Orals

2017 Diabetes  
Lower serum uromodulin (umod) levels correlate with decreasing kidney function, but their relationship with coronary artery disease (CAD) is unknown. We examined the relationships between serum umod, and the development of albuminuria, chronic kidney disease (CKD) and progression of coronary artery calcium (CAC) in adults with type 1 diabetes (T1D), over 12-years. Participants with T1D (n=539, mean age of 40±9, HbA1c 7.7±1.2%, 53% women) in the Coronary Artery Calcification in Type 1 Diabetes
more » ... udy were assessed for CAC progression (128-slice spiral CT), urinary albumin to creatinine ratio (UACR) and estimated GFR (eGFR) calculated by CKD-EPI creatinine. CKD was defined as eGFR <60mL/min/1.73m 2 , albuminuria as UACR ≥30 mg/g, and CAC progression as a change in the square root transformed CAC volume ≥2.5. Serum umod was measured using immunoassay kits from Meso Scale Discovery. Logistic regression was used to examine the relationship between umod and incident albuminuria, CKD, or CAC progression, controlling for age, sex, diabetes duration, HbA1c, SBP and LDL-C. Integrated discrimination index (IDI) and net-reclassification improvement (NRI) were used to assess the added prediction performance of umod to a model with age, sex, diabetes duration and ABC risk factors. CAC progression was observed in 49%, incident albuminuria in 6% and incident CKD in 6% of the subjects. Serum umod at baseline was associated with CAC progression (OR: 0.66 95% CI [0.47-0.94] per one SD=138.7 mcg/mg), incident albuminuria (0.27 [0.11-0.65]) and incident ) in adjusted models. Results were similar for CAC progression when adjusting for baseline eGFR and UACR, and when excluding participants with CKD or albuminuria. The addition of umod to the baseline model improved relative IDI for CAC progression by 6% (p=0.008) and correctly re-classified 22% cases of CAC progression (p=0.02). In conclusion, lower serum umod levels independently predict development of CAC in adults with T1D. Connective tissue growth factor (CTGF) is a potent chemotactic and extracellular matrix-inducing growth factor that has been implicated in progression of inflammatory and fibroproliferative disorders. An emerging role of CTGF is that of a prosclerotic factor implicated in the development of cardiac disease. Therefore, our objective was to determine the role of CTGF as a predictor of cardiovascular disease events in type 2 diabetes in the VADT cohort. Levels of CTGF were measured in 952 VADT patients, a median of 1.9 years after entry into the study. Participants were followed for an average of 3.3 years for vascular outcomes. CTGF categories were defined as below the detectable limit (i.e., referent, 54.5%), lower half of detectable values (i.e., 22.8%) and upper half of detectable values (22.7%). Hazard ratios (HRs) for CV endpoints in relation to CTGF categories were calculated by Cox proportional hazard models. During follow-up, 4.8% had an MI and 6.9% had an MI or cardiovascular death. After adjustments by conventional risk factors, individuals in the highest category of CTGF were at higher risk of MI [HR=2.40 (95% CI: 1.18, 4.87)] and MI or cardiovascular death [HR=2.73 (95% CI: 1.50, 4.96)], relative to individuals with CTGF below the detectable limit. Our study indicates that high levels of CTGF predict future MI and cardiovascular death in patients with type 2 diabetes. Background: The association between serum high-sensitivity C-reactive protein (hsCRP) and cardiovascular disease (CVD) in type 2 diabetes (T2DM) remains controversial. Previous studies, performed mostly in Western populations, demonstrated its prognostic importance only in T2DM subjects with known CVD but not in those without. Here, we investigated prospectively whether serum hsCRP could predict incident cardiovascular outcomes in Chinese subjects with T2DM with no known CVD. Method: Baseline serum hsCRP levels were measured in 5,746 Chinese subjects with T2DM recruited from the Hong Kong West Diabetes Registry. The role of serum hsCRP in predicting incident CVD was analyzed using Cox regression analysis. Results: Amongst 3,742 subjects with no known CVD, 295 (7.9%) developed incident CVD over a median follow-up of 3.8 years. On multivariable Cox regression analysis, baseline serum hsCRP levels independently predicted incident CVD (Hazard ratio [HR] 1.11; 95% confidence interval [CI] 1.01-1.22; p = 0.024). Serum hsCRP ≥3mg/L, derived either by hsCRP quartiles or from cut-points suggested by the American Heart Association, was an independent predictor of incident CVD (HR 1.50, 95% CI 1.06-2.13, p = 0.022 and HR 1.51, 95% CI 1.13-2.03, p = 0.006, respectively), with significantly improved category free net reclassification index (NRI; p=0.036) and integrated discrimination improvement (IDI; p=0.012), beyond the prediction by conventional cardiovascular risk factors including gender, age, smoking status, diabetes duration, HbA1c, hypertension, dyslipidemia, estimated glomerular filtration rate and albuminuria status. Conclusions: Serum hsCRP, at a cut-off of ≥3mg/L, was an independent predictor of incident CVD and could be usefully employed for risk stratification in primary prevention of CVD among Chinese subjects with T2DM. Both type 2 diabetes (T2DM) and chronic kidney disease (CKD) are associated with a high risk of cardiovascular disease (CVD) and premature death. We aimed at investigating the single and joint effects of T2DM and of CKD on all-cause mortality in high-risk patients with established CVD. We prospectively investigated 2,108 patients with established CVD (1,789 with angiographically proven coronary artery disease and 319 with sonographically proven peripheral artery disease) over 7.0±2.7 years. Deaths occurred more frequently in T2DM patients (n=652) than in nondiabetic subjects (38.2% vs. 19.6%; p <0.001) and in patients with CKD (estimated glomerular filtration ratee GFR (eGFR) <60ml/min/1.73m²; n=357) than in those with an eGFR ≥60ml/min/1.73m² (48.8% vs. 19.8%; p <0.001). When both, T2DM and CKD were considered, 1,248 subjects had neither T2DM nor CKD, 503 had T2DM but not CKD, 208 did not have diabetes but had CKD, and 149 had both diabetes and CKD. When compared with mortality among patients with neither T2DM nor CKD (16.1%), mortality was significantly higher in patients with T2DM who did not have CKD (30.5%; p<0.001) as well as in nondiabetic patients with CKD (40.1%; p<0.001) and was highest in patients with both, T2DM and CKD (62.4%; p <0.001), in whom mortality was higher than in those with T2DM but no CKD (p<0.001) or those without T2DM but with CKD (p=0.045); mortality was higher in nondiabetic CKD patients than in in diabetic patients who did not have CKD (p=0.013). We conclude that CKD in patients with established CVD confers an even higher mortality risk than T2DM. Mortality is extremely high in CVD patients with the combination of CKD and diabetes. EMPA significantly reduced CV death, body weight, and visceral adiposity (VA) vs. placebo (PBO) in the EMPA-REG OUTCOME trial. We explored for heterogeneity of effects on adiposity by age, sex, and degree of abdominal obesity. Patients with T2D and CVD were randomized to receive PBO, EMPA 10 or EMPA 25 mg daily added to standard care. Changes from baseline to week 164 for body weight and validated markers of VA (waist circumference, index of central obesity, and estimated total body fat), were assessed for PBO and EMPA across subgroups of age, sex, and baseline waist circumference using a mixed model repeated measures analysis in randomized patients who received ≥1 dose of study drug using all measurements obtained until study end. 2333, 2345 and 2342 patients received PBO, EMPA 10 mg and EMPA 25 mg. Mean (SE) baseline weight was 86.7 (0.4), 86.0 (0.4), 86.5 (0.4) kg, respectively. There were greater reductions in weight and markers of VA among patients treated with EMPA compared with PBO across most age, sex, and abdominal obesity groups (Table) . EMPA consistently reduced body weight and markers of VA mostly irrespective of age, sex, or degree of baseline VA. Further analyses are needed to determine the potential contribution of these changes to the observed CV mortality benefit with EMPA. Table. Most of the high morbidity and mortality associated with type 2 diabetes (T2D) is due to cardiovascular (CV) disease. Higher systolic blood pressure (BP) increases CV risk in T2D, but intensively reducing systolic BP to <120mmHg as compared to a standard regimen (<140mmHg) did not improve CV outcomes in high risk T2D subjects in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial. To identify individuals that could yet benefit from intensive BP control, we used an unbiased genome-wide approach testing 6.8M common variants to discover polymorphisms (SNPs) predicting the primary composite outcome (CV death, non-fatal myocardial infarction and stroke) among 1,151 white subjects in the intensive BP arm of the ACCORD genetic substudy. A SNP near LOC101929596 at 2p22.1 attained genome-wide significance (p=3x10 -8 ). SNPs close to LINC00161 at 22q21.3, HDAC9 at 7p21.1, STX8 at 17p13.1, and LINC01630 at 18q21.2 reached p<1x10 -7 and 16 other SNPs attained notable significance at p<1x10 -6 . In a joint analysis of both treatment arms (n=2,295), the top SNP was a significant modulator of the CV response to treatment (p=0.0004). Major allele homozygotes at this locus experienced a significant benefit on the primary outcome from intensive vs. standard BP control [HR 0.66, 95% CI 0.49-0.88, p=0.006], whereas minor allele carriers experienced a 2-fold increase in CV events in response to intensive therapy [HR 2.22, 95% CI 1.21-4.06, p=0.01]. These findings suggest that a personalized medicine approach could be potentially used to improve the effectiveness of intensive BP control in preventing CV complications of T2D. While several genes near the top loci (such as HDAC9, AUTS2, ESSRG, PTPRM, FHIT, SLC8A1, SPHKAP and GRIN2B) have been previously implicated in CV risk factors and/or disease, the genome-wide significant locus (LOC101929596) is a novel CV locus. Mechanistic studies of these genetic effects may expand our understanding of the pathophysiology of atherosclerosis in diabetes. Plasma branched-chain amino acids (BCAA), including valine (Val), leucine (Leu), and isoleucine (Ile) are related to adiposity, associated with insulin resistance, and predict incident type 2 diabetes in adults. These associations are not well defined in youth. We examined the cross-sectional and longitudinal relations of BCAA with BMI and insulin sensitivity in children randomly recruited at mean age 12.9±1.1 (baseline; n=300) and re-examined at mean age 21.6±1.7 (follow-up; n=160). Body mass index (BMI), insulin sensitivity (measured by the hyperinsulinemic euglycemic insulin clamp; expressed as M lbm ), and plasma BCAA (measured by NMR spectroscopy) were obtained at each visit. All data are mean±SE. Cross-sectional and longitudinal associations were estimated for individual BCAA or composite BCAA score (Val+Lea+Ile) for dependent variables M lbm and BMI using repeated measures regression models, adjusting for Tanner stage, sex, and race. At baseline, insulin sensitivity was significantly, inversely related to Val (β= -29.7±7.7, p=0.0002), Leu (β = -77.2±19.9, p=0.0001), Ile (β = -89.2± 23.5, p=0.0002), and composite BCAAs (β = -19.2±4.8, p<0.001), and BCAA was also directly related to BMI (p<0.001 all). These associations also were seen at follow-up. Longitudinal changes in BMI were significantly, positively associated with concurrent changes in Val (β= 0.23±0.07, p=0.0016), Leu (β = 0.23±0.07, p=0.0003), Ile (β = -0.20±0.05, p=0.0002), and composite BCAA (β = -0.27±0.07, p=0.0002), and longitudinal changes in insulin sensitivity were inversely related to concurrent changes in Val (β= -0.44±018, p=0.014) and composite BCAA (β= -0.38±017, p=0.029). However, baseline BCAA did not predict changes in M lbm or BMI. These results show that: 1) BCAA are already significantly related to M lbm and BMI in childhood; 2) these relations persist and track into young adulthood; and 3) adverse metabolic processes effecting insulin sensitivity begins early in biologic development. Background: Few studies assess the long-term risk of developing type 2 diabetes (T2DM) in obese youth. The objective of this study was to determine T2DM risk among obese and severely obese American Indian youth from the southwestern U.S. Methods: Incidence of T2DM was computed in 4,883 nondiabetic youths ages 10-17 years who were enrolled between 1965 and 2007 and followed for up to 20 years or until the onset of T2DM. Age-sex adjusted BMI %iles were defined using the CDC 2000 growth charts. Obese youth were further classified by % of 95 th %ile to demonstrate the effect of severity of obesity on incidence. Results: Median age of the cohort at baseline was 12.1 years (IQR: 11.7-13.7), 53.4% were female. Over a median follow-up of 11.7 years (IQR: 5.3-20.0), 648 youths developed T2DM (11.1 per 1000 person-years). T2DM incidence rates increased with severity of obesity and were generally higher in girls ( Figure A) . Compared to those with a BMI between the 50 th -75 th %ile, obese girls had 3 to 7-fold higher and obese boys had 6 to 20-fold higher diabetes incidence rates ( Figure B) . Conclusion: This longitudinal study assesses long-term diabetes risk with incremental increase in BMI among obese youth, it shows that risk continues to increase with increasing obesity severity above the 95 th %ile; our study adds to the understanding of the metabolic risk gradient in obesity and will help in planning early therapeutic interventions to mitigate this risk. Figures. Background: Spexin is a novel peptide predominantly produced in human white adipose tissue and recently implicated in the regulation of obesity, energy homeostasis and satiety. It evokes weight loss in rodents with diet induced obesity. A recent study showed that its concentration solely could discriminate between obese and lean children with extreme accuracy, suggesting its potential as a target for obesity management and potentially type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). We hypothesized that dramatic weight reduction would be associated with increased endogenous spexin levels in youth with severe obesity. Methods: Changes in circulating spexin, body mass index (BMI), insulin resistance (HOMA-IR), total (T)-and high molecular weight (HMW)-adiponectin and leptin were measured longitudinally (baseline, 6-m and 12-m) following roux en Y gastric bypass (RYGB) surgery in youth with severe obesity (n= 12; Age=16.7±1.5 years; BMI=51.6±2.9 kg.m -2 ). Pearson and Spearman rank correlations were used, as appropriate, to explore associations of spexin with other biomarkers of diabetes and CVD at baseline as well as changes overtime; t-test was used to compare changes at 6-m and 12-m following surgery. Data were expressed as mean±SD. Results: Spexin increased (p=0.01) at 6-mo following surgery; the magnitude of change in spexin was correlated with corresponding decreases in BMI at 6-mo and stabilized afterwards. Spexin also showed significant correlations with HOMA-IR (r= -0.796; p=0.002) and T-and HMW-adiponectins (r=0.512 and 0.691 and p=0.08 and 0.01 respectively). Conclusions: Dramatic weight reduction after RYGB was associated with enhanced circulating levels of spexin in youth with severe obesity. The findings suggest the relevance of spexin in the regulation of BMI, insulin resistance and adiponectin following RYGB in humans. Individuals with rare mutations in human Ether-a-go-go related gene (hERG) have an increased risk of arrhythmias (alterations in QT interval) and also exhibit alterations in secretion of insulin, glucagon and incretin hormones due to a dysfunctional Kv11.1 voltage-gated potassium channel. The aim of this study was to evaluate the effect of coding polymorphisms in hERG (the minor A-allele of rs36210421 R1047L and the minor G-allele of rs1805123 K897T) on electrocardiogram-derived QT interval and circulating plasma levels of of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic popypeptide (GIP), insulin and glucagon. Electrocardiograms from the population-based Inter99 study (n=5895) were used for assessment of heart rate corrected QT-interval. Participants from the ADDITION-PRO study of individuals at high risk of diabetes were included (n=1351) to study the genetic association with glucose homeostasis and incretins. The amino acid polymorphisms, rs36210421 and rs1805123, were associated with shorter QT interval (β =-0.12, p=0.025 and β= -0.11, p= 1.9 x 10 -7 ) and with alterations in plasma incretin response and pancreatic hormone secretion. Rs36210421 was associated with higher plasma GLP-1 levels (p< 0.03), while rs1805123 was associated with lower plasma fasting insulin, fasting glucagon, glucagon AUC30min and glucagon AUC120min (p-values ranging from 0.003-0.02) levels. The additive effect of both variants was negatively associated with fasting insulin, GIP and glucagon as well as GIP AUC30min , glucagon AUC30min , GLP-1 IAUC30min and GLP-1 IAUC120min (p values ranging from 0.005-0.02). Amino acid polymorphisms of hERG, rs36210421 and rs180512, affect circulating plasma levels of insulin, GLP-1, GIP and glucagon, suggesting that the examined hERG channel play an important role in fasting and glucosestimulated release of the specified pancreatic and intestinal hormones. Insulin resistance syndromes are a group of rare, but clinically important, conditions typically inherited in a monogenic fashion. These conditions help contribute to our knowledge of insulin signaling and resistance. Fibroblast growth factor-21 (FGF-21) is a recently discovered peptide that has gained attention for its important effects on insulin sensitivity, growth hormone, and fertility. We report a case of a 12 year old female presenting to pediatric diabetes clinic with extremely tall stature, acanthosis nigricans, severe hirsutism, obesity, and acromegaloid features. The subject and her first-degree relatives underwent metabolic phenotyping and whole exome sequencing. The subject's IGF-1 was normal, however she was noted to have extremely elevated insulin (1279 uIU/mL) postprandially. She also had biochemical hyperandrogenism with elevated free testosterone (16 pg/mL). The subject's bone age was 14 years, giving her a predicted adult height of 1.83m (+3.23 SDS). Two hour oral glucose tolerance testing indicated an undetectable growth hormone at 90 minutes, however her insulin was elevated to 799 uIU/mL at 60 minutes. Whole exome sequencing identified 2 rare, predicted deleterious, variants in 2 genes critical to the FGF-21 signaling pathway, Fibroblast Growth Factor Receptor-1 (FGF-R1) and beta Klotho (KLB). FGF-R1 and KLB are transmembrane co-factors that bind FGF-21. These variants (p.V102I and p.S9Y) were inherited in trans from each parent. They are extremely rare, and are predicted to be damaging by the majority of in-silico variant prediction programs. The subject's FGF-21 level was elevated (391.3 pg/mL) compared to her father (104.3 pg/mL) and mother (225.2 pg/mL). We hypothesize that together, the FGF-R1 and KLB mutations act in a dominant and synergistic manner, resulting in this subject's severe insulin resistance, tall stature, and hirsutism. If true, this would represent a novel category of insulin resistance syndromes related to FGF-21. Diagnosis of type 2 diabetes occurs long after underlying metabolic changes have occurred. Prediabetes is currently defined by three tests: fasting glucose, 2-hr glucose, and HbA1c. Although all three predict diabetes, they differ somewhat in their biological underpinnings. Furthermore, only 12.3% of prediabetics in Starr County meet all three criteria. We recently performed untargeted metabolomic and lipidomic assays to obtain a total of 7,661 raw features on 155 samples from 127 unrelated females as a pilot analysis at the University of Michigan. 28 individuals were profiled at two time points 10 years apart with selection based on their BMI profiles; 14 showing significant BMI increases vs. 14 showing no changes. Results show distinctive amino acid signatures in normal and prediabetic individuals. Moreover, we observed differences in amino acid levels between subtypes of prediabetes. We also performed multi-dimensional variable selection to take full advantage of the untargeted metabolomics data with an Elastic Net. The model selected 74 metabolites out of the thousands (k-NN imputed). The resulting PCA plot showed excellent separation of prediabetes samples from normal individuals based on these 74 metabolites. We will extend our analyses with full metabolomic and genomic profiles, to enable understanding the biology of the development, progression, and subtypes of type 2 diabetes. Figures. Compensation for β-cell loss is an important therapeutic goal for countering type 1 diabetes (T1D). To explore whether enhanced β-cell replication prior to immune cell infiltration, protects against T1D we crossed the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, characterized by robust β-cell proliferation, onto the Nonobese Diabetic (NOD) background. Similar to NOD mice, female NOD-Lox (control) mice developed diabetes and died; however, surprisingly, >95% of NOD-LIRKO mice were normoglycemic and survived up to 2 years. NOD-LIRKOs showed increased β-cell proliferation, hyperplastic islets and decreased β-cell apoptosis. While NOD-LIRKO mice exhibited virtually absent lymphocyte infiltration in islets, it was clearly detected in salivary glands in both groups suggesting islet specific protection. FACS analyses revealed a significant increase in regulatory T-cells (Tregs) (p=0.008) in NOD-LIRKO mice. Adoptive transfer studies showed that total splenocytes (SPLs) from normoglycemic NOD-LIRKO mice failed to transfer diabetes into 66.6% of immunodeficient NOD.Rag1 (-) mice (n=12) and prevented development of diabetes in 69.2% of prediabetic NOD-Lox animals (n=13). In contrast, 100% of mice developed diabetes after receiving NOD-Lox SPLs (n=12). Additionally, transfer of SPLs, mixed from NOD-Lox and NOD-LIRKO mice in a ratio of 1:1 or 3:1, protected 40% and 65% of recipient NSG mice from diabetes development respectively. Finally, transfer of diabetogenic SPLs from NOD mouse donors led to diabetes only in NSG but not in NOD-LIRKOs. Immunoflourescent staining of pancreas and proteomics analyses of β-cells revealed significantly reduced expression of β-cell Beta-2-Microglobulin (B2M) in NOD-LIRKOs. These data provide novel evidence that enhanced proliferation early in life alters the identity of β-cells leading to altered self-reactivity of effector cells and a beneficial increase in Tregs to prevent progression of T1D.
doi:10.2337/db17-1-380 fatcat:fcp34ta7dbhc5dg747d3mepca4