1,721,064 research outputs found
What are the pharmacotherapy options for treating prediabetes?
No full textIntroduction: The incidence of type 2 diabetes mellitus (T2DM) has risen to epidemic proportions, and this is associated with enormous cost. T2DM is preceded by 'prediabetes', and the diagnosis of impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) provides an opportunity for targeted intervention. Prediabetic subjects manifest both core defects characteristic of T2DM, that is, insulin resistance and β-cell dysfunction. Interventions which improve insulin sensitivity and/or preserve β-cell function are logical strategies to delay the conversion of IGT/IFG to T2DM or revert glucose tolerance to normal.Areas covered: The authors examine pharmacologic agents that have proven to decrease the conversion of IGT to T2DM and represent potential treatment options in prediabetes.Expert opinion: Weight loss improves whole body insulin sensitivity, preserves β-cell function and decreases progression of prediabetes to T2DM. In real life long-term weight loss is the exception and, even if successful, 40-50% of IGT individuals still progress to T2DM. Pharmacotherapy provides an alternative strategy to improve insulin sensitivity and preserve β-cell function. Thiazolidinediones (TZDs) are highly effective in T2DM prevention. Long-acting glucagon-like peptide-1 (GLP-1) analogs, because they augment β-cell function and promote weight loss, are effective in preventing IGT progression to T2DM. Metformin is considerably less effective than TZDs or GLP-1 analogs
Managing insulin resistance: the forgotten pathophysiological component of type 2 diabetes
No full textGlucagon-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 beta-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. Because of side-effects associated with type 2 diabetes therapy, these drugs have not gained widespread use. In lieu of the important role of insulin resistance in the cause of type 2 diabetes and in the pathogenesis of atherosclerotic cardiovascular disease in type 2 diabetes, development of potent insulin-sensitising drugs that can be used in combination with GLP-1 receptor agonists remains a large unmet need in the management of individuals with type 2 diabetes
SGLT2 inhibitors and cardiovascular risk: Lessons learned from the EMPA-REG Outcome study
Full text linkAlthough cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium-glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin's metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients
Fiber orientation measurements by diffusion tensor imaging improve hydrogen-1 magnetic resonance spectroscopy of intramyocellular lipids in human leg muscles
No full textTwelve healthy subjects underwent hydrogen-1 magnetic resonance spectroscopy ([Formula: see text]) acquisition ([Formula: see text]), diffusion tensor imaging (DTI) with a [Formula: see text]-value of [Formula: see text], and fat-water magnetic resonance imaging (MRI) using the Dixon method. Subject-specific muscle fiber orientation, derived from DTI, was used to estimate the lipid proton spectral chemical shift. Pennation angles were measured as 23.78 deg in vastus lateralis (VL), 17.06 deg in soleus (SO), and 8.49 deg in tibialis anterior (TA) resulting in a chemical shift between extramyocellular lipids (EMCL) and intramyocellular lipids (IMCL) of 0.15, 0.17, and 0.19 ppm, respectively. IMCL concentrations were [Formula: see text], [Formula: see text], and [Formula: see text] in SO, VL, and TA, respectively. Significant differences were observed in IMCL and EMCL pairwise comparisons in SO, VL, and TA ([Formula: see text]). Strong correlations were observed between total fat fractions from [Formula: see text] and Dixon MRI for VL ([Formula: see text]), SO ([Formula: see text]), and TA ([Formula: see text]). Bland-Altman analysis between fat fractions (FFMRS and FFMRI) showed good agreement with small limits of agreement (LoA): [Formula: see text] (LoA: [Formula: see text] to 0.69%) in VL, [Formula: see text] (LoA: [Formula: see text] to 1.33%) in SO, and [Formula: see text] (LoA: [Formula: see text] to 0.47%) in TA. The results of this study demonstrate the variation in muscle fiber orientation and lipid concentrations in these three skeletal muscle types
Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males
No full textTo investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals
Determinants of the Increase in Fasting Plasma Ketone Concentration during SGLT2 Inhibition in NGT, IFG and T2DM Patients
Full text linkTo examine metabolic factors that influence ketone production after sodium-glucose cotransport inhibitor (SGLT2) administration RESEARCH DESIGN AND METHODS: Fasting plasma glucose, insulin, glucagon, free fatty acid and ketone concentrations were measured in 15 type 2 diabetes mellitus (T2DM) and 16 non-diabetic subjects before and at 1 and 14 days after treatment with empagliflozin
Pioglitazone Inhibits Mitochondrial Pyruvate Metabolism and Glucose Production in Hepatocytes
No full textPioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2. In cultured H4IIE hepatocytes, pioglitazone inhibited [2-(14) C]-pyruvate oxidation and pyruvate-driven oxygen consumption and, in mitochondria isolated from both hepatocytes and human skeletal muscle, pioglitazone selectively and dose-dependently inhibited pyruvate-driven ATP synthesis. Pioglitazone also suppressed hepatocellular glucose production (HGP), without influencing the mRNA expression of key HGP regulatory genes. Targeted siRNA silencing of MPC1 and 2 caused a modest inhibition of pyruvate oxidation and pyruvate-driven ATP synthesis, but did not alter pyruvate-driven HGP and, importantly, it did not influence the actions of pioglitazone on either pathway. In summary these findings outline a novel mode of action of pioglitazone relevant to the pathogenesis of T2DM and suggest that targeting pyruvate metabolism may lead to the development of effective new T2DM therapies. This article is protected by copyright. All rights reserved
Inhibition of Renal Sodium-Glucose Co-Transport with Empagliflozin Lowers Fasting Plasma Glucose and Improves Beta Cell Function in Subjects With Impaired Fasting Glucose
Full text linkTo examine the effect of renal sodium glucose co-transporter inhibition with empagliflozin on the fasting plasma glucose concentration and beta cell function in subjects with impaired fasting glucose (IFG).8 subjects with normal fasting glucose and 8 subjects with IFG received empagliflozin (25 mg/day) for 2 weeks. Fasting plasma glucose concentration and beta cell function was measured with a 9-step hyperglycemic clamp before and 48 hours and 14 days after the start of empagliflozin.Empagliflozin caused 50±4 and 45±4 grams glucosuria on day 2 in IFG and NFG subjects, respectively, and the glucosuria was maintained for 2 weeks in both groups. The fasting plasma glucose (FPG) concentration decreased only in IFG subjects from 110±2 to 103±3 mg/dl (p<0.01) after 14 days. The FPG concentration remained unchanged (95±2 to 94±2 mg/dl) in NFG subjects. Empagliflozin enhanced beta cell function only in IFG subjects. The incremental area under the plasma C-peptide concentration curve during the hyperglycemic clamp increased by 22±4% and 23±4% after 48 hours and 14 days, respectively (p<0.01); the plasma C-peptide response remained unchanged in NFG subjects. Insulin sensitivity during the hyperglycemic clamp was not affected by empagliflozin in either IFG or NFG. Thus, beta cell function measured with the insulin secretion/insulin sensitivity (disposition) index increased significantly in IFG, but not in NGT subjects.Inhibition of renal sodium-glucose co-transport with empagliflozin in IFG and NFG subjects produces comparable glucosuria but lowers the plasma glucose concentration and improves beta cell function only in IFG subjects
Erratum: Cardiovascular disease and type 2 diabetes: Has the dawn of a new era arrived? (Diabetes Care (2017) 40 (813-820) DOI: 10.2337/dc16-2736)
No full textIn the article listed above, the sentence on page 814 that reads "There also weremore serious hypoglycemic events in the liraglutide arm and more sulfonylurea and insulin use in the placebo group" has been corrected to read "There was more sulfonylurea and insulin use in the placebo group." The online version has been corrected to reflect this change
Empagliflozin and kinetics of renal glucose transport in healthy individuals and individuals with type 2 diabetes
No full textRenal glucose reabsorption was measured with the stepped hyperglycemic clamp in 15 subjects with type 2 diabetes mellitus (T2DM) and 15 without diabetes after 2 days and after more chronic (14 days) treatment with empagliflozin. Patients with T2DM had significantly greater maximal renal glucose transport (TmG) compared with subjects without diabetes at baseline (459 ± 53 vs. 337 ± 25 mg/min; P < 0.05). Empagliflozin treatment for 48 h reduced the TmG in both individuals with and without diabetes by 44 ± 7 and 53 ± 6%, respectively (both P < 0.001). TmG was further reduced by empagliflozin in both groups on day 14 (by 65 ± 5 and 75 ± 3%, respectively). Empagliflozin reduced the plasma glucose concentration threshold for glucose spillage in the urine similarly in individuals with T2DM and without diabetes to <40 mg/dL, which is well below the normal fasting plasma glucose concentration. In summary, sodium-glucose transporter-2 inhibition with empagliflozin reduces both TmG and threshold for glucose spillage in the urine in patients with T2DM and those without diabetes
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