Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes

Aims/hypothesis

Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes.

Methods

We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007–2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n?=?345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n?=?784]) and non-diabetic (Malmö Preventive Project [n?=?2,523], Botnia study [n?=?2,247]) cohorts.

Results

In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p?=?0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n?=?1,233 cases, n?=?2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p?=?0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n?=?2,499, β?±?SEM, ?3.7?±?1.2 ml/min, p?=?0.002) and also in non-diabetic individuals (n?=?17,602, β?±?SEM, ?0.008?±?0.003 ml/min (log _e ), p?=?0.006).

Conclusions/interpretation

These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.     

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.     

Early Response to Preventive Strategies in the Diabetes Prevention Program

BACKGROUND

Recommendations for diabetes prevention in patients with prediabetes include lifestyle modification and metformin. However, the significance of early weight loss and glucose measurements when monitoring response to these proven interventions is unknown.

OBJECTIVE

To quantify the relationship between early measures of weight and glucose and subsequent diabetes in patients undergoing diabetes prevention interventions.

DESIGN

Analysis of results from a randomized controlled trial in 27 academic medical centers in the United States.

PARTICIPANTS/INTERVENTIONS

3,041 adults with hyperglycemia randomized to lifestyle (n?=?1,018), metformin (n?=?1,036), or placebo (n?=?987) with complete follow-up in The Diabetes Prevention Program.

MAIN MEASURES

Independent variables were weight loss at 6 and 12 months; fasting glucose (FG) at 6 months; hemoglobin A1c (HbA1c) at 6 months; and post-load glucose at 12 months. The main outcome was time to diabetes diagnosis.

KEY RESULTS

After 6 months, 604 participants developed diabetes in the lifestyle (n?=?140), metformin (n?=?206), and placebo (n?=?258) arms over 2.7 years. In the lifestyle arm, 6-month weight loss predicted decreased diabetes risk in a graded fashion: adjusted HR (95 % CI) 0.65 (0.35–1.22), 0.62 (0.33–1.18), 0.46 (0.24–0.87), 0.34 (0.18–0.64), and 0.15 (0.07–0.30) for 0–<3 %, 3–<5 %, 5–<7 %, 7–<10 %, and ≥10 % weight loss, respectively (reference: weight gain). Attainment of optimal 6-month FG and HbA1c and 12-month post-load glucose predicted >60 % lower diabetes risk across arms. We found a significant interaction between 6-month weight loss and FG in the lifestyle arm (P?=?0.038).

CONCLUSION

Weight and glucose at 6 and 12 months strongly predict lower subsequent diabetes risk with a lifestyle intervention; lower FG predicts lower risk even with substantial weight loss. Early reduction in glycemia is a stronger predictor of future diabetes risk than weight loss for metformin. We offer the first evidence to guide clinicians in making interval management decisions for high-risk patients undertaking measures to prevent diabetes.     

Genetic variation in MTNR1B is associated with gestational diabetes mellitus and contributes only to the absolute level of beta cell compensation in Mexican Americans

Aims/hypothesis

MTNR1B is a type 2 diabetes susceptibility locus associated with cross-sectional measures of insulin secretion. We hypothesised that variation in MTNR1B contributes to the absolute level of a diabetes-related trait, temporal rate of change in that trait, or both.

Methods

We tested rs10830963 for association with cross-sectional diabetes-related traits in up to 1,383 individuals or with rate of change in the same phenotypes over a 3–5 year follow-up in up to 374 individuals from the family-based BetaGene study of Mexican Americans.

Results

rs10830963 was associated cross-sectionally with fasting glucose (p?=?0.0069), acute insulin response (AIR; p?=?0.0013), disposition index (p?=?0.00078), glucose effectiveness (p?=?0.018) and gestational diabetes mellitus (OR 1.48; p?=?0.012), but not with OGTT 30 min Δinsulin (the difference between the 30 min and fasting plasma insulin concentration) or 30 min insulin-based disposition index. rs10830963 was also associated with rate of change in fasting glucose (p?=?0.043), OGTT 30 min Δinsulin (p?=?0.01) and AIR (p?=?0.037). There was no evidence for an association with the rate of change in beta cell compensation for insulin resistance.

Conclusions/interpretation

We conclude that variation in MTNR1B contributes to the absolute level of insulin secretion but not to differences in the temporal rate of change in insulin secretion. The observed association with the rate of change in insulin secretion reflects the natural physiological response to changes in underlying insulin sensitivity and is not a direct effect of the variant.     

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.     

A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes

Aims/hypotheses

Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1.

Methods

Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T?=?0 min) and lunch (T?=?240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays.

Results

Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T?=?0–240 min, area under the curve (AUC) 2,075?±?368 vs 2,216?±?163 mmol/l?×?min) and lunch (T?=?240–480 min, AUC 1,916?±?115 vs 2,088?±?151 mmol/l?×?min) (p?=?0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p?=?0.08) and lunch (p?=?0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p?=?0.002 for each) for active pellets.

Conclusions/interpretation

Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes.

Trial registration

Australian New Zealand Clinical Trials Registry ACTRN12612000600842.

Funding

The study was funded by Meyer Nutriceuticals.     

Improved patient survival with simultaneous pancreas and kidney transplantation in recipients with diabetic end-stage renal disease

Aims/hypothesis

We aimed to determine whether simultaneous pancreas and kidney (SPK) transplantation would improve patient and kidney graft survival in diabetic end-stage renal disease (ESRD) compared with kidney transplantation alone (KTA).

Methods

Follow-up data were retrieved for all 630 patients with diabetic ESRD who had received SPK or KTA at our centre from 1983 to the end of 2010. Recipients younger than 55 years of age received either an SPK (n?=?222) or, if available, a single live donor kidney (LDK; n?=?171). Older recipients and recipients with greater comorbidity received a single deceased donor kidney (DDK; n?=?237). Survival was analysed by the Kaplan–Meier method and in multivariate Cox regression analysis adjusting for recipient and donor characteristics.

Results

Patient survival was superior in SPK compared with both LDK and DDK recipients in univariate analysis. Follow-up time (mean?±?SD) after transplantation was 7.1?±?5.7 years. Median actuarial patient survival was 14.0 years for SPK, 11.5 years for LDK and 6.7 years for DDK recipients. In multivariate analyses including recipient age, sex, treatment modality, time on dialysis and era, SPK transplantation was protective for all-cause mortality compared with both LDK (p?=?0.02) and DDK (p?=?0.029) transplantation. After the year 2000, overall patient survival improved compared with previous years (HR 0.40, 95% CI 0.30, 0.55; p?<?0.001). Pancreas graft survival also improved after 2000, with a 5 year graft survival rate of 78% vs 61% in previous years (1988–1999).

Conclusions/interpretation

Recipients of SPK transplants have superior patient survival compared with both LDK and DDK recipients, with improved results seen over the last decade.     

Effect of Colesevelam HCl Monotherapy on Lipid Particles in Type 2 Diabetes Mellitus

Purpose

In addition to lowering hemoglobin A1C, colesevelam has been shown to improve the atherogenic lipoprotein profile of subjects with type 2 diabetes mellitus (T2DM) when used in combination with metformin and/or sulfonylureas. A recent study evaluated the effects of colesevelam as antidiabetes monotherapy in adults with T2DM who had inadequate glycemic control (hemoglobin A1C ≥7.5 to ≤9.5 %) with diet and exercise alone; we report here the effects on lipoprotein particle subclasses.

Methods

Subjects were randomized to receive oral colesevelam 3.75 g/day (n?=?176) or placebo (n?=?181) for 24 weeks. Changes in lipoprotein particle subclasses were determined by nuclear magnetic resonance spectroscopy.

Results

At Week 24 with last observation carried forward, colesevelam produced a reduction in total low-density lipoprotein (LDL) particle concentration (baseline: 1,611 nmol/L; least-squares [LS] mean treatment difference: ?143 nmol/L, p?<?0.0001) versus placebo; reductions were also seen in large, small, and very small LDL particle concentrations (all p?<?0.05). There was also a reduction in total very low-density lipoprotein (VLDL) and chylomicron particle concentration (baseline: 88 nmol/L; LS mean treatment difference: ?1 nmol/L, p?=?0.82) that resulted from a lowering in small VLDL particle concentration (baseline: 45 nmol/L; LS mean treatment difference: ?5 nmol/L, p?=?0.03). In addition, with colesevelam there was an increase in total high-density lipoprotein (HDL) particle concentration versus placebo (baseline: 31 μmol/L; LS mean treatment difference: +0.6 μmol/L, p?=?0.20), due to increases in the large (baseline: 5 μmol/L; LS mean treatment difference: +0.5 μmol/L, p?=?0.007) and medium (baseline: 3 μmol/L; LS mean treatment difference: +0.8 μmol/L, p?=?0.02) HDL subclasses.

Conclusions

Colesevelam monotherapy in subjects with T2DM resulted in generally favorable changes in certain lipoprotein subclass profiles compared with placebo.     

Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes

Aims/hypothesis

The aim of this study was to compare glycaemic control and maternal–fetal outcomes in women with type 1 diabetes managed on insulin pumps compared with multiple daily injections of insulin (MDI).

Methods

In a retrospective study, glycaemic control and outcomes of 387 consecutive pregnancies in women with type 1 diabetes who attended specialised clinics at three centres 2006–2010 were assessed.

Results

Women using insulin pumps (129/387) were older and had a longer duration of diabetes, more retinopathy, smoked less in pregnancy, and had more preconception care (p?<?0.01 for each). Among 113 pregnancies >20 weeks’ gestation in women on insulin pumps and 218 in women on MDI, there was a significant difference in HbA_1c in the first trimester (mean HbA_1c 6.90?±?0.71% (52?±?7.8 mmol/mol) vs 7.60?±?1.38% (60?±?15.1 mmol/mol), p?<?0.001), which persisted until the third trimester (mean HbA_1c 6.49?±?0.52% (47?±?5.7 mmol/mol) vs 6.81?±?0.85% (51?±?9.3 mmol/mol), p?=?0.002). Rates of diabetic ketoacidosis were similar in women on insulin pumps vs MDI (1.8% vs 3.0%, p?=?0.72). Despite lower HbA_1c, women on insulin pumps did not have an increased incidence of severe hypoglycaemia (8.0% vs 7.6%, p?=?0.90) or more weight gain (16.3?±?8.7 vs 15.2?±?6.2 kg, p?=?0.18). More large-for-gestational-age infants in the pump group (55.0% vs 39.2%, p?=?0.007) may have resulted from confounding by parity.

Conclusions/interpretation

In this large multicentre study, women using insulin pumps in pregnancy had lower HbA_1c without increased risk of severe hypoglycaemia or diabetic ketoacidosis but no improvement in other pregnancy outcomes. This information can help inform care providers and patients about the glycaemic effectiveness and safety of insulin pumps in pregnancy.     

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.     

Genetics correlates with lung function and nocturnal ventilation in myotonic dystrophy

Background

Dystrophia myotonica (DM) is the most frequent adult-onset muscular dystrophy. Type 1 is caused by the cytosine–thymine–guanine (CTG) repeat expansion in the DM protein kinase gene. Respiratory muscle weakness and altered central ventilatory control lead to hypercapnia and lung volume restriction.

Purpose

This study aims to review the respiratory involvement in DM patients and study its relation with genetics.

Methods

Retrospective study of patients with DM referred for respiratory assessment was made. Noninvasive ventilation (NIV) was considered to daytime hypercapnia or symptoms of nocturnal hypoventilation.

Results

Forty-two consecutive patients (37.9?±?13.6 years) were evaluated. Mean CTG length was 642.8?±?439.2 repeats. In the first evaluation, mean forced vital capacity (FVC) was 74.4?±?20.2 %, maximal expiratory pressure (MEP) 35?±?16 %, maximal inspiratory pressure 52?±?23 %, peak cough flow (PCF) 327.3?±?97.7 L/min, arterial pressure of oxygen 79.7?±?11.3 mmHg, arterial pressure of carbon dioxide 45.5?±?6.2 mmHg, overnight minimal peripheral oxygen saturation (SpO₂) 79.6?±?11.6 %, and apnea–hypopnea index 13.9?±?9.9. CTG length was found to be related with MEP (r?=??0.67; p?=?0.001) and SpO₂ (r?=??0.37; p?=?0.039). NIV was started in 25 patients. Ventilated patients had lower FVC (2.19 to 3.21 L; p?<?0.001) and PCF (285.3 to 388.5 L/min; p?=?0.003) and more CTG repeats (826.6 to 388.5 repeats; p?=?0.02). NIV compliance was poor in seven patients (28 %) and related with hypercapnia (r?=?0.87; p?=?0.002) and inspiratory positive airway pressure setting (r?=?0.65; p?=?0.009). Ventilation improved symptoms and nocturnal hypoventilation. Comparing the first and last evaluations, only PCF was significantly lower (275.0 to 310.8 L/min; p?=?0.019).

Conclusions

Ventilatory insufficiency is very common in patients with DM and CTG length may be useful to predict it. Prolonged NIV improves symptoms, nocturnal hypoventilation and maintains daily blood gases. Routine evaluation of PCF should not be forgotten and assisted coughing training provided.     

Atrial fibrillation following open heart surgery: long-term incidence and prognosis

Introduction

While early postoperative atrial fibrillation (post op AF) following valve and coronary artery bypass surgery is a known common cause of increased morbidity and mortality, the late recurrence of AF long term in this group of patients has not been well studied.

Objective

The objective of this study was to assess the late recurrence and predictors of AF in patients undergoing open heart surgery.

Methods

From a prospective cardiovascular surgery registry, 519 patients with no prior history of AF who underwent open heart surgery for cardiac bypass/valvular surgeries between May 2000 and April 2004 were followed until May 2009. A Cox proportional hazards model was used to assess the impact of early post op AF on the long-term AF after adjusting for significant covariates

Results

Of these patients, 25.6 % (133) had early (0–3 months) post op AF (group A). The remainder of patients were considered as controls (group B, n?=?386). Late occurrence of AF (3–84 months) was 5.3 % (n?=?28) after a mean follow up duration of 5?±?1.9 years. The late occurrence of AF in group A (recurrent AF) was significantly higher than in group B (11 vs 3 % n?=?15 vs 13, p?=?0.0002). Early postoperative AF was a significant predictor of late recurrence of AF in multivariate analysis (hazard ratio (HR) 3.9, CI 1.8–8.4, p?=?0.0003). Group A also had higher mortality compared to group B (21 vs 13 %, n?=?28 vs n?=?51, p?=?0.003) with early postoperative AF showing a trend towards higher mortality on multivariate analysis (HR 1.7, p?=?0.06).

Conclusions

Late recurrence of AF is higher than was previously thought to be in patients experiencing early post operative AF with a trend towards higher long-term mortality. Post op AF should not be dismissed as a benign entity and these patients should be followed closely.     

Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis

Aims/hypothesis

End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients.

Methods

We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with (n?=?739) and those without diabetes (n?=?774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9.

Results

According to the Kaplan–Meier method, the 10?year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p?p?=?0.0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA_1c levels showed that the highest quartile group (≥6.8% [51?mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p?=?0.0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p?=?0.023).

Conclusions/interpretation

Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA_1c levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations.     

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.     

Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study

Aims/hypothesis

The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern. We investigated the risk of all-cause mortality associated with individual glucose-lowering treatment regimens used in current clinical practice in Denmark.

Methods

All patients aged ≥30 years hospitalised for the first time for heart failure in 1997–2006 were identified and followed until the end of 2006. Patients who received treatment with metformin, a sulfonylurea and/or insulin were included and assigned to mono-, bi- or triple therapy groups. Multivariable Cox proportional hazard regression models were used to assess the risk of all-cause mortality.

Results

A total of 10,920 patients were included. The median observational time was 844 days (interquartile range 365–1,395 days). In total, 6,187 (57%) patients died. With sulfonylurea monotherapy used as the reference, adjusted hazard ratios for all-cause mortality associated with the different treatment groups were as follows: metformin 0.85 (95% CI 0.75–0.98, p?=?0.02), metformin?+?sulfonylurea 0.89 (95% CI 0.82–0.96, p?=?0.003), metformin?+?insulin 0.96 (95% CI 0.82–1.13, p?=?0.6), metformin?+?insulin?+?sulfonylurea 0.94 (95% CI 0.77–1.15, p?=?0.5), sulfonylurea?+?insulin 0.97 (95% CI 0.86–1.08, p?=?0.5) and insulin 1.14 (95% CI 1.06–1.20, p?=?0.0001).

Conclusions/interpretation

Treatment with metformin is associated with a low risk of mortality in diabetic patients with heart failure compared with treatment with a sulfonylurea or insulin.     

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.     

Impact of childhood-onset type 1 diabetes on schooling: a population-based register study

Aims/hypothesis

We investigated the impact of type 1 diabetes on educational achievements in compulsory and upper secondary school, as well as potential long-lasting effects.

Methods

Altogether 2,485 individuals with type 1 diabetes, diagnosed at the age of <15 years and born in 1972–1978, were selected from the Swedish Childhood Diabetes Register, which was linked to national population registers including the Swedish Education Register. For each individual, four controls from the general population, matched for year of birth and residence at the time of diagnosis, were selected by Statistics Sweden (n?=?9,940). We analysed the impact of diabetes on final school grades at 16 years (compulsory school) and 19 years (upper secondary school) and on participation in the labour market at 29 years using linear, logistic, ordered logistic and quantile regression analyses, controlling for demographics and socioeconomic background.

Results

Diabetes had a negative effect on mean final grades (scale of 1–5) in compulsory school (?0.07, p?<?0.001) and theoretical programmes in upper secondary school (?0.07, p?=?0.001). Children with early-onset diabetes (0–4 years) suffered a greater disadvantage as a result of the disease (?0.15, p?=?0.001 in compulsory school). The strongest effect was seen in the lowest deciles of the conditional distribution on mean final grades. At age 29, individuals with diabetes were less likely to be gainfully employed (OR 0.82, 95% CI 0.73, 0.91).

Conclusions/interpretation

The small but significant negative effect of type 1 diabetes on schooling could affect opportunities for further education and career development. Attention must be paid in school to the special needs of children with diabetes.     

The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers

Aims/hypothesis

The increased all-cause mortality in patients with chronic diabetic foot ulcers cannot fully be explained by traditional cardiovascular risk factors. The significance of heart-rate-corrected QT (QTc) prolongation, a finding often seen in these patients, is unknown. Recently, the importance of metabolic control and hypoglycaemia has been discussed. The aim of this study was to evaluate the impact of different HbA_1c levels and QTc prolongation on all-cause mortality in the high-risk population of patients with type 2 diabetes mellitus and foot ulcers.

Methods

All patients with type 2 diabetes, younger than 80 years, visiting our diabetes foot unit, with a foot ulcer duration >4 weeks, were screened for participation. Patients on dialysis were excluded. Patients were grouped according to HbA_1c level and QTc time ≤ or >?440 ms.

Results

Patients (n?=?214, median age 69.1 years) were grouped according to HbA_1c level (HbA_1c?<?7.5% [<58 mmol/mol] n?=?81, 7.5–8.9% [58–74 mmol/mol] n?=?70, >8.9% [>74 mmol/mol] n?=?63). Baseline characteristics, including use of potential hypoglycaemic drugs, were similar between groups. During the 8 years of follow-up 151 patients died (70.6%) and HbA_1c?<?7.5% (<58 mmol/mol) was strongly associated with increased mortality. The highest mortality was seen in patients with a combination of HbA_1c?<?7.5% (<58 mmol/mol) and QTc prolongation, with an 8 year mortality of 92.1% as compared with 48.8% in those with HbA_1c?<?7.5% (<58 mmol/mol) but without QTc prolongation.

Conclusion/interpretations

HbA_1c?<?7.5% (<58 mmol/mol) in a high-risk population of patients with type 2 diabetes and foot ulcers is associated with a significantly higher mortality, particularly in patients with QTc prolongation.     

The relationship between defibrillation threshold and total mortality

Background

The relationship between the defibrillation threshold (DFT) and total mortality is unclear.

Methods

A university hospital prospectively maintained implantable defibrillator (ICD) database identified 508 patients who underwent ICD implantation and had DFT testing performed at implant. Patients were placed in one of three groups based on the implant DFT (high (≥20 J), moderate (19–11 J), or low DFT (≤10 J)).

Results

Sixty-seven patients had a high DFT, 216 had a moderate DFT, and 225 had a low DFT. The mean left ventricular ejection fraction (LVEF) was 0.25, 0.28, and 0.30 in the high, moderate, and low DFT groups, respectively, (p?=?0.04). There were significantly more patients with a subcutaneous electrode in the high DFT group (p?<?0.001), more patients taking amiodarone (p?<?0.001), and more patients on oral anticoagulation (p?=?0.04). There were a total of 140 deaths during the follow-up period (mean 3.2?±?1.7 years). There were 24 deaths in the high DFT group (35.8 %), 62 in the moderate DFT group (28.7 %), and 54 in the low DFT group (24.0 %) (p?=?0.05). Implant DFT was a significant predictor of mortality (p?=?0.01), as was age, LVEF (p?<?0.001), CAD (p?=?0.01), amiodarone use (p?=?0.02), and hematoma at implant (p?=?0.01). An elevated DFT was an independent predictor of mortality after controlling for all significant univariate variables (p?=?0.004).

Conclusions

A high-implant DFT predicts an adverse prognosis, even when an adequate ICD safety margin is present.     

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.