Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes : the PROLONG study

Type 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes.Peer reviewe

Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men

Context Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified. Objective To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL) response to a fat-rich meal. Design Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m(2)) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal. Main Outcome Measures Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins. Results The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p <0.0001; r = 0.46, p <0.001 and r = 0.69, p <0.001, respectively). Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest. Conclusions In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor.Peer reviewe

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Effect of tight control of HbA1c and blood pressure on cardiovascular diseases in type 2 diabetes: An observational study from the Swedish National Diabetes Register (NDR)

Aim: To estimate hazard ratio (HR) of first incident fatal/non-fatal cardiovascular diseases (CVD) in female/male type 2 diabetic patients, with tight versus adverse control of HbA1c and blood pressure (BP) at baseline, age 30-70 years, no baseline CVD, followed for mean 5.7 years. Methods: 2593 patients with tight control of HbA1c <7.5% and BP <= 140/90 mmHg (median 6.5%/130/80 mmHg), and 2160 patients with adverse control 7.5-9.0%/141-190/91-110 mmHg (median 8.1%/155/85 mmHg). Results: The hazard ratio (HR) for CVD with tight/adverse control was 0.67 (0.55-0.80; p < 0.001), adjusting for age, sex, duration, hypoglycaemic treatment, smoking, BMI, lipid-lowering drugs, antihypertensive drugs, microalbuminuria. Adjusted HR for myocardial infarction, coronary heart disease, stroke and total mortality were 0.72 (0.56-0.92; p = 0.01), 0.69 (0.55-0.86; p < 0.001), 0.62 (0.45-0.84; p < 0.001), 1.00 (0.72-1.39). The partial population-attributable risk percent for myocardial infarction, stroke and CVD was 23%, 33%, 29% if adverse HbA1c/BP control could be avoided, while 43%, 38%, 39% with overweight and smoking also avoided. Baseline lower BMI and absence of microalbuminuria were associated with tight control. Conclusion: Median difference of HbA1c/BP 1.6%/25/5 mmHg between tight and adverse control considerably reduced the risk of cardiovascular diseases. The findings call for a multi-factorial approach to improve HbA1c, BP, obesity, smoking, and microalbuminuria. (C) 2009 Elsevier Ireland Ltd. All rights reserved

Blood lipids in 75,048 type 2 diabetic patients: a population-based survey from the Swedish National diabetes register

Background: Type 2 diabetes and diabetic dyslipidemia are high-risk conditions for cardiovascular disease. However, the description of the distribution of blood lipids in diabetic patients has not been based on population-based surveys. The aim of this study was to describe diabetic dyslipidemia in a large unselected sample of patients from the Swedish National Diabetes Register. Methods: Blood lipid profiles and clinical characteristics in 75,048 type 2 diabetic patients (57% men) were studied. Results: Pronounced hypertriglyceridemia (triglycerides >4.0mmol/l) was seen in 3.4% of the patients. Total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and non-HDL-C were generally higher, and LDL-C/HDL-C and Non-HDL-C/HDL-C ratios were lower in women. Mean TC, LDL-C as well as HDL-C values were lower in patients treated with lipid-lowering agents, whereas triglycerides was higher than in the untreated patients. In patients not treated with lipid-lowering agents all blood lipids increased in women and decreased in men (except HDL-C) at higher ages. Patients with LDL-C/HDL-C ratio >= 3 were slightly younger, less frequently used lipid-lowering drugs and had not so often a history of coronary heart disease or stroke. Conclusion: The distribution of blood lipids in this large sample of unselected type 2 diabetic patients challenges the previous conception of diabetic dyslipidemia, and calls for new studies to explain the roles of LDL-C and HDL-C as strong cardiovascular risk factors in type 2 diabetes

Data from: Cephalic phase of insulin secretion in response to a meal is unrelated to family history of Type 2 diabetes

The pre-absorptive cephalic phase of insulin secretion is elicited during the first ten min of a meal and before glucose levels rise. Its importance for insulin release during the post-absorptive phase has been well documented in animals but its presence or importance in man has become increasingly controversial. We here examined the presence of an early cephalic phase of insulin release in 31 well matched individuals without (n=15) or with (n=16) a known family history of type 2 diabetes (first-degree relatives; FDR). We also examined the potential differences in individuals with or without impaired fasting (IFG) and impaired glucose tolerance (IGT). We here demonstrate that a cephalic phase of insulin secretion was present in all individuals examined and without any differences between control persons and FDR or IFG/IGT. However, the overall importance of the cephalic phase is conjectural since it was unrelated to the subsequent post-absorptive insulin release or glucose tolerance. One of the best predictors of the incremental cephalic phase of insulin release was fasting insulin level and, thus, a relation to degree of insulin sensitivity is likely. In conclusion, an early pre-absorptive and cephalic phase of insulin release is robustly present in man. However, we could not document any relation to family history of Type 2 diabetes nor to the post-absorptive phase and, thus, confirm its importance for subsequent degree of insulin release or glucose tolerance

Data from: Cephalic phase of insulin secretion in response to a meal is unrelated to family history of Type 2 diabetes

The pre-absorptive cephalic phase of insulin secretion is elicited during the first ten min of a meal and before glucose levels rise. Its importance for insulin release during the post-absorptive phase has been well documented in animals but its presence or importance in man has become increasingly controversial. We here examined the presence of an early cephalic phase of insulin release in 31 well matched individuals without (n=15) or with (n=16) a known family history of type 2 diabetes (first-degree relatives; FDR). We also examined the potential differences in individuals with or without impaired fasting (IFG) and impaired glucose tolerance (IGT). We here demonstrate that a cephalic phase of insulin secretion was present in all individuals examined and without any differences between control persons and FDR or IFG/IGT. However, the overall importance of the cephalic phase is conjectural since it was unrelated to the subsequent post-absorptive insulin release or glucose tolerance. One of the best predictors of the incremental cephalic phase of insulin release was fasting insulin level and, thus, a relation to degree of insulin sensitivity is likely. In conclusion, an early pre-absorptive and cephalic phase of insulin release is robustly present in man. However, we could not document any relation to family history of Type 2 diabetes nor to the post-absorptive phase and, thus, confirm its importance for subsequent degree of insulin release or glucose tolerance