Effects of hypertriglyceridemia with or without NEFA elevation on β-cell function and insulin clearance and sensitivity.

Aims: Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of non-esterified fatty acids (NEFAs). This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in non-diabetic subjects.

Methods: Twenty-two healthy lean volunteers underwent two 5-h intravenous infusions of either saline or Intralipid, without (n=12) or with heparin (I+H; n=10) to activate the release of NEFAs.

Loss of the Incretin Effect in Type 2 Diabetes: A Systematic Review and Meta-analysis.

Context: Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear.

Objective: To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach.

Methods: PubMed, Scopus, and Web-of-Science were searched.

New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms.

Objective: Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.

Dapagliflozin increases the lean-to total mass ratio in type 2 diabetes mellitus.

We compared the effect of dapagliflozin versus glibenclamide on the ratio of lean-to total mass in patients with type 2 diabetes mellitus, carotid subclinical atherosclerosis, HbA1c 7.0-9.0% and 40-70 years-old.

Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect - a narrative review.

Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans.

Rationale and design of the expanded combination of evolocumab plus empagliflozin in diabetes: EXCEED-BHS3 trial.

Background: Patients with type 2 diabetes mellitus (T2DM) remain at increased cardiovascular residual risk and endothelial dysfunction, even after optimizing metabolic control and treatment by sodium-glucose-2 transporter inhibitors (SGLT2-is). The present study was based on the hypothesis that proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9i) therapy may mitigate endothelial dysfunction in T2DM patients who are on regular treatment by SGLT2-i.

Methods: The EXCEED-BHS3 is a prospective, single-center, investigator-blinded, open-label, randomized clinical trial.

Mechanisms of Sodium-Glucose Cotransporter 2 Inhibition: Insights From Large-Scale Proteomics.

Objective: To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics.

Research Design And Methods: Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected < 0.

Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport.

Introduction: Insulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known.

Methods: We applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects.

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review.

Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules.

Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man.

Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease.

Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes.

Aims/hypothesis: Incretin effect-the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route-is impaired in dysglycaemic states.

Renal Handling of Ketones in Response to Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes.

Objective: Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes.

Research Design And Methods: We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ≥60 mL · min · 1.

Glucose uptake saturation explains glucose kinetics profiles measured by different tests.

It is known that for a given insulin level glucose clearance depends on glucose concentration. However, a quantitative representation of the concomitant effects of hyperinsulinemia and hyperglycemia on glucose clearance, necessary to describe heterogeneous tests such as euglycemic and hyperglycemic clamps and oral tests, is lacking. Data from five studies (123 subjects) using a glucose tracer and including all the above tests in normal and diabetic subjects were collected.

Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes.

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [(2)H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating β-hydroxybutyrate concentrations).

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes.

Aims/hypothesis: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes.

The amino acid response to a mixed meal in patients with type 2 diabetes: effect of sitagliptin treatment.

Aims: Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of α-hydroxybutyrate (α-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and α-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment.

Methods: Forty-seven T2D patients [56 ± 7 years, body mass index (BMI) 29.

Altered pattern of the incretin effect as assessed by modelling in individuals with glucose tolerance ranging from normal to diabetic.

Aims/hypothesis: Oral glucose elicits a higher insulin secretory response than intravenous glucose at matched glucose concentrations. This potentiation, known as the incretin effect, is typically expressed as the difference between the total insulin response to oral vs intravenous glucose. This approach does not describe the dynamics of insulin secretion potentiation.

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes.

Methods: We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.

Long-term effects of bariatric surgery on meal disposal and β-cell function in diabetic and nondiabetic patients.

Gastric bypass surgery leads to marked improvements in glucose tolerance and insulin sensitivity in obese type 2 diabetes (T2D); the impact on glucose fluxes in response to a physiological stimulus, such as a mixed meal test (MTT), has not been determined. We administered an MTT to 12 obese T2D patients and 15 obese nondiabetic (ND) subjects before and 1 year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of β-cell function. In both groups postsurgery, tracer-derived appearance of oral glucose was biphasic, a rapid increase followed by a sharp drop, a pattern that was mirrored by postprandial glucose levels and insulin secretion.

Biliopancreatic diversion in nonobese patients with type 2 diabetes: impact and mechanisms.

Context: Diabetes remission is frequent after biliopancreatic diversion (BPD) in morbidly obese patients with type 2 diabetes (T2D). Data, mechanisms, and clinical indications in nonobese T2D patients are scanty.

Objective: The objective of the study was to assess remission and investigate insulin sensitivity and β-cell function after BPD in nonobese patients with long-standing T2D.

Direct effect of GLP-1 infusion on endogenous glucose production in humans.

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) lowers glucose levels by potentiating glucose-induced insulin secretion and inhibiting glucagon release. The question of whether GLP-1 exerts direct effects on the liver, independently of the hormonal changes, is controversial. We tested whether an exogenous GLP-1 infusion, designed to achieve physiological postprandial levels, directly affects endogenous glucose production (EGP) under conditions mimicking the fasting state in diabetes.

Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes.

Context: Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known.

Objective: The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors.

Body weight, not insulin sensitivity or secretion, may predict spontaneous weight changes in nondiabetic and prediabetic subjects: the RISC study.

Objective: Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes.

Research Design And Methods: In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19-44 kg/m(2), 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and β-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose).

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes.

Aims/hypothesis: Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss.

Methods: We studied 25 morbidly obese patients (BMI 51.