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Age and Ageing Advance Access originally published online on March 10, 2008
Age and Ageing 2008 37(3):330-333; doi:10.1093/ageing/afn038
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Copyright © The Author 2008. Published by Oxford University Press on behalf of the British Geriatrics Society.

Insulin sensitivity and beta-cell function in older Japanese adults without diabetes

SIR—Currently, Japan is facing the threat of a rapidly ageing society. With advancing age, glucose tolerance declines and the prevalence of type 2 diabetes increases [1, 2]. It is generally recognised that both insulin resistance and decreased insulin secretion are major factors associated with glucose intolerance [3]. Many [4–6] but not all [7, 8] studies have reported that older individuals are more insulin resistant than younger individuals. In addition, obesity plays a central role in insulin resistance, although most elderly Japanese subjects are not obese. On the other hand, the effect of age on beta-cell function has been a matter of debate [9–12]. Notably, Japanese subjects have lower beta-cell function compared with other ethnic groups [13]. In the present study, we investigated the relationship between insulin resistance and beta-cell dysfunction in older Japanese adults without diabetes.

Methods

Subjects
A total of 579 non-diabetic Japanese subjects aged 50 or older were included in this analysis. The study sample was drawn from a database of 954 individuals who had undergone a 75-g oral glucose tolerance test (OGTT) at our institution as part of an evaluation of glucose intolerance based on the presence of one or more risk factors: overweight, a first-degree relative with diabetes, past diagnosis of gestational diabetes mellitus, hypertension, dyslipidemia or a history of vascular disease. Exclusion criteria were known diabetes, individuals with fasting hyperglycemia ≥7.0 mmol/l or 2-h plasma glucose ≥11.1 mmol/l, incomplete data for calculating the insulin sensitivity index (ISI), or those with signs of serious liver diseases (clinically diagnosed chronic hepatitis or liver cirrhosis), renal failure [estimated glomerular filtration rate (GFR) ≥15 ml/min], chronic infectious diseases, endocrine diseases that affect insulin secretion or insulin sensitivity, cancer, or those with a prior gastrectomy. This study was performed in accordance with the Helsinki Declaration, and written informed consent was obtained from each participant.

Measures
A 75-g OGTT was performed after a 10-h overnight fast. Plasma glucose was determined using a glucose oxidase autoanalyser. Plasma insulin was measured using an electrochemiluminescence immunoassay (ECL-IA, Roche-Diagnostic, Basel, Switzerland), which does not cross-react with pro-insulin. Insulin sensitivity was evaluated by the homeostasis model assessment of insulin resistance (HOMA-R) [14], quantitative insulin check index (QUICKI) [15] and the ISI-composite proposed by Matsuda and DeFronzo [16]. To assess insulin secretion, insulinogenic index was defined as the ratio of the increment of plasma insulin to that of plasma glucose 30 min after glucose loading [17]. Estimated GFR was calculated using the formula of the modification of diet in renal disease study [18].

Statistical analysis
All statistical analyses were performed using the SYSTAT statistical package (Systat Software, Inc., CA). One-way analysis of variance was used to compare variables among age tertiles (50–60, 61–68, and 69–90 years). P-values < 0.05 were considered statistically significant.

Results

Subjects were divided into three groups based on age tertiles (Table 1). A higher proportion of women was found in older subjects. Body mass index (BMI) and waist circumference decreased in parallel with ageing. Of note, only 25 to 35% of study subjects were overweight as defined by BMI ≥25 kg/m2. Significant differences among age tertiles were detected in diastolic blood pressure (DBP), fasting insulin, total cholesterol and triglycerides. In addition, estimated GFR decreased significantly as age advanced. No difference among age tertiles was found in other variables. Table 2 shows the various markers of insulin resistance and beta-cell function among the age tertiles after adjustment for confounding factors (gender, BMI, waist circumference, DBP, total cholesterol, triglycerides and estimated GFR). HOMA-R and QUICKI were comparable among the age tertiles, whereas ISI-composite decreased significantly as age advanced. Insulinogenic index did not differ among age tertiles.


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  		Table 1. Clinical characteristics of study subjects classified by age tertiles

 


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  		Table 2. Insulin resistance and beta-cell function of study subjects classified by age tertiles

 
Discussion

This study focused on Japanese aged 50 or older without diabetes. Of the risk factors for insulin resistance in older people, obesity appears to be most common in Caucasian populations. Importantly, the degree of obesity seen in older Japanese is lower than that seen in Western countries [19]. Indeed, in our older subjects, only 25–35% of study subjects were considered overweight as defined by BMI ≥25 kg/m2. In addition, BMI and waist circumference decreased in parallel with advancing age.

To our knowledge, the present study provides the first precise information on insulin resistance and insulin secretion in older Japanese adults without diabetes. We considered the effect of kidney function because it has recently been suggested that impaired kidney function may affect insulin resistance [20]. After adjustment for confounding factors, including kidney function, our data demonstrated a decline in insulin sensitivity (obtained by ISI-composite) as age advances.

Age-related beta-cell dysfunction may contribute to the high rate of glucose tolerance in the older population [12]. Importantly, it has been reported that Japanese have lower beta-cell function compared with other ethnic groups [13]. In the present study, insulinogenic index did not differ among the age tertiles. These findings could have several explanations. An insulin response to oral glucose load with advancing age may be abolished after adjustment for obesity-related insulin resistance [21], although our older subjects were not obese. Another possibility is that insulin clearance may be changed in the elderly [22]. Decreased insulin clearance as a result of impaired renal function potentially may affect plasma insulin levels, but we believe this to be unlikely. In our data, fasting insulin levels were lower in older people despite decreased kidney function with ageing.

This study had several limitations. First, the validity of surrogate indices of insulin sensitivity must be considered. To date, clinical research has used HOMA-R or QUICKI as surrogate measures of insulin resistance. However, HOMA-R and QUICKI have obvious limitations, as they measure insulin sensitivity using only fasting values of glucose and insulin. Fasting glucose concentrations primarily depend on hepatic glucose production, and the ability of fasting insulin levels to predict insulin resistance is relatively modest. The concordance between compensatory fasting hyperinsulinemia and peripheral insulin resistance is not strong [23]. In addition, fasting hyperinsulinemia is not common, especially in lean Japanese subjects. In this context, we used a more elaborate OGTT-based method (ISI-composite) because this index was thought to be better for assessing insulin sensitivity than HOMA-R or QUICKI. Secondly, we did not measure other confounding factors. Age-related changes in body fat composition, decline in physical activity, and decreases in sex-hormone levels have been hypothesised as being among the main causes of insulin resistance [5]. Finally, as a cross-sectional study, the present analysis is limited in its ability to elucidate causal relationships between advancing age and insulin resistance. The participants of the current study were from a single institution and may not represent the overall elderly population in Japan.

In conclusion, in Japanese adults without diabetes, insulin sensitivity decreased significantly with advancing age after adjustment of other confounding factors, whereas beta-cell function did not decline as age advanced.

Key points

  • Older Japanese adults without diabetes are not obese; only 25–35% of the study subjects were overweight as defined by BMI ≥25 kg/m2.
  • Insulin sensitivity decreased significantly with advancing age after adjustment for other confounding factors.
  • Beta-cell function did not decline with advancing age.

Funding

This study was supported by a grant for Scientific Research (19 500 607) from the Ministry of Education, Science, Sports and Culture, Japan.

Conflicts of interest

None.

Masao Kanauchi1,*, Kimiko Kanauchi1,2, Tomoko Inoue1,2, Kuniko Kimura1 and Yoshihiko Saito1

1 Nara Medical University, First Department of Internal Medicine, 840, Shijo-cho Kashihara Nara 634-0813, Japan
2 SHARP Corporation, Health Care Unit, Japan

* To whom correspondence should be addressed Email: kanauchi{at}nmu-gw.naramed-u.ac.jp

References

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