Normal Glucose Tolerance Subjects Research Articles

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.

Prevalence of diabetes related vascular complications in subjects with normal glucose tolerance, prediabetes, newly detected diabetes and known diabetes

AimsVarying prevalence of individual diabetes related vascular complications in prediabetes has been reported. However, very few studies have looked at both macrovascular and microvascular complications in prediabetes. MethodsStudy subjects without any history of diabetes underwent oral glucose tolerance test (OGTT) and were classified as either normal glucose tolerance (NGT), prediabetes (PD), newly detected diabetes mellitus (NDDM) on the basis of American Diabetes Association (ADA) criteria. Age and sex matched known diabetes mellitus (KDM) patients were also recruited. All the participants were subsequently screened for both macrovascular (CAD, CVA,PVD) and microvascular (retinopathy, nephropathy and neuropathy)complications of diabetes. ResultsPrevalence of vascular complications among prediabetes subjects was 11.1% as compared to 1.4% among NGT subjects, 13.9% among NDDM subjects and 23.8% among KDM subjects. There was no significant between complication rates in prediabetes and NDDM group (p = 0.060). The prevalence of macrovascular and microvascular complications among prediabetes subjects was 4.2% and 6.9% while the same in NDDM was 4.2% and 9.7%. ConclusionsThe proportion of subjects with prediabetes and vascular complications was about half of those with known diabetes and almost similar to those with newly detected diabetes mellitus.

257-OR: Short-Term Hyperglucagonemia Induces Adipose Tissue Insulin Resistance and Inflammation In Vivo

Although the effect of glucagon on glucose metabolism has been well characterized, its effect on adipose tissue and lipid metabolism in humans in vivo has been poorly studied with controversial results. We examined the effect of short-term hyperglucagonemia on adipocyte metabolism 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) with 14C-glycerol infusion; subcutaneous abdominal adipose tissue biopsy was obtained at 6AM. 8 weeks later subjects returned for a repeat study with 12-hour infusion of normal saline. Plasma glucagon increased from 57±3 to 219±21 pg/ml within one hour and remained elevated throughout the study. Glycerol turnover rate (5.1±0.6 vs. 3.8±0.6 µmol/kg•min, p&amp;lt;0.05) increased by 34%, and the adipose tissue insulin resistance index (fasting plasma FFA x Insulin) more than doubled (5.8±0.8 vs. 2.8±0.7 mM•mU/L, p&amp;lt;0.05) after 12-hour glucagon infusion compared to saline. mRNA expression of genes involved in lipolysis in adipose tissue were upregulated after glucagon infusion (ATGL, 1.14±0.07 vs. 0.77±0.03; HSL, 1.17±0.03 vs. 0.9±0.13; MGL, 1.2±0.04 vs. 0.82±0.2, all p&amp;lt;0.05). Plasma concentration of proinflammatory markers (IL-1β, 0.65±0.05 vs. 0.49±0.05 pg/mL; TNF-α, 2.03±0.23 vs. 1.75±0.17 pg/mL, both p&amp;lt;0.05) and lipidomes involved in inflammatory pathways (lysophosphatidylcholine, 126±11 vs. 51±7 nmol/ml, p&amp;lt;0.005; phosphatidylcholine, 385±24 vs. 306±25 nmol/ml, p&amp;lt;0.01; ceramide, 1.7±0.2 vs. 1.2±0.2 nmol/ml, p&amp;lt;0.01) also increased after 12-hour glucagon infusion. H&amp;E and CD68 immunofluorescence staining in adipose tissue displayed the crown-like structures (CLS) and increased infiltration of macrophages following glucagon infusion. Conclusion: Short-term (12-hour) physiologic hyperglucagonemia stimulates adipose tissue lipolysis, induces adipocyte insulin resistance, and promotes adipose tissue and systemic inflammation. Disclosure X. Chen: None. M. Fourcaudot: None. L. Norton: None. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. D. Tripathy: None. Funding Foundation for Advancing Veterans’ Health Research

The Impact of Glucose Tolerance States on Bone Mineral Density and Fracture Rate

It is generally acknowledged that fracture rate is higher in diabetic subjects than non-diabetic subjects. However, the impact of diabetes on bone is less clear due to contradictory results of bone mineral density (BMD) and fracture rate. To date, most of reports were based on the studies from relatively small sample sizes. To clarify the issues, we examined the fracture rates and BMD across a spectrum of glucose tolerance in a representative US population.The participants of the National Health and Nutrition Survey 2005–2010 were used in this study. Among adult subjects (age≥20 years old) with reported BMI, we were able to define the states of glucose tolerance in 31,073 subjects cording to the diagnostic criteria based on HbA1c, fasting glucose, and/or 2-h post-changed glucose with established diabetes and using diabetes medications, into normal glucose tolerance (NGT), abnormal glucose tolerance (AGT), and diabetes mellitus (DM). Those who received osteoporosis medications were excluded from BMD analysis. Fracture information was available in 15,547 subjects; validated hip BMD was available in 12,317 subjects; and validated lumbar spine BMD was available in 10,329 subjects. Fracture rates were compared among 3 groups of glucose tolerance states and odds ratio (OR) with 95% confidence intervals (95% CI) were calculated in reference to the NGT group with sample weighting. BMD was compared among 3 groups of glucose tolerance with consideration of covariates.The reported osteoporosis diagnosed rate differed among 3 groups of glucose tolerances (3.99%, 5.77%, and 8.41%, P<0.001, for NGT, AGT, and DM respectively). Worsening states of glucose tolerance were associated increased fracture OR at Hip [AGT, 2.1770 (95% CI: 2.1732–2.1807) and DM, 2.7369 (95% CI: 2.7315–2.7423)], spine [AGT, 0.9924 (95% CI: 0.9912–0.9936); DM, 1.2405 (95% CI: 1.2387–1.2423)]. In contrast, a different trend was observed on the wrist fracture rate [AGT, 0.9556 (95% CI: 0.9551–0.9562); DM, 0.9053 (95% CI: 0.9045–0.9060)]. After adjustment for covariates, higher BMD was noted in AGT and DM when compared to NGT at total femur (NGT, 0.9760±0.0015 gm/cm2; AGT, 0.9853±0.0021 gm/cm2; DM 0.9847±0.0034 gm/cm2, mean±SE, P=0.001) and femoral neck (NGT, 0.8388±0.0015 gm/cm2; AGT, 0.8474±0.0020 gm/cm2; DM, 0.8496±0.0032 gm/cm2, P=0.0007) while no difference was found in lumbar spine BMD (NGT, 0.1.0441±0.0018 gm/cm2; AGT, 1.0406±0.0025 gm/cm2; DM, 1.0464±0.0041 gm/cm2, P=0.35).Our observed significant increased fracture risk at hip (OR: 2.7369) and lumbar spine (OR: 1.2405) in DM subjects when compared to NGT subjects. DM subjects had higher BMD at total femur and femoral neck than NGT subjects while no difference was noted at lumbar spine BMD when compared to NGT subjects. Further studies are required to explore the discrepancy between the increased fracture risk with higher BMDs in diabetes.

Fetal Abdominal Obesity Detected At 24 to 28 Weeks of Gestation Persists Until Delivery Despite Management of Gestational Diabetes Mellitus.

BackgroundFetal abdominal obesity (FAO) has been reported to be affected at gestational diabetes mellitus (GDM) diagnosis at 24 to 28 weeks of gestation in older and/or obese women. This study investigated whether the management of GDM improves FAO in GDM subjects near term.MethodsMedical records of 7,099 singleton pregnant women delivering at CHA Gangnam Medical Center were reviewed retrospectively. GDM was diagnosed by 100-g oral glucose tolerance test after 50-g glucose challenge test based on Carpenter–Coustan criteria. GDM subjects were divided into four study groups according to maternal age and obesity. FAO was defined as ≥90th percentile of fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference per actual GA by the last menstruation period, biparietal diameter, or femur length, respectively.ResultsAs compared with normal glucose tolerance (NGT) subjects near term, FAORs and odds ratio for FAO were significantly higher in old and/or obese women with GDM but not in young and nonobese women with GDM. For fetuses of GDM subjects with FAO at the time of GDM diagnosis, the odds ratio for exhibiting FAO near term and being large for GA at birth were 7.87 (95% confidence interval [CI], 4.38 to 14.15) and 10.96 (95% CI, 5.58 to 20.53) compared with fetuses of NGT subjects without FAO at GDM diagnosis.ConclusionDespite treatment, FAO detected at the time of GDM diagnosis persisted until delivery. Early diagnosis and treatment might be necessary to prevent near term FAO in high-risk older and/or obese women.

PCSK9 Levels and Metabolic Profiles in Elderly Subjects with Different Glucose Tolerance under Statin Therapy.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol (LDL-C) receptors, and thus regulates the LDL-C levels in the circulation. Type 2 diabetics often have elevated LDL-C levels. However, the functions of PCSK9 in patients with alterations of glu-cose metabolism and statin therapy are still unclear. Method: we investigated a large cohort of 608 subjects, born in 1945 in Oulu, Finland (Oulu Cohort 1945). We studied the effects of PSCK9 lev-els with different glucose tolerances (normal glucose tolerance (NGT), prediabetes (PreDM) or type 2 diabetes (T2D)) with and without statin medication, and analyzed clinical data, NMR metabolomics and PCSK9 plasma levels. Results: PCSK9 plasma levels did not significantly differ between the three groups. Statin therapy significantly increased the PCSK9 levels in NGT, PreDM and T2D groups compared with subjects with no statins. In the NGT group, negative associations between PCSK9 and LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density lipoprotein cholesterol (VLDL-C), total cholesterol and LDL and IDL triglycerides were observed under statin medication. In contrast, in the PreDM and T2D groups, these associa-tions were lost. Conclusions: our data suggest that in subjects with abnormal glucose metabolism and statin therapy, the significant PCSK9-mediated effects on the lipid metabolites are lost com-pared to NGT subjects, but statins reduced the LDL-C and VLDL-C levels.

Epidemiology and risk factors for diabetes in the suburbs of Beijing: a retrospective cohort study

ObjectiveWe aimed to detect the incidence and risk factors of type 2 diabetes mellitus (T2DM) development in the suburbs of Beijing.DesignCohort study with record linkage to incidence data.SettingWe performed a...

Fasting Glucagon Level in Type 2 Diabetes and Impaired Glucose Tolerance and Its Association With Diabetes-Associated Clinical Parameters: A Study From Karachi, Pakistan.

Aim and objectiveThe study aims to analyze fasting glucagon in patients with type 2 diabetes and impaired glucose tolerance and correlate it with anthropometric and biochemical parameters in a large proportion of Pakistani people with diabetes. MethodologyThe participants of the study were categorized into three groups based on oral glucose tolerance test, as per American Diabetes Association guidelines. Group A consisted of normal glucose tolerance subjects (n=30), Group B consisted of subjects with impaired glucose tolerance (n=30), and Group C had full-blown subjects with type 2 diabetes (n=30). Biochemical parameters, such as fasting glucagon, fasting plasma and 2-hour glucose, glycated hemoglobin, and lipid profile, and anthropometric parameters, such as body mass index (BMI), waist and hip circumference, waist-to-hip ratio, and systolic and diastolic blood pressure, were measured.ResultsThe mean values of fasting glucagon level in Group A, Group B, and Group C were 39.24±4.5, 44.5±8.25, and 49.02±9.15 pg/ml, respectively. Statistically significant difference was not found in fasting glucagon level among these groups (p-value 0.614). Fasting glucagon was positively and independently correlated with 2-hour plasma glucose, systolic blood pressure, diastolic blood pressure, BMI, hip and waist circumference, and hip-to-waist ratio in Group C. In Group B, fasting glucagon was positively correlated with 2-hour plasma glucose, BMI, and hip circumference, while it was not correlated with fasting plasma glucose in both groups. In Group A, fasting glucagon found positively correlated with systolic blood pressure and hip circumference.ConclusionOur observation suggests that fasting plasma glucose is not concomitant with glucagon levels; however, glucagon suppression, after glucose intake, was dysregulated in type 2 diabetes and impaired glucose tolerance. Moreover, glucagon is associated with central obesity in type 2 diabetic patients..

Impact of oral anticholinergic on insulin response to oral glucose load in patients with impaired glucose tolerance.

Background:Preliminary data indicates there is a cholinergic basis to insulin secretion.Aims & Objective:To investigate the impact of oral anticholinergics on insulin secretion in subjects with impaired glucose tolerance (IGT), in comparison with volunteers having normal glucose tolerance (NGT). Material & Methods: This prospective observational study recruited 10 IGT and 10 NGT subjects. An oral glucose tolerance test (OGTT) was conducted twice in the absence and presence of hyoscine butyl-bromide (HBB). The plasma glucose (PG) and insulin levels were serially estimated at 30-min increments for 2 h after the OGTT. Early (ΔI30/ΔPG30) & late (insulin/PGAUC 60-120) phase insulin activity were assessed subsequently.Results:The study constituted of 10 IGT (4M/6F, BMI: 28.80 ± 2.30) and 10 NGT (5M/5F, BMI: 23.00 ± 0.80) subjects. In the NGT group, the pre-HBB mean glucose levels (0-120 min) were comparable with those recorded after HBB intake. However, after HBBB, the mean insulin levels decreased significantly at t = 90 and 120min, confirmed by attenuated late phase insulin activity in IGT (P = 0.023) & NGT (P = 0.006) group. On the other hand, in the IGT group, however, HBB did not impact on the mean PG and insulin levels (0-120 min).Conclusions:Our study findings indicate that insulin secretion is influenced by cholinergic system and that oral anticholinergics may attenuate the late phase insulin activity in varying degrees of glycemic status.

Research on consistency of different measurement methods for saliva 1,5-anhydroglucitol

Objective: To evaluate the consistency of different measurement methods of saliva 1,5-anhydroglucitol (1,5-AG) in different glucose metabolism populations. Methods: From January 2018 to June 2019, 175 healthy volunteers (21-65 years, 58 males and 117 females) with normal glucose tolerance (NGT) and 80 diabetic patients (18-70 years, 44 males and 36 females) were enrolled in Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Saliva was collected by saliva collection tube, and 1,5-AG was measured using both enzymatic and mass spectrometry methods. Serum 1,5-AG was determined by enzymatic method. Results: In NGT subjects, both serum and saliva 1,5-AG levels detected by enzymatic method were positively correlated with the saliva 1,5-AG levels detected by liquid chromatography-mass spectrometry (r=0.247 and 0.523, respectively, both P<0.05). However, there was no significant correlation between saliva and serum 1,5-AG levels detected by enzymatic method (r=-0.074, P=0.333). In diabetic patients, both serum and saliva 1,5-AG levels detected by enzymatic method were positively correlated with the saliva 1,5-AG levels detected by gas chromatography-mass spectrometry (r=0.284 and 0.423, respectively, both P<0.05). However, there was no significant correlation between saliva and serum 1,5-AG levels detected by enzymatic method (r=-0.079, P=0.487). Conclusions: Both serum and saliva 1,5-AG levels detected by enzymatic method have a good consistency with saliva 1,5-AG levels detected by mass spectrometry method. The saliva and serum 1,5-AG levels detected by enzymatic method are not well correlated, and thus the enzymatic detection of saliva 1,5-AG needs further improvement in clinical practice.

Analysis of the Exonic Single Nucleotide Polymorphism rs182428269 of the NRF2 Gene in Patients with Diabetic Foot Ulcer

The pivotal role of Nuclear factor erythroid-2-related factor 2 (NRF2) in redox homeostasis and wound healing has been well documented. However, the genetic mechanisms that regulate NRF2 in type 2 diabetes and diabetic foot ulcers remain unexplored. The present study investigated the association of single nucleotide polymorphism rs182428269 (-127C/T) in subjects with type 2 diabetes and diabetic foot ulcers. This cross-sectional study comprised 400 participants that included group I: normal glucose tolerant subjects (NGT, n=150), group II: type 2 diabetes mellitus subjects (T2DM, n=150) and group III: infected diabetic foot ulcer subjects (DFU, n=100). The non-synonymous SNP rs182428269 was selected based on in silico analysis and genotyped by PCR-restriction fragment length polymorphism (RFLP) followed by bidirectional Sanger sequencing. In addition, the gene expression of NRF2 in patients with polymorphism was analyzed by qPCR to evaluate the functional impact of the SNP. NRF2 expression was significantly decreased among the T2DM and DFU subjects when compared to the NGT subjects. Of particular interest, the homozygous mutant (TT) genotype of rs182428269 polymorphism was significantly associated with an increased risk for the development of T2DM (OR=1.95 (1.02-3.72), p=0.04) and DFU (OR=5.66 (2.98-10.76), p=0.0001). Furthermore, a progressive decline in NRF2 expression was observed among the T2DM and DFU subjects with "TT" genotype compared to the "CC" and "CT" genotypes. NRF2 polymorphism rs182428269 is associated with the pathogenesis of T2DM and DFU.

Different mechanisms of GIP and GLP-1 action explain their different therapeutic efficacy in type 2 diabetes

Background and aimsThe reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. MethodsWe used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. Resultsa) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. ConclusionWe show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.

Pioglitazone corrects dysregulation of skeletal muscle mitochondrial proteins involved in ATP synthesis in type 2 diabetes

ContextIn this study, we aimed to identify the determinants of mitochondrial dysfunction in skeletal muscle (SKLM) of subjects with type 2 diabetes (T2DM), and to evaluate the effect of pioglitazone (PIO) on SKLM mitochondrial proteome. MethodsTwo different groups of adults were studied. Group I consisted of 8 individuals with normal glucose tolerance (NGT) and 8 with T2DM, subjected to SKLM mitochondrial proteome analysis by 2D-gel electrophoresis followed by mass spectrometry-based protein identification. Group II included 24 individuals with NGT and 24 with T2DM, whose SKLM biopsies were subjected to immunoblot analysis. Of the 24 subjects with T2DM, 20 were randomized to receive placebo or PIO (15 mg daily) for 6 months. After 6 months of treatment, SKLM biopsy was repeated. ResultsMitochondrial proteomic analysis on Group I revealed that several mitochondrial proteins involved in oxidative metabolism were differentially expressed between T2DM and NGT groups, with a downregulation of ATP synthase alpha chain (ATP5A), electron transfer flavoprotein alpha-subunit (ETFA), cytochrome c oxidase subunit VIb isoform 1 (CX6B1), pyruvate dehydrogenase protein X component (ODPX), dihydrolipoamide dehydrogenase (DLDH), dihydrolipoamide-S-succinyltransferase (DLST), and mitofilin, and an up-regulation of hydroxyacyl-CoA-dehydrogenase (HCDH), 3,2-trans-enoyl-CoA-isomerase (D3D2) and delta3,5-delta2,4-dienoyl-CoA-isomerase (ECH1) in T2DM as compared to NGT subjects. By immunoblot analysis on SKLM lysates obtained from Group II we confirmed that, in comparison to NGT subjects, those with T2DM exhibited lower protein levels of ATP5A (−30%, P = 0.006), ETFA (−50%, P = 0.02), CX6B1 (−30%, P = 0.03), key factors for ATP biosynthesis, and of the structural protein mitofilin (−30%, P = 0.01). T2DM was associated with a reduced abundance of the enzymes involved in the Krebs cycle DLST and ODPX (−20%, P ≤ 0.05) and increased levels of HCDH and ECH1, enzymes implicated in the fatty acid catabolism (+30%, P ≤ 0.05).In subjects with type 2 diabetes treated with PIO for 6 months we found a restored SKLM protein abundance of ATP5A, ETFA, CX6B1, and mitofilin. Moreover, protein levels of HCDH and ECH1 were reduced by −10% and − 15% respectively (P ≤ 0.05 for both) after PIO treatment. ConclusionType 2 diabetes is associated with reduced levels of mitochondrial proteins involved in oxidative phosphorylation and an increased abundance of enzymes implicated in fatty acid catabolism in SKLM. PIO treatment is able to improve SKLM mitochondrial proteomic profile in subjects with T2DM.

Effect of Mild Physiologic Hyperglycemia on Insulin Secretion, Insulin Clearance, and Insulin Sensitivity in Healthy Glucose-Tolerant Subjects.

The aim of the current study was to evaluate the effect of sustained physiologic increase of ∼50 mg/dL in plasma glucose concentration on insulin secretion in normal glucose-tolerant (NGT) subjects. Twelve NGT subjects without family history of type 2 diabetes mellitus (T2DM; FH-) and 8 NGT with family history of T2DM (FH+) received an oral glucose tolerance test and two-step hyperglycemic clamp (100 and 300 mg/dL) followed by intravenous arginine bolus before and after 72-h glucose infusion. Fasting plasma glucose increased from 94 ± 2 to 142 ± 4 mg/dL for 72 h. First-phase insulin secretion (0-10 min) increased by 70%, while second-phase insulin secretion during the first (10-80 min) and second (90-160 min) hyperglycemic clamp steps increased by 3.8-fold and 1.9-fold, respectively, following 72 h of physiologic hyperglycemia. Insulin sensitivity during hyperglycemic clamp declined by ∼30% and ∼55% (both P < 0.05), respectively, during the first and second hyperglycemic clamp steps. Insulin secretion/insulin resistance (disposition) index declined by 60% (second clamp step) and by 62% following arginine (both P < 0.005) following 72-h glucose infusion. The effect of 72-h glucose infusion on insulin secretion and insulin sensitivity was similar in subjects with and without FH of T2DM. Following 72 h of physiologic hyperglycemia, metabolic clearance rate of insulin was markedly reduced (P < 0.01). These results demonstrate that sustained physiologic hyperglycemia for 72 h 1) increases absolute insulin secretion but impairs β-cell function, 2) causes insulin resistance, and 3) reduces metabolic clearance rate of insulin.

Placenta expression of vitamin D and related genes in pregnant women with gestational diabetes mellitus

Objectives and MethodsA total of 41 GDM and 40 normal glucose tolerance subjects were recruited. Through detecting the level of Serum vitamin D with electrochemical luminescence and vitamin D receptor (VDR) with Enzyme-linked immunosorbent assay (ELISA) in maternal and cord blood, the expression leves of CYP24A1, CYP27B1, VDR protein and mRNA in placenta and umbilical cord with western blotting and RT-PCR, and the DNA methylation levels of CYP24A1 and CYP27B1 gene in placenta with methylation-specific PCR (MSP) and direct bisulfite sequencing (BSP) analysis to explore the potential role of the vitamin D and its related genes in gestational diabetes mellitus (GDM). ResultsSerum vitamin D concentrations were significantly higher in normal pregnant than women with GDM in maternal blood (P < 0.01) and cord blood (P = 0.014). Compared to the control group, the expression levels of CYP24A1 protein (P < 0.01) and mRNA (P = 0.021) and VDR protein (P = 0.026) and mRNA (P = 0.023) in the GDM group were significantly higher in placenta and umbilical cord tissues (P = 0.015, P < 0.01, P = 0.028, P < 0.01, respectively), while that of CYP27B1 protein (P < 0.01) and mRNA (P = 0.042) was significantly lower (P = 0.022, P = 0.032, respectively). Moreover, partial DNA methylation of CYP24A1 and CYP27B1 genes was observed in both GDM and control groups. ConclusionsVitamin D deficiency participates in the pathogenesis of GDM, and changes in the expression of genes related to the vitamin D metabolic pathway are closely related to vitamin D levels in the pregnancy and fetus. However, DNA methylation of CYP24A1 and CYP27B1 might not be involved in the pathogenesis of GDM.

Impact of type 2 diabetes variants identified through genome-wide association studies in early-onset type 2 diabetes from South Indian population.

The prevalence of early-onset type 2 diabetes (EOT2D) is increasing in Asian countries. Genome-wide association studies performed in European and various other populations have identified associations of numerous variants with type 2 diabetes in adults. However, the genetic component of EOT2D which is still unexplored could have similarities with late-onset type 2 diabetes. Here in the present study we aim to identify the association of variants with EOT2D in South Indian population. Twenty-five variants from 18 gene loci were genotyped in 1,188 EOT2D and 1,183 normal glucose tolerant subjects using the MassARRAY technology. We confirm the association of the HHEX variant rs1111875 with EOT2D in this South Indian population and also the association of CDKN2A/2B (rs7020996) and TCF7L2 (rs4506565) with EOT2D. Logistic regression analyses of the TCF7L2 variant rs4506565(A/T), showed that the heterozygous and homozygous carriers for allele ‘T’ have odds ratios of 1.47 (95% confidence interval [CI], 1.17 to 1.83; p = 0.001) and 1.65 (95% CI, 1.18 to 2.28; p = 0.006) respectively, relative to AA homozygote. For the HHEX variant rs1111875 (T/C), heterozygous and homozygous carriers for allele ‘C’ have odds ratios of 1.13 (95% CI, 0.91 to 1.42; p = 0.27) and 1.58 (95% CI, 1.17 to 2.12; p = 0.003) respectively, relative to the TT homozygote. For CDKN2A/2B variant rs7020996, the heterozygous and homozygous carriers of allele ‘C’ were protective with odds ratios of 0.65 (95% CI, 0.51 to 0.83; p = 0.0004) and 0.62 (95% CI, 0.27 to 1.39; p = 0.24) respectively, relative to TT homozygote. This is the first study to report on the association of HHEX variant rs1111875 with EOT2D in this population.

Prediabetes uncovers differential gene expression at fasting and in response to oral glucose load in immune cells

Metabolic disorders including diabetes are associated with immune cell dysfunction. However, the effect of normal glucose metabolism or impairment thereof on immune cell gene expression is not well known. Hence, in this cross-sectional pilot study, we sought to determine the differences in gene expression in the peripheral blood mono-nuclear cells (PBMCs) of normal glucose tolerant (NGT) and prediabetic (PD) Asian Indian men, at fasting and in response to 75g oral glucose load. Illumina HT12 bead chip-based microarray was performed on PBMCs at fasting and 2-h post load conditions for NGT (N=6) and PD (N=9) subjects. Following normalization and due quality control of the raw data, differentially expressed genes (DEGs) under different conditions within and across the two groups were identified using GeneSpring GX V12.0 software. Paired and unpaired Student's t-tests were applied along with fold change cut-offs for appropriate comparisons. Validation of the microarray data was carried out through real-time qPCR analysis. Significantly regulated biological pathways were analyzed by employing DEGs and DAVID resource. Deconvolution of the DEGs between NGT and PD subjects at fasting was performed using CIBERSORT and genes involved in regulatory T-cell (Treg) function were further analyzed for biological significance. Glucose load specifically altered the expression of 112 genes in NGT and 356 genes in PD subjects. Biological significance analysis revealed transient up-regulation of innate and adaptive immune response related genes following oral glucose load in NGT individuals, which was not observed in PD subjects. Instead, in the PD group, glucose load led to an increase in the expression of pro-atherogenic and anti-angiogenic genes. Comparison of gene expression at fasting state in PD versus NGT revealed 21,707 differentially expressed genes. Biological significance analysis of the immune function related genes between these two groups (at fasting) revealed higher gene expression of members of the TLR signaling, MHC class II molecules, and T-cell receptor, chemotaxis and adhesion pathways in PD subjects. Expression of interferon-γ (IFN-γ) and TNFα was higher and that of type-1 interferons and TGF-β was lower at fasting state in PD subjects compared to NGT. Additionally, expression of multiple proteasome subunits and protein arginine methyl transferase genes (PRMTs) were higher and that of Treg specific genes was significantly distinct at fasting in PD subjects compared to NGT. Prediabetes uncovers constitutive TLR activation, enhanced IFN-γ signaling, and Treg dysfunction at fasting along with altered gene expression response to oral glucose load.

Obstructive Sleep Apnea Exacerbates Glucose Dysmetabolism and Pancreatic β-Cell Dysfunction in Overweight and Obese Nondiabetic Young Adults.

PurposeThis study aimed to investigate the effects of obstructive sleep apnea (OSA) on the pancreatic β-cells dysfunction and their implications in the glucose dysmetabolism of overweight and obese nondiabetic young adults.Materials and MethodsThe cross-sectional analysis included 422 subjects (261 males/161 females) with the mean age of 27.77 ± 7.51 years and average body mass index (BMI) of 34.84 ± 5.69 kg/m2. All subjects underwent polysomnography (PSG), oral glucose tolerance-insulin releasing test (OGTT-IRT) and serum glycosylated hemoglobin A1 (HbA1c) measurement. The glucose metabolism and pancreatic β-cell function in relation to measures of OSA were determined adjustment for important confounders such as age and sex.ResultsOSA subjects accounted for 54.91% in the normal glucose tolerance (NGT) group and 72.11% in the prediabetes (preDM) group (P =0.001). HbA1c was the highest in the preDM subjects with severe OSA. In the NGT subjects, the 1-h glucose level significantly elevated with the OSA severity, and the homeostasis model assessment-β (HOMA-β) was negatively related to nocturnal mean SpO2 (P <0.05). In the preDM subjects, HOMA-β, early phase insulinogenic index (∆I30/∆G30), total area under the curve of insulin in 180 min (AUC-I180), and the oral disposition index (DIO) were the lowest in the severe OSA group. DIO was associated with higher oxygen desaturation index (ODI) and lower nocturnal mean SpO2, and AUC-I180 was negatively related to TS90 (P <0.05).ConclusionOur study indicated higher prevalence of OSA in overweight and obese nondiabetic young adults, especially preDM subjects. The impaired glucose tolerance was observed early after glucose intake in the NGT subjects. OSA induces compensatory increase in the pancreatic β-cell function in the NGT subjects, while pancreatic β-cell dysfunction is present in the preDM subjects with severe OSA.

SAT-623 Glucose Intolerance Modifies the Association Between Insulin-Like Growth Factor-1 and All-Cause Mortality

Background: Despite an increase in literature on insulin-like growth factor-1 (IGF-1) and its impact on insulin sensitivity, there remains controversy over its association with all-cause mortality. Insulin interacts with IGF-1 and its binding proteins, forming a growth hormone/IGF-1/insulin axis that may be impaired in Type II diabetes and/or prediabetes. We hypothesized that the association between insulin and IGF-1 with all-cause mortality differs in those with glucose intolerance (GI) in a nationally representative U.S. population with long-term follow-up. Methods: A total of 5,283 non-pregnant adults >20 years from the National Health and Nutrition Examination Survey (NHANES)-III (1988-1994) were linked to the National Death Index through 2015. Glucose intolerance was classified as per fasting blood sugar (≥100 mg/dl), hemoglobin A1c (≥5.7%), medication use, or self-reported diagnosis. IGF-1 was categorized into sex-specific quartiles. To analyze the joint impact of insulin and IGF-1, we also categorized participants into four groups: Group I) IGF-1 <230 ng/mL & insulin ≥11 uIU/mL, II) IGF-1 <230 & insulin <11, III) IGF-1 ≥230 & insulin ≥11, and IV) IGF-1 ≥230 & insulin <11. Our primary outcome was all-cause mortality. We used survey design-adjusted Cox regression to estimate the risk of all-cause mortality, adjusting for confounders. Results: Among the 5,283 subjects, 2,214 (42%) had GI. Participants had a mean follow-up of 22.1 years, during which 1,835 (34%) of them died. Those with GI in the highest quartile of IGF-1 had an unadjusted 64% lower risk of all-cause mortality compared to the lowest quartile (GI = unadjusted OR [95% CI]: 0.37 [0.24,0.55]). This association, although protective, was significantly less protective than those with normal glucose tolerance (NGT) (unadjusted OR: 0.16 [0.12,0.23]). After adjusting for confounders, these associations became insignificant (GI = aOR: 1.02 [0.73,1.42], NGT = aOR: 1.04 [0.74,1.46]). When estimating risk of mortality among joint groups of insulin and IGF-1 levels, those in Group I with NGT had 20% increased adjusted odds of mortality (1.30 [1.01,1.71]), while in GI subjects, there was an insignificant increased odds of mortality (1.17 [0.84, 1.62]). Neither subgroup in Group 2 had significant adjusted odds of mortality relative to Group 4. Group 3 subjects with GI had an adjusted, insignificant 24% increased odds of mortality (1.24 [0.91, 1.70]) compared to 70% increased odds in NGT subjects (1.69 [1.18, 2.42]). Conclusion: The differences in odds of all-cause mortality across IGF-1 quartiles in glucose tolerant vs. intolerant individuals suggests that IGF-1 may play less of a protective role in Type II diabetes and prediabetes. Among those with normal glucose, higher insulin levels, regardless of IGF-1 levels, was associated with all-cause mortality. This association did not hold in those with glucose intolerance.