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Troglitazone Reduces Hyperglycaemia and Selectively Acute-Phase Serum Proteins in Patients with Type II Diabetes

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Troglitazone Reduces Hyperglycaemia and Selectively Acute-Phase Serum Proteins in Patients with Type II Diabetes Diabetologia (1999) 42: 1433±1438 Ó Springer-Verlag 1999 Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with Type II diabetes P. Ebeling1, A.-M. Teppo2, H.A. Koistinen1, J. Viikari3, T. Rönnemaa3, M. NissØn4, S. Bergkulla4, P. Salmela5, J. Saltevo6, V.A. Koivisto1 1 Division of Internal Medicine and Geriatrics, Department of Medicine, Helsinki University Central Hospital, Finland 2 Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Finland 3 Department of Medicine, Turku University Central Hospital, Finland 4 Department of Medicine, Vaasa Central Hospital, Finland 5 Department of Medicine, Oulu University Hospital, Finland 6 Department of Medicine, Jyväskylä Central Hospital, Finland Abstract one reduced fasting glucose (from 10.4 ± 0.6 mmol/l to 8.1 ± 0.5 mmol/l, p < 0.01), HbA1c (from Aims/hypothesis. Inflammation could play a part in 8.7 ± 0.3% to 7.5 ± 0.3%, p < 0.01), insulin require- insulin resistance. Thiazolidinediones, new antidia- ments (from 75 ± 10 U/day to 63 ± 10 U/day, betic drugs, possess anti-inflammatory effects in vit- p < 0.05), serum amyloid A (from 6.3 ± 1.5 mg/l to ro. We investigated if acute-phase serum proteins 4.0 ± 1.3 mg/l, p = 0.001), a-1-acid glycoprotein are increased in patients with Type II (non-insulin- (from 906 ± 51 mg/l to 729 ± 52 mg/l, p = 0.001) and dependent) diabetes mellitus who had been treated C3 (from 1.72 ± 0.07 g/l to 1.66 ± 0.06 g/l, p < 0.05) with insulin and whether troglitazone has anti-inflam- but not a-1-antitrypsin, ceruloplasmin, C-reactive matory effects in vivo. protein or haptoglobin significantly. Concentrations Methods. A total of 27 patients (age 63.0 ± 1.7 years, of glucose and acute-phase reactants had returned to 2 HbA1c 8.8 ± 0.3%, BMI 32.7 ± 0.8 kg/m , duration those before treatment at the follow-up visit. 15.2 ± 1.4 years, insulin dose 73.3 ± 7.0 U/day) partic- Conclusion/interpretation. In Type II diabetic pati- ipated in the study. The patients received daily either ents serum amyloid A and complement protein C3 400 mg troglitazone or placebo for 16 weeks. Blood are raised. Troglitazone exerts a selective reversible samples were taken at baseline, at the end of therapy action on some acute-phase proteins and C3 but not and after a follow-up time of 23 ± 4 days. on others in conjunction with the improvement in Results. The concentrations of serum amyloid A glucose metabolism. [Diabetologia (1999) 42: 1433± (6.2 ± 1.1 mg/l) and C-reactive protein (6.1 ± 1.1 mg/ 1438] l) were increased (p < 0.001) and complement protein C3 (1.69 ± 0.05 g/l) was also above the reference Keywords Type II diabetes, inflammation, troglitaz- range for healthy subjects. Placebo treatment had no one, hyperglycaemia, serum amyloid A, complement effect on glucose or inflammation, whereas troglitaz- protein C3. Recent evidence suggests abnormalities in the in- flammatory factors in Type II (non-insulin-depen- Received: 31 May 1999 and in final revised form: 3 August dent) diabetes mellitus. Increased concentrations of 1999 haptoglobin, a-1-acid glycoprotein, C-reactive pro- tein (CRP), serum amyloid A (SAA) and interleu- Corresponding author: Pertti Ebeling, MD, Helsinki Universi- kin-6 have been reported in Type II diabetes or in im- ty Central Hospital, Department of Medicine, P.O. Box 341, paired glucose tolerance [1, 2]. In addition, athero- FIN-00029 HYKS, Finland sclerosis, which is often associated with Type II diabe- Abbreviations: A1GP, a-1-Acid glycoprotein; C3, complement tes, is increasingly considered to be a chronic inflam- protein C3; CRP, C-reactive protein; PPAR, peroxisome pro- liferator-activated receptor; SAA, serum amyloid A; SAP, se- matory disease [3]. Insulin resistance is associated rum amyloid P protein; sTNFRII, soluble tumour necrosis fac- both with Type II diabetes and with cardiovascular tor-a type II receptor. disease. The inflammatory cytokine tumour necrosis 1434 P.Ebeling et al.: Troglitazone reduces acute-phase proteins in Type II diabetes factor-a (TNF-a) [4] and the complement protein C3 Table 1. Characteristics of the patients at randomizationa concentrations [5] are closely related to insulin resist- Characteristics Placebo Troglitazone ance and obesity. n 12 (6/6) 15 (5/10) Thiazolidinediones are a new group of pharma- ceutical agents, with both glucose and lipid lowering Age (years) 63.5 ± 2.8 62.6 ± 2.2 2 effects and the ability to reduce insulin resistance [6, BMI (kg/m ) 33.1 ± 1.0 32.3 ± 1.3 7]. Thiazolidinediones possess affinity for peroxi- Diabetes duration (years) 14.3 ± 1.9 15.9 ± 2.1 some proliferator-activated receptor (PPAR)g Fasting plasma glucose [8±10]. A positive correlation exists between the (mmol/l) 12.2 ± 0.9 10.4 ± 0.6 HbA (%) 8.8 ± 0.3 (n = 9) 8.7 ± 0.3 (n = 12) PPARg activity and the antidiabetic responsiveness 1c [11]. Recent in vitro data suggest that thiazolidinedi- Insulin dosage (U/day) 75 ± 10 72 ± 10 ones inhibit the production of inflammatory cyto- a There are no significant differences in any of the characteris- kines as well as downstream markers of inflammation tics between the two groups such as nitric oxide produced by monocytic cells [12, 13]. Data from the Wistar fatty rats show that the an- tidiabetic and lipid lowering action of a thiazolidine- the patients. Other medication was kept practically unchanged dione (pioglitazone) is associated with the suppres- during the study. Blood samples were drawn at the screening visit for HbA and C peptide screening measurement in the sion of TNF-a production [14]. Recently the relation 1c central laboratory. At baseline, at the end of the 16-week treat- between PPARg and inflammation has become the ment period and after the mean follow-up time of 23 4 days focus of great interest [15]. We are not aware of any blood samples after an overnight fast were taken for this sub- data in humans concerning the effect of thiazolidin- study for measurements at the research laboratory of Helsinki ediones or any other specific agonist for PPARg on University Hospital. The study was approved by the ethics inflammation. Consequently, in the present study we committees of each participating centre. Each patient gave examined the effects of troglitazone on various posi- his/her written, informed consent and the study was conducted tive (SAA, CRP, a-1-acid glycoprotein (A1GP), a-1- according to the rules of good clinical practice. antitrypsin, C3, ceruloplasmin, haptoglobin) and one Methods. Fasting plasma glucose concentration was deter- negative (albumin) acute-phase serum proteins and mined using glucose oxidase method (Beckman glucose ana- glucose and lipid homeostasis in patients with Type lyzer, Beckman Instruments, Fullerton, Calif., USA). Serum II diabetes. C peptide, total and HDL-cholesterol and triglyceride concen- trations were determined as described previously [16]. Haemo- globin A1c (reference range 4.0±6.0%) at baseline (n = 21) and at the end of the treatment (n = 26) were determined with a Subjects and methods DCA 2000 analyser (Bayer Diagnostics). Serum apolipopro- tein A1 (apoA-I) and apolipoprotein B (apoB) were deter- mined by commercially available kits (Orion Diagnostica, Patients. A total of 27 patients (11 men, 16 women) with Type Espoo, Finland). Serum albumin (reference range 36.1±47.5 g/ II diabetes who had been treated with insulin from five Finnish l for men and 34.8±46.1 g/l for women) was measured with au- centres (Helsinki, Turku, Vaasa, Oulu and Jyväskylä) partici- tomated Bromcresol Purple method (Hitachi 917, Tokyo, Ja- pated in this study, which was a part of a large international pan). Serum haptoglobin (reference range 0.29±2.00 g/l), a-1- troglitazone trial. Patients were included, if their age was over acid glycoprotein (A1GP) (reference range 500±1200 mg/l), 35 years, duration of diabetes was over 1 year, daily insulin a-1-antitrypsin (reference range 0.98±1.78 g/l), ceruloplasmin dosage was 20 or more and less than 150 units, C peptide was (reference range 200±550 mg/l) and complement C3 protein (C3) (reference range 0.7±1.6 g/l ) concentrations were deter- more than 0.3 nmol/l and they had HbA1c 7.0% or more at the screening visit. Oral antidiabetic treatment was not al- mined with automated immunoturbidimetric methods (Hit- achi 911). Serum amyloid A protein (SAA) was measured by lowed. The mean ( ± SEM) age was 63.0 ± 1.7 years, HbA1c 8.8 ± 0.3%, body mass index 32.7 ± 0.8 kg/m2, diabetes dura- enzyme immunoassay (Cytoscreen, Biosource International tion 15.2 ± 1.4 years, insulin dose 73 ± 7 U/day. Most patients Calif., USA), C-reactive protein (CRP) by radioimmunoassay (twelve in the troglitazone and ten in the placebo group) used as described previously [17]. The detection limit for SAA is concomitant medication during the study with no clear differ- 0.005 mg/l and for CRP 0.05 mg/l. In 50 healthy control sub- ences between the groups. These medicines consisted mainly jects (33 men/17 women, age 38 ± 2 years) the mean ± SEM of angiotensin converting enzyme inhibitors, beta blockers, for SAA was 2.1 ± 0.5 mg/l and for CRP 2.7 ± 0.5 mg/l. Serum calcium channel blockers, long-acting nitrates and low dose amyloid P protein (SAP) was measured by radial immunodif- (50 to 150 mg/d) aspirin prescribed for hypertension and car- fusion by using pure SAP [18] as standard and polyclonal anti- diovascular diseases.
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