European Journal of Clinical Nutrition (2000) 54, Suppl 3, S112±S120 ß 2000 Macmillan Publishers Ltd All rights reserved 0954±3007/00 $15.00 www.nature.com/ejcn Carbohydrate metabolism in the elderly D Elahi1,2* and DC Muller2 1Massachusetts General Hospital, Geriatric Research Laboratory, Boston MA 02114, USA; and 2Gerontology Research Center, National Institute on Aging, Laboratory of Clinical Investigation, Baltimore MD 21224, USA In this short review we summarize the effect of age on glucose homeostasis. The concept of decreased glucose tolerance with increasing age is introduced, followed by evidence for this phenomenon. Speci®cally we review the evidence for changes in fasting glucose as a function of age and the effect of age on HbA1c. The role of age on hepatic glucose production and glucose uptake is then discussed in detail and we review the evidence that supports the concept that with advancing age hepatic glucose sensitivity to insulin is unaltered. We then review the large evidence for the role of age on the purported decrease in peripheral tissue sensitivity to insulin and conclude that the issue is unsettled. The decrease attributed to age is no longer signi®cant when confounders are controlled for, the largest being obesity. We next present evidence that b-cell sensitivity to glucose remains intact with aging. A review of age-related disorders due to hyperglycemia and confounding effects on the relationships of age and glucose tolerance is presented next. Finally we present new evidence that when the revised criteria for the diagnosis of type 2 diabetics as proposed by the American Diabetes Association and WHO are used, a greater percentage of the elderly will not be diagnosed. We conclude that, although glucose intolerance increases with aging, which is accompanied with other disorders, it is possible to ameliorate this effect with alteration of diet and exercise. Descriptors: aging; carbohydrate metabolism; glucose tolerance; diabetes European Journal of Clinical Nutrition (2000) 54, Suppl 3, S112±S120 Introduction US have abnormal glucose tolerance as de®ned by the American Diabetes Association. The reduction in whole-body carbohydrate metabolism in the elderly is one of the hallmarks of the aging process. Substantial evidence has been provided showing that Other evidence of carbohydrate intolerance in the increasing age is associated with decreased glucose toler- elderly ance (Andres, 1971; Broughton & Taylor, 1991; Davidson, 1979; DeFronzo, 1981; Reaven et al, 1989). Figure 1 shows Fasting glucose In the basal state, the decline in carbohydrate metabolism results of a 2 h glucose tolerance test in healthy men from as assessed by the fasting glucose is relatively small. A the Baltimore Longitudinal Study of Aging across the adult review of the literature (Davidson, 1979) had estimated that age span. There is a progressive decline in glucose toler- ance from the third decade through the ninth decade of age. fasting glucose levels rise approximately 1 mg=dl per decade. Subsequent studies in populations that covered The 2 h plasma glucose level during an oral glucose the adult age span have produced more ambiguous results. tolerance test rises on average, 5.3 mg=dl per decade and the fasting plasma glucose rises on average, 1 mg=dl per In 263 healthy subjects aged 20 ± 69 y, age was positively related to fasting glucose even after adjustment for differ- decade (Davidson, 1979). This decline in glucose tolerance ences in adiposity (Berger et al, 1978). The Baltimore is also re¯ected in the NHANES III survey on the pre- valence of diabetes and impaired fasting glucose and Longitudinal Study of Aging also has shown a positive cross-sectional correlation between age and fasting plasma impaired glucose tolerance in US adults (Harris et al, glucose in both men and women (Muller et al, 1996; 1998). Comparison of the percentage of physician-diag- Shimokata et al, 1991). Zavaroni et al (1986) demonstrated nosed diabetes in middle-aged adults (40 ± 49 y) and elderly an age-related increase in fasting glucose levels in Italian adults ( 75 y) reveals an increase of 3.9 ± 13.2%. Like- factory workers; this was signi®cantly reduced in women wise, the percentage of adults with undiagnosed diabetes after adjustments were made for the presence of other age- (de®ned as a fasting plasma glucose 126 mg=dl) rises from 2.5% to 5.7% and the percentage of adults with related variables. Small increases in fasting glucose levels with age were noted in 4170 men and women living in impaired fasting glucose (de®ned as a fasting plasma suburban California (0.7 mg=dl=decade in men; glucose of 110 ± 125 mg=dl) rises from 7.1% to 14.1%. Therefore, approximately a third of the elderly adults in the 2.0 mg=dl=decade in women) (Barrett-Connor, 1980). In a retirement community in California in subjects aged 47 ± 90 y, Maneatis et al (1982) found no signi®cant changes *Correspondence: D Elahi, Massachusetts General Hospital, Geriatric Research Laboratory, GRB SB 0015C, 55 Fruit Street, Boston, MA 02114, with age in fasting glucose levels in men but did observe a USA. small signi®cant positive correlation in women. However in E-mail: [email protected] other studies, age had little if any, effect on fasting glucose. Carbohydrate metabolism D Elahi and DC Muller S113 Figure 2 Effect of age and BMI on HbA1c in men. Values are means Æ s.e.m.; BMI 20 (d); 20.1 ± 23 (s); 23.1 ± 26 (j);>26 (n). (b) P < 0.01 vs group with BMI 20. (C) P < 0.01 vs group one decade younger. (CC) P < 0.05 vs group one decade younger. male Japanese workers (Hashimoto et al, 1995) aged 20 ± 59 was similar in both lean and obese (Figure 2). While there was no effect of gender on HbA1c levels in French men and women (Simon et al, 1989), a cross-sectional survey of Chinese men and women (Yang et al, 1997) found that women had lower levels before the age of 55 but Figure 1 Time course of plasma glucose level after oral glucose at older ages the levels were almost identical. administration in men of the Baltimore Longitudinal Study on Aging. Twenty minute values are presented by age decades where 2 represents values for 20 ± 29 year old subjects and 3 represents values for 30 ± 39 year Effect of age on hepatic glucose production and glucose old subjects, etc. uptake During the post-prandial state plasma glucose levels are Age was not independently related to fasting glucose in a maintained stable by coordinated balance between hepatic population survey of 740 Danes of the Second Generation glucose production and glucose uptake by peripheral tis- Fredericia Study (Vestbo et al, 1996). In a study of 710 sues (primary muscle). There are numerous techniques to healthy individuals, fasting glucose levels increased by assess the contribution of these two regulators of glucose only 8% and 6% over seven decades in men and women, homeostasis. However, many confounders, which are exa- respectively (Colman et al, 1995). cerbated in the elderly, make it dif®cult to delineate accurately the exact contribution of these two major reg- HbA1c ulators of glucose homeostasis. The two most commonly Glucose is known to bind irreversibly to the NH2 terminus used methods to quantitate regulation of glucose home- of the b-chains of globin protein in hemoglobin during the ostasis are the Min Mod (frequently sampled intravenous life span of the erythrocytes. It is this glycosylated species glucose tolerance test) (Bergman et al, 1987) and the that appears as HbA1c when hemoglobin is analyzed glucose clamp techniques (DeFronzo et al, 1979). Although by ion-exchange chromatography (Nuttall, 1998). HbA1c they both have their advantages and disadvantages, it is provides an objective means of quantifying the average generally agreed that the most rigorous and reproducible blood glucose concentration present in the weeks before test for examination of glucose homeostasis in the whole sampling. There have been many studies that examined body or a speci®c organ is the glucose clamp methodology. the effect of age on HbA1c levels. Most (Arnetz et al, 1982; The clamp technique has been more commonly used to Dunn et al, 1979; Graf et al, 1978; Hashimoto et al, examine differences between young and old, while fewer 1995; Kilpatrick et al, 1996; Nakashima et al, 1993; investigators have used the Min Mod to examine the issue Simon et al, 1989; Vestbo et al, 1996; Yang et al, 1997) in the elderly. Our own experience has been entirely with but not all studies (Kabadi, 1988; Van Wersch et al, 1991) the clamp technique and since this technique is considered have found elevations in glycohemoglobin levels with the reference method for assessment of glucose home- increasing age in non-diabetic subjects. In several of the ostasis a brief description will be provided. There are above studies (Hashimoto et al, 1995; Vestbo et al, 1996; several variants to this methodology and the most com- Yang et al, 1997), the increase in HbA1c was independent monly used ones are the hyperinsulinemic euglycemic form of other confounding effects on glucose tolerance (see and the hyperglycemic form. In all clamp protocols an below). The age-dependent increase in Hba1c in 7664 antecubital intravenous polyethylene catheter is inserted for European Journal of Clinical Nutrition Carbohydrate metabolism D Elahi and DC Muller S114 infusion of insulin, and=or 20% dextrose, isotopes. A second polyethylene catheter is inserted in a retrograde fashion into a dorsal hand or wrist vein for obtaining blood samples. The hand is then enclosed in an insulated grounded warming chamber with the air heated to 68C to arterialize the blood.