Download PDF
Horm Metab Res 2005; 37(8): 510-515
DOI: 10.1055/s-2005-870320
Original Clinical
© Georg Thieme Verlag KG Stuttgart · New York

Pioneer Study: PPARγ Activation Results in Overall Improvement of Clinical and Metabolic Markers Associated with Insulin Resistance Independent of Long-term Glucose Control

A.  Pfützner1, 2 , C.  Hohberg1 , G.  Lübben3 , S.  Pahler1 , A.  H.  Pfützner1 , P.  Kann1, 4 , T.  Forst1
  • 1 IKFE-Institute for Clinical Research and Development, Mainz, Germany
  • 2 University of Applied Sciences, Rheinbach, Germany
  • 3 Takeda Pharma GmbH, Aachen, Germany
  • 4 University Hospital, Department of Endocrinology and Diabetes, Marburg, Germany
Further Information

Publication History

Received 15 December 2004

Accepted after revision 22 March 2005

Publication Date:
01 September 2005 (online)

Also available at
    Permissions and Reprints

Abstract

New scores and biochemical markers have recently been published for diagnosis of insulin resistance and β-cell dysfunction (such as intact proinsulin, adiponectin, IRISII-score). One goal of this 6-month prospective controlled study was to evaluate the impact of pioglitazone (45 mg) vs. glimepiride (1-6 mg, in the intend to optimize therapy) on these markers. Observation parameters were: IRIS-II score, HOMA-score, ATP III score, HbA1c, fasting glucose, lipids, intact proinsulin, adiponectin, and adverse events. The study was completed by 173 patients (66 female, 107 male, age ± STD: 63 ± 8 years, disease duration: 7.2 ± 7.2 years, HbA1c: 7.53 ± 0.85 %, pioglitazone arm: 89 patients). The groups were not different for any of the observation parameters at baseline, and a similar reduction in HbA1c was seen in both groups (p < 0.001). In the pioglitazone group, reductions were observed for the IRIS-II and HOMA scores (p < 0.001 vs. glimepiride at endpoint) fasting glucose (p < 0.001), insulin (p < 0.001), LDL/HDL ratio (p < 0.001), hsCRP (p < 0.05), intact proinsulin (p < 0.001), and an increase was seen in HDL (p < 0.001), adiponectin (p < 0.001) and BMI (p < 0.001). In conclusion, treatment with pioglitazone resulted in an improvement of markers for insulin resistance and β-cell dysfunction, independent from blood glucose control. Adiponectin, intact proinsulin, and the IRIS-II score may be suitable parameters for monitoring of these additional beneficial therapeutic effects.

Key words

Intact proinsulin · Adiponectin · IRIS-II score · HOMA score

  • 1 Howard B, Rodriguez B, Bennet P, Harris M, Hamman R, Kuller L, Pearson T, Wylie-Roset J. Prevention Conference VI: diabetes and cardiovascular disease: Writing group I: epidemiology.  Circulation. 2002;  105 e132-e137
    CrossrefPubMedGoogle Scholar
  • 2 Haffner S M, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.  N Engl J Med. 1998;  339 229-234
    CrossrefPubMedGoogle Scholar
  • 3 Coates P A, Luzio S D, Brunel P, Owens D R. Comparison of estimates of insulin sensitivity from minimal model analysis of the insulin-modified frequently sampled intravenous glucose tolerance test and the isoglycemic hyperinsulinemic clamp in subjects with NIDDM.  Diabetes. 1995;  44 631-635
    PubMedGoogle Scholar
  • 4 Forst T, Standl E, Hohberg C, Konrad T, Schulze J, Strotmann H J, Lubben G, Pahler S, Bachinger A, Langenfeld M, Pfutzner A. IRIS II study: the IRIS II score-assessment of a new clinical algorithm for the classification of insulin resistance in patients with Type 2 diabetes.  Diabet Med. 2004;  21 1149-1153
    CrossrefPubMedGoogle Scholar
  • 5 Pfützner A, Kunt T, Mondok A, Pahler S, Konrad T, Luebben G, Forst T. Fasting Intact Proinsulin is a Highly Specific Predictor of Insulin Resistance in Type 2 Diabetes.  Diabetes Care. 2004;  27 682-687
    CrossrefPubMedGoogle Scholar
  • 6 Pfützner A, Pfützner A H, Larbig M, Forst T. Role of intact proinsulin in diagnosis and treatment of type 2 diabetes mellitus.  Diab Technol Ther. 2004;  6 405-412
    CrossrefPubMedGoogle Scholar
  • 7 Langenfeld M, Forst T, Standl E, Strotmann H J, Luebben G, Pahler S, Kann P, Pfützner A. IRIS II Study: Sensitivity and Specificity of Intact Proinsulin, Adiponectin and the Proinsulin/Adiponectin Ratio as Markers for Insulin Resistance.  Diab Technol Ther. 2004;  6 836-843
    CrossrefPubMedGoogle Scholar
  • 8 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 1595-1599
    CrossrefPubMedGoogle Scholar
  • 9 Kubo K. Effect of Pioglitazone on blood proinsulin levels in patients with type 2 diabetes.  Endocrine Journal. 2002;  49 323-328
    PubMedGoogle Scholar
  • 10 Langenfeld M, Forst T, Hohberg C, Kann P, Lübben G, Konrad T, Füllert S, Sachara C, Pfützner A. Pioglitazone decreases carotid intima-media thickness independent of glycemic control in patients with type 2 diabetes mellitus.  Circulation. 2005;  111 2525-2531
    CrossrefPubMedGoogle Scholar
  • 11 Pfützner A, Marx N, Lübben G, Walcher D, Konrad T, Forst T. Improvement or Cardiovascular Risk Markers by Pioglitazone is Independent from Glycemic Control - Results from the Pioneer Study.  J Am Coll Card. 2005;  45 1925-1931
    CrossrefPubMedGoogle Scholar
  • 12 Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
    Google Scholar
  • 13 Hedblad B, Nilsson P, Janzon L, Berglund G. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmo, Sweden.  Diabet Med. 2000;  17 299-307
    CrossrefPubMedGoogle Scholar
  • 14 Bonora E, Targher G, Alberiche M, Bonadonna R C, Saggiani F, Zenere M B, Monauni T, Muggeo M. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.  Diabetes Care. 2000;  23 57-63
    CrossrefPubMedGoogle Scholar
  • 15 Anderson R L, Hamman R F, Savage P J, Saad M F, Laws A, Kades W W, Sands R E, Cefalu W. Exploration of simple insulin sensitivity measures derived from frequently sampled intravenous glucose tolerance (FSIGT) tests. The Insulin Resistance Atherosclerosis Study.  Am J Epidemiol. 1995;  142 724-732
    PubMedGoogle Scholar
  • 16 Vague P, Nguyen L. Rationale and methods for the estimation of insulin secretion in a given patient.  Diabetes. 2001;  51(Suppl. 1) S240-S244
    PubMedGoogle Scholar
  • 17 Avignon A, Boegner C, Mariano-Goulart D, Colette C, Monnier L. Assessment of insulin sensitivity from plasma insulin and glucose in the fasting or post oral glucose-load state.  Int J Obes Relat Metab Disord. 1999;  23 512-517
    CrossrefPubMedGoogle Scholar
  • 18 Jayagopal V, Kilpatrick E S, Jennings P E, Hepburn D A, Atkin S L. Biological variation of homeostasis model assessment-derived insulin resistance in type 2 diabetes.  Diabetes Care. 2002;  25 2022-2025
    CrossrefPubMedGoogle Scholar
  • 19 Saad M F, Anderson R L, Laws A, Watanabe R M, Kades W W, Chen Y D, Sands R E, Pei D, Savage P J, Bergman R N. A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin Resistance Atherosclerosis Study.  Diabetes. 1994;  43 1114-1121
    PubMedGoogle Scholar
  • 20 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
    CrossrefPubMedGoogle Scholar
  • 21 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley R E, Tataranni P A. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.  J Clin Endocrinol Metab. 2001;  86 1930-1935
    CrossrefPubMedGoogle Scholar
  • 22 Schulze M B, Rimm E B, Shai I, Rifai N, Hu F B. Relationship between adiponectin and glycemic control, blood lipids, and inflammatory markers in men with type 2 diabetes.  Diabetes Care. 2004;  27 1680-1687
    CrossrefPubMedGoogle Scholar
  • 23 Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner A J, Tomiyama Y, Matsuzawa Y. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages.  Blood. 2000;  96 1723-1732
    PubMedGoogle Scholar
  • 24 Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin.  Circulation. 1999;  100 2473-2476
    CrossrefPubMedGoogle Scholar
  • 25 Zoccali C, Mallamaci F, Tripepi G, Benedetto F A, Cutrupi S, Parlongo S, Malatino L S, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M, Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease.  J Am Soc Nephrol. 2002;  13 134-141
    PubMedGoogle Scholar
  • 26 Zethelius B, Byberg L, Hales C N, Lithell H, Berne C. Proinsulin and acute Insulin response independently predict Type 2 diabetes mellitus in men-report from 27 years of follow-up study.  Int J Obes Relat Metab Disord. 2003;  46 20-26
    PubMedGoogle Scholar
  • 27 Yudkin J S. Circulating proinsulin-like molecules.  J Diab Compl. 1993;  7 113-123
    CrossrefPubMedGoogle Scholar
  • 28 Haffner S M, D’Agostino R, Mykkanen L, Hales C N, Savage P J, Bergman R N, O’Leary D, Rewers M, Selby J, Tracy R, Saad M F. Proinsulin and insulin concentrations in relation to carotid wall thickness: Insulin Resistance Atherosclerosis Study.  Stroke. 1998;  29 1498-1503
    PubMedGoogle Scholar
  • 29 Haffner S M, Mykkanen L, Stern M P, Valdez R A, Heisserman J A, Bowsher R R. Relationship of proinsulin and insulin to cardiovascular risk factors in nondiabetic subjects.  Diabetes. 1993;  42 1297-1302
    CrossrefPubMedGoogle Scholar
  • 30 Festa A, D’Agostino R Jr, Mykkanen L, Tracy R P, Zaccaro D J, Hales C N, Haffner S M. Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS).  Arterioscler Thromb Vasc Biol. 1999;  19 562-568
    PubMedGoogle Scholar
  • 31 Yudkin J S, May M, Elwood P, Yarnell J W, Greenwood R, Davey S G. Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study.  Diabetologia. 2002;  45 327-336
    CrossrefPubMedGoogle Scholar
  • 32 Tan M H, Johns D, Strand J. et al . Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes.  Diabet Med. 2004;  21 859-866
    CrossrefPubMedGoogle Scholar
  • 33 Derosa G, Cicero A F, Gaddi A. et al . Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: A twelve-month, multicenter, double-blind, randomized, controlled, parallel-group trial.  Clin Ther. 2004;  26 744-754
    CrossrefPubMedGoogle Scholar
  • 34 King A B, Armstrong D U. Lipid response to pioglitazone in diabetic patients: clinical observations from a retrospective chart review.  Diab Technol Ther. 2002;  4 145-151
    CrossrefPubMedGoogle Scholar
  • 35 Saad M F, Greco S, Osei K. et al . Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm.  Diabetes Care. 2004;  27 1324-1329
    PubMedGoogle Scholar
  • 36 Tordjman J, Chauvet G, Quette J, Beale E G, Forest C, Antoine B. Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells.  J Biol Chem. 2003;  278 18 785-18 790
    PubMedGoogle Scholar
  • 37 Törüner F, Akbay E, Cakir N, Sancak B, Elbeg S, Taneri F, Aktürk M, Karakoc A, Ayvaz G, Arslan M. Effects of PPARγ and PPARα agonists on serum leptin levels in diet-induced obese rats.  Horm Metab Res. 2004;  36 226-330
    Article in Thieme ConnectPubMedGoogle Scholar

Prof. Dr. Andreas Pfützner

Institute for Clinical Research and Development

Parcusstr. 8 · D-55116 Mainz · Germany

Phone: +49 (6131) 576 36 10

Fax: +49 (6131) 576 36 11

Email: AndreasP@ikfe.de

      >