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I.R.F. / Aging news / Diseases / 03101501

Diabetes in Elderly Humans
Posted on: October 15, 2003

Glucose tolerance progressively declines with age, resulting in a high prevalence of type 2 diabetes and impaired glucose tolerance in the older population. The interaction of many factors associated with aging likely contributes to the alterations in glucose tolerance in this population. These factors include increased adiposity, decreased physical activity, medications, coexisting illness, and insulin secretory defects associated with the aging process. The mechanism of age-related glucose intolerance is not completely clear.

Age-related insulin secretory dysfunction may have a role in the alterations in glucose metabolism with age and may contribute to the high rates of glucose intolerance in the older population. Many studies have examined the effects of aging on pancreatic β-cell function in humans, although there is a great deal of variability in the outcomes of these studies. This variability may be due to multiple factors, including the small magnitude of the age effect, the use of different measures of insulin secretion, and confounding factors associated with aging such as obesity, decreased physical activity, and concomitant insulin resistance. One challenge in studying the time course of development of abnormal glucose tolerance in any population is the sensitivity of tests to detect early abnormalities of β-cell function. The earliest insulin secretory defects in the progression from normal to abnormal glucose tolerance may be subtle. Thus sensitive measures of β-cell function are crucial.

Aging and Insulin Secretion in Nondiabetic Humans

β-Cell function can be evaluated with the technique, in which plasma glucose levels are increased to the same extent above basal levels in subjects by means of intravenous glucose infusions. Older subjects with glucose tolerance comparable to young subjects had similar insulin response. However, the subgroup of older subjects with mild glucose intolerance tended to have increased early insulin response and a decrease in the 3rd-h response. None of these studies took into account the effect of age-related insulin resistance on β-cell function.

Other methods to evaluate β-cell function, such as pulsatile insulin release and the use of nonglucose stimuli such as arginine, have detected age-related defects in insulin secretion. Normal insulin secretion is pulsatile and orderly, with both rapid, low-amplitude pulses, which occur every 8-15 min, and ultradian pulses, which have larger amplitude and occur every 60-140 min. In the fasting state, older subjects have been found to have more disorderly insulin release, with decreased amplitude and mass of rapid insulin pulses and reduced frequency of ultradian pulses compared with young subjects. β-Cell function can also be evaluated using a nonglucose stimulus such as arginine. Studied arginine-stimulated insulin response in young and old men showed that β-cell secretory capacity was 48% lower with arginine stimulus in the old subjects.

Pancreatic islet function can also be assessed by C-peptide measurements and kinetics. This approach bypasses the issue of hepatic clearance of insulin and possible changes in insulin clearance with aging, since the liver does not metabolize C-peptide. This method was used to assess insulin secretion in older adults in response to meal and intravenous glucose challenges. No age differences were found in absolute insulin secretion with 24-h meal profiles or with intravenous glucose challenge. However, this study suggested a decreased relative insulin response to stepped glucose infusion in old subjects when differences in glucose levels and insulin sensitivity between old and young subjects were considered. Endogenous clearance of insulin was also evaluated on the basis of this method. Insulin clearance during basal and mixed-meal conditions was similar in old and young subjects.

Fig. 1. Model for normal adaptation to insulin resistance. In response to insulin resistance of any cause, β-cell function adapts with compensatory hyperinsulinemia to maintain euglycemia.

Potential explanations for variable results when aging-related defects in β-cell function are assessed include the lack of age standardization and differences in age-related variables such as insulin resistance, obesity, and physical activity in young and old subjects. Findings of similar insulin secretion in young and old subjects may suggest relative defects in pancreatic β-cell function in light of concomitant insulin resistance and relative glucose intolerance in the older population. When young and old subjects are matched for these variables, reduced β-cell function with aging has been detected.

Insulin Secretion in Older People with Type 2 Diabetes

Fig. 2. Model for age-related hyperglycemia. Multiple risk factors for type 2 diabetes associated with aging predispose older adults to develop glucose intolerance and increased insulin resistance. However, in elderly humans, β-cell function is impaired, and compensatory hyperinsulinemia does not occur. With further loss of β-cell function, impaired glucose tolerance (IGT) and type 2 diabetes develop.

Numerous studies have investigated glucose metabolism in adults with type 2 diabetes, although relatively few have included people >65 yr of age. Studies of people with type 2 diabetes of all ages have clearly shown impaired insulin secretion with intravenous glucose tolerance testing. Assessed insulin secretion in obese older people with normal glucose tolerance and type 2 diabetes showed that older type 2 diabetic subjects were found to have normal fasting insulin levels, whereas obese older type 2 diabetic subjects had increased fasting insulin levels. Obese diabetic subjects had greater insulin responses to oral glucose than lean diabetic subjects. The obese diabetic subjects also had similar insulin responses compared with obese age-matched controls, but these responses were clearly impaired given the much higher glucose levels in the diabetic subjects. In confirmation of this defective insulin secretion, both lean and obese older diabetic subjects had absent first-phase insulin release to intravenous glucose with the hyperglycemic clamp, as in younger diabetic patients. Lean older diabetic subjects had marked defects in second-phase insulin secretion. Obese older diabetic subjects had second-phase insulin secretion similar to control subjects, but this likely reflects β-cell dysfunction in light of increased insulin resistance in the diabetic subjects.

Glucose tolerance progressively declines with age, and there is a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. More than 40% of Americans 65 yr and older meet diagnostic criteria for type 2 diabetes or IGT. Isolated post challenge hyperglycaemia (IPH) is particularly common in this age group. Individuals with type 2 diabetes (including IPH) or IGT have associated increased morbidity and mortality. As shown in Fig. 1, a model of normal adaptation to insulin resistance of any cause and at any age may include compensatory hyperinsulinemia to maintain normal glucose metabolism. In contrast, a model of age-related hyperglycemia is displayed in Fig. 2. The interaction of many diabetes risk factors associated with aging is likely to contribute to the development of age-related glucose intolerance and increased insulin resistance. On average, studies of the effect of aging on insulin secretion suggest that relative insulin secretory defects are associated with advancing age in light of increased insulin resistance and possible decreased insulin clearance with aging. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, β-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired β-cell compensation to age-related insulin resistance may predispose older people to develop IGT and type 2 diabetes. Sensitive measures of β-cell function are essential to further delineate the effects of normal aging on insulin secretion. Impaired β-cell compensation to age-related insulin resistance may predispose older people to develop IGT and type 2 diabetes. Sensitive measures of β-cell function are essential to further delineate the effects of normal aging on insulin secretion. A better understanding of the metabolic alterations associated with aging is important for the continued development of preventive and therapeutic strategies for this population at high risk for the development of diabetes.

Source: Annette M. Chang and Jeffrey B. Halter; Aging and insulin secretion. Am J Physiol Endocrinol Metab 284: E7-E12, 2003;
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