Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance

Mireille J. Serlie; Gideon Allick; Johanna E. Groener; Mariette T. Ackermans; Rik Heijligenberg; Barbara C. Voermans; Johannes M. Aerts; Alfred J. Meijer; Hans P. Sauerwein

doi:https://doi.org/10.1210/jc.2006-1518

Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance

Mireille J. Serlie, Gideon Allick, Johanna E. Groener, Mariette T. Ackermans, Rik Heijligenberg, Barbara C. Voermans, Johannes M. Aerts, Alfred J. Meijer, Hans P. Sauerwein

Research output: Contribution to journal › Article › Academic › peer-review

24 Citations (Scopus)

Abstract

CONTEXT: Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated. OBJECTIVE: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids. DESIGN: We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids. PATIENTS: Patients were obese with poorly controlled type 2 diabetes mellitus. INTERVENTION: Patients were treated with 30 mg pioglitazone once daily. Main Outcome Measure: The change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion was the main outcome measure. RESULTS: Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change. CONCLUSIONS: Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with type 2 diabetes mellitus from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids

Original language	English
Pages (from-to)	166-171
Journal	Journal of clinical endocrinology and metabolism
Volume	92
Issue number	1
DOIs	https://doi.org/10.1210/jc.2006-1518
Publication status	Published - 2007

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Serlie, M. J., Allick, G., Groener, J. E., Ackermans, M. T., Heijligenberg, R., Voermans, B. C., Aerts, J. M., Meijer, A. J., & Sauerwein, H. P. (2007). Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance. Journal of clinical endocrinology and metabolism, 92(1), 166-171. https://doi.org/10.1210/jc.2006-1518

@article{d6201106e9494bb09a22f232f6bb6778,

title = "Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance",

abstract = "CONTEXT: Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated. OBJECTIVE: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids. DESIGN: We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids. PATIENTS: Patients were obese with poorly controlled type 2 diabetes mellitus. INTERVENTION: Patients were treated with 30 mg pioglitazone once daily. Main Outcome Measure: The change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion was the main outcome measure. RESULTS: Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change. CONCLUSIONS: Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with type 2 diabetes mellitus from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids",

author = "Serlie, {Mireille J.} and Gideon Allick and Groener, {Johanna E.} and Ackermans, {Mariette T.} and Rik Heijligenberg and Voermans, {Barbara C.} and Aerts, {Johannes M.} and Meijer, {Alfred J.} and Sauerwein, {Hans P.}",

year = "2007",

doi = "https://doi.org/10.1210/jc.2006-1518",

language = "English",

volume = "92",

pages = "166--171",

journal = "Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

number = "1",

}

Serlie, MJ, Allick, G, Groener, JE, Ackermans, MT, Heijligenberg, R, Voermans, BC, Aerts, JM, Meijer, AJ & Sauerwein, HP 2007, 'Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance', Journal of clinical endocrinology and metabolism, vol. 92, no. 1, pp. 166-171. https://doi.org/10.1210/jc.2006-1518

Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance. / Serlie, Mireille J.; Allick, Gideon; Groener, Johanna E. et al.
In: Journal of clinical endocrinology and metabolism, Vol. 92, No. 1, 2007, p. 166-171.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance

AU - Serlie, Mireille J.

AU - Allick, Gideon

AU - Groener, Johanna E.

AU - Ackermans, Mariette T.

AU - Heijligenberg, Rik

AU - Voermans, Barbara C.

AU - Aerts, Johannes M.

AU - Meijer, Alfred J.

AU - Sauerwein, Hans P.

PY - 2007

Y1 - 2007

N2 - CONTEXT: Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated. OBJECTIVE: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids. DESIGN: We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids. PATIENTS: Patients were obese with poorly controlled type 2 diabetes mellitus. INTERVENTION: Patients were treated with 30 mg pioglitazone once daily. Main Outcome Measure: The change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion was the main outcome measure. RESULTS: Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change. CONCLUSIONS: Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with type 2 diabetes mellitus from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids

AB - CONTEXT: Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated. OBJECTIVE: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids. DESIGN: We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids. PATIENTS: Patients were obese with poorly controlled type 2 diabetes mellitus. INTERVENTION: Patients were treated with 30 mg pioglitazone once daily. Main Outcome Measure: The change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion was the main outcome measure. RESULTS: Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change. CONCLUSIONS: Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with type 2 diabetes mellitus from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids

U2 - https://doi.org/10.1210/jc.2006-1518

DO - https://doi.org/10.1210/jc.2006-1518

M3 - Article

C2 - 17062758

SN - 0021-972X

VL - 92

SP - 166

EP - 171

JO - Journal of clinical endocrinology and metabolism

JF - Journal of clinical endocrinology and metabolism

IS - 1

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