Eur J Endocrinol
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DOI: 10.1530/eje.1.02219
European Journal of Endocrinology, Vol 155, Issue 2, 293-296
Copyright © 2006 by European Society of Endocrinology
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CLINICAL STUDY

Short-term administration of an angiotensin-receptor antagonist in patients with impaired fasting glucose improves insulin sensitivity and increases free IGF-I

Adrienne A M Zandbergen, Steven W J Lamberts, Joop A M J L Janssen and Aart H Bootsma

Department of Internal Medicine, Erasmus University Medical Centre, Dr Molewaterplein 40 3015 GD Rotterdam, The Netherlands

(Correspondence should be addressed to A A M Zandbergen; Email: adrienne_zandbergen{at}yahoo.com)


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Objective: Blocking the renin–angiotensin system (RAS) may reduce the risk of developing type-2 diabetes, but data are inconclusive and the mechanisms involved are unclear. RAS and RAS inhibition also influence the IGF-I system, which is important in glucose homeostasis. We investigated the effects of the angiotensin-receptor antagonist, losartan, on insulin resistance and IGF-I levels

Design and methods: In this hypothesis-generating study, five individuals with impaired fasting glucose received 100 mg losartan during 8 weeks. Before and after the treatment period, insulin sensitivity was assessed using the homeostasis model assessment of insulin resistance (HOMA), as well as the 2-h continuous infusion of glucose with model assessment (CIGMA). Furthermore, serum levels of free and total IGF-I, IGF-binding protein-3 (IGFBP-3), lipids and HbAlc were measured.

Results: After the treatment period, the HOMA score for insulin resistance had decreased from 5.3 ± 1.1 to 3.7 ± 0.9 (P = 0.004) and the 2-h CIGMA score from 23.4 ± 3.1 to 15.9 ± 2.1 (P = 0.07). The serum levels of free IGF-I had increased from 57 ± 18.8 to 134 ± 31.3 pmol/l (P = 0.04). In terms of percentage, the decrease of HOMA correlated with the increase in free IGF-I levels (Pearson’s correlation coefficient r = –0.8; P = 0.07). A trend in the same direction was observed with 2-h CIGMA. No differences were observed in lipids, total IGF-I, IGFBP-3 or HbAlc.

Conclusions: Losartan raised serum levels of free IGF-I, which might contribute to the improvement of insulin resistance associated with losartan treatment. These observations, if confirmed in broader studies, will help our understanding of the pathogenesis of type-2 diabetes mellitus, as well as the role of angiotensin-receptor antagonists in its prevention.


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Type-2 diabetes mellitus is a major health burden, associated with excess morbidity and mortality (1). The prevalence of type-2 diabetes mellitus is increasing rapidly and interventions to prevent or delay its onset are becoming more important. Preventative measures should address insulin resistance, as this is the major identifiable defect in subjects at risk of type-2 diabetes.

Recent publications suggest that blocking the renin–angiotensin system (RAS) may reduce the risk of developing type-2 diabetes (2). Development of diabetes in these trials was considered as secondary endpoint or post hoc analysis and large-scale prospective placebo-controlled clinical trials are necessary, designed to assess the protective benefits of RAS inhibition in subjects at risk of developing type-2 diabetes. The mechanisms involved in the effects of RAS inhibition on glucose metabolism and insulin sensitivity are still unclear (3).

Insulin-like growth factor (IGF)-I is important in glucose homeostasis and might play a protective role in the development of glucose intolerance (4). Interactions between RAS and the IGF-I system are complex and not fully clarified. It has previously been hypothesized that production of IGF-I is reduced by angiotensin-II, which is reversed by losartan (5). RAS inhibition seems to have metabolic and growth-promoting effects, which could be mediated by increased IGF-I levels (6).

We performed a proof of principle study in subjects with impaired fasting glucose to investigate the effects of short-term administration of the angiotensin-receptor antagonist, losartan, on insulin resistance, assessed using the homeostasis model assessment of insulin resistance (HOMA), as well as the 2-h continuous infusion of glucose with model assessment (CIGMA). Furthermore, serum levels of total and free IGF-I, IGF-binding protein-3 (IGFBP-3), HbAlc, as well as lipids were measured to investigate the effect of losartan on these parameters. Finally, possible correlations between changes in insulin resistance and the IGF-I system were studied.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients

Five subjects (one man and four women; mean age 53.4 ± 1.3 years) participated in the study. They had neither relevant medical history or medication. The individuals had impaired fasting glucose by the present World Health Organization criteria (mean fasting glucose levels 6.5 ± 0.1 mmol/l, mean HbAlC 6.6 ± x 0.3%) (7). They were normotensive (mean systolic blood pressure 137.2 ± 4.6 mmHg, mean diastolic pressure 84.6 ± 1.9 mmHg) and obese (mean body mass index 30.6 ± 2.1 kg/m2).

The study was performed according to the guidelines of good clinical practice and was approved by the institutional review board. All persons gave written informed consent prior to participation.

Methods

Insulin resistance was assessed using HOMA and 2-h CIGMA. Previous studies showed that the insulin resistance score, based on these methods, strongly correlates with insulin resistance assessed by the glucose clamp technique in both diabetic and non-diabetic subjects. Furthermore, the 2-h CIGMA can be considered as a test of glucose tolerance, analogous to the oral glucose tolerance test (8).

HOMA uses mathematical modelling of fasting plasma glucose and insulin levels to estimate insulin resistance: fasting serum insulin (µU/ml) x fasting plasma glucose (mmol/l)/22.5 (8). Three baseline samples, taken at 5-min intervals, were averaged for the mean levels of glucose and insulin. High HOMA scores denote low insulin sensitivity. The 2-h CIGMA consists of a 180 mg min/m2 glucose infusion for 120 min. Three blood samples were taken afterwards, at 120, 125 and 130 min, for the measurement of glucose and insulin levels. Again, the means of these three samples were used to estimate the insulin resistance score, using the above-mentioned formula.

During the 8-week study period, the subjects received 100 mg losartan orally, once daily. They were instructed not to change their diet or exercise pattern during this period. Blood pressure and body weight were measured at weeks 0 and 8.

Just before the start of treatment, we performed HOMA and 2-h CIGMA. Furthermore, venous blood samples were taken for the measurement of free and total IGF-I, IGFBP-3, lipids and HbAlc. Serum levels of total and free IGF-I were measured using direct IRMA (Diagnostic System Laboratories, Inc., Webster, TX, USA) (9, 10). All the samples were measured at once. After 8 weeks of losartan treatment, insulin sensitivity was measured again, as well as serum levels of total and free IGF-I, IGFBP-3, lipids and HbAlc.

Statistical analysis

Results are presented as means ± S.E.M., unless otherwise noted. The paired Student’s t-test was used for comparisons before and after losartan treatment. Associations between the variables were quantified using the Pearson correlation coefficient; the results are given including P value. We used GraphPad Prism software, version 3.00 (GraphPad Software, Inc., San Diego, CA, USA), for all statistical analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
After 8 weeks of treatment with 100 mg losartan, the HOMA score for insulin resistance decreased from 5.3 ± x 1.1 to 3.7 ± 0.9 (P = 0.004) and the 2-h CIGMA score decreased from 23.4 ± 3.1 to 15.9 ± 2.1 (P = 0.07). Serum levels of free IGF-I increased from 57 ± 18.8 to 134 ± 31.3 pmol/l (P = 0.04; Table 1Go). Normal values of free IGF-I at this age vary between 87.1–660.4 pmol/l for men and 76.7–770.9 pmol/l for women (11). The difference, in terms of percentage, in the decrease of HOMA correlated with the difference in the increase in free IGF-I levels (Pearson’s correlation coefficient r = –0.8; P = 0.07; Fig. 1Go). A trend in the same direction was observed in the correlation between the difference in the decrease of CIGMA and the difference in the increase in free IGF-I levels (r = –0.8; P = 0.1). No differences were observed in lipid levels, total IGF-I, IGFBP-3 or HbAlc.


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  		Table 1 Effects of losartan after 8 weeks of treatment on total and free insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, homeostasis model assessment of insulin resistance (HOMA), 2-h continuous infusion of glucose with model assessment (CIGMA), HbA1c and blood pressure Data presented as means ± S.E.M.
 

Figure 1
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  		Figure 1 Effect of 8-weeks of losartan treatment on HOMA and plasma levels of free IGF-I in each of the five participants.

 
Systolic blood pressure reduced from 137.2 ± 4.6 to 127.0 ± 5.3 mmHg (n.s.) after 8 weeks of losartan treatment, and diastolic blood pressure from 84.6 ± 1.9 to 82.6 ± 2.2 mmHg (n.s.). Body weight did not differ significantly. In these normotensive subjects, 100 mg losartan was well tolerated; no side effects were reported.


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In this proof of principle study, we investigated the effects of short-term administration of the angiotensin-receptor antagonist, losartan, on insulin resistance and variables of the IGF-I system in individuals with impaired fasting glucose. Insulin resistance was reduced after the 8-week treatment period. At baseline, plasma levels of free IGF-I were reduced compared to healthy subjects and normalized during the treatment period. This increase might contribute to the improvement in insulin sensitivity, as suggested by close to significant correlation between the decrease in insulin resistance scores and the increase in serum levels of free IGF-I.

Previous studies showed that the incidence of new-onset diabetes was lowered by inhibitors of the RAS, suggesting active positive effects of these drugs on long-term glucose metabolism. As stated in Introduction, prospective studies are required to confirm these observations as well as to elucidate the underlying mechanisms. We observed a significant reduction of the insulin resistance score, measured using HOMA; when measured using 2-h CIGMA, the reduction of the insulin resistance score just failed to reach significance. After this short-term treatment period, no differences in mean HbAlc levels were noticed. Since insulin resistance is one of the main predictors for the development of type-2 diabetes mellitus, improvement of insulin sensitivity might be the underlying mechanism in delaying or preventing this disease.

The IGF-I system plays an important contributory role in the regulation of glucose metabolism. IGF-I, like insulin, increases peripheral glucose uptake and decreases hepatic glucose production. Free IGF-I is the unbound, biologically active form. Serum levels of free IGF-I are often reduced in diabetic patients, which associate with increased insulin resistance and reduced metabolic control. Furthermore, increasing circulating IGF-I levels by means of recombinant human IGF-I is associated with improvement of insulin sensitivity and reduced insulin requirements in both type-1 and type-2 diabetes (4, 12). The association observed between the decrease in insulin resistance and the increase in free IGF-I is in accordance with these data.

The RAS interacts with the IGF-I system in several ways. These interactions are complex and not completely clarified. A previous study in rats showed that circulating levels of IGF-I are reduced by angiotensin-II infusion through reduction of the hepatic IGF-I mRNA levels, which is reversed by losartan (13). Only few clinical trials have been performed investigating the effects of RAS inhibition on the IGF-I system in humans (5, 6). A previous study showed metabolic and growth-promoting effects of an ACE inhibitor that might result from an increased IGF-I concentration (6).

An important limitation of our study is the short follow-up period. Although insulin resistance was significantly reduced, we cannot ascertain from these results whether the onset of new-diabetes will be prevented or delayed. Obviously, the significance of our observations should be viewed with the limitations germane to the small sample size. The results are promising in these subjects, but are preliminary and need to be confirmed in a large-scale and long-term study. Furthermore, the limited number of patients restricts our analysis to a univariate one.

In conclusion, short-term treatment with losartan raises the serum levels of free IGF-I, which might contribute to the improvement of insulin resistance associated with losartan treatment. The results of this hypothesis-generating study form a basis for further studies that improve our understanding of the pathogenesis of type-2 diabetes mellitus, which might ultimately result in new preventive interventions.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

    1. Zandbergen AA, Baggen MG, Lamberts SW, Bootsma AH, de Zeeuw D & Ouwendijk RJ. Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus. A randomized clinical trial. Annals of Internal Medicine 2003 139 90–96.[Abstract/Free Full Text]

    2. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B & Zanchetti A. For the value trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the value randomised trial. Lancet 2004 363 2022–2031.[CrossRef][ISI][Medline]

    3. Leiter LA & Lewanczuk RZ. Of the renin–angiotensin system and reactive oxygen species type 2 diabetes and angiotensin II inhibition. American Journal of Hypertension 2005 18 121–128.[CrossRef][ISI][Medline]

    4. Sandhu MS, Heald AH & Gibson JM. Circulating concentrations of insulin-like growth factor-I and development of glucose tolerance: a prospective observational study. Lancet 2002 359 1740–1745.[CrossRef][ISI][Medline]

    5. Zandbergen AA, Lamberts SW, Baggen MG, Janssen JA, Boersma E & Bootsma AH. The insulin-like growth factor I (IGF-I) system and the renal and haemodynamic effects of losartan in normotensive patients with type 2 diabetes mellitus. A randomised clinical trial. Clinical Endocrinology 2006 64 203–208.[Medline]

    6. Onder G, Penninx B, Balkrishnan R, Fried LP, Chaves PH, Williamson J, Carter C, Di Bari M, Guralnik JM & Pahor M. Relation between use of angiotensin-converting enzyme inhibitors and muscle strenght and physical function in older women: an observational study. Lancet 2002 359 926–930.[CrossRef][ISI][Medline]

    7. Alberti KG & Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetes Medicine 1998 15 539–553.

    8. Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, Monauni T & Muggeo M. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity. Diabetes Care 2000 23 57–63.[Abstract]

    9. Blum WF & Breier BH. Radioimmunoassays for IGFs and IGFBPs. Growth Regulation 1994; 4: (Suppl 1) 11–19.[Medline]

    10. Frystyk J, Ivarsen P, Stoving RK, Dall R, Bek T, Hagen C & Ørskov H. Determination of free insulin like growth factor-I in human serum: comparison of ultrafiltration and direct immunoradiometric assay. Growth Hormone and IGF Research 2001 11 117–127.

    11. Juul A, Holm K, Kastrup KW, Pedersen SA, Michaelsen KF, Scheike T, Rasmussen S, Muller J & Skakkebaek NF. Free insulin-like growth factor I serum levels in 1430 healthy children and adults and its diagnostic value in patients suspected of growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 1997 82 2497–2502.[Abstract/Free Full Text]

    12. Saukkonen T, Amin R, Williams RM, Fox C, Yuen KC, White MA, Umpleby AM, Acerini CL & Dunger DB. Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes. Journal of Clinical Endocrinology and Metabolism 2004 89 4634–4641.[Abstract/Free Full Text]

    13. Brink M, Wellen J, Delafontaine P & Angiotensin, II. causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. Journal of Clinical Investigation 1996 97 2509–2516.[ISI][Medline]

Received 10 March 2006
Accepted 24 May 2006





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