type 1 diabetes mellitus (FT1DM), and normal glucose tolerance (NGT) were enrolled. Serum cytokine levels were measured using Milliplex MAP multifactor detection.ResultsThere was a significant increase in the levels of transforming growth factor β (TGFβ1) and TGFβ2 and decrease in programmed death-1 (PD-1), PD ligand 1 (PD-L1), pro-inflammatory cytokines, and anti-inflammatory cytokines in type 1 diabetes patients compared with the NGT subjects (all P < 0.05). There was no significant difference in C-reactive protein (CRP) and blood routine indicators between the two groups. Type 1 diabetes was further divided into T1ADM and FT1DM subgroups. FT1DM patients had much higher CRP levels than T1ADM patients (4.90 [0.95–26.05] mg/L vs 0.39 [0.20–0.74] mg/L, P < 0.01). Blood routine results showed that the number of leukocytes was significantly increased in FT1DM compared with that in T1ADM (9.2 [5.1–18.8] × 109 cells/L vs 5.4 [4.5–6.7] × 109 cells/L, P < 0.01). In FT1DM patients, neutrophil% was increased, and lymphocyte% was declined significantly, compared with that in T1ADM patients (neutrophil%: 80.2 [59.2–85.2]% vs 59.5 [54.8–64.0]%; lymphocyte%: 18.3 [10.1–32.3]% vs 32.6 [26.8–35.9]%; both P < 0.01). However, there was no difference between FT1DM and T1ADM in cytokine profile except for the decrease in CTLA-4 in T1ADM (P < 0.05).ConclusionCompared with T1ADM, CRP and leukocytes’ levels were increased significantly in FT1DM, with an increase in neutrophil% and decline in lymphocyte%, suggesting that FT1DM may have more abrupt onset and occur as a more serious subtype of type 1 diabetes mellitus.