Pioglitazone Improved Insulin Sensitivity and First Phase Insulin Secretion Among Obese and Lean People with Diabetes: A Multicenter Clamp Study

Abstract

IntroductionTo investigate the effects of pioglitazone (PIO) on insulin resistance and first phase insulin secretion among obese and lean Chinese people with type 2 diabetes mellitus (T2DM).MethodsSixty-eight drug-naïve patients with T2DM were treated with PIO for 16 weeks. Before and after the treatment, insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test. Plasma insulin levels at 0, 3, 5, 7, and 10 min during intravenous glucose tolerance test were determined to calculate the first phase insulin secretion and pancreatic β-cell function. Circulating adiponectin levels were quantified.ResultsIn both the lean and the obese patients with T2DM, the reduction of HbA1c following the PIO treatment was more than 1% (P < 0.001) and glucose infusion rate, acute insulin response, glucose disposal index, and β-cell glucose sensitivity increased significantly (P < 0.001). A multiple linear regression analysis showed that the improvements of first phase insulin secretion and insulin sensitivity were independently associated with the changes of HbA1c, but the change of first phase insulin secretion exhibited a higher correlation coefficient (R2 = 0.20, P = 0.001) than the change of insulin sensitivity did (R2 = 0.07, P = 0.040). The PIO treatment led to a significant increase in adiponectin levels only in the obese group (P < 0.05).ConclusionA 16-week treatment of PIO significantly increased insulin sensitivity and β-cell function in the lean group as well as in the obese group among Chinese T2DM patients, demonstrating that both lean and obese diabetic adults would profit from PIO.Trial registrationThe ChiCTR registry number is ChiCTR-OPC-17011571.FundingTakeda Pharmaceutical Co. Ltd. and Pfizer Pharmaceutical Co. Ltd.

Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide

“…Of interest, MPC inhibition with the tool-compound UK-5099 appears to alleviate the metabolic stress of islets cultured in high glucose ( 38 ). Finally, the preserved islet insulin content with TZDs can lead to enhanced insulin secretion during glucose challenge ( 31 , 32 ), and this was noted with 0602K or 0602K+Lira treatment in this study ( Fig. 5 A ).…”

“…This decrease in insulinemia with TZDs has been well described in both humans and animal models of insulin resistance and diabetes ( 29 , 30 , 31 ). The presiding dogma is that improved insulin sensitivity indirectly reduces the need for insulin hypersecretion, and thus TZDs can improve beta cell insulin content and function ( 3 , 31 , 32 , 33 ). However, it has recently been recognized that traditional and PPARγ-sparing TZDs can bind and inhibit the MPC ( 8 , 9 , 10 ), and pyruvate import into the mitochondria via the MPC plays an important role in beta cell glucose sensing and GSIS ( 26 , 34 ).…”

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

“…TZDs, such as pioglitazone and rosiglitazone increase adiponectin expression through the activation of proliferator-activated receptor gamma (PPARγ) (110,111). Pioglitazone treatment for 16-weeks increased adiponectin levels in an obese population of Chinese subjects with diabetes and this correlated with improved insulin secretion and insulin sensitivity (112). Clinical studies in subjects across different ethnic, age and metabolic disease groups have consistently observed increased adiponectin levels with pioglitazone (113)(114)(115) or rosiglitazone (116) treatment.…”

MSDC-0602K, A Novel Insulin-Sensitizer Improves Insulinemia and Fatty Liver Disease Alone and in Addition to Liraglutide in Mice

“…This decrease in insulinemia with TZDs has been well described in both humans and animal models of insulin resistance and diabetes [33][34][35]. The presiding dogma is that improved insulin sensitivity indirectly reduces the need for insulin hyper-secretion, and thus TZDs can improve beta cell insulin content and function [3,[35][36][37]. However, it has recently been recognized that traditional and PPARγ-sparing TZDs can bind and inhibit the MPC [8][9][10], and pyruvate import into the mitochondria via the MPC plays an important role in beta cell glucose sensing and GSIS [27,38].…”

“…Interestingly, MPC-inhibition with the tool-compound UK-5099 appears to alleviate the metabolic stress of islets cultured in high glucose [42]. Lastly, the preserved islet insulin content with TZDs can lead to enhanced insulin secretion during glucose challenge [35, 36]. Altogether, these findings suggest that TZDs are not directly inhibiting GSIS, rather improved peripheral insulin sensitivity indirectly reduces the need for excessive insulin secretion.…”