Genetic predisposition to nephropathy and associated cardiovascular disease in people with type 1 diabetes: role of the angiotensinI-converting enzyme (ACE), and beyond; a narrative review.

Hypertension, cardiovascular disease and kidney failure are associated with persistent hyperglycaemia and the subsequent development of nephropathy in people with diabetes. Diabetic nephropathy is associated with widespread vascular disease affecting both the kidney and the heart from an early stage. However, the risk of diabetic nephropathy in people with type 1 diabetes is strongly genetically determined, as documented in familial transmission studies.

Intensive Glucose Lowering and Its Effects on Vascular Events and Death According to Age at Diagnosis and Duration of Diabetes: The ADVANCE Trial.

Objective: To compare the vascular effects of pursuing more versus less glucose lowering in patients with younger or older age at diabetes diagnosis, and with shorter or longer diabetes duration.

Research Design And Methods: We studied 11,138 participants from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, classified into subgroups defined by age at diabetes diagnosis (≤50, >50-60, and >60 years) and diabetes duration (≤5, >5-10, and >10 years).

Results: Intensive glucose lowering significantly lowered the risk of the primary composite outcome of major macrovascular and microvascular events (hazard ratio 0.

Monoallelic pathogenic variants in LEPR do not cause obesity.

Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous variants in LEPR and to evaluate their effect on obesity.

Lipids and apolipoproteins and the risk of vascular disease and mortality outcomes in women and men with type 2 diabetes in the ADVANCE study.

Aim: Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very-low-density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. The aim of this study was to assess the association between established risk markers, apolipoproteins and the risk of macro- and microvascular disease and death in a large study of women and men with diabetes and to assess the potential sex differences in the associations.

Materials And Methods: Established lipid risk markers were studied in 11 140 individuals with type 2 diabetes from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial, and apolipoproteins (A1, B, ApoB/ApoA1 ratio) and VLDL cholesterol from nuclear magnetic resonance (NMR) lipid analyses in biobanked samples from 3586 individuals included in the ADVANCE case-cohort study (ADVANCE CC).

Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function.

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes.

Pathogenic, Total Loss-of-Function DYRK1B Variants Cause Monogenic Obesity Associated With Type 2 Diabetes.

Objective: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated.

Research Design And Methods: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes.

Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.

Objective: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D).

Methods: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D.

Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas.

Aims/hypothesis: GLIS3 encodes a transcription factor involved in pancreatic beta cell development and function. Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk. Because rare, functional variants located in other susceptibility genes for type 2 diabetes have already been shown to strongly increase individual risk for common type 2 diabetes, we aimed to investigate the contribution of rare pathogenic GLIS3 variants to type 2 diabetes.

Genetic variants of interferon-response factor 5 are associated with the incidence of chronic kidney disease: the D.E.S.I.R. study.

Inflammation has been associated with renal diseases. The Interferon Regulatory Factor (IRF)-5 is a key transcription factor in the pro-inflammatory polarization of M1-like macrophages. GWAS have reported that the IRF5 locus is associated with autoimmune diseases and with the estimated glomerular filtration rate (eGFR).

Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity.

The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in individuals with type 2 diabetes and obesity. The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we show an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain of function (GoF) and loss of function (LoF), after performing a functional profiling of 60 GLP1R variants across four signalling pathways.

Contribution of heterozygous PCSK1 variants to obesity and implications for precision medicine: a case-control study.

Background: Rare biallelic pathogenic mutations in PCSK1 (encoding proprotein convertase subtilisin/kexin type 1 [PC1/3]) cause early-onset obesity associated with various endocrinopathies. Setmelanotide has been approved for carriers of these biallelic mutations in the past 3 years. We aimed to perform a large-scale functional genomic study focusing on rare heterozygous variants of PCSK1 to decipher their putative impact on obesity risk.

Redox Genetic Risk Score and the Incidence of End-Stage Kidney Disease in People with Type 1 Diabetes.

End-stage kidney disease (ESKD) is a multifactorial condition influenced by genetic background, but the extent to which a genetic risk score (GRS) improves ESKD prediction is unknown. We built a redox GRS on the base of previous association studies (six polymorphisms from six redox genes) and tested its relationship with ESKD in three cohorts of people with type 1 diabetes. Among 1012 participants, ESKD (hemodialysis requirement, kidney transplantation, eGFR < 15 mL/min/1.

Initiation of the Fixed Combination IDegLira in Patients with Type 2 Diabetes on Prior Injectable Therapy: Insights from the EASY French Real-World Study.

Introduction: Combining basal insulin (BI) with glucagon-like peptide-1 receptor agonist (GLP-1RA) is recognized as a relevant option to optimize glucose control in type 2 diabetes (T2D). The EASY real-world study aimed to evaluate the modalities of initiation and the effectiveness of the insulin Degludec plus Liraglutide (IDegLira) fixed-ratio combination in the French health care system.

Methods: A retrospective analysis included all patients with T2D and prior injectable therapy (GLP1-RA and/or insulin) who started treatment with IDegLira from September 2016 to December 2017 in 11 French diabetes centers.

Leukocyte telomere length, allelic variations in related genes and risk of coronary heart disease in people with long-standing type 1 diabetes.

Background: Type 1 diabetes is associated with accelerated vascular aging and advanced atherosclerosis resulting in increased rates of cardiovascular disease and premature death. We evaluated associations between Leukocyte telomere length (LTL), allelic variations (SNPs) in LTL-related genes and the incidence of coronary heart disease (CHD) in adults with long-standing type 1 diabetes.

Methods: We assessed associations of LTL, measured at baseline by RT-PCR, and of SNPs in 11 LTL-related genes with the risk of coronary heart disease (CHD: myocardial infarction or coronary revascularization) and all-cause death during follow-up in two multicenter French-Belgian prospective cohorts of people with long-standing type 1 diabetes.

Associations of microvascular complications with all-cause death in patients with diabetes and COVID-19: The CORONADO, ABCD COVID-19 UK national audit and AMERICADO study groups.

Aim: To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD-19.

Materials And Methods: We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID-19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all-cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID-19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer.

Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors.

Background And Objectives: Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear.

Design, Setting, Participants, & Measurements: Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide).

Plasma Adrenomedullin, Allelic Variations in the ADM Gene, and Risk for Lower-Limb Amputation in People With Type 2 Diabetes.

Objective: Patients with diabetes have an increased risk for lower-limb amputation (LLA), but biomarkers to assess risk of LLA are lacking. Adrenomedullin (ADM) is a vasodilator peptide that also plays a role in fluid and electrolyte homeostasis in the kidney, increasing natriuresis and diuresis. ADM was shown to be associated with cardiovascular and renal events in diabetes, but it was not investigated in terms of LLA risk.

Effects of glucose and blood pressure reduction on subclinical cardiac damage: Results from ADVANCE.

Objective: Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial.

Methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Research Controlled Evaluation (ADVANCE) study was a factorial, randomized trial designed to test the effects of intensive blood glucose (hemoglobin A1c ≤6.

Association Between the ACE Insertion/Deletion Polymorphism and Risk of Lower-Limb Amputation in Patients With Long-Standing Type 1 Diabetes.

Objective: The ACE insertion/deletion (I/D) polymorphism has been widely studied in people with diabetes, albeit not with regard to lower-limb amputation (LLA). We examined associations among this polymorphism, plasma ACE concentration, and LLA in people with type 1 diabetes.

Research Design And Methods: ACE I/D genotype and plasma ACE were assessed in three prospective cohorts of participants with type 1 diabetes.

Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment: A subgroup analysis from the FIDELIO-DKD trial.

Aims: Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease and type 2 diabetes in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone.

Materials And Methods: Patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate 25-<75 ml/min per 1.