Multi-ancestry polygenic risk scores for the prediction of type 2 diabetes and complications in diverse ancestries.

Background: Polygenic risk scores (PRSs) improve type 2 diabetes (T2D) prediction beyond clinical risk factors but perform poorly in non-European populations, where T2D burden is often higher, undermining their global clinical utility.

Methods: We conducted the largest global effort to date to harmonize T2D genome-wide association study (GWAS) meta-analyses across five ancestries-European (EUR), African/African American (AFR), Admixed American (AMR), South Asian (SAS), and East Asian (EAS)-including 360,000 T2D cases and 1·8 million controls (41% non-EUR). We constructed ancestry-specific and multi-ancestry PRSs in training datasets including 11,000 T2D cases and 32,000 controls, and validated their performance in independent datasets including 39,000 T2D cases and 126,000 controls of diverse ancestries.

Impact of diabetes mellitus type-2 on the outcomes following mitral transcatheter edge-to-edge repair (TEER): A meta-analysis.

Background: Diabetes mellitus (DM) has been linked to unfavorable outcomes in patients undergoing Mitral Transcatheter Edge-to-Edge Repair (TEER). Nevertheless, the literature contains conflicting data. This meta-analysis aimed to assess the impact of DM on outcomes following Mitral TEER.

Empagliflozin Enhances Hepatic Glucose Production and Reduces Total-Body Norepinephrine Turnover Rate: A Randomized Trial.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 h) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate.

Cushing Syndrome, Hypercortisolism, and Glucose Homeostasis: A Review.

Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S.

Changes in β-Cell Function and Insulin Sensitivity During Treatment With Dapagliflozin Alone or in Combination With Exenatide in Type 2 Diabetes.

Objective: To examine the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) alone or with glucagon-like peptide 1 receptor agonists (GLP-1RAs) on β-cell function (BCF) in type 2 diabetes. The hypothesis was that an SGLT2i combined with a GLP-1RA provides superior improvement in BCF than either agent alone.

Research Design And Methods: Ninety patients underwent a 180-min oral glucose tolerance test (OGTT) 1) after one drug dose (acute study) (placebo [n = 15], dapagliflozin [n = 25], exenatide [n = 25], and dapagliflozin/exenatide [n = 25]) and 2) after 1 and 4 months of therapy.

Inadequately Controlled Type 2 Diabetes and Hypercortisolism: Improved Glycemia With Mifepristone Treatment.

Objective: In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control.

Glycemic and non-glycemic benefits of initial triple therapy versus sequential add-on therapy in patients with new-onset diabetes: results from the EDICT study.

Introduction: To compare carotid intima-media thickness (cIMT) and liver fat content in subjects who maintained good glycemic control for 6 years on initial triple therapy with metformin/exenatide/pioglitazone versus sequential add-on therapy with metformin followed with glipizide and basal insulin in subjects with new-onset diabetes.

Research Design And Methods: Liver fat content and cIMT were compared among patients with T2DM who received initial triple therapy with metformin/pioglitazone/exenatide (n=29) versus metformin, followed by stepwise addition of glipizide and then insulin glargine (n=26) and who maintained HbA1c<6.5% for 6 years in Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes.

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (n = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping.

Differential Treatment Effects on β-Cell Function Using Model-Based Parameters in Type 2 Diabetes: Results From the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

Objective: To evaluate how model-based parameters of β-cell function change with glucose-lowering treatment and associate with glycemic deterioration in adults with type 2 diabetes (T2D).

Research Design And Methods: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), β-cell function parameters derived from mathematical modeling of oral glucose tolerance tests were assessed at baseline (N = 4,712) and 1, 3, and 5 years following randomization to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin. Parameters included insulin secretion rate (ISR), glucose sensitivity (insulin response to glucose), rate sensitivity (early insulin response), and potentiation.

Impact of pulmonary hypertension on short and long-term outcome after mitral transcatheter edge-to-edge repair: A meta-analysis.

Background: Pulmonary hypertension (pHTN) has been associated with increased morbidity and mortality after mitral Transcatheter Edge-to-Edge Repair (TEER), but the association remains uncertain. This study aims to evaluate the impact of pHTN on cardiovascular outcomes following TEER.

Methods: We searched PubMed, Scopus, and Medline to identify studies reporting outcomes after TEER in individuals with pHTN.

Mesenteric Visceral Lipectomy Improves Glucose Tolerance in Patients With Type 2 Diabetes: A Pilot Study.

Context: Increased mesenteric visceral fat is associated with the metabolic syndrome, insulin resistance, and type 2 diabetes.

Methods: Using targeted cell separation and extraction technology (TC-SET), we examined the effect of removal of intra-abdominal fat, specifically small bowel mesenteric fat, on glycemic control and insulin sensitivity in 7 individuals with obesity and poorly controlled type 2 diabetes (T2D) (glycated hemoglobin [HbA1c] = 8.9% ± 0.

Effect of dapagliflozin on renal haemodynamics in hyperfiltering T2D patients.

Aims: To investigate the effect of sodium-glucose co-transporter 2 inhibitor [SGLT-2i] therapy on renal haemodynamics in T2D patients with glomerular hyperfiltration.

Materials And Methods: Sixty T2D patients with elevated [HYPER] and normal [NORMO] GFR were randomized to dapagliflozin 10 mg/day [DAPA/HYPER, n = 15; DAPA/NORMO, n = 15] or to metformin/glipizide [CONTROL/HYPER, n = 15; CONTROL/NORMO, n = 15] to reach similar glycaemic control after 4 months. GFR was measured with Iohexol and hyperfiltration was empirically defined as >125 mL/min/1.

Effect of Hyperketonemia on Myocardial Function in Patients With Heart Failure and Type 2 Diabetes.

We examined the effect of increased levels of plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in patients with type 2 diabetes (T2DM) with heart failure. Three groups of patients with T2DM (n = 12 per group) with an LV ejection fraction (EF) ≤50% received incremental infusions of β-hydroxybutyrate (β-OH-B) for 3-6 h to increase the plasma β-OH-B concentration throughout the physiologic (groups I and II) and pharmacologic (group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function.

Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects.

Introduction: Low carbohydrate ketogenic diets have received renewed interest for the treatment of obesity and type 2 diabetes. These diets promote weight loss, improve glycemic control, and reduce insulin resistance. However, whether the improvements in glycemic control and insulin sensitivity are secondary to the weight loss or result from a direct effect of hyperketonemia is controversial.

Advances and counterpoints in type 2 diabetes. What is ready for translation into real-world practice, ahead of the guidelines.

This review seeks to address major gaps and delays between our rapidly evolving body of knowledge on type 2 diabetes and its translation into real-world practice. Through updated and improved best practices informed by recent evidence and described herein, we stand to better attain A1c targets, help preserve beta cell integrity and moderate glycemic variability, minimize treatment-emergent hypoglycemia, circumvent prescribing to "treatment failure," and prevent long-term complications. The first topic addressed in this review concerns updates in the 2023 and 2024 diabetes treatment guidelines for which further elaboration can help facilitate integration into routine care.

Pre-Prediabetes: Insulin Resistance Is Associated With Cardiometabolic Risk in Nonobese Patients (STOP DIABETES).

Context: Prior studies have demonstrated glycemic and cardiometabolic risk in the prediabetic state.

Objective: This work aims to examine if insulin resistance (IR) is associated with markers of glycemic, cardiometabolic, and atherosclerotic risk in nonobese, nonprediabetic individuals compared to insulin-sensitive (IS) individuals matched for body mass index (BMI), sex, and age.

Methods: Of 1860 patients from the STOP DIABETES study, 624 had normal fasting plasma glucose, BMI less than 30, and glycated hemoglobin A1c (HbA1c) less than 5.

Managing insulin resistance: the forgotten pathophysiological component of type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists have gained widespread use in the treatment of individuals with type 2 diabetes because of their potent weight loss promoting effect, ability to augment β-cell function, and cardiovascular protective effects. However, despite causing impressive weight loss, GLP-1 receptor agonists do not normalise insulin sensitivity in people with type 2 diabetes and obesity, and the long-term effects of this class of antidiabetic medication on muscle mass, frailty, and bone density have been poorly studied. Although GLP-1 receptor agonists improve insulin sensitivity secondary to weight loss, the only true direct insulin-sensitising drugs are thiazolidinediones.

Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.

Introduction: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper ortisolism in P ients with Difficult to Control Type 2 Di betes Despite Receiving Standard-of-Care Therapies: Preva ence and Treatment with Korl m (Mifepri one) (CATALYST) trial.

Unexplained Residual Risk In Type 2 Diabetes: How Big Is The Problem?

Purpose Of Review: What is new? Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D) individuals. Of the major risk factors for CVD, less than 10% of T2D people meet the American Diabetes Association/American Heart Association recommended goals of therapy. The present review examines how much of the absolute cardiovascular (CV) risk in type 2 diabetes patients can be explained by major CV intervention trials.

Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2D and NGT Subjects.

Acute and chronic sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP). However, the organ-liver versus kidney-responsible for the increase in EGP has not been identified. In this study, 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) received [3-3H]glucose infusion (to measure total EGP) combined with arterial and renal vein catheterization and para-aminohippuric acid infusion for determination of renal blood flow.

Empagliflozin Reduces Liver Fat in Individuals With and Without Diabetes.

Objective: To examine the effect of empagliflozin on liver fat content in individuals with and without type 2 diabetes (T2D) and the relationship between the decrease in liver fat and other metabolic actions of empagliflozin.

Research Design And Methods: Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. Participants underwent 75-g oral glucose tolerance testing and measurement of liver fat content with MRS before therapy and at study end.