Aging is associated with a deterioration of glucose

Prevalence of Diabetes and Impaired Glucose Tolerance in Elderly Subjects and Their Association With and Family History of Diabetes Leena Mykkanen, MD Markku Laakso, MD Matti Uusitupa, MD Kalevi Pyorala, MD The goal of this study was to investigate the prevalence of impaired glucose tolerance (IGT) and non-insulindependent diabetes mellitus (NIDDM) in elderly subjects and their association with obesity, central obesity, and a family history of diabetes. A representative population sample of 13 subjects (471 men, 829 women) aged 65-74 yr participated in the study. The participation rate was 71%. The prevalence rates of previously and newly diagnosed NIDDM and IGT, based on a history of diabetes and an oral glucose tolerance test, were 8.7, 7., ^ind 17.8% in men and 11.7, 7.1, and 19.1% in women. Thus, 33.8% of men and 37.9% of women had abnormal glucose tolerance according to World Health Organization criteria. (body mass index >27 kg/m 2 in men and ^25 kg/m 2 in women) and central obesity (waist-hip ratio >.98 in men and >.89 in women) doubled the prevalence of IGT or NIDDM. The combination of obesity and a family history of diabetes was associated with a more marked increase in the prevalence of IGT or NIDDM in men than in women. Simultaneous presence of obesity, central obesity, and a family history of diabetes was associated with a threefold increase in the prevalence of IGT or NIDDM (65.4 vs. 24.1% in men, 52.8 vs. 19.6% in women, P <.1). The major risk factors for NIDDM, e.g., obesity, central fat distribution, and a family history of diabetes, explained 1% of the variance in 2-h glucose values in multiple regression analysis. In conclusion, the prevalence of IGT and NIDDM was high in elderly subjects. Although obesity, central fat distribution, and a family history of diabetes were significantly associated with the increased prevalence of From the Departments of Medicine and Clinical Nutrition, University of Kuopio, Kuopio, Finland. Address correspondence and reprint requests to Leena Mykkanen, MD, Department of Medicine, Kuopio University Central Hospital, SF-721 Kuopio, Finland. Received for publication 12 February 199 and accepted in revised form 13 lune 199. IGT or NIDDM, they explained only a minor proportion of the variance in 2-h glucose values. Diabetes Care 13:199-15, 199 Aging is associated with a deterioration of glucose tolerance (1,2). Fasting blood glucose has been estimated to increase by an average of.6 mm and 2-h blood glucose by.5 mm each decade after 5 yr of age (1,3). Although information about the degree of age-related deterioration in glucose tolerance is available, few studies have been published on the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) in representative elderly populations. With the World Health Organization (WHO) criteria (4) for the diagnosis of diabetes and IGT, the prevalence rate of diabetes has been estimated to be 1-19% and that of IGT 14-23% in elderly populations in the United States (5,6), Denmark (7), and Sweden (8). Other studies that have reported prevalence rates for diabetes and IGT in elderly subjects have not applied the WHO criteria, or they have been based on unrepresentative population samples (9-11). and a family history of diabetes are the major factors contributing to the occurrence of NIDDM and IGT in middle-aged subjects (12-19). Central body-fat distribution, measured as waist-hip ratio, is also associated with an increased risk for NIDDM in middle-aged subjects even after the effect of overall obesity is accounted for (2,21). Waist-hip ratio correlates positively with the amount of intra-abdominal visceral fat mass, which is associated with hyperinsulinemia and insulin resistance and thereby with the impairment of glucose tolerance (22,23). DIABETES CARE, VOL. 13, NO. 11, NOVEMBER 199 199

DIABETES IN ELDERLY SUBJECTS Although the occurrence of abnormalities in glucose tolerance has been shown to be frequent in elderly populations (5-8), little is known about the association of obesity, body-fat distribution, and a family history of diabetes with abnormal glucose tolerance in elderly subjects. Therefore, we investigated the prevalence of ICT and NIDDM with a particular emphasis on the association of obesity, distribution of obesity, and a family history of diabetes with the prevalence of IGT and NIDDM in a population aged 65-74 yr from east Finland. No answer to postal questionnaire 262 Exclusion criteria 83 Random sample 191 I Postal questionnaire I Answer to postal questionnaire 1648 No exclut>ion criteria 1565 RESEARCH DESIGN AND METHODS i Unwlling to participate 85 Wiling to participate 148 The study was conducted in Kuopio, east Finland, between February 1986 and April 1988. Altogether, 191 subjects born from 1912 to 1921 were randomly selected from the population register including all inhabitants of Kuopio. This random sample covered 35% of all residents in the age-group of 65-74 yr. A postal questionnaire containing questions about diagnosis of diabetes, ability to move, and willingness to participate in the study was sent to these subjects. Two hundred sixtytwo subjects did not respond to the postal questionnaire, and 85 subjects were originally unwilling to participate. Eighty-three subjects were excluded because they were too ill to participate. Of those who were invited, 26 subjects died, 13 moved outside of the study area, and 41 became seriously ill before clinical examination. One hundred subjects refused later on to participate in the examination, giving an overall participation rate of 71%. Formation of the final study population of 13 subjects is shown in Fig. 1. All diabetic people in Finland who need drug therapy are registered. Representativeness of the study population was evaluated on the basis of this register. The mean age of subjects who participated (71 %) in the study was almost identical to that of those who failed to participate (29%; 69 vs. 69 yr in men, 69 vs. 7 yr in women). There were no differences in the proportion of subjects receiving drug reimbursement for diabetes (4.7 vs. 6.8% in men, 7.1 vs. 8.1% in women, NS) or in the duration of diabetes (9 vs. 9 yr in men, 9 vs. 1 yr in women) between participants and nonparticipants. Information about a family history of diabetes in nonparticipants was not available. Thus, the study population was a representative sample of subjects aged 65-74 yr living in Kuopio. Standing height was measured without shoes. Height was read to the nearest 1 cm. Body weight was measured without shoes in light clothes to the nearest 1 kg. Body mass index (BMI) was calculated from the formula BMI = weight (kg)/height (m 2 ). Body-fat distribution pattern was measured as waist-hip ratio. Waist circumference was measured to the nearest 1 cm at the level of the umbilicus with the subject dressed in shorts and standing and breathing normally. Hip circumference was measured to the nearest 1 cm at the level of the Died before examination 26 Moved before examination 13 Seriously ill before examln- 41 Refused to participate after Invitation to examination too -i - - - FIG. 1. Formation of study population. Invitai ion to examlnation Participants 13 greatest hip girth. All anthropometric measurements were performed by the same specially trained nurse. was defined as BMI >27 kg/m 2 in men and ^25 kg/m 2 in women (24). Because there is no international consensus on the'criteria for central obesity and because mean values for waist-hip ratio are different for men and women, the cutoff points for central obesity were based on the 5th percentiles of the distribution of waist-hip ratios for men and women separately. Family history of diabetes was regarded as positive if one of the parents or siblings had NIDDM. All laboratory specimens were taken after a 12-h fast at 8. All subjects, except for those receiving insulin, underwent an oral glucose tolerance test (75 g glucose in 1% solution). Venous blood samples for glucose determinations were taken before and 1 and 2 h after the glucose load. Plasma glucose was determined by the glucose oxidase method (Glucose Auto & Stat HGA- 112 analyzer, Daiichi, Kyoto, Japan). Diabetic subjects who used insulin had C-peptide levels measured at fasting and 6 min after intravenous glucagon administration (25). Plasma C-peptide was determined from samples stored at -7 C by a commercial radioimmunoassay (C-peptide of insulin 125J RIA kit, Incstar, Stillwater, MN) with a detection limit of.7 nm and an intraassay variation of <5%. The WHO diagnostic criteria for diabetes mellitus 11 DIABETES CARE, VOL. 13, NO. 11, NOVEMBER 199

L MYKKANEN AND ASSOCIATES TABLE 1 Plasma glucose concentrations in 2-h oral glucose tolerance test Plasma glucose (mm) Oh 65- to 69-yr-old age-group 1 h 2 h 7- to 74-yr-old age-group Oh 1 h 2 h Men Range 5th percentile 95th percentile Mean ± SE Women Range 5th percentile 95th percentile Mean ± SE 3.8-22.7 5.9 12.2 6.6 ±.1 4.1-22.9 5.8 12.2 6.5 ±.1 2.2-32.7 9. 19.5 1.1 ±.3 3.2-35.3 8.1 21.7 9.5 ±.2 2.4-39. 3 6.7 2.5 3.3 ±.3 2.4-34. 8 6.8 24.4 3.8 ±.3 4.6-21. 8 5.8 9.7 6. 4 ±.2 4.1-19. 1 5.7 11.4 6. 5 ±.1 3.5-3. 6 9.2 17.5 9. 7 ±.3 2.5-28. 1 8.2 19.1 9. 4 ±.3 1.9-34. 6.5 17.8 7.9 ±.3 2.3-32.2 7. 2.3 8.7 ±.3 were used in the classification of subjects without previously known diabetes (4). The criteria are as follows: 7) diabetes mellitus, fasting venous plasma glucose >7.8 mm or 2-h venous plasma glucose >11.1 mm in an oral glucose tolerance test (75 g glucose); 2) IGT, fasting venous plasma glucose <7.8 mm and 2-h venous plasma glucose 7.8-11. mm; and 3) normal glucose tolerance, fasting and 2-h venous plasma glucose <7.8 mm. Previously known diabetes was considered to be present if the diagnosis of diabetes had been previously made by a physician. Medical records were checked for diabetic subjects who had been treated with diet therapy only and who showed normal glucose tolerance in an oral glucose tolerance test. Insulin-treated diabetic subjects whose C-peptide level 6 min after intravenous glucagon (1 mg) stimulation (25) was <.2 nm were regarded as having insulin-dependent diabetes mellitus (IDDM; 26). Statistical methods. Data analyses were conducted with the SPSSX programs (27). The results for continuous variables are given as means ± SE. Student's two-tailed t test for independent samples was used in the assessment of the significance of the differences between two group means. x 2 -Test was used in the assessment of the significance of differences in prevalence rates. Analysis of variance was used in testing the differences between more than two group means. Multiple stepwise linear regression analysis was used to investigate the association of age, BMI, waist-hip ratio, and a family history of diabetes (absent, present) with plasma glucose. RESULTS The mean age of the participating men and women was similar (68.9 vs. 69.1 yr, NS). There were no differences in fasting, 1-, or 2-h plasma glucose concentrations between the two 5-yr age-groups or between men and women (Table 1). In both sexes, distributions for fasting and 1- and 2-h plasma glucose levels were skewed to the right but were unimodal (data not shown). Table 2 shows the prevalence of diabetes and ICT by sex. The prevalence of previously diagnosed NIDDM was 8.7% among men and 11.7% among women (4% were treated with diet, 53% with oral hypoglycemic drugs, and 7% with insulin). Newly diagnosed NIDDM was detected in 7.% of men and 7.1% of women. In this elderly population, NIDDM was as frequent in men as in women, and the ratio of newly diagnosed to previously diagnosed NIDDM was 1.:1.2 in men and 1.:1.6 in women. Only one insulin-treated man had IDDM (glucose-stimulated C-peptide value <.2 nm). IGT was found in 17.8% of men and 19.1% of women. Abnormal glucose tolerance, including previously and newly diagnosed NIDDM and IGT, was detected in 33.8% of men and 37.9% of women. Men with IGT and newly diagnosed NIDDM had higher indices of obesity (BMI, waist-hip ratio) and were more often obese by categorical criteria (BMI >27 kg/ m 2 or waist-hip ratio >.98, 5th percentile of the waist-hip ratio distribution in men) than men with normal glucose tolerance, but men with previously diag- TABLE 2 Prevalence of impaired glucose tolerance and diabetes by sex Glucose tolerance status Normal glucose tolerance (%) Impaired glucose tolerance (%) Newly diagnosed non-insulindependent diabetes mellitus (%) Previously diagnosed non-insulindependent diabetes mellitus (%) Previously diagnosed insulindependent diabetes mellitus (%) Total number in parentheses. Men Women (n = 471) (n = 829) 66.2 (312) 62.1 (515) 17.8 (84) 19.1 (158) 7. (33) 7.1 (59) 8.7 (41) 11.7 (97).2 (1) DIABETES CARE, VOL. 13, NO. 11, NOVEMBER 199 111

DIABETES IN ELDERLY SUBJECTS nosed NIDDM were not different from men with normal glucose tolerance in this respect (Table 3). In women, all subjects with abnormal glucose tolerance (IGT and newly and previously diagnosed NIDDM) showed higher mean values of BMI and waist-hip ratio and were more often obese (BMI >25 kg/m 2 or waist-hip ratio ^.89, 5th percentile of waist-hip ratio distribution in women) than subjects with normal glucose tolerance. In both sexes, the prevalence of positive family history of diabetes was higher in subjects with previously diagnosed NIDDM than in subjects with normal glucose tolerance. Figure 2 shows the effects of obesity and central obesity on the prevalence of IGT or NIDDM in the absence or presence of a family history of diabetes. In the absence of a family history of diabetes, the prevalence of IGT or NIDDM was about twice as high in obese women compared with that in nonobese women (39. vs. 22.5%), whereas in men, the effect of obesity on the prevalence of IGT or NIDDM was less marked (34.5 vs. 24.7%). The results were similar (33.5 vs. 24.1% in men, 46.8 vs. 24.% in women) for central obesity in the absence of a family history of diabetes. In the presence of a positive family history, the excess of IGT or NIDDM among obese men was more marked than among obese women (63.5 vs. 29.4% in men, 46.9 vs. 32.8% in women). A similar increase in the prevalence of IGT or NIDDM was seen in the presence of a family history of diabetes and central obesity (61.2 vs. 29.7% in men, 5.6 vs. 34.4% in women). In both sexes, simultaneous presence of obesity, central obesity, and a family history of diabetes was associated with a threefold increase in the prevalence of IGT or NIDDM compared with that observed in subjects who did not have these risk factors (65.4 vs. 24.1% in men, 52.8 vs. 19.6% in women, P <.1). To investigate the association of age, BMI, waist-hip ratio, and a family history of diabetes (absent, present) with plasma glucose in subjects with normal glucose tolerance, IGT, and newly diagnosed NIDDM, multiple stepwise linear regression analyses were performed (Table 4). BMI was independently associated with 2-h plasma glucose in men and BMI and waist-hip ratio in women. Interaction terms of age x BMI, age x waist-hip ratio, age x family history of diabetes, BMI x waist-hip ratio, BMI x family history of diabetes, and waist-hip ratio x family history of diabetes were not significantly associated with plasma glucose. Age, BMI, waist-hip ratio, and a family history of diabetes explained 1.3% of the variance in 2-h plasma glucose values in men and 11.% in women. DISCUSSION The prevalence of NIDDM and IGT varies markedly between populations (28). In the Second National Health and Nutrition Examination Survey (NHANES II), which covered a representative sample of the U.S. population aged 65-74 yr, the prevalence rates of previously and newly diagnosed diabetes and IGT were 9.1, 1., and 22.8%, respectively, in White men and 8.8, 8.2, and 23.%, respectively, in White women according to WHO criteria (5). In our study, the prevalence rates of previously and newly diagnosed NIDDM and IGT were 8.7, 7., and 17.8%, respectively, in men and 11.7, 7.1, and 19.1%, respectively, in women, which were comparable to the prevalence rates in the U.S. population. The prevalence of diabetes in elderly subjects in Denmark (7) and Sweden (8) was only 5% of that observed in east Finland. Reasons for that are unknown, but the higher prevalence TABLE 3 Indices and frequency of obesity and positive family history of diabetes in men and women with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and non-insulin-dependent diabetes mellitus (NIDDM) Variable NGT ICT Newly diagnosed NIDDM Previously diagnosed NIDDM Men Weight (kg) Body mass index (kg/m 2 ) Waist-hip ratio Body mass index >27. (%) Waist-hip ratio >.98 (%) Family history of diabetes (%) Women Weight (kg) Body mass index (kg/m 2 ) Waist-hip ratio Body mass index 2:25. (%) Waist-hip ratio >.89 (%) Family history of diabetes (%) 74.6 ±.6 26. ±.2.97 ±.1 37.8 45.2 22.8 66.1 ±.4 27.1 ±.2.88 ±.1 7.4 42.2 32. 79.9 ± 1.2* 27.9 ±.4* 1.1 ±.1* 57.1t 66.7* 32.1 7.1 ±.9* 29.1 ±.4*.9 ±.1* 84.2* 6.8* 33.5 82.6 ± 2.6t 28.9 ±.8* 1.2 ±.1* 63.6t 72.7t 33.3 72.9 ± 1.7* 3.3 ±.6*.93 ±.1* 89.8t 74.6* 44.1 77.9 ± 1.6 26.7 ±.5.98 ±.1 51.2 46.3 53.7* 7.8 ± 1.3t 29.5 ±.5*.92 ±.1* 77.3 64.9* 5.5* Values are means ± SE. *P <.1, tp <.1 for IGT and NIDDM groups vs. NGT group; x 2 -test or t test used for comparisons. P <.1 over all glucose tolerance status groups (analysis of variance or x 2 -test). 112 DIABETES CARE, VOL. 13, NO. 11, NOVEMBER 199

L MYKKANEN AND ASSOCIATES ~ 5 3 1 ~ 5 ) o S 3 15 «* 1 FH- *** FH+ *** FH- *** FH+ - + Central Central Central Central obesity obesity obesity obesity FH- FH+ FH- FH+ MEN WOMEN ED Impaired glucose tolerance Mi Newly diagnosed NIDDM Previously diagnosed NIDDM FIG. 2. Prevalence of impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM) in relation to obesity (body mass index >27 kg/m 2 in men and >25 kg/m 2 in women) and central obesity (waist-hip ratio >.98 in men and >.89 in women) by sex in absence or presence of family history of diabetes (FH). *P <.5, *P<.1, ***P<.1. of obesity in elderly Finnish subjects could be one explanation (8,29). The prevalence of ICT was approximately twofold higher than the prevalence of newly diagnosed NIDDM in this study, which was in accordance with previously published studies (5,7,8). Several follow-up studies in middle-aged and younger populations have indicated that -5% of IGT subjects revert to normal glucose tolerance, 25% remain permanently glucose intolerant, and <25% progress to diabetes (3-33). However, middle-aged subjects with IGT have an approximately fourfold risk for developing diabetes compared with normoglycemic subjects (3,32,33). Corresponding information about the natural history and predictive value of IGT for future risk of NIDDM in the elderly is not available. Variations in the prevalence of abnormal glucose tolerance, particularly IGT, could be due to the performance of the oral glucose tolerance test. We repeated the oral glucose tolerance test 1-6 mo after the first test in ** a random sample of 45 subjects (2 men, 25 women) who had IGT, and 47% of them (4% of men, 52% of women) had normal glucose tolerance in the second test, which is in accordance with previously published studies in middle-aged and elderly subjects (34,35). Furthermore, the length of the fast was standardized, and glucose tolerance tests were conducted in the morning to avoid the effect of diurnal variation in glucose tolerance (1,36). Thus, the high prevalence of abnormal glucose tolerance observed in elderly subjects in this study cannot be due to the performance of the oral glucose tolerance test but is probably explained by an increase of "true" IGT. The predominant mechanism of age-related deterioration in glucose tolerance is peripheral insulin resistance (2,37). Reduction in lean body mass, decreased physical activity, and changes in diet favoring low-fiber and high-fat intake associated with aging tend to worsen the degree of insulin resistance and thus lead to the impairment of glucose metabolism (37). However, little is known about the role of obesity, distribution of obesity, and a family history of diabetes as risk factors for abnormal glucose tolerance in the elderly. We found that obesity (high BMI) and central obesity (high waist-hip ratio), which are independent risk factors for NIDDM in middle-aged subjects (2,21,38,39), doubled the prevalence rate of IGT or NIDDM above that in nonobese subjects (Fig. 2). Thus, our results confirmed the recent findings of Landin et al. (4) and Coon et al. (41) that obesity and high waist-hip ratio are determinants of glucose tolerance in elderly subjects and extended these observations to include the entire range of abnormal glucose metabolism from IGT to known NIDDM. The association of obesity and a family history of diabetes with glucose tolerance was further analyzed by combining men and women to compare the results with NHANES II. Prevalence of IGT or NIDDM in nonobese subjects increased from 23.8 to 31.1 % if the subjects had a positive family history of diabetes. In obese subjects, the corresponding prevalence rates were 37.8 TABLE 4 Multiple stepwise linear regression analyses on association of risk factors with 2-h plasma glucose in subjects with normal glucose tolerance, impaired glucose tolerance, and newly diagnosed non-insulin-dependent diabetes mellitus Independent variable Age (yr) Body mass index (kg/m 2 ) Waist-hip ratio Family history of diabetes R 2 for model (%) 3 -.2 +.32* +.4 +.2 Men R 2 (%) 1.3 1.3 +.2 +.25* +.14* +.4 Women R 2 (%) 9.5 1.5 11. (3, Standardized regression coefficient; R 2, proportion of variance in 2-h plasma glucose explained by given variable (%). *P<.1. DIABETES CARE, VOL. 13, NO. 11, NOVEMBER 199 113

DIABETES IN ELDERLY SUBJECTS and 5.5%, respectively. These results agree with the findings of NHANES II, which reported similar effects of obesity and parental history of diabetes on the prevalence of abnormal glucose tolerance (5,42). Although obesity, central fat distribution, and a family history of diabetes were significantly associated with the increased prevalence of IGT and NIDDM in the elderly, this explained only 1% of the variance in 2-h plasma glucose values in multiple regression analysis. Our results suggest that there are more powerful determinants of glucose tolerance than the traditional risk factors that were evaluated in this study. In the U.S. population aged 2-74 yr, the proportion of the variance in glucose tolerance explained by these and other risk factors was greater but the effect of age was so overwhelming that other risk factors explained only a minor part of the variation in glucose tolerance (43). The age range of our study population was 1 yr; therefore, age was not significantly associated with 2-h glucose. Heterogeneity of the IGT category could in part explain the low proportion of variance in glucose tolerance explained by BMI, waist-hip ratio, and a family history of diabetes. In addition, in a cross-sectional study, associations of risk factors with abnormal glucose tolerance tend to be underestimated. In conclusion, abnormalities in glucose tolerance are frequent in the elderly, and obesity, distribution of obesity, and a family history of diabetes increase this risk. However, it is not known whether the clinical significance of abnormalities in glucose tolerance in the older ages is different from that in the middle ages. For example, it remains to be determined whether IGT increases the risk for morbidity and mortality from atherosclerotic vascular disease in the elderly as in middle-aged subjects. 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