1,721,083 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
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
Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived?
No full textHyperglycemia is the major risk factor for microvascular complications in patients with type 2 diabetes (T2D). However, cardiovascular disease (CVD) is the principal cause of death, and lowering HbA1c has only a modest effect on reducing CVD risk and mortality. The recently published LEADER and SUSTAIN-6 trials demonstrate that, in T2D patients with high CVD risk, the glucagon-like peptide 1 receptor agonists liraglutide and semaglutide reduce the primary major adverse cardiac events (MACE) end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) by 13% and 24%, respectively. The EMPA-REG OUTCOME, IRIS (subjects without diabetes), and PROactive (second principal end point) studies also demonstrated a significant reduction in cardiovascular events in T2D patients treated with empagliflozin and pioglitazone. However, the benefit of these four antidiabetes agents (liraglutide, semaglutide, empagliflozin, and pioglitazone) on the three individual MACE end points differed, suggesting that different underlying mechanisms were responsible for the reduction in cardiovascular events. Since liraglutide, semaglutide, pioglitazone, and empagliflozin similarly lower the plasma glucose concentration but appear to reduce CVD risk by different mechanisms, there emerges the intriguing possibility that, if used in combination, the effects of these antidiabetes agents may be additive or even multiplicative with regard to cardiovascular benefit
Empagliflozin Treatment is Associated with Improved Beta Cell Function in T2DM
No full textTo examine whether lowering the plasma glucose concentration with empagliflozin (SGLT2 inhibitor) improves beta cell function in T2DM
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
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
Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes
Full text linkOBJECTIVE Insulin resistance is associatedwithmitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DMto dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg · min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg · min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production
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