Pioglitazone enhances splanchnic glucose uptake as well as peripheral glucose uptake in non-insulin-dependent diabetes mellitus

doi:10.1016/S0168-8227(98)00056-4

Diabetes Research and Clinical Practice

Volume 41, Issue 1, July 1998, Pages 35-43

https://doi.org/10.1016/S0168-8227(98)00056-4 Get rights and content

Abstract

To evaluate the effect of pioglitazone on insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) patients, a double-blind placebo-controlled trial was carried out with 30 NIDDM patients. Twenty-one subjects, three on diet alone and 18 on sulfonylurea (SU), orally received 30 mg pioglitazone once daily for 12 weeks. Nine subjects, one on diet alone and eight on SU, received a matching placebo once daily for 12 weeks. Euglycemic (5.2 mmol/l) hyperinsulinemic (1200 pmol/l) clamp combined with an oral glucose load (OGL) was performed before and after 3-month treatment with pioglitazone or placebo to determine insulin-stimulated glucose disposal and splanchnic glucose uptake (SGU). No significant differences existed in the patients' characteristics, including age and body mass index, between the two study groups. The pioglitazone treatment increased the mean glucose infusion rate (GIR) prior to OGL from 8.2±2.2 to 9.2±2.0 mg/kg·min (means±SD, P=0.003) and increased the SGU rate from 28.5±19.4 to 59.4±27.1% (P=0.010). The placebo treatment produced no significant changes in either GIR or SGU after treatment. A significant difference (P=0.042) was observed in change of SGU between the pioglitazone and placebo treatment groups. In conclusion, the results indicate that pioglitazone is effective for ameliorating insulin resistance in NIDDM by enhancing SGU as well as peripheral glucose uptake.

Introduction

The pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) is known to be a combination of impaired insulin secretion and insulin resistance 1, 2. Treatment with insulin or sulfonylurea (SU), the main hypoglycemic drugs in current use, chiefly targets poor insulin secretion. Recently, more attention has been directed to research and development on drugs which ameliorate the insulin resistance in NIDDM patients.

Pioglitazone, used in the present clinical study, is a thiazolidinedione derivative which can ameliorate insulin resistance. Pioglitazone decreases hyperglycemia and hyperlipidemia and thus improves the hyperinsulinemia of obese NIDDM animal models, such as Wistar fatty rats and KKA^y mice 3, 4. In addition, study using a euglycemic clamp technique showed that pioglitazone could reduce hepatic glucose production (HGP) and increase peripheral glucose utilization in Wistar fatty rats [5]. The results of these animal studies suggest that pioglitazone ameliorates hyperglycemia without promoting insulin secretion from the pancreatic B cells and that the mechanism of this action may be the reduction of insulin resistance in insulin target organs such as the liver, skeletal muscles and adipose tissues. However, there is still a lack of quantitative analyses to explain how the improvement of insulin resistance by pioglitazone contributes to the improvement of glucose metabolism in NIDDM patients.

For clinical evaluation of insulin sensitivity, the euglycemic clamp technique, developed by DeFronzo et al., has been employed to quantify insulin secretion and resistance [6]. Although this technique can also be used to obtain information on glucose disposal in peripheral tissues mainly of muscles [7], it cannot be used to evaluate glucose uptake in the liver, which is the regulating center of blood glucose levels. To overcome this problem, we have developed a technique of loading glucose by the oral route under euglycemic hyperinsulinemic clamp (clamp-OGL method), as a non-invasive approach for separately analyzing glucose uptake in splanchnic tissues, mainly in the liver and peripheral tissues. We used this technique to examine the effects of various treatments on the insulin resistance of NIDDM patients [8].

The present placebo-controlled, double-blind, comparative study was conducted to evaluate the effect of pioglitazone on the insulin resistance in NIDDM patients in the peripheral and splanchnic tissues using the clamp-OGL method.

Section snippets

Subjects

This multicenter study was conducted with the participation of four medical institutions during the period from July 1994 to December 1995. Approval of the institutional review board was obtained at each site of the study in accordance with the good clinical practice (GCP) guidelines of the Ministry of Health and Welfare of Japan.

The subjects were selected from patients who were diagnosed as NIDDM based on World Health Organization criteria and who fulfilled the following criteria: (a) patients

Plasma glucose (PG)-related tests

The body weight was comparable between pioglitazone and placebo groups (Table 2). In the placebo group, the body weight remained constant until 12 weeks of treatment. In the pioglitazone group, the body weight increased gradually during treatment with pioglitazone, these changes of body weight being significantly higher than those in the placebo group.

In the pioglitazone group, the FPG levels declined significantly from 8.7±2.1 mmol/l at the start of treatment to 7.3±1.3 and 7.2±1.5 mmol/l at

Discussion

The present study was conducted to evaluate the clinico–pharmacological effects of pioglitazone after 12 weeks of treatment on the insulin resistance in patients with NIDDM at the peripheral and hepatic tissues using the euglycemic hyperinsulinemic clamp technique combined with an OGL (clamp-OGL method) [8]. The study was conducted as a placebo-controlled, double-blind, comparative study to separately evaluate the effects of pioglitazone on the peripheral and splanchnic tissues. Therefore, the

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Pioglitazone enhances splanchnic glucose uptake as well as peripheral glucose uptake in non-insulin-dependent diabetes mellitus

Abstract

Introduction

Section snippets

Subjects

Plasma glucose (PG)-related tests

Discussion

Diabetes Res. Clin. Pract.

Metabolism

Am. J. Clin. Nutr.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus

New Engl. J. Med.

Hormonal responses and future treatment of non-insulin-dependent diabetes mellitus (NIDDM)

J. Intern. Med.

Effects of pioglitazone on glucose and lipid metabolism in Wistar fatty rats

Arzneim-Forsch. Drug Res.

Effects of pioglitazone on glucose and lipid metabolism in normal and insulin resistant animals

Arzneim-Forsch. Drug Res.

Effects of pioglitazone on hepatic and peripheral insulin resistance in Wistar fatty rats

Arzneim-Forsch. Drug Res.

Glucose clamp technique: a method for quantifying insulin secretion and resistance

Am. J. Physiol.

The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catheterization

Diabetes

Clinical applications of a bedside-type artificial endocrine pancreas-development and application of the control algorithm

Artif. Organs Today