Objectives The purpose of this study was to compare myocardial triglyceride content and function between patients with uncomplicated type 2 diabetes mellitus (T2DM) and healthy subjects within the ...same range of age and body mass index (BMI), and to study the associations between myocardial triglyceride content and function. Background T2DM is a major risk factor for cardiovascular disease. Increasing evidence is emerging that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, by causing lipotoxic injury and myocardial steatosis. Methods Myocardial triglyceride content and myocardial function were measured in 38 T2DM patients and 28 healthy volunteers in the same range of age and BMI by proton magnetic resonance (MR) spectroscopy and MR imaging, respectively. Myocardial triglyceride content was calculated as a percentage relative to the signal of myocardial water. Results Myocardial triglyceride content was significantly higher in T2DM patients compared with healthy volunteers (0.96 ± 0.07% vs. 0.65 ± 0.05%, p < 0.05). Systolic function did not significantly differ between both groups. Indexes of diastolic function, including the ratio of maximal left ventricular early peak filling rate and the maximal left ventricular atrial peak filling rate (E/A) and E peak deceleration, were significantly impaired in T2DM compared with those in healthy subjects (1.08 ± 0.04 ml/s2 × 10−3 vs. 1.24 ± 0.06 ml/s2 × 10−3 and 3.6 ± 0.2 ml/s2 × 10−3 vs. 4.4 ± 0.3 ml/s2 × 10−3 , respectively, p < 0.05). Multivariable analysis indicated that myocardial triglyceride content was associated with E/A and E peak deceleration, independently of diabetic state, age, BMI, heart rate, visceral fat, and diastolic blood pressure. Conclusions Myocardial triglyceride content is increased in uncomplicated T2DM and is associated with impaired left ventricular diastolic function, independently of age, BMI, heart rate, visceral fat, and diastolic blood pressure.
Regional left ventricular (LV) myocardial functional changes in early diabetic cardiomyopathy have not been well documented. LV multidirectional strain and strain rate analyses by 2-dimensional ...speckle tracking were used to detect subtle myocardial dysfunction in 47 asymptomatic, male patients (age 57 ± 6 years) with type 2 diabetes mellitus. The results were compared to those from 53 male controls matched by age, body mass index, and body surface area. No differences were found in the LV end-diastolic volume index (40.7 ± 8.9 vs 44.1 ± 7.8 ml/m2 , p = NS), end-systolic volume index (16.0 ± 4.8 vs 17.8 ± 4.3 ml/m2 , p = NS), ejection fraction (61.0 ± 5.5% vs 59.8 ± 5.3%, p = NS). The transmitral E/A (0.95 ± 0.21 vs 1.12 ± 0.32, p = 0.007) and pulmonary S/D (1.45 ± 0.28 vs 1.25 ± 0.27, p = 0.001) ratios were more impaired in the patients with diabetes mellitus. Importantly, the diabetic patients had impaired longitudinal, but preserved circumferential and radial systolic and diastolic, function. Diabetes mellitus was an independent predictor for longitudinal strain, systolic strain rate and early diastolic strain rate on multiple linear regression analysis (all p <0.001). In conclusion, the LV longitudinal systolic and diastolic function were impaired, but the circumferential and radial functions were preserved in patients with uncomplicated type 2 diabetes mellitus.
Objectives The purpose of this study was to investigate the relationship between hepatic triglyceride content and both myocardial function and metabolism in type 2 diabetes mellitus (T2DM). ...Background Heart disease is the leading cause of mortality in T2DM. Central obesity and hepatic steatosis, both hallmark abnormalities in T2DM, have been related to increased risk of heart disease. Methods Sixty-one T2DM patients underwent myocardial perfusion and substrate metabolism measurements by positron emission tomography, using 15 Owater, 11 Cpalmitate, and 18 F-2-fluoro-2-deoxy- d -glucose. In addition, whole-body insulin sensitivity (M/I) was determined. Myocardial left ventricular function and high-energy phosphate metabolism were measured using magnetic resonance imaging and 31 P-magnetic resonance spectroscopy, respectively. Hepatic triglyceride content was measured by proton magnetic resonance spectroscopy. Patients were divided according to hepatic triglyceride content (T2DM-low ≤5.56% vs. T2DM-high >5.56%). Results In addition to decreased M/I (p = 0.002), T2DM-high patients had reduced myocardial perfusion (p = 0.001), glucose uptake (p = 0.005), and phosphocreatine/adenosine triphosphate (PCr/ATP) ratio (p = 0.003), compared with T2DM-low patients, whereas cardiac fatty acid metabolism and left ventricular function were not different. Hepatic triglyceride content correlated inversely with M/I (Pearson's r = −0.620, p < 0.001), myocardial glucose uptake (r = −0.413, p = 0.001), and PCr/ATP (r = −0.442, p = 0.027). Insulin sensitivity correlated positively with myocardial glucose uptake (r = 0.528, p < 0.001) and borderline with myocardial PCr/ATP (r = 0.367, p = 0.072), whereas a positive association was found between cardiac glucose uptake and PCr/ATP (r = 0.481, p = 0.015). Conclusions High liver triglyceride content in T2DM was associated with decreased myocardial perfusion, glucose uptake, and high-energy phosphate metabolism in conjunction with impaired M/I. The long-term clinical implications of hepatic steatosis with respect to cardiac metabolism and function in the course of T2DM require further study.
Objectives To determine the prevalence of traditional cardiometabolic risk factors and to assess the effect of overweight/obesity on the occurrence of these risk factors in a cohort of children with ...type 1 diabetes mellitus (T1DM). Study design Two hundred eighty-three consecutive patients (3 to 18 years of age) attending an outpatient clinic for T1DM care were included. The prevalence of cardiometabolic risk factors, the metabolic syndrome, and high alanine aminotransferase, were assessed before and after stratification for weight status. Results Of all children (median age, 12.8 years; interquartile range, 9.9 to 16.0; median diabetes duration, 5.3 years; interquartile range, 2.9 to 8.6), 38.5% were overweight/obese ( Z -body mass index ≥1.1). Overall, median HbA1c levels were 8.2% (interquartile range, 7.4 to 9.8), and HbA1c ≥7.5% was present in 73.9%. Microalbuminuria was found in 17.7%, high triglycerides (>1.7 mmol/L) in 17.3%, high LDL-cholesterol (>2.6 mmol/L) in 28.6%, low HDL-cholesterol (<1.1 mmol/L) in 21.2%, and hypertension in 13.1% of patients. In the overweight/obese children with T1DM, versus normal-weight children, a higher prevalence of hypertension (23.9% vs 5.7%), the metabolic syndrome (25.7% vs 6.3%), and alanine aminotransferase >30 IU/L (15.6% vs 4.5%) was found (all P < .05). Conclusions Overweight/obesity and cardiometabolic risk factors were highly prevalent in a pediatric cohort with T1DM. Hypertension, the metabolic syndrome, and high alanine aminotransferase were significantly more prevalent in overweight/obese compared with normal-weight children with T1DM.
Objectives This study was designed to evaluate myocardial substrate and high-energy phosphate (HEP) metabolism in asymptomatic men with well-controlled, uncomplicated type 2 diabetes with verified ...absence of cardiac ischemia, and age-matched control subjects, and to assess the association with myocardial function. Background Metabolic abnormalities, particularly an excessive exposure of the heart to circulating nonesterified fatty acids and myocardial insulin resistance are considered important contributors to diabetic cardiomyopathy in animal models of diabetes. The existence of myocardial metabolic derangements in uncomplicated human type 2 diabetes and their possible contribution to myocardial dysfunction still remain undetermined. Methods In 78 insulin-naive type 2 diabetes men (age 56.5 ± 5.6 years, body mass index 28.7 ± 3.5 kg/m2 , glycosylated hemoglobin A1c 7.1 ± 1.0%; expressed as mean ± SD) without cardiac ischemia and 24 normoglycemic control subjects (age 54.5 ± 7.1 years, body mass index 27.0 ± 2.5 kg/m2 , glycosylated hemoglobin A1c 5.3 ± 0.2%), we assessed myocardial left ventricular (LV) function by magnetic resonance imaging, and myocardial perfusion and substrate metabolism by positron emission tomography using H215 O, carbon11 C-palmitate, and 18-fluorodeoxyglucose 2-fluoro-2-deoxy-D-glucose. Cardiac HEP metabolism was assessed by phosphorous P 31 magnetic resonance spectroscopy. Results In patients, compared with control subjects, LV diastolic function (E/A ratio: 1.04 ± 0.25 vs. 1.26 ± 0.36, p = 0.003) and myocardial glucose uptake (260 ± 128 nmol/ml/min vs. 348 ± 154 nmol/ml/min, p = 0.015) were decreased, whereas myocardial nonesterified fatty acid uptake (88 ± 31 nmol/ml/min vs. 68 ± 18 nmol/ml/min, p = 0.021) and oxidation (85 ± 30 nmol/ml/min vs. 63 ± 19 nmol/ml/min, p = 0.007) were increased. There were no differences in myocardial HEP metabolism or perfusion. No association was found between LV diastolic function and cardiac substrate or HEP metabolism. Conclusions Patients versus control subjects showed impaired LV diastolic function and altered myocardial substrate metabolism, but unchanged HEP metabolism. We found no direct relation between cardiac diastolic function and parameters of myocardial metabolism.
Summary Background Diabetes treatments are needed that are convenient, provide effective glycaemic control, and do not cause weight gain. We aimed to test the hypothesis that improvement in ...haemoglobin A1c (HbA1c ) achieved with once weekly exenatide was superior to that achieved with insulin glargine titrated to glucose targets. Methods In this 26-week, open-label, randomised, parallel study, we compared exenatide with insulin glargine in adults with type 2 diabetes who had suboptimum glycaemic control despite use of maximum tolerated doses of blood-glucose-lowering drugs for 3 months or longer. Patients were randomly assigned to add exenatide (2 mg, once-a-week injection) or insulin glargine (once-daily injection, starting dose 10 IU, target glucose range 4·0–5·5 mmol/L) to their blood-glucose-lowering regimens. Randomisation was with a one-to-one allocation and block size four, stratified according to country and concomitant treatment (70% metformin only; 30% metformin plus sulphonylurea). Participants and clinical investigators were not masked to assignment, but investigators analysing data were. The primary endpoint was change in HbA1c from baseline, and analysis of this outcome was by modified intention to treat for all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov , number NCT00641056. Findings 456 patients were randomly allocated to treatment and were included in the modified intention-to-treat analysis (233 exenatide, 223 insulin glargine). Participants who received at least one dose of study drug and for whom baseline and at least one postbaseline measurement of HbA1c were available were included in the primary efficacy analysis. Change in HbA1c at 26 weeks was greater in patients taking exenatide (n=228; −1·5%, SE 0·05) than in those taking insulin glargine (n=220; −1·3%, 0·06; treatment difference −0·16%, 0·07, 95% CI −0·29 to −0·03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p=0·012). A planned extension period (up to 2·5 years' duration) is in progress. Interpretation Once weekly exenatide is an important therapeutic option for patients for whom risk of hypoglycaemia, weight loss, and convenience are particular concerns. Funding Amylin Pharmaceuticals; Eli Lilly and Company.
When patients with type 2 diabetes start their first injectable therapy, clinicians can choose between glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulins. In DURATION-3, exenatide ...once weekly was compared with insulin glargine (henceforth, glargine) as first injectable therapy. Here, we report the results of the final 3-year follow-up.
DURATION-3 was an open-label randomised trial done between May 13, 2008, and Jan 30, 2012. Patients with type 2 diabetes aged 18 years or older were enrolled at 72 sites worldwide. They were eligible when they had suboptimum glycaemic control (HbA1c 7.1-11.0% 54-97 mmol/mol) despite maximum tolerated doses of metformin alone or with a sulfonylurea for at least 3 months, a stable bodyweight for at least 3 months, and a BMI of 25-45 kg/m(2) (23-45 kg/m(2) in South Korea and Taiwan). Patients were randomly assigned (1:1) by computer-generated random sequence with an interactive voice-response system (block size four, stratified by country and concomitant therapy) to once-weekly exenatide (2 mg subcutaneous injection) or once-daily glargine (titrated to target) to be given in addition to their existing oral glucose-lowering regimens. The primary efficacy measure at 3 years was change in HbA1c from baseline in patients given at least one dose of the assigned drug (ie, analyses by modified intention to treat). Patients, investigators, and data analysts were not masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00641056.
456 patients underwent randomisation and received at least one dose of the assigned drug (233 given exenatide, 223 glargine). At 3 years, least-squares mean HbA1c change was -1.01% (SE 0.07) in the exenatide group versus -0.81% (0.07) in the glargine group (least-squares mean difference -0.20%, SE 0.10, 95% CI -0.39 to -0.02; p=0.03). Transient gastrointestinal adverse events characteristic of GLP-1 receptor agonists were more frequent with exenatide than glargine (nausea: 36 15% of 233 patients vs five 2% of 223; vomiting: 15 6% vs six 3%; diarrhoea: 32 14% vs 15 7%), although frequency of these events did decrease after week 26 in the exenatide group. The proportion of patients who reported serious adverse events in the exenatide group (36 patients 15%) was the same as that in the glargine group (33 15%). The exposure-adjusted rate of overall hypoglycaemia was three times higher in patients given glargine (0.9 events per patient per year) than in those given exenatide (0.3 events per patient per year).
Efficacy of once-weekly exenatide is sustained for 3 years. GLP-1 receptor agonists could be a viable long-term injectable treatment option in patients with type 2 diabetes who have not yet started taking insulin.
Amylin Pharmaceuticals and Eli Lilly.
Patients with coronary artery disease and/or type 2 diabetes mellitus (DM) generally exhibit more epicardial adipose tissue (EAT) than healthy controls. Recently, it has been proposed that EAT ...affects vascular function and structure by secreting proinflammatory and vasoactive substances, thereby potentially contributing to the development of cardiovascular disease. In the present study, the interrelation of EAT, coronary vasomotor function, and coronary artery calcium was investigated in patients with and without DM, who were evaluated for coronary artery disease. Myocardial blood flow (MBF) was assessed at rest and during adenosine-induced hyperemia using 15 O-water positron emission tomography combined with computed tomography to quantify coronary artery calcium and EAT in 199 patients (46 with DM). In this cohort (mean age 58 ± 10 years), the patients with DM had a greater body mass index, heart rate, and systolic blood pressure at rest (all p <0.05). Coronary artery calcium and the EAT volumes were comparable between those with and without DM. Both patient groups showed comparable MBF at rest and coronary vascular resistance. A lower hyperemic MBF and coronary flow reserve (CFR) and greater hyperemic coronary vascular resistance (all p <0.05) was observed in the patients with DM. A pooled analysis showed a positive association of EAT volume with hyperemic coronary vascular resistance but not with the MBF at rest, hyperemic MBF, or coronary vascular resistance at rest. In the group analysis, the EAT volume was inversely associated with hyperemic MBF (r = −0.16, p = 0.05) and CFR (r = −0.17, p = 0.04) and positively with hyperemic coronary vascular resistance (r = 0.26, p = 0.002) only in patients without DM. Multivariate regression analysis, adjusted for age, gender, and body mass index, showed an independent association between the EAT volume and hyperemic MBF (β = −0.16, p = 0.02), CFR (β = −0.16, p = 0.04), and hyperemic coronary vascular resistance (β = 0.25, p <0.001) in the non-DM group. In conclusion, these results suggest a role for EAT in myocardial microvascular dysfunction; however, once DM has developed, other factors might be more dominant in contributing to impaired myocardial microvascular dysfunction.
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