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Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes.

ABSTRACT: Type 2 diabetes is caused by insulin resistance coupled with an inability to produce enough insulin to control blood glucose, and thiazolidinediones (TZDs) are the only current antidiabetic agents that function primarily by increasing insulin sensitivity. However, despite clear benefits in glycemic control, this class of drugs has recently fallen into disuse due to concerns over side effects and adverse events. Here we review the clinical data and attempt to balance the benefits and risks of TZD therapy. We also examine potential mechanisms of action for the beneficial and harmful effects of TZDs, mainly via agonism of the nuclear receptor PPAR?. Based on critical appraisal of both preclinical and clinical studies, we discuss the prospect of harnessing the insulin sensitizing effects of PPAR? for more effective, safe, and potentially personalized treatments of type 2 diabetes.

SUBMITTER: Soccio RE

PROVIDER: S-EPMC4192012 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes.

Soccio Raymond E RE Chen Eric R ER Lazar Mitchell A MA

Cell metabolism 20140918 4

Type 2 diabetes is caused by insulin resistance coupled with an inability to produce enough insulin to control blood glucose, and thiazolidinediones (TZDs) are the only current antidiabetic agents that function primarily by increasing insulin sensitivity. However, despite clear benefits in glycemic control, this class of drugs has recently fallen into disuse due to concerns over side effects and adverse events. Here we review the clinical data and attempt to balance the benefits and risks of TZD ...[more]

PMID: 25242225

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Is thiazolidinediones use a factor in delaying the need for insulin therapy in type 2 patients with diabetes? A population-based cohort study.

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Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis.

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| S-EPMC2612065 | biostudies-other

Differential Effects of Thiazolidinediones and Dipeptidyl Peptidase-4 Inhibitors on Insulin Resistance and β-Cell Function in Type 2 Diabetes Mellitus: A Propensity Score-Matched Analysis.

Project description:IntroductionComparisons of the glycemic durability between thiazolidinediones (TZDs) and dipeptidyl peptidase-4 (DPP-4) inhibitors remain insufficient. This study aimed to find clues for the differences in glycemic durability between TZDs and DPP-4 inhibitors by comparing the insulin resistance and β-cell function among patients using these agents.MethodsA total of 241 patients with type 2 diabetes mellitus (T2DM) treated with either pioglitazone (a TZD) or DPP-4 inhibitors as combination therapy with metformin for at least 1 year were analyzed. A propensity score based on the patients' baseline characteristics and glycated hemoglobin (HbA1c) was used to match them. Indices for insulin resistance and secretory function of β-cells, namely the homeostasis model assessment of insulin resistance (HOMA-IR) or β-cells (HOMA-β), were calculated and compared. Multiple regression analysis was performed to find the independent variables correlated with β-cell function or insulin resistance.ResultsEvaluation of the data from 168 matched patients with T2DM showed that TZD users had significantly better insulin sensitivity compared with DPP-4 inhibitor users (HOMA-IR 2.3 ± 1.9 vs. 3.5 ± 3.2, p = 0.003). Conversely, DPP-4 inhibitor users secreted more insulin than TZD users (HOMA-β 45.7 ± 31.6 vs. 61.4 ± 49.5, p = 0.016). Multiple linear regression analysis showed that these agents were independently associated with both insulin resistance and β-cell function.ConclusionTZD users showed significantly better insulin sensitivity, whereas DPP-4 inhibitor users secreted more insulin from β-cells under similar glycemic control.

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Human Insulin Resistance and Thiazolidinedione-Mediated Insulin Sensitization

2010-05-17 | GSE13070 | GEO

Lack of association between thiazolidinediones and macular edema in type 2 diabetes: the ACCORD eye substudy.

Project description:OBJECTIVE:To assess the cross-sectional association of thiazolidinediones with diabetic macular edema (DME). METHODS:The cross-sectional association of DME and visual acuity with thiazolidinediones was examined by means of baseline fundus photographs and visual acuity measurements from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Visual acuity was assessed in 9690 participants in the ACCORD trial, and 3473 of these participants had fundus photographs that were centrally read in a standardized fashion by masked graders to assess DME and retinopathy from October 23, 2003, to March 10, 2006. RESULTS:Among the subsample, 695 (20.0%) people had used thiazolidinediones, whereas 217 (6.2%) people had DME. Thiazolidinedione use was not associated with DME in unadjusted (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.71-1.44; P = .95) and adjusted (OR, 0.97; 95% CI, 0.67-1.40; P = .86) analyses. Significant associations with DME were found for retinopathy severity (P < .001) and age (OR, 0.97; 95% CI, 0.952-0.997; P = .03) but not for hemoglobin A(1c) (P = .06), duration of diabetes (P = .65), sex (P = .72), and ethnicity (P = .20). Thiazolidinedione use was associated with slightly greater visual acuity (0.79 letter; 95% CI, 0.20-1.38; P = .009) of uncertain clinical significance. CONCLUSIONS:In a cross-sectional analysis of data from the largest study to date, no association was observed between thiazolidinedione exposure and DME in patients with type 2 diabetes; however, we cannot exclude a modest protective or harmful association. Trial Registration clinicaltrials.gov Identifier: NCT00542178.

| S-EPMC3010554 | biostudies-literature

Sitagliptin compared with thiazolidinediones as a third-line oral antihyperglycemic agent in type 2 diabetes mellitus.

Project description:To compare sitagliptin and thiazolidinediones as third-line oral antihyperglycemic agents among ethnic minority patients with poorly controlled type 2 diabetes mellitus.In an open-label, single-arm design, we treated type 2 diabetic patients who had suboptimal diabetes control on maximum tolerated dosages of metformin plus sulfonylureas with the addition of sitagliptin, 100 mg daily, and compared their responses with findings from a historical control group of similar patients treated with rosiglitazone, 8 mg daily, or pioglitazone, 45 mg daily, as their third-line oral agent. Patients were assessed bimonthly, and those who achieved hemoglobin A1c levels less than 7.5% at 4 months continued through 1 year of follow-up.One hundred eight patients were treated with sitagliptin, and 104 patients constituted the historical control group treated with rosiglitazone or pioglitazone. At baseline, sitagliptin- and thiazolidinedione-treated patients had identical hemoglobin A1c levels (mean ± SD) (9.4 ± 1.8% and 9.4 ± 1.9%, respectively) and similar known diabetes duration (6.7 ± 5.0 years and 7.6 ± 5.8 years, respectively). Hemoglobin A1c was reduced in both groups at 4 months (P<.001), but the reduction was greater with thiazolidinediones than with sitagliptin (-2.0 ± 1.7% vs -1.3 ± 1.8%; P = .006), as was the proportion of patients achieving a hemoglobin A1c level less than 7.5% (62% vs 46%; P = .026). Of all patients achieving a hemoglobin A1c level less than 7.5% at 4 months, the same proportions in each group sustained their hemoglobin A1c level less than 7.5% by 12 months (59% vs 58%). Sitagliptin was well tolerated.Among ethnic minority patients with poorly controlled type 2 diabetes while taking maximum tolerated dosages of metformin and sulfonylureas, third-line add-on therapy with a thiazolidinedione controlled hyperglycemia more effectively than sitagliptin after 4 months.

| S-EPMC4452112 | biostudies-literature

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