Insulin-resistance (IR) in older age

Archives of Gerontology and Geriatrics 46 (2008) 203–209 www.elsevier.com/locate/archger

Insulin-resistance (IR) in older age Massimo Motta *, Ettore Bennati, Laura Ferlito, Michela Passamonte, Mariano Malaguarnera Department of Aging Sciences, Urology and Neurology, University of Catania, Cannizzaro Hospital, Via Messina 829, I-95124 Catania, Italy Received 19 September 2006; received in revised form 28 March 2007; accepted 3 April 2007 Available online 4 June 2007

Abstract A study pool of 1549 normoglycemic elderly in the age range of 65–84 years, taken from the epidemiological Italian Longitudinal Study on Aging (ILSA), was constructed. The values of IR, %B and %S were analyzed using the homeostasis assessment model-2 (HOMA-2). In the subjects displaying normal values of several studied parameters such as the arterial blood pressure, total cholesterol (T-CH), high-density lipoproteins (HDL), and triglycerides (TG), the values of IR, %B and %S remained in the normal ranges (in average 1.66  1.11, 133.64  63.56 and 91.12  79.75, respectively). These latter values increase in the subjects who had altered values of the studied basic parameters listed above, and the increases were higher with the higher frequency of the altered parameters. The results seem to confirm the possibility that the normoglycemic elderly subjects having a compensatory insulin hypersecretion against the IR, may develop a type 2 diabetes or a metabolic syndrome. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Insulin-resistance (IR) in elderly; Homeostasis model assessment (HOMA-2); Metabolic syndrome

1. Introduction IR has a peculiar position in the metabolic syndrome. Such syndrome does not include only metabolic features, therefore, Balkau and Charles (1999) proposed to define it as ‘‘IR syndrome’’. IR can be quantified using detailed protocols, such as the euglycemichyperinsulinemic clamp technique, or the frequently sampled intravenous glucose tolerance test (FSIGT) (De Fronzo et al., 1979; Anderson et al., 1995). These methods, * Corresponding author. Tel.: +39 095 726 2050; fax: +39 095 49 8811. E-mail address: [email protected] (M. Motta). 0167-4943/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2007.04.001

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however, are very complex, invasive, and expensive, therefore cannot be used in large observational epidemiological studies (Cagnacci et al., 2001). Consequently, a number of simple surrogate indexes have been proposed for projects that require the estimation of IR in large number of subjects (Radikova, 2003). Matthews et al. (1985) created a more comprehensive structural model known as the homeostasis assessment model (HOMA). This model took into account of peripheral glucose uptake and could use fasting levels of specific insulin or C-peptide in addition to radio-immuno-assay (RIA)-determined insulin. HOMA assessment is based on the determination of fasting glycemia and insulinemia, which should not be modified by therapeutical interventions. Successively, Levy et al. (1998) published an updated HOMA model (HOMA-2) which considered variations in hepatic and peripheral glucose resistance and increases in the insulin secretion curve for plasma glucose concentrations above 10 mmol/l (180 mg/dl). The model was calibrated in order to define, in normal young adults, an insulin resistance value = 1.0 and %B and %S values as of 100%. The parameter %B indicates the secretory ability of pancreatic b-cells, while %S measures the peripheral sensitivity to insulin. The model was calibrated in order to define, in normal young adults, an IR = 1.0 and %B and %S values as of 100%. The parameter %B indicates the secretory ability of pancreatic b-cells, while %S measures the peripheral sensitivity to insulin. It was widely demonstrated and accepted that such method is a valid alternative, statistically significant predictor of insulin resistance (Ferrara and Goldberg, 2001). IR values reported in literature in normal adults display wide variations, e.g., 1.6  0.9 (Taniguchi et al., 2000), 2.06  0.14 (Bonora et al., 2000), 2.3  1.4 (Carnevale Schianca et al., 2003). Therefore, a discriminating cut-off between normal and insulin resistant subjects was also used. Matsumoto et al. (1997) defined as insulin resistant those subjects whose IR value was above the 90th percentile for the non-obese subjects with normal glucose tolerance (i.e., IR > 1.97). Subjects whose values of IR exceeded the 75th percentile (i.e., 2.0) were considered to have insulin resistance by Hedblad et al. (2000), according to European Group for the Study of Insulin Resistance (EGIR) (Balkau and Charles, 1999). Bonora et al. (1998) reported a wide range of IR values. They subdivided the normal adults in five quintiles, and considered as normal those values below the 5th quintile of distribution values (2.77). At the actual state of the art, there are few specific contributions about insulin resistance in the elderly, with poor sample sizes, and the reference values are not yet established. Lichnovska et al. (2002), in a study pool of 30 normal subjects (10 males of 60.3  11.0 years, and 20 females of 56.9  13.0 years) observed mean values of IR, respectively, 1.685  0.771 and 1.717  0.893. They have reported, in addition, that in 40 hypertriglyceridemic elderly subjects, the IR values were significantly higher (in males 3.137  1.419, in females 2.694  1.011). Ferrara and Goldberg (2001), in 21 elderly subjects with normal glucose tolerance (of mean age 61.9  8.5 years) described a mean IR value of 2.2  0.8. Matsubara et al. (2003) studied 486 non-diabetic women in the age range 16–86 years, with an average of 55. They divided arbitrarily this total pool in 3 tertiles (IR <1.5; 1.5 <3; and >3). The first group covered 55% of all cases, the second one 35%, and the third one amounted to 10%, within mean values of IR = 0.98, 2.09 and 4.61, respectively. The mean age of

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these three groups was not different. The third group contained prevalently subjects with hypertension. Starting from this basis, in order to establish the reference values of IR, %B and %S for the elderly, we measured these parameters in 1549 normoglycemic elderly subjects (glycemia < 100 mg/dl), enrolled in an epidemiological study, not only the insulinemia, but also the arterial blood pressure, the triglyceridemia, the total cholesterolemia and the HDL levels.

2. Research design and methods This study has been performed on the subjects involved in the epidemiological ILSA (Maggi et al., 1994; ILSAWorking Group, 1997). They were in the age range of 65–84 years. The ILSA study was realized on the basis of internationally validated criteria. A clinical record has been filled in for each subject, multiple laboratory tests and instrumental examinations have been performed, as described before (Maggi et al., 1994). We considered only the 1549 subjects who displayed a normal glycemia as defined by the diagnostic criteria of ADA 2003 (normal fasting glucose, NFG < 100 mg/dl) (The Expert Committee, 2003). In this study pool we considered the arterial blood pressure, the total cholesterol and the HDL (by enzymatic method), the triglyceridemia (by enzymatic method), glycemia (by the gluco-oxidase method), as well as the insulinemia (by RIA). The normal reference values of the studied parameters were taken from the Second Joint Task Force of European and other Societies on Coronary Prevention and the WHO (Wood et al., 1998; WHO, 1999). Values of glycemia and insulinemia were utilized for the determination of IR, %B and %S, calculated according to the computer-based HOMA-2 calculator, Version 2.2 (available at www.dtu.ox.ac.uk/homa). It should be underlined that a differentiating cut-off was used to distinguish the insulin-resistant subjects from those with normal values. Taking into account that 25% of the population is insulin-resistant, and specifying that the study pool has been representative for Italian older people, EGIR indicated this differentiating cut-off the value of IR exceeding the 75th percentile (Balkau and Charles, 1999). Our study was performed in agreement with the Helsinki Declaration and written informed consent was obtained from each participant. The statistical evaluation was performed by means of the t-test for independent samples, using the Primit.exe Version 3.03 per DOS. We defined the statistical significance level as p < 0.05.

3. Results Our results obtained are reported in Table 1. In more details, we report that: (i) The mean value of IR in the total pool of normoglycemic subjects was 1.99  1.32, with a 75th percentile of 2.7. These values are representative for the normoglycemic elderly Italian population, regardless the pathologies.

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Table 1 The measured parameters in the total study pool as well as in the subgroups of age and of various pathologies (mean  S.D.) Groups

N

IR

75%

%B

%S

Total pool

1549

1.99  1.32

2.7

153.36  73.97

73.53  72.51

Normals (normoglycemic, normotensive, with normal T-CH, HDL-CH and TG) 65–84 years 144 1.66  1.11 2.3 133.64  63.56 65–74 years 68 1.71  1.11 2.3 138.55  68.96 75–84 years 76 1.63  1.11 2.3 129.84  56.52

91.12  79.75 94.03  80.54 90.27  77.25

With total hypercholesterolemia (normoglycemic, normotensive, normal HDL-CH and TG)

213

2.00  1.33

2.6

155.68  71.13

76.46  77.64

With HDL-hypocholesterolemia (normoglycemic, normotensive, normal T-CH and TG)

136

1.85  0.98

2.4

146.66  101.88

85.63  80.80

29

2.12  1.21

2.6

165.64  75.99

52.53  36.36

202

1.99  1.38

2.6

155.91  68.64

71.30  72.50

With hypertriglyceridemia (normoglycemic, normotensive, with normal T-CH and HDL-CH) With hypertension (normoglycemic, with normal T-CH, HDL-CH and TG)

t-Test for normal/hypertensive comparison: p = 0.031.

(ii) The mean value of IR found in 144 subjects displaying non-altered parameters (9.3% of the total pool) was 1.67  1.11, with a 75th percentile value of 2.3, %B and %S amounted to 133.64  63.56 and 91.12  79.75, respectively. The mean value of IR in the younger elderly (65–74 years) was 1.71  1.11 with a 75th percentile of 2.3, while in the older elderly (75–84 years) the same values were 1.63  1.11 and 2.3, respectively ( p = 0.667). (iii) In relation with the progressive presence of the various diseases, are reported. One can see that the increase of the number of altered parameters is followed by a reduction of the values of %S, and by an increase of IR, %B, and their 75th percentile values.

4. Discussion The analysis of the available literary data revealed that the contributions are of modest entity, and the normal levels of IR are not yet definitively established. The values of IR found by our study in normoglycemic elderly having also the other parameters in normal range, fall into the lower limits of IR values of the literature (Bonora et al., 2000; Taniguchi et al., 2000; Ferrara and Goldberg, 2001; Lichnovska et al., 2002; Carnevale Schianca et al., 2003). Also the values of the 75th percentiles in the normoglycemic elderly subjects without pathologies are in the normal range of the adults (Matsumoto et al., 1997; Bonora

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et al., 1998; Hedblad et al., 2000). There are no significant differences between the observed values of the younger and older age groups ( p = 0.667). These findings indicate that age itself does not affect significantly the values of IR and the differentiating cut-off of normality. The finding of modifications in the insulin-sensibility in a population-wide study performed on the normoglycemic elderly, like the present one, should therefore be interpreted as due to the presence of particular pathological conditions, and not to the age (Table 1). Our data are in agreement with those of Lichnovska et al. (2002) and of Matsubara et al. (2003), who have found increased IR values in subjects with hypertriglyceridemia and hypertension, respectively. In addition, the contemporary alteration of the parameters considered in our study has revealed a significant increase of IR, of %B and their 75th percentiles, and a decrease of %S. These results indicate that these alterations have a significant impact on the behavior of IR. Metabolic syndrome has been defined in different manners in these last years. Amongst the most recent definitions, four are of particular importance. The WHO (1999) considered as alternative the glycemic changes with increased values of IR. On the other hand, the Adult Treatment Panel III (ATP III) (National Cholesterol Education Program, 2002), according to the previous definitions, underlined that insulin resistance should have been considered as emerging factor, especially in relation with the evolution of metabolic disorders. The EGIR version (Balkau and Charles, 1999), previous to ATP III and designed for non-diabetics only, can be simply used in epidemiological studies because it is based on fasting insulin levels to estimate insulin resistance and impaired fasting glucose (IFG) in place of IGT (avoiding the need for either an euglycemic clamp or an oral glucose tolerance test (OGTT)) (IDF, 2005a). Finally, the IDF (2005b) considered the presence of IR not prominent in the metabolic syndrome. In metabolic syndrome the contemporary presence of all the component factors is not necessary. At least three of the five most significant factors should be present for this diagnosis. Our results show that in elderly subjects having no alterations of the indicated parameters, the insulin-sensitivity is only slightly lower than the normal reference value (91% versus 100%). The contemporary alteration of the metabolic parameters (total hypercholesterolemia, HDL-hypocholesterolemia, hypertriglyceridemia and hypertension) results in a decreased insulin-sensibility and an increased IR. This causes an insulinhypersecretion, as a response. This compensatory hyperinsulinemia serves to maintain normal plasma glucose levels in the face of IR (Goodarzi et al., 2005). In cases where this cannot be maintained any more (pancreatic atherosclerosis, central obesity, lifestyle, etc.), a typical metabolic syndrome comes into being, in which the hyperglycemia is a constant component. Because the patients were selected to have normal fasting glucose levels (<100 mg/dl), one can assume that they still had an adequate b-cell function. It is important to emphasize that an increased IR is always accompanied in all studied conditions, by an increased %B. This could lead with time to a b-cell exhaustion and development of type 2 diabetes mellitus (Saad et al., 1991).

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5. Conclusion Our data demonstrate normal IR and 75th percentile levels in normoglycemic elderly, if they do not have altered levels of total or HDL cholesterol, triglycerides, or arterial hypertension. On the other hand, these pathological conditions are accompanied by a reduced %S, an increased IR, by an increased differentiating cut-off, and an increased insulin-secretion, expressed as %B. This means that the evaluation of the significance of the values of IR and its 75th percentile in the elderly should involve the eventual presence of the alterations sized by us. The elderly subjects with an increased IR and an increased insulin-secretion, even if they are in fact normoglycemic, have an increased risk of diabetic disease because of a possible b-cell exhaustion, and therefore, in presence of the altered parameters studied by us, of the possibility of metabolic syndrome.

Appendix A The list of authors in the ILSA Working Group: Luigi Amaducci, Guglielmo Scarlato, Marzia Baldereschi, Livia Candelise, Antonio Di Carlo, Francesco Grigoletto, Stefania Maggi, Nadia Minicuci, Elio Scarpini, Giuseppina Volonnino, Giovanni Bortolan, Marta Bressan, Carlo Loeb, Carlo Gandolfo, Nicola Canal, Massimo Franceschi, Leontino Battistin, Giuliano Enzi, Augusto Ghetti, Domenico Inzitari, Rossano Vergassola, Salvatore Bonaiuto, Franco Rengo, Antonio Capurso, Paolo Livrea, Luciano Motta.

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