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
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
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
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
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
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
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
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
9
Kubo K.
Effect of Pioglitazone on blood proinsulin levels in patients with type 2 diabetes.
Endocrine Journal.
2002;
49
323-328
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
27
Yudkin J S.
Circulating proinsulin-like molecules.
J Diab Compl.
1993;
7
113-123
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
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
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
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
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
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
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
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
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
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
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