Pioglitazone Increases Insulin Sensitivity by Activating Insulin Receptor Kinase

Kobayashi, Masashi; Iwanishi, Masanori; Egawa, Katsuya; Shigeta, Yukio

doi:10.2337/diab.41.4.476

Cited by 97 publications

(35 citation statements)

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“…Multiple studies have shown that thiazolidinediones improve hepatic insulin action relative to placebo (6,16,30,31). The present studies establish that thiazolidinediones also improve hepatic insulin action relative to metformin.…”

Section: Discussionsupporting

confidence: 62%

Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

et al. 2008

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OBJECTIVE-To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action.RESEARCH DESIGN AND METHODS-Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2,000 mg) for 4 months.RESULTS-Glucose was clamped before and after therapy at ϳ5 mmol/l, insulin raised to ϳ180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at ϳ75 pg/ml, and glycerol maintained at ϳ200 mmol/l to ensure comparable and equal portal concentrations on all occasions. Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 Ϯ 3 vs. 24 Ϯ 2 mol ⅐ kg. In contrast, pioglitazone enhanced (P Ͻ 0.01) insulin-induced suppression of both glucose production (6.0 Ϯ 1.0 vs. 0.2 Ϯ 1.6 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and gluconeogenesis (n ϭ 11; 4.5 Ϯ 0.9 vs. 0.8 Ϯ 1.2 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Metformin did not alter either suppression of glucose production (5.8 Ϯ 1.0 vs. 5.0 Ϯ 0.8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or gluconeogenesis (n ϭ 9; 3.7 Ϯ 0.8 vs. 2.6 Ϯ 0.7 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Insulin-induced suppression of free fatty acids was greater (P Ͻ 0.05) after treatment with pioglitazone (0.14 Ϯ 0.03 vs. 0.06 Ϯ 0.01 mmol/l) but unchanged with metformin (0.12 Ϯ 0.03 vs. 0.15 Ϯ 0.07 mmol/l).CONCLUSIONS-Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake. Diabetes 57: 24-31, 2008

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Section: Discussionsupporting

confidence: 62%

Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

et al. 2008

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“…11,14 Although the mechanisms by which thiazolidinedione derivatives improve insulin resistance are not entirely understood, a wide variety of mechanisms has so far been proposed. Pioglitazone was reported to ameliorate insulin resistance by increasing insulinstimulated autophosphorylation of insulin receptor and its kinase activity, 15 whereas this agent caused no increases in autophosphorylation and kinase activity of the receptor in the corresponding lean littermates. Under the same conditions, plasma insulin and triglyceride (TG) concentrations were signi®cantly decreased by this agent although plasma glucose concentration remained unchanged.…”

Section: Introductionmentioning

confidence: 99%

Role of plasma insulin concentration in regulating glucose and lipid metabolism in lean and obese Zucker rats

Noshiro¹,

Hirayama²,

Shimaya³

et al. 1997

Int J Obes

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OBJECTIVE: To determine the role of plasma insulin concentration in regulating glucose and lipid metabolism in insulin-resistant obese Zucker rats and to compare obese rats with lean controls with respect to changes in insulin sensitivity. DESIGN: Animal study of lean and obese rats with or without insulin sensitizer, YM268. ANIMALS: Nine week old male lean (Fa/±) and obese (fa/fa) Zucker rats. MEASUREMENTS: Plasma glucose, insulin, triglyceride (TG), non-esteri®ed fatty acid (NEFA), cholesterol at baseline and after 14 d, the dose of YM268 for exhibiting a 30% decrease in each parameter (ED 30 ). RESULTS: Insulin, TG, and NEFA concentrations were approximately 2±6 times higher in obese rats. YM268 had no effect on glucose but decreased insulin in lean and obese rats with ED 30 of 3.0 and 2.9 mg/kg. YM268 also reduced TG and NEFA in lean and obese rats [ED 30 (mg/kg): lean; 4.1 (TG), 5.0 (NEFA), obese; 2.1, 3.0]. A signi®cant correlation of either TG or NEFA level to insulin was established in lean and obese rats. CONCLUSION: Plasma TG and NEFA, but not cholesterol concentration, are dependent on plasma insulin in lean and obese Zucker rats, and insulin sensitivity with respect to TG and NEFA metabolism in obese rats may not be different from that in lean rats.

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“…The α subunit is responsible for binding insulin, whilst the β subunit has intrinsic tyrosine protein kinase (TPK) activity that initiates downstream intracellular signaling events (27). Numerous studies have demonstrated that diabetic hyperglycemia is associated with aberrant insulin receptor phosphorylation and reduced TPK activity (28,29). In the present GK model, insulin Rβ dual tyrosine 1162 and 1163 phosphorylation was markedly reduced.…”

Section: Discussionmentioning

confidence: 71%

Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Non-insulin-dependent diabetes mellitus (NIDDM)is associated with chronic inflammatory activity and disrupted insulin signaling, leading to insulin resistance (IR). The present study investigated the benefits of neurolytic celiac plexus block (NCPB) on IR in a rat NIDDM model. Goto-Kakizaki rats fed a high-fat, high-glucose diet to induce signs of NIDDM were randomly divided into NCPB and control groups; these received daily bilateral 0.5% lidocaine or 0.9% saline injections into the celiac plexus, respectively. Following 14 and 28 daily injections, rats were subject to oral glucose tolerance tests (OGTTs) or sacrificed for the analysis of serum free fatty acids (FFAs), serum inflammatory cytokines and skeletal muscle insulin signaling. Compared with controls, rats in the NCPB group demonstrated significantly (P<0.05) lower baseline, 60-min and 120-min OGTT values, lower 120-min serum insulin, lower IR [higher insulin sensitivity index (ISI 1 ) and lower ISI 2 ) and lower serum FFAs, tumor necrosis factor-α, interleukin (IL)-1β and IL-6. Conversely, NCPB rats exhibited higher basal and insulin-stimulated skeletal muscle glucose uptake and higher skeletal muscle insulin receptor substrate-1 (IRS-1) and glucose transporter type 4 expression. There were no differences between the groups in insulin receptor β (Rβ) or Akt expression; however Rβ-Y1162/Y1163 and Akt-S473 phosphorylation levels were higher and IRS-1-S307 phosphorylation were lower in NCPB rats than in the controls.These results indicate that NCPB improved insulin signaling and reduced IR, possibly by inhibiting inflammatory cytokine release.

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Pioglitazone Increases Insulin Sensitivity by Activating Insulin Receptor Kinase

Cited by 97 publications

References 0 publications

Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

Role of plasma insulin concentration in regulating glucose and lipid metabolism in lean and obese Zucker rats

Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats

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