Decline In Glucose Tolerance Research Articles

Beta cell function declines with age in glucose tolerant Caucasians.

As type 2 diabetes results from an imbalance between insulin sensitivity and beta cell function, either or both may worsen with age. However, existing data are controversial on the effect of ageing on both insulin sensitivity and beta cell function. We enrolled 149 healthy, glucose tolerant and normotensive Caucasians (age 35 +/- 1 years, body mass index 26.07 +/- 0.44 kg/m2, waist-hip ratio 0.842 +/- 0.009 cm/cm, mean +/- standard error). A cross-sectional study was designed to examine the impact of age on insulin sensitivity and beta cell function. Their beta cell function (percentage B [%B]) and insulin sensitivity (percentage S [%S]) were estimated using the homeostasis model assessment. Simple regression analysis revealed that %B declined with age (P = 0.008) while no relation was found between %S and age (P = 0.769). A stepwise regression analysis revealed that body mass index and diastolic blood pressure explained 14.7% of variation in %S, while age, waist-hip ratio, gender, and systolic blood pressure had no influence on %S. Age, body mass index and diastolic blood pressure together accounted for 21.7% of variation in %B, with age being an independent variable. In the present study, we showed that beta cell function declined with age at a rate of about 1% per year. In contrast, insulin sensitivity was not affected by ageing. Our observations suggest that the age-related decline in glucose tolerance is primarily related to the loss of beta-cell function.

Discussion

The TRoglitazone In the Prevention Of Diabetes (TRIPOD) trial is a single-center, randomized, placebo-controlled, double-masked study. The primary aim of the TRIPOD trial is to test the hypothesis that chronic administration of troglitazone to nondiabetic women with prior gestational diabetes mellitus (GDM) will improve whole-body insulin sensitivity and reduce the incidence of non–insulin-dependent diabetes (NIDDM). Because troglitazone is already known to lower blood glucose concentrations in persons who have developed NIDDM, an additional aim of the project will be to determine whether early intervention with troglitazone will achieve better final glycemic control than can be achieved by later intervention. In addition, since troglitazone treatment is expected to improve insulin sensitivity and may prevent or delay a decline in glucose tolerance, we also plan to determine whether long-term troglitazone treatment alters the development or progression of atherosclerosis. In this article we describe the experiment's design, the study's endpoints and methods for determining those endpoints, methods for assessing quality of life, and proposed methods for statistical analyses. The unique two-phase study design of the TRIPOD trial will permit testing not only of the biological question about reversal of insulin resistance and prevention of diabetes, but also of the clinical question about whether early intervention is superior to late intervention. Results from this trial will have an important impact on the monitoring and treatment of patients at high risk for NIDDM.

Metabolic and endocrine effects of the desogestrel-containing oral contraceptive Mircette™

OBJECTIVE: The purpose was to evaluate the metabolic effects of Mircette™ (brand of desogestrel/ethinyl estradiol and ethinyl estradiol), a low-estrogen, desogestrel-containing oral contraceptive. STUDY DESIGN: Women taking Mircette™ were evaluated to determine its effects on lipid profiles ( n = 74), carbohydrate metabolism ( n = 25), and endocrine parameters ( n = 53). RESULTS: During cycles 3 and 6 of Mircette™ treatment, changes from baseline included mean increases in serum triglycerides and very low–density lipoprotein cholesterol ranging between 50% and 60%. Smaller mean increases were observed at these time points in high-density lipoprotein cholesterol subfraction 2 (range between 17% and 25%), total cholesterol (<10%), high-density lipoprotein cholesterol (range between 10% and 15%), and high-density lipoprotein cholesterol subfraction 3 (range between 9% and 13%), with only nominal changes (<6%) in low-density lipoprotein cholesterol and lipoprotein. Patients receiving Mircette™ showed no mean changes in fasting plasma glucose or serum insulin levels but did have modest increases in glucose and insulin levels after a glucose challenge. Mircette™ treatment suppressed follicle-stimulating hormone, luteinizing hormone, 17β-estradiol, and progesterone to levels consistent with inhibition of ovulation and increased concentrations of thyroid- and cortisol-binding globulins. CONCLUSIONS: Overall, Mircette™ treatment was associated with expected effects on the pituitary-ovarian axis, triglycerides, and serum binding proteins; a modest decline in glucose tolerance; and a favorable effect on lipid profiles as a result of increases in total high-density lipoprotein cholesterol and high-density lipoprotein cholesterol subfraction 2 in the absence of changes in total cholesterol or low-density lipoprotein cholesterol. (Am J Obstet Gynecol 1998;179:S9-17.)

TRIPOD (TRoglitazone In the Prevention Of Diabetes): A Randomized, Placebo-Controlled Trial of Troglitazone in Women with Prior Gestational Diabetes Mellitus

The TRoglitazone In the Prevention Of Diabetes (TRIPOD) trial is a single-center, randomized, placebo-controlled, double-masked study. The primary aim of the TRIPOD trial is to test the hypothesis that chronic administration of troglitazone to nondiabetic women with prior gestational diabetes mellitus (GDM) will improve whole-body insulin sensitivity and reduce the incidence of non–insulin-dependent diabetes (NIDDM). Because troglitazone is already known to lower blood glucose concentrations in persons who have developed NIDDM, an additional aim of the project will be to determine whether early intervention with troglitazone will achieve better final glycemic control than can be achieved by later intervention. In addition, since troglitazone treatment is expected to improve insulin sensitivity and may prevent or delay a decline in glucose tolerance, we also plan to determine whether long-term troglitazone treatment alters the development or progression of atherosclerosis. In this article we describe the experiment's design, the study's endpoints and methods for determining those endpoints, methods for assessing quality of life, and proposed methods for statistical analyses. The unique two-phase study design of the TRIPOD trial will permit testing not only of the biological question about reversal of insulin resistance and prevention of diabetes, but also of the clinical question about whether early intervention is superior to late intervention. Results from this trial will have an important impact on the monitoring and treatment of patients at high risk for NIDDM.

Effects of glucose/insulin perturbations on aging and chronic disorders of aging: the evidence.

Among changes associated with aging is a decline in glucose tolerance. The reported causes are increased insulin resistance from receptor and/or post receptor disturbances and diminished pancreatic islet B-cell sensitivity to glucose. Many recent reports indicate that insulin resistance with hyperinsulinemia and/or hyperglycemia contribute to or even causes many chronic disorders associated with aging, i.e., chronic metabolic perturbations including noninsulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerosis. How could such disturbances in glucose/insulin metabolism lead to many chronic disorders associated with aging? In aging, similar to diabetes, the elevation in circulating glucose and other reducing sugars secondary to age-induced insulin resistance can react nonenzymatically with proteins and nucleic acids to form products that affect function and diminish tissue elasticity. Also, perturbations in glucose/insulin metabolism are associated with enhanced lipid peroxidation secondary to greater free radical formation. Free radicals of oxygen are important known causes of tissue damage and have been associated with many aspects of aging including inflammatory diseases, cataracts, diabetes, and cardiovascular diseases. Augmented free radical formation and lipid peroxidation are not uncommon in diabetes mellitus, commonly associated with “premature aging”. Ingestion of sugars, fats, and sodium have been linked to decreased insulin sensitivity, while caloric restriction, exercise, ingestion of chromium, vanadium, soluble fibers, magnesium, and certain antioxidants are associated with greater insulin sensitivity. Thus, manipulation of diet by influencing the glucose/insulin system may favorably affect lifespan and reduce the incidence of chronic disorders associated with aging.

Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats.

Wistar rats develop glucose intolerance and have a diminished insulin response to glucose with age. The aim of this study was to investigate if these changes were reversible with glucagon-like peptide-1 (GLP-1), a peptide that we have previously shown could increase insulin mRNA and total insulin content in insulinoma cells. We infused 1.5 pmol/ kg-1.min-1 GLP-1 subcutaneously using ALZET microosmotic pumps into 22-mo-old Wistar rats for 48 h. Rat infused with either GLP-1 or saline were then subjected to an intraperitoneal glucose (1 g/kg body weight) tolerance test, 2 h after removing the pump. 15 min after the intraperitoneal glucose, GLP-1-treated animals had lower plasma glucose levels (9.04+/-0.92 mmol/liter, P < 0.01) than saline-treated animals (11.61+/-0.23 mmol/liter). At 30 min the plasma glucose was still lower in the GLP-1-treated animals (8.61+/-0.39 mmol/liter, P < 0.05) than saline-treated animals (10.36+/-0.43 mmol/liter). This decrease in glucose levels was reflected in the higher insulin levels attained in the GLP-1-treated animals (936+/-163 pmol/liter vs. 395+/-51 pmol/liter, GLP-1 vs. saline, respectively, P < 0.01), detected 15 min after glucose injection. GLP-1 treatment also increased pancreatic insulin, GLUT2, and glucokinase mRNA in the old rats. The effects of GLP-1 were abolished by simultaneous infusion of exendin [9-39], a specific antagonist of GLP-1. GLP-1 is therefore able to reverse some of the known defects that arise in the beta cell of the pancreas of Wistar rats, not only by increasing insulin secretion but also by inducing significant changes at the molecular level.

Influence of aging on progression of cardiovascular complications associated with insulin resistance in patients with essential hypertension.

Hyperinsulinemia or insulin resistance is suggested to play a role in the pathogenesis of hypertension and its target organ diseases. It is also well documented that aging is associated with a decline in glucose tolerance and insulin sensitivity, but there are few reports on the relationship between aging and insulin sensitivity or on the effects of aging on the progression of cardiovascular complications in patients with essential hypertension. To clarify these effects of aging in essential hypertension, 44 patients were examined by the euglycemic hyperinsulinemic glucose clamp test and ultrasonography of the heart and carotid arteries. There was a significant negative correlation between aging and insulin sensitivity (r = -0.37, p < 0.05). Significant increases in left ventricular mass index and carotid wall thickening accompanied by insulin resistance were seen in only non-elderly patients but not in elderly patients. These results suggest that aging decreases insulin sensitivity even in essential hypertensive subjects and that insulin resistance does not affect the progression of cardiac hypertrophy and atherosclerosis in elderly patients with essential hypertension.

Human studies with glucagon-like-peptide-1: potential of the gut hormone for clinical use.

So far, a wealth of data originating from in vitro or animal experiments has been collected supporting the concept that the gut hormone, glucagon-like peptide-1 (GLP-1) may serve as a model molecule for the design of a new drug for the treatment of diabetes mellitus. This is supported by observations that GLP-1 has potent insulinotropic action in patients with non-insulin-dependent diabetes mellitus (NIDDM). It enhances beta-cell sensitivity to glucose stimulated insulin secretion. GLP-1 may also have a role in the treatment of impaired glucose tolerance, where the beta-cell is already insensitive to changes in plasma glucose concentrations. It may, as has previously been shown in animal models of 'prediabetes', delay the progressive decline in glucose tolerance to NIDDM. The glucose-dependent action of this peptide is an important feature in the treatment of NIDDM as it will protect against hypoglycaemic reactions, the most serious acute side-effect of antidiabetic therapy. Glucose utilization may be enhanced which would improve metabolic control in both NIDDM and IDDM. A glucagon lowering effect will further enhance metabolic control. This article reviews current experiences of the effects of GLP-1 in human studies. It points out the outcomes and limitations of previous trials and discusses future directions for the investigation of its potential use as a new agent in diabetes treatment.

Continuous Combined Estrogen/Progestin Hormone Replacement Therapy

Women entering menopause should be informed of the benefits and risks of hormone replacement therapy and of the variety of regimens available. One option, a continuous combined regimen of conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg, maintains the beneficial effects of estrogen on cardiovascular risk factors, although its effects on high-density lipoprotein cholesterol levels are less pronounced than with estrogen alone. The addition of progestin does not affect carbohydrate metabolism except for a slight decline in glucose tolerance. Blood coagulation factors and blood pressure showed no clinically significant changes different from those resulting from unopposed estrogen. Bone mineral density is increased more with the continuous combined regimen than with a cyclical regimen of the same hormones. The incidence of endometrial hyperplasia is substantially less than that observed with unopposed estrogen. The overall frequency of irregular bleeding is lower than with estrogen alone and diminishes with continuation of therapy, whereas the incidence of amenorrhea increases from 52.1% to 75.1% between cycles 2 and 11. Epidemiologic evidence linking any hormonal therapy with breast cancer remains inconsistent, possibly because the risk, if any, is small. The relative risk of breast cancer for the continuous regimen has not been extensively studied in large-scale studies.

Glucose tolerance in women: the effects of age, body composition, and sex hormones.

To determine the separate and interactive effects of age, phase of the menstrual cycle, menopausal hormone status, body fat mass, and regional fat distribution on glucose tolerance in healthy women. Retrospective study. The Baltimore Longitudinal Study of Aging. Two hundred sixty healthy women aged 22-89 years. Plasma levels of estradiol and progesterone, body mass index (BMI), waist-to-hip ratio (WHR), and plasma glucose values in the fasting state (FPG) as well as 120 minutes after 40 gm/m2 of oral glucose (G120) were measured for each participant. We found a progressive decline in oral glucose tolerance of 0.4 mM (6.7 mg/dL)/decade at G120) in women from early to late adult years, with no relationship to phase of the menstrual cycle and no abrupt change associated with the menopause. Multiple regression analysis revealed significant, independent effects of BMI and WHR on FPG and G120. The influence of age (P less than 0.01) on G120 was stronger than that of the BMI or WHR (P less than 0.05). There was no significant relationship between the levels of endogenous sex hormones and glucose tolerance after adjustments for age, BMI, and WHR. However, women taking oral contraceptives, but not those receiving postmenopausal replacement therapy, did exhibit mildly elevated G120 values. Age per se, and to a lesser extent BMI and WHR, but not levels of endogenous sex steroids, contribute to the physiological decline in glucose tolerance in older women.

Deterioration in Carbohydrate Metabolism and Lipoprotein Changes Induced by Modern, High Fat Diet in Pima Indians and Caucasians

The transition from a high carbohydrate to a high fat diet may explain in part the dramatic increase in the prevalence of noninsulin-dependent diabetes mellitus among Pima Indians over the last century. In this study, 12 Pimas and 12 caucasians, all nondiabetic, were admitted to a metabolic ward and, in random order, fed 2 14-day weight-maintaining diets: a traditional Pima diet (percentage of calories: carbohydrate, 70% fat, 15%; protein, 15%) and a high fat modern diet (carbohydrate, 30%; fat, 50%; protein, 20%). Carbohydrate metabolism was characterized using the modified iv glucose tolerance test (minimal model), the acute insulin responses to arginine during a 3-step glycemic clamp, and the oral glucose tolerance test. Compared with the traditional diet, the modern diet was associated with a decrease in oral glucose tolerance (P less than 0.01) and higher plasma cholesterol concentrations (P less than 0.02). The decline in glucose tolerance was associated with similar insulin-mediated, but 23% lower glucose-mediated (P less than 0.001), glucose disposal, a 17% lower acute insulin response to glucose (P less than 0.03), a 9% lower beta-cell sensitivity to glucose (P less than 0.02), and similar beta-cell capacities. Pimas and caucasians responded similarly, except for larger changes in plasma lipids among the Pimas. Since glucose-mediated glucose disposal, beta-cell function, and glucose tolerance deteriorated on the modern diet, it is likely that diet composition affects the prevalence of noninsulin-dependent diabetes mellitus in both Pimas and caucasians.

Age as Independent Determinant of Glucose Tolerance

It has been proposed that the decline in glucose tolerance with age is not a primary aging effect but is secondary to a combination of other age-associated characteristics, i.e., disease, medication, obesity, central and upper-body fat deposition, and inactivity. To test this hypothesis, we first eliminated from analysis the Baltimore Longitudinal Study of Aging participants with identifiable diseases or medications known to influence glucose tolerance. Seven hundred forty-three men and women, aged 17-92 yr, remained for analysis. As indices of fatness, body mass index and percent body fat were determined. As indices of body fat distribution, waist-hip ratio and subscapular triceps skin-fold ratio were calculated. As indices of fitness, physical activity level, determined by detailed questionnaire, and maximum 02 consumption were calculated. We tested whether the effect of age on glucose tolerance remains when data were adjusted for fatness, fitness, and fat distribution; 2-h glucose values were 6.61, 6.78, and 7.83 mM for young (17-39 yr), middle-aged (40-59 yr), and old (60-92 yr) men and 6.22, 6.22, and 7.28 mM for the three groups of women, respectively. The differences between the young and middle-aged groups were not significant, but the old groups had significantly higher values than young or middle-aged groups. Fatness, fitness, and fat distribution can account for the decline in glucose tolerance from the young adult to the middle-aged years. However, age remains a significant determinant of the further decline in glucose tolerance of healthy old subjects.

Effect of Physical Activity on Age-Related Glucose Intolerance

Glucose tolerance tends to deteriorate with age, but a major portion of this deterioration can be explained by changes in other age-related variables--obesity, physical inactivity, use of medications, and chronic illness. This review has focused on the role that physical activity can play in preventing the age-associated decline in glucose tolerance. Pathophysiologically, most of the decline in glucose tolerance appears to be caused by a decrease in insulin action with aging. Given that it has been shown that exercise increases insulin action, there is a plausible biologic mechanism explaining the observed association between physical activity and the preservation of insulin sensitivity and glucose tolerance with aging. Finally, it appears from the published data that it is life-long maintenance of physical activity, beginning long before individuals reach the geriatric age group, that will be most beneficial to the health of aging Americans.

Determinants of estimated insulin resistance and β-cell function in Indian, Creole and Chinese Mauritians

Associations with insulin resistance and islet β-cell function have been studied cross-sectionally in a population-based sample of 4278 Mauritians comprising Asian Indian, Creole and Chinese subjects. Insulin resistance and β-cell function were estimated by a computer solved model based on fasting plasma glucose and insulin concentrations. Insulin resistance increased with declining glucose tolerance, whereas β-cell function was highest in subjects with impaired glucose tolerance (IGT) and lowest in those with non-insulin-dependent diabetes mellitus (NIDDM). Indian subjects had the highest β-cell function, while ethnic differences in insulin sensitivity were-less marked. This may indicate that deranged β-cell function rather than insulin resistance is the primary determinant of hyperinsulinaemia and glucose intolerance in Asian Indians. β-Cell function declined with age more sharply than did insulin sensitivity, suggesting that the age-related decline in glucose tolerance is primarily related to loss of β-cell function. Body mass index, waist/hip ratio, physical inactivity and female sex were independently associated with insulin resistance and β-cell function. Subjects with a family history of diabetes had increased insulin resistance, irrespective of glucose tolerance. This or similar models may have application in longitudinal population-based studies which seek to determine the relative contributions of insulin resistance and β-cell function to the aetio-pathogenesis of NIDDM.

Effect of 10 days of physical inactivity on glucose tolerance in master athletes

Master athletes who exercise regularly appear to avoid the development of insulin resistance and deterioration of glucose tolerance (GT) commonly seen with aging. To evaluate the possibility that exercise prevents rather than masks the aging-related changes responsible for development of insulin resistance, we investigated the effects of 10 days of physical inactivity in 14 master athletes aged 61 +/- 2 (SE) yr. The response of 10 of these men to inactivity was similar to that of young athletes, with an unchanged plasma glucose response and a significantly greater insulin response to an oral glucose tolerance test (OGTT) after 10 days of inactivity. These 10 athletes appeared to have been protected against the aging-related changes in GT because their plasma glucose and insulin levels during the OGTT after 10 days of inactivity were not significantly different from those of young lean sedentary men. In contrast, a deterioration in GT occurred in four of the master athletes during 10 days of inactivity; this was sufficiently marked in two of them to be classified as impaired GT. We conclude that regular exercise may 1) protect against the development of insulin resistance and decline in GT with aging in individuals with normal GT and 2) normalize GT by means of short-term effects of exercise in some individuals with abnormal GT.

What Geriatricians Should Know About Diabetes Mellitus

Aging is associated with a progressive decline in glucose tolerance to the extent that most elderly people have abnormal carbohydrate metabolism and an increasing proportion have type II (non-insulin-dependent) diabetes mellitus. This review focuses on the pathophysiology, evaluation, and treatment of this process and emphasizes that although normal glucose tolerance and diabetes mellitus are strictly defined, there is a large subset of elderly individuals who, although nondiabetic, fall into the carbohydrateintolerant zone. This diminished carbohydrate tolerance is the result of a decrease in insulin sensitivity and an impairment of pancreatic β-cell function, which both may result, in part, from changes in sensitivity to dietary carbohydrate associated with aging. Similar defects in insulin action and insulin secretion are also present in type II diabetes. Although the macro- and microvascular complications of diabetes mellitus occur in older individuals with hyperglycemia, carbohydrate intolerance does not appear to be associated with microvascular events. Thus, therapeutic decisions must be based on an understanding of the degree of impairment in carbohydrate tolerance and the risk of acute and chronic complications associated with this abnormality. This is of even more importance when managing a group of subjects whose life expectancy is reduced and who may be less amenable to interventions that could include diet, oral sulfonylureas, or insulin. Furthermore, although all these interventions may result in a decline in glucose level and improved health, they are also associated with risks, some of which may be life threatening in this population.

Peripheral tissue insulin sensitivity in healthy elderly subjects.

To determine whether the decline in glucose tolerance with age is related to changes in peripheral tissue insulin sensitivity, 11 healthy older (65-85 years) and 12 healthy younger (20-38 years) subjects, matched for physical activity and body mass index, were studied. The glucose-insulin infusion technique, in which glucose and insulin are infused at constant rates over 150 min, was used to assess peripheral tissue insulin sensitivity. The metabolic clearance rate (MCR) of glucose, which reflects peripheral tissue insulin sensitivity, is derived from the resulting steady-state blood glucose. Fasting blood glucose was similar in the two groups, but mean blood glucose 2 h after an oral glucose load was higher in the older group. MCR of glucose expressed per kilogram lean body mass was almost identical in both groups (13.3 +/- 1.3 vs. 13.5 +/- 1.3 ml/kg lean body mass/min, respectively). Evidence of decreased glucose tolerance with normal peripheral tissue insulin sensitivity suggests that changes in other factors may be more important than previously recognised.

Effects of exercise on glucose tolerance and insulin resistance. Brief review and some preliminary results.

With aging, glucose tolerance (GT) declines, plasma insulin concentration increases, and sensitivity to the action of insulin declines. Evidence is accumulating that this decline in glucose tolerance and insulin sensitivity can be prevented by regularly performed vigorous exercise. Preliminary results are presented in this paper showing that prolonged, strenuous and frequent exercise can also completely normalize GT by decreasing resistance to insulin in some patients with mild non insulin dependent diabetes mellitus (NIDDM) and in some individuals with impaired glucose tolerance (IGT). Exercise appears to be effective in normalizing GT only in patients who still have an adequate capacity to secrete insulin, and in whom insulin resistance is the major cause for abnormal GT. The amount of exercise required to normalize GT in such patients appears to be in the range of 25 to 35 km per week of running, or a comparable amount of another form of exercise, performed on a regular basis.

Effect of age and weight on plasma glucose and insulin responses in the rat.

Plasma glucose and insulin responses to orally administered glucose were determined in rats of varying ages and weights. The results indicated that glucose tolerance tends to deteriorate as rats grow from 1 month to 9 months of age. This change in glucose tolerance was associated with an increase in the response of plasma insulin to glucose, consistent with the hypothesis that the decline in glucose tolerance is due to a loss of normal insulin sensitivity. The changes in glucose and insulin responses could not be explained entirely on the basis of the associated weight gain. They seemed to be at least partially secondary to either age or an age-related factor other than obesity.

Influence of pregnancy on the kinetics of insulin

The disappearance rate of intravenously injected insulin was investigated in the serum of 30 women during the third trimester of pregnancy and 6 to 8 weeks post partum, in order to determine whether pregnancy has an influence on insulin kinetics in human subjects. Both women with unimpaired glucose tolerance and those with latent diabetes were included in this study. The disappearance rate of exogenous serum insulin in pregnancy was characterized by a two-compartment model. Multivariate analyses of variance were used to determine whether the estimated parameters of this model during pregnancy differ from those obtained after the puerperium and whether the insulin kinetics are altered when carbohydrate metabolism is disturbed. The kinetics of insulin during pregnancy did not differ from those after pregnancy. Thus, hyperinsulinemia observed in pregnancy cannot be explained by a change in the insulin kinetics. It appears improbable that the insulin-degrading enzyme activities of the placenta participate in degradation of insulin circulating in the maternal blood. A connection between the decline of glucose tolerance during pregnancy and the kinetics of exogenous insulin could not be found.