Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP

Aim/hypothesis

A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians.

Methods

Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians.

Results

SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p?=?0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (β?=??1.451%, p?=?4.8?×?10^?4). Another SNP, rs3130501 near to POU5F1–TCF19, was associated with BMI (β?=??0.012, p?=?0.004), type 2 diabetes adjusted for BMI (p?=?0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (β?=?0.080 mmol/l, p?=?0.02) and insulin resistance estimated by homeostatic model (β?=?0.039, p?=?0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p?=?8.9?×?10^?6, OR 1.29 [95% CI 1.15, 1.45]).

Conclusions/interpretation

For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus.     

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

Aims/hypothesis

The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies.

Methods

Midwife records from the Danish State Archives provided information on mother’s age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes.

Results

Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β?=??33 g [95% CI ?55, ?10], p?=?0.004) and CDKAL1 rs7756992 (β?=??22 g [95% CI ?43, ?1], p?=?0.04). The association for the latter locus was confirmed in a meta-analysis (n?=?24,885) (β?=??20 g [95% CI ?29, ?11], p?=?5?×?10^?6). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p?=?0.09); however, in a meta-analysis (n?=?25,164) this type 2 diabetes risk allele was associated with lower birthweight (β?=??16 g [95% CI ?24, ?8], p?=?8?×?10^?5). On average, individuals with high genetic risk (≥25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (β?=??35 g [95% CI ?69, ?2], p?=?0.037).

Conclusions/interpretation

We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.     

The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes

Aims/hypothesis

Recent genome-wide association studies have suggested that a polymorphism in GCKR, the gene encoding the glucokinase regulatory protein, is involved in triacylglycerol regulation. Our aim was to examine in large-scale studies the common GCKR rs780094 polymorphism in relation to metabolic traits (mainly fasting hypertriacylglycerolaemia) and traits related to pancreatic beta cell function.

Methods

The polymorphism was genotyped in 16,853 Danes using Taqman allelic discrimination. Association was analysed in case–control studies and quantitative trait analyses. We also analysed the possible interactive effect between the GCK –30G>A polymorphism and the GCKR rs780094 variant on metabolic traits.

Results

The minor GCKR A-allele of rs780094 is associated with an increased level of fasting serum triacylglycerol (p?=?6?×?10^?14), impaired fasting (p?=?0.001) and OGTT-related insulin release (p?=?3?×?10^?6), reduced homeostasis model assessment of insulin resistance (p?=?0.0004), WHO-defined dyslipidaemia (p?=?6?×?10^?9) and a modestly decreased risk of type 2 diabetes (p?=?0.01). Significantly increased fasting serum insulin concentrations were demonstrated when analysing the GCK ?30A and GCKR rs780094 G-alleles in an additive model.

Conclusions/interpretation

The GCKR rs780094 polymorphism, or another variant with which it is in tight linkage disequilibrium, is likely to increase glucokinase regulatory protein activity to induce improved glycaemic regulation at the expense of hypertriacylglycerolaemia as reflected in the present study of 16,853 Danes. We also suggest an additive effect of GCK and GCKR risk alleles on plasma glucose and serum insulin release.     

HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion

Aims/hypothesis

We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona.

Methods

Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits.

Results

The A allele at rs9268852, which tags HLA-DRB1*02(1602), was associated both with higher HLA-DRB1 mRNA expression (n?=?133, p?=?4.27?×?10^?14) and decreased risk of type 2 diabetes (n?=?3,265, OR 0.723, p?=?0.002). Among persons with normal glucose tolerance (n?=?266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p?=?0.005), higher mean 30?min insulin concentration during an oral glucose tolerance test (p?=?0.017) and higher body fat percentage (p?=?0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity.

Conclusions/interpretation

HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.     

The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1

Aims/hypothesis

Methylglyoxal (MGO) is a major precursor for advanced glycation end-products (AGEs), which are thought to play a role in vascular complications in diabetes. Known MGO-arginine-derived AGEs are 5-hydro-5-methylimidazolone (MG-H1), argpyrimidine and tetrahydropyrimidine (THP). We studied THP in relation to type 1 diabetes, endothelial dysfunction, low-grade inflammation, vascular complications and atherosclerosis.

Methods

We raised and characterised a monoclonal antibody against MGO-derived THP. We measured plasma THP with a competitive ELISA in two cohort studies: study A (198 individuals with type 1 diabetes and 197 controls); study B (individuals with type 1 diabetes, 175 with normoalbuminuria and 198 with macroalbuminuria [>300 mg/24 h]). We measured plasma markers of endothelial dysfunction and low-grade inflammation, and evaluated the presence of THP and N ^ε-(carboxymethyl)lysine (CML) in atherosclerotic arteries.

Results

THP was higher in individuals with type 1 diabetes than in those without (median [interquartile range] 115.5 U/μl [102.4–133.2] and 109.8 U/μl [91.8–122.3], respectively; p?=?0.03). THP was associated with plasma soluble vascular cell adhesion molecule 1 in both study A (standardised β?=?0.48 [95% CI 0.38, 0.58]; p?<?0.001) and study B (standardised β?=?0.31 [95% CI 0.23, 0.40]; p?<?0.001), and with secreted phospholipase A2 (standardised β?=?0.26 [95% CI 0.17, 0.36]; p?<?0.001) in study B. We found no association of THP with micro- or macro-vascular complications. Both THP and CML were detected in atherosclerotic arteries.

Conclusions/interpretation

Our results suggest that MGO-derived THP may reflect endothelial dysfunction among individuals with and without type 1 diabetes, and therefore may potentially play a role in the development of atherosclerosis and vascular disease.     

Type 2 diabetes-related genetic risk scores associated with variations in fasting plasma glucose and development of impaired glucose homeostasis in the prospective DESIR study

Aims/hypothesis

Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes.

Methods

Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis.

Results

The two most inclusive GRS were significantly associated with increased FPG (β?=?0.0011 mmol/l per year per risk allele, p _GRS-1 ?=?8.2?×?10^?5 and p _GRS-2 ?=?6.0?×?10^?6), increased incidence of IFG and type 2 diabetes (per allele: HR _GRS-1 1.03, p?=?4.3?×?10^?9 and HR _GRS-2 1.04, p?=?1.0?×?10^?16), and the 9 year prevalence (OR _GRS-1 1.13 [95% CI 1.10, 1.17], p?=?1.9?×?10^?14 for type 2 diabetes only; OR _GRS-2 1.07 [95% CI 1.05, 1.08], p?=?7.8?×?10^?25, for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI _GRS-1 17.3%, p?=?6.6?×?10^?7; NRI _GRS-2 17.6%, p?=?4.2?×?10^?7; NRI _GRS-3 13.1%, p?=?1.7?×?10^?4).

Conclusions/interpretation

Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population.     

A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads

Aims/hypothesis

An association between elevated fasting plasma glucose and the common rs560887 G allele in the G6PC2/ABCB11 locus has been reported. In Danes we aimed to examine rs560887 in relation to plasma glucose and serum insulin responses following oral and i.v. glucose loads and in relation to hepatic glucose production during a hyperinsulinaemic–euglycaemic clamp. Furthermore, we examined rs560887 for association with impaired fasting glycaemia (IFG), impaired glucose tolerance (IGT), type 2 diabetes and components of the metabolic syndrome.

Methods

rs560887 was genotyped in the Inter99 cohort (n?=?5,899), in 366 young, healthy Danes, in non-diabetic relatives of type 2 diabetic patients (n?=?196), and in young and elderly twins (n?=?159). Participants underwent an OGTT, an IVGTT or a 2 h hyperinsulinaemic–euglycaemic clamp.

Results

The rs560887 G allele associated with elevated fasting plasma glucose (p?=?2?×?10^?14) but not with plasma glucose levels at 30 min (p?=?0.9) or 120 min (p?=?0.9) during an OGTT. G allele carriers had elevated levels of serum insulin at 30 min during an OGTT (p?=?1?×?10^?4) and relatives of type 2 diabetes patients carrying the G allele had an increased acute insulin response (p?=?4?×?10^?4) during an IVGTT. Among elderly twins, G allele carriers had higher basal hepatic glucose production (p?=?0.04). Finally, the G allele associated with the risk of having IFG (OR 1.26, 95% CI 1.08–1.47, p?=?0.002), but not with IGT (OR 0.94, 95% CI 0.82–1.08, p?=?0.4) or type 2 diabetes (OR 0.93, 95% CI 0.84–1.04, p?=?0.2).

Conclusions/interpretation

The common rs560887 G allele in the G6PC2/ABCB11 locus is associated with increased fasting glycaemia and increased risk of IFG, associations that may be partly related to an increased basal hepatic glucose production rate.     

Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study

Aims/hypothesis

Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration.

Methods

Using prospective data on American Indians from the Strong Heart Family Study, we identified 373 individuals defined as progressors (diabetes incident cases), 566 individuals with transitory impaired fasting glucose (IFG) and 1,011 controls (normal fasting glycaemia at all visits). We estimated the heritability (h²) of the traits and the evidence for association with 16 known variants identified in type 2 diabetes genome-wide association studies.

Results

We noted high h² for diabetes progression (h²?=?0.65??±??0.16, p?=?2.7?×?10^?6) but little contribution of genetic factors to transitory IFG (h²?=?0.09??±??0.10, p?=?0.19) for models adjusted for multiple risk factors. At least three variants (in WFS1, TSPAN8 and THADA) were nominally associated with diabetes progression in age- and sex-adjusted analyses with estimates showing the same direction of effects as reported in the discovery European ancestry studies.

Conclusions/interpretation

Our findings do not exclude these loci for diabetes susceptibility in American Indians and suggest phenotypic heterogeneity of the IFG trait, which may have implications for genetic studies when diagnosis is based on a single time-point measure.     

Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes

Aims/hypothesis

Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA).

Methods

We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n?=?911) or type 1 diabetes (n?=?406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n?=?4,002).

Results

Variants in the ZMIZ1 (rs12571751, p?=?4.1?×?10^?5) and TCF7L2 (rs7903146, p?=?5.8?×?10^?4) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p?=?0.0012), HHEX (rs1111875, p?=?0.0024 in Finns) and MTNR1B (rs10830963, p?=?0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p?=?9.5?×?10^?4 in Finns), TP53INP1 (rs896854, p?=?0.005), CDKAL1 (rs7756992, p?=?7.0?×?10^?4; rs7754840, p?=?8.8?×?10^?4) and PROX1 (rs340874, p?=?0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p?=?3.2?×?10^?6) and HNF1A (rs2650000, p?=?0.0012).

Conclusions/interpretation

LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.     

Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance

Aims/hypothesis

Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance.

Methods

Hyperinsulinaemic–euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA_1c. This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts.

Results

In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance (p?<?0.001). The top signals for each locus were rs10241087 (DGKB/TMEM195 [TMEM195 also known as AGMO]) (p?=?4.4?×?10^?5); chr1:217605433 (LYPLAL1) (p?=?3.25?×?10^?4); rs2380949 (GLIS3) (p?=?3.4?×?10^?4); rs55903902 (FADS1) (p?=?5.6?×?10^?4); rs849334 (JAZF1) (p?=?6.4?×?10^?4); rs35749 (IGF1) (p?=?6.7?×?10^?4); and rs9460557 (CDKAL1) (p?=?6.8?×?10^?4).

Conclusions/interpretation

While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.     

In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone

Aims/hypothesis

In patients with type 1 diabetes and end-stage renal disease (ESRD) we aimed to determine whether long-term normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, would preserve kidney graft structure and function better than live donor kidney (LDK) transplantation alone.

Methods

Estimated GFR (eGFR) was calculated in SPK (n?=?25) and LDK (n?=?17) recipients in a stable phase 3 months after transplantation and annually during follow-up. Kidney graft biopsies were obtained at follow-up for measurement of glomerular volume (light microscopy), glomerular basement membrane (GBM) and podocyte foot process widths and mesangial volume fraction (electron microscopy).

Results

SPK and LDK recipients were similar in age and diabetes duration at engraftment. Donor age was higher in the LDK group. Median follow-up time was 10.1 years. Mean HbA_1c levels during follow-up were 5.5?±?0.4% (37?±?5 mmol/mol) and 8.3?±?1.5% (68?±?16 mmol/mol) in the SPK and LDK group, respectively (p?p?=?0.008) and increased mesangial volume fraction (median 0.23 [range 0.13–0.59] vs 0.16 [0.10–0.41]; p?=?0.007) at follow-up. Absolute eGFR change from baseline was ?11?±?21 and ?23?±?15 ml min^?1 1.73 m^?2 (p?=?0.060), whereas eGFR slope was ?1.1 (95% CI ?1.7, ?0.5) and ?2.6 (95% CI ?3.1, ?2.1)?ml min^?1 1.73 m^?2 per year in the SPK and LDK group, respectively (p?=?0.001).

Conclusions/interpretation

In patients with type 1 diabetes and long-term normoglycaemia after successful SPK transplantation, kidney graft ultrastructure and function were better preserved compared with LDK transplantation alone.     

Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: implications for prevention trials

Aims/hypothesis

We investigated whether screening for insulinoma-associated protein (IA-2) beta (IA-2β) autoantibodies (IA-2βA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A).

Methods

IA-2βA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA⁺, GADA⁺ and/or IA-2A⁺ siblings or offspring (<40 years) of type 1 diabetic patients consecutively recruited by the Belgian Diabetes Registry. The median (interquartile range) age of the first-degree relatives was 12 (6–19) years.

Results

Of the first-degree relatives, 24% were IA-2A⁺ (n?=?97), 14% (n?=?59) IA-2βA⁺ and 20% (n?=?80) ZnT8A⁺. IA-2βA and ZnT8A were significantly (p?<?0.001) associated with IA-2A and prediabetes (n?=?86); in IA-2A^? first-degree relatives (n?=?312) the presence of IA-2βA and ZnT8A was associated with an increased progression rate to diabetes (p?<?0.001). Positivity for IA-2A and/or ZnT8A emerged as the most sensitive combination of two markers to identify first-degree relatives with a 5-year progression rate to diabetes of 45% (survival analysis) and as strongest predictor of diabetes (Cox regression analysis). Omission of first-degree relatives protected by HLA-DQ genotypes or maternal diabetes reduced the group to be followed from n?=?409 to n?=?246 (40%) with minor loss in the number of prediabetic IA-2A⁺ or ZnT8A⁺ first-degree relatives identified (n?=?3).

Conclusions/interpretation

IA-2A⁺ and/or ZnT8A⁺ first-degree relatives may be the participants of choice in future secondary prevention trials with immunointervention in relatives of type 1 diabetic patients.     

Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study

Aims/hypothesis

The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes.

Methods

We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR >?3.4 mg/mmol) or an estimated (eGFR) <?60 ml min^?1 1.73 m^?2. CKD progression was based on repeated eGFR measurements and/or the development of albuminuria. CAN was assessed using heart rate variability.

Results

Two hundred and four patients were included in the analysis. At baseline, the prevalence of CKD and CAN was 40% and 42%, respectively. Patients with CAN had lower eGFR and higher prevalence of albuminuria and CKD. Spectral analysis variables were independently associated with eGFR, albuminuria and CKD at baseline. After a follow-up of 2.5 years, eGFR declined to a greater extent in patients with CAN than in those without CAN (?9.0?±?17.8% vs ?3.3?±?10.3%, p?=?0.009). After adjustment for baseline eGFR and baseline differences, CAN remained an independent predictor of eGFR decline over the follow-up period (β?=??3.5, p?=?0.03). Spectral analysis variables were also independent predictors of eGFR decline.

Conclusions/interpretation

CAN was independently associated with CKD, albuminuria and eGFR in patients with type 2 diabetes. In addition, CAN was an independent predictor of the decline in eGFR over the follow-up period. CAN could be used to identify patients with type 2 diabetes who are at increased risk of rapid decline in eGFR, so that preventative therapies might be intensified.     

Weight Loss Success in Metabolic Syndrome by Telephone Interventions: Results from the SHINE Study

BACKGROUND

The Diabetes Prevention Program (DPP) intensive lifestyle intervention resulted in significant weight loss, reducing the development of diabetes, but needs to be adapted to primary care provider (PCP) practices.

OBJECTIVES

To compare a DPP-translation using individual (IC) vs. conference (CC) calls delivered by PCP staff for the outcome of percent weight loss over 2 years.

DESIGN

Randomized clinical trial.

SETTING

Five PCP sites.

PARTICIPANTS

Obese patients with metabolic syndrome, without diabetes (IC, n?=?129; CC, n?=?128).

INTERVENTION

Telephone delivery of the DPP Lifestyle Balance intervention [16-session core curriculum in year 1, 12-session continued telephone contact in year 2 plus telephone coaching sessions (dietitians).

MAIN MEASURES

Weight (kg), body mass index (BMI), and waist circumference.

KEY RESULTS

Baseline data: age?=?52 years, BMI?=?39 kg/m², 75 % female, 85 % non-Hispanic White, 13 % non-Hispanic Black, and 48 % annual incomes <$40,000/year. In the intention-to-treat analyses at year 2, mean percent weight loss was ?5.6 % (CC, p?<?0.001) and ?1.8 % (IC, p?=?0.046) and was greater for CC than for IC (p?=?0.016). At year 2, mean weight loss was 6.2 kg (CC) and 2.2 kg (IC) (p?<?0.001). There was similar weight loss at year 1, but between year 1 and year 2 CC participants continued to lose while IC participants regained. At year 2, 52 % and 43 % (CC) and 29 % and 22 % (IC) of participants lost at least 5 % and 7 % of initial weight. BMI also decreased more for CC than IC (?2.1 kg/m² vs. ?0.8 kg/m² p?<?0.001). Waist circumference decreased by 3.1 cm (CC) and 2.4 cm (IC) at year 2. Completers (≥9 of 16 sessions; mean 13.3 sessions) lost significantly more weight than non-completers (mean 4.3 sessions).

CONCLUSIONS

PCP staff delivery of the DPP lifestyle intervention by telephone can be effective in achieving weight loss in obese people with metabolic syndrome. Greater weight loss may be attained with a group telephone intervention.     

Glucocorticoid treatment impairs microvascular function in healthy men in association with its adverse effects on glucose metabolism and blood pressure: a randomised controlled trial

Aims/hypothesis

Glucocorticoids (GCs) are widely used anti-inflammatory agents that frequently induce side effects, including insulin resistance, diabetes and hypertension. Here, we investigated the contribution of microvascular dysfunction to the development of these adverse effects in healthy men.

Methods

In a randomised, placebo-controlled, dose–response intervention study, 32 healthy normoglycaemic men (age: 21?±?2 years; BMI: 21.9?±?1.7 kg/m²) were allocated to receive prednisolone 30 mg once daily (n?=?12), prednisolone 7.5 mg once daily (n?=?12) or placebo (n?=?8) for 2 weeks using block randomisation. A central office performed the treatment allocation, and medication was dispersed by the hospital pharmacy that was also blinded. Treatment allocation was kept in concealed envelopes. Participants, study personnel conducting the measures and assessing the outcome were blinded to group assignment. The study was conducted at a university hospital. Primary endpoint was prednisolone-induced changes in microvascular function, which was assessed by capillary microscopy. Insulin sensitivity was determined by hyperinsulinaemic–euglycaemic clamp and postprandial glycaemic excursions by standardised meal tests.

Results

Compared with placebo, prednisolone 7.5 mg and 30 mg decreased insulin-stimulated capillary recruitment by 9?±?4% and 17?±?3%, respectively (p?<?0.01). In addition, prednisolone 7.5 mg and 30 mg reduced insulin sensitivity (M value) by ?11.4?±?4.5 μmol kg^?1 min^?1 and ?25.1?±?4.1 μmol kg^?1 min^?1 (p?<?0.001) and increased postprandial glucose levels by 11?±?5% and 27?±?9% (p?<?0.001), respectively. Only high-dose prednisolone increased systolic blood pressure (6?±?1.2 mmHg, p?=?0.006). Prednisolone-induced changes in insulin-stimulated capillary recruitment were associated with insulin sensitivity (r?=?+0.76; p?<?0.001), postprandial glucose concentrations (r?=??0.52; p?<?0.03) and systolic blood pressure (r?=??0.62; p?<?0.001). Prednisolone increased resistin concentrations, which were negatively related to insulin-stimulated capillary recruitment (r?=??0.40; p?=?0.03). No effects were noted on adiponectin and leptin concentrations. Prednisolone treatment was well tolerated; none of the participants left the study.

Conclusions/interpretation

Prednisolone-induced impairment of insulin-stimulated capillary recruitment was paralleled by insulin resistance, increased postprandial glucose levels, hypertension and increased circulating resistin concentrations in healthy men. We propose that GC-induced impairments of microvascular function may contribute to the adverse effects of GC treatment on glucose metabolism and blood pressure.

Trial registration

isrctn.org ISRTCN 78149983

Funding

The study was funded by the Dutch Top Institute Pharma T1-106.     

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Aims/hypothesis

High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus.

Methods

Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFR_INULIN] ≥135 ml? min^?1 1.73 m^?2, n?=?28) or normofiltration (n?=?21) and healthy control individuals (n?=?18).

Results

Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA_1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165?±?9 vs 113?±?2 and 116?±?4 ml min^?1 1.73 m^?2, respectively, p?<?0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p?<?0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophage-derived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colony-stimulating factor (p?≤?0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p?<?0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p?<?0.01).

Conclusions/interpretation

Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.     

Incidence,predictors, and clinical course of atrial tachyarrhythmias in patients with pulmonary hypertension

Background

The prevalence and predictors of atrial tachyarrhythmias (ATa) in patients with pulmonary hypertension (PH) is less well understood.

Methods

We performed a retrospective study including 311 patients with PH, confirmed by right heart catheterization in our center between 2007 and 2011. Baseline characteristics, clinical, echocardiographic, and hemodynamic data were collected and compared between patients with and without ATa.

Results

The mean age was 61?±?13 years with 64 % females. The mean pulmonary artery pressure (mPAP) was 46?±?20 mmHg, mean left ventricular ejection fraction (LVEF) was 55?±?13 %, and mean pulmonary capillary wedge pressure (PCWP) was 19?±?9 mmHg. Of the 311 patients with PH, 121 (39 %) patients had ATa. Patients with ATa were older (p?p?=?0.03), diabetes (p?=?0.015), coronary artery disease (p?p?p?=?0.001), impaired LVEF (p?=?0.02), and left atrial enlargement (p?p?=?0.022). In multivariate analysis using Cox-proportional hazard model, the independent predictors of mortality were age (HR 1.05; p?=?0.003), coronary artery disease (HR 2.34; p?=?0.047), LVEF (HR 0.793; p?=?0.023), and mPAP (HR 1.023; p?=?0.003).

Conclusion

ATa are common in patients with PH. Left heart disease, left atrial enlargement, and elevated PCWP but not right atrial enlargement or mPAP predict the occurrence of ATa in patients with PH.     

Anorectal manometric parameters are influenced by gender and age in subjects with normal bowel function

Purpose

Anorectal manometry provides objective information about anorectal function, but its results depend on the examiner’s skill, the type of equipment, and subject characteristics like age or gender. This single institution, prospective study was performed to investigate the effect of gender and age on the results of anorectal manometry.

Methods

All included subjects completed a questionnaire to assess their bowel function. The survey included 13 validated questions (eight on constipation and five on incontinence) and was used to exclude subjects with pathological constipation or incontinence. Subjects with normal bowel function underwent anorectal manometry to measure anal sphincter length (ASL), maximum resting pressure (MRP), and maximum squeeze pressure (MSP), and the results were compared by gender and age.

Results

The mean age of the 154 participants (94 male and 60 female) was 59.1 years. ASL was greater in men (4.23 vs. 3.85 cm, p?p?=?0.93), but MSP was higher in men (190.18 vs. 116.49 mmHg, p?p?=?0.707). MRP was inversely related to age in both men (R ²?=?0.152, p?R ²?=?0.282, p?R ²?=?0.210, p?Conclusions Anorectal manometric parameters are influenced by gender and age. This should be taken into consideration when interpreting manometric readings in a clinical setting.     

Laparoscopic adjustable gastric banding and progression from impaired fasting glucose to diabetes

Aims/hypothesis

Obesity and dysglycaemia are major risk factors for type 2 diabetes. We determined if obese people undergoing laparoscopic adjustable gastric banding (LAGB) had a reduced risk of progressing from impaired fasting glucose (IFG) to diabetes.

Methods

This was a retrospective cohort study of obese people with IFG who underwent LAGB. Weight and diabetes outcomes after a minimum follow-up period of 4 years (mean ± SD 6.1?±?1.7 years) were compared with those of Australian adults with IFG from a population-based study (AusDiab).

Results

We identified 281 LAGB patients with baseline IFG. Their mean ± SD age and BMI were 46?±?9 years and 46?±?9 kg/m², respectively. The diabetes incidence for patients in the lowest, middle and highest weight loss tertile were 19.1, 3.4 and 1.8 cases/1,000 person-years, respectively. The AusDiab cohort had a lower BMI (28?±?5 kg/m²) and a diabetes incidence of 12.5 cases/1,000 person-years. This increased to 20.5 cases/1,000 person-years when analysis was restricted to the 322 obese AusDiab participants, which was higher than the overall rate of 8.2 cases/1,000 person-years seen in the LAGB group (p?=?0.02). Multivariable analysis of the combined LAGB and AusDiab data suggested that LAGB was associated with ～75% lower risk of diabetes (OR 0.24 [95% CI 0.10, 0.57], p?=?0.004).

Conclusions/interpretation

In obese people with IFG, weight loss after LAGB is associated with a substantially reduced risk of progressing to diabetes over ≥4 years. Bariatric surgery may be an effective diabetes prevention strategy in this population.