Characterization of the insulin resistance of aging.

To clarify the nature of the insulin resistance of aging we studied the dose response for insulin-induced glucose disposal and the binding of insulin to circulating monocytes in healthy young and old men. A total of 49 two-hour euglycemic insulin clamp studies were performed in 17 young and 10 old healthy nonobese subjects. While the old group had lower estimates of lean body mass and greater estimates of total body fat than the young group, these differences did not exceed 5% and did not reach statistical significance. Insulin was infused at 20 mU/m2 per min (young = 8, old = 5); 80 mU/m2 per min (young = 13, old = 9); 200 mU/m2 per min (young = 9, old = 5). Increasing levels of hyperinsulinemia were associated with dose-dependent increases in steady-state glucose infusion rates in young and old. The maximal glucose infusion rates (milligrams per kilogram body weight per minute) were the same for young and old. However, the dose-response curve was shifted to the right in the old subjects. In the four individuals in each age group in whom studies were performed at each dose level, the Km was 54 +/- 14 microU/ml in the young and 113 +/- 11 microU/ml in the old (P less than 0.02). Correction of glucose infusion rate for lean body mass had no effect on comparisons between age groups. These data indicate an age-associated decline in sensitivity of peripheral tissues to insulin without a change in maximal tissue responsiveness. Studies of insulin binding with 14 young and 9 old subjects indicated no effect of age on the insulin binding to receptors on circulating monocytes (young = 5.25 +/- 0.35; old = 6.22 +/- 0.53% of 125I-insulin bound/10(7) cells). These studies suggest that aging may be associated with a postreceptor defect in insulin action manifested by decreased whole-body tissue sensitivity to insulin without a change in tissue responsiveness.

Insulin-mediated reduction of whole body protein breakdown. Dose-response effects on leucine metabolism in postabsorptive men.

In vivo effects of insulin on plasma leucine and alanine kinetics were determined in healthy postabsorptive young men (n = 5) employing 360-min primed, constant infusions of L-[1-13C]leucine and L-[15N]alanine during separate single rate euglycemic insulin infusions. Serum insulin concentrations of 16.4 +/- 0.8, 29.1 +/- 2.7, 75.3 +/- 5.0, and 2,407 +/- 56 microU/ml were achieved. Changes in plasma 3-methyl-histidine (3-MeHis) were obtained as an independent qualitative indicator of insulin-mediated reduction in proteolysis. Hepatic glucose output was evaluated at the lowest insulin level using D-[6,6-2H2]glucose. The data demonstrate a dose-response effect of insulin to reduce leucine flux, from basal values of 77 +/- 1 to 70 +/- 2, 64 +/- 3, 57 +/- 3, and 52 +/- 4 mumol(kg X h)-1 at the 16, 29, 75, and 2,407 microU/ml insulin levels, respectively (P less than 0.01). A parallel, progressive reduction in 3-MeHis from 5.8 +/- 0.3 to 4.3 +/- 0.3 microM was revealed. Leucine oxidation estimated from the 13C-enrichment of expired CO2 and plasma leucine (12 +/- 1 mumol[kg X h]-1) and from the 13C-enrichment of CO2 and plasma alpha-ketoisocaproate (19 +/- 2 mumol[kg X h]-1) increased at the 16 microU/ml insulin level to 16 +/- 1 and 24 +/- 2 mumol(kg X h)-1, respectively (P less than 0.05 for each), but did not increase at higher insulin levels. Alanine flux (206 +/- 13 mumol(kg X h)-1) did not increase during the clamp, but alanine de novo synthesis increased in all studies from basal rates of 150 +/- 13 to 168 +/- 23, 185 +/- 21, 213 +/- 29, and 187 +/- 15 mumol(kg X h)-1 at 16, 29, 75, and 2,407 microU/ml insulin levels, respectively (P less than 0.05). These data indicate the presence of insulin-dependent suppression of leucine entry into the plasma compartment in man secondary to a reduction in proteolysis and the stimulation of alanine synthesis during euglycemic hyperinsulinemia.

Influence of age on clearance of insulin in man.

With advancing age, glucose-induced insulin release is decreased in vitro, yet circulating insulin levels after glucose challenge are not decreased in the elderly. Age-related changes in insulin clearance may contribute to this discrepancy. We employed the 2-h euglycemic clamp technique to examine insulin clearance (C1) during steady-state insulin infusions (N = 53) at rates of 20, 80, and 200 mU/m2/min in healthy young (N = 16, age range 22-37 yr, relative weight 1.07 +/- 0.03) and old (N = 10, age range 63-77 yr, relative weight 1.14 +/- 0.03) men. Steady-state insulin levels were statistically significantly higher (P less than 0.01) in the elderly at each infusion rate. C1 was 40% lower (p less than 0.01) in the infusion rate. There was no effect of increasing relative weight on C1 within age groups. Within each age group, C1 was similar in insulin infusion rates of 20 and 80 mU/m2/min (young P less than 0.05, old P less than 0.001), implying a saturable system for insulin clearance. Alterations in C1 contribute to changes in insulin levels with age and may reconcile the discrepancy between in vivo and in vitro studies of glucose-induced insulin release. These results indicate the value of evaluating C1 as one determinant of circulating insulin level in states of abnormal insulin physiology.

Impaired in vivo insulin clearance in patients with severe target-cell resistance to insulin.

The concentration of insulin in plasma is determined by both its rate of secretion and its rate of clearance from the plasma compartment. The effect of marked insulin resistance on insulin clearance in vivo has not been determined in man. We have employed the euglycemic insulin clamp technique to measure insulin sensitivity and insulin clearance in 16 control subjects and in 4 subjects with marked target-cell resistance to insulin. Two insulin-resistant patients had reduced receptor concentration on peripheral mononuclear cells, and two patients had normal receptor number and affinity. During 80-mU/m2/min insulin clamp studies, the clearance rate in each insulin-resistant patient was lower than that in any controls; the mean insulin clearance rate was 511 +/- 74 ml/m2/mon in control subjects and 205 ml/m2/min (P less than 0.001) in insulin-resistant patients. These findings demonstrate an association between marked target-cell resistance to insulin and impaired in vivo insulin clearance, and suggest an important role for receptor-mediated pathways in insulin clearance in vivo.

Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes.

Acanthosis nigricans and hyperandrogenism are commonly found in patients with extreme target cell resistance to insulin, as in the type A and B syndromes of insulin resistance. However, the significance of concurrent acanthosis nigricans and hyperandrogenism in other clinical settings is not clear. We observed acanthosis nigricans to be present in 5% (15 of 300) of patients being evaluated for hyperandrogenism, and carried out studies of insulin binding and action in a group (7) of these women. Although none were diabetic, all were insulin resistant as assessed by hyperinsulinemia when fasting and after oral glucose administration. All patients were obese (mean IBW, 169%). However, when matched to hyperandrogenized women of similar body weight, patients with acanthosis nigricans were clearly more hyperinsulinemic. Insulin binding to monocytes and red cells was decreased in patients with acanthosis, and the extent of decrease was predicted by the fasting insulin level. There was also marked resistance to exogenous insulin during euglycemic insulin clamp studies in the two patients so tested. Anti-insulin receptor antibodies were not detectable, ruling out the type B syndrome. Unlike the type A syndrome, insulin binding to monocytes of these patients increased after acute (2/2) and chronic (1/1) caloric restriction. In the latter patient, acanthosis nigricans remitted as insulin resistance and the insulin binding defect improved. We conclude that acanthosis nigricans is present in as many as 5% of women with clinically significant hyperandrogenism. These women, although not diabetic, have fairly marked insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum albumin level on admission as a predictor of death, length of stay, and readmission.

We studied the serum albumin level within 48 hours of hospitalization for acute illness to predict in-hospital death, length of stay, and readmission in 15,511 patients older than 40 years. Patients with low serum albumin levels (less than 34 g/L), who made up 21% of the population, were more likely to die, had longer hospital stays, and were readmitted sooner and more frequently than patients with normal albumin levels. The in-hospital mortality was 14% among patients with low albumin levels, as compared with 4% among patients with normal levels. Although the serum albumin level was a nonspecific marker, it was a stronger predictor of death, length of stay, and readmission than age. We conclude that the serum albumin level on admission is an important variable that should be incorporated in severity-of-illness measures based on physiologic indexes.

Reporting of age data in clinical trials of arthritis. Deficiencies and solutions.

OBJECTIVE: We studied recent nonsteroidal anti-inflammatory drug (NSAID) randomized control trials of arthritis to identify the age and number of older people (> or = 65 years) and to document the way information on age was presented. We hypothesized that older people, who are most likely to take NSAIDs are underrepresented and underreported. STUDY SELECTION AND DATA EXTRACTION: All NSAID articles (n = 1008) in MEDLINE between September 1987 and May 1990 were identified. Eighty-three trials employing NSAIDs in a randomized control trial of arthritis reported in 73 articles were identified and studied in detail for age-related information. RESULTS: A total of 9664 subjects with a female-to-male ratio of 2.3:1 were enrolled. Forty-four trials studied osteoarthritis (53.0%), 37 studied rheumatoid arthritis (44.6%), and two studied both conditions (2.4%). More than half of the studies reviewed included people 65 years of age or older, only 207 people in this older age group could be identified (2.1%). While there was inclusion of the 'young-old' (65 to 74 years of age), only 14 of the 9664 people studied were between 75 and 84 years of age, and no one 85 years or older could be identified. The inclusion of the young-old is documented by the weighted mean age that ranged from 59.6 to 64.9 years for patients with osteoarthritis (mean, 62.9; SD, 1.67) and from 47.4 to 53.0 years (mean, 49.9; SD, 2.16) for those with rheumatoid arthritis. CONCLUSION: We demonstrate that older people, who represent a high proportion of the population treated with NSAIDs in practice, are generally omitted from drug trials. Recommendations designed to improve the reporting of age information to make clinical trials more informative and applicable to older people are presented.

Bowel habit in relation to age and gender. Findings from the National Health Interview Survey and clinical implications.

BACKGROUND: Constipation is widely considered to be a common problem among the elderly, as evidenced by the high rate of laxative use in this population. Yet, age-related prevalence studies of constipation generally do not distinguish between actual alteration in bowel movement frequency and subjective self-report of constipation. OBJECTIVE: To determine the relationship between advancing age and bowel habit. METHODS: We employed data collected on 42,375 subjects who participated in the National Health Interview Survey on Digestive Disorders based on interviews with a random nationwide sample of US households. We examined the following characteristics reported by this population according to selected age groupings by decade: constipation, levels of laxative use, and two bowel movements per week or less. RESULTS: Contrary to conventional wisdom, there was no age-related increase in the proportion of subjects reporting infrequent bowel movements. Nonetheless, the prevalence of self-report of constipation increased with advancing age, with a greater proportion of women reporting this symptom than men across all age groups. Laxative use also increased substantially with aging; while women were more likely to use laxatives than men, this effect attenuated with advancing age. A U-shaped relationship was observed between advancing age and bowel habit in men and women; 5.9% of individuals younger than 40 years reported two bowel movements per week or less compared with 3.8% of those aged 60 to 69 years and 6.3% of those aged 80 years or older. This relationship persisted after adjusting for laxative use. CONCLUSION: These findings suggest that a decline in bowel movement frequency is not an invariable concomitant of aging. In elderly patients who report being constipated, it is essential to take a careful physical, psychological, and bowel history rather than to automatically assume the need for laxative use.

A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis.

BACKGROUND: To study the relation between reported drug performance in published trials and support of the trials by the manufacturer of the drug under evaluation, we studied a sample of trials of nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of arthritis. METHODS: All randomized control trials of NSAIDs published between September 1987 and May 1990 identified by MEDLINE were reviewed. If an article met the following criteria (n = 61), it was selected: trials involving adult patients with osteoarthritis or rheumatoid arthritis (n = 180), use of nonsalicylate NSAIDs marketed in the United States (n = 101), randomized control trial (n = 81), duration of the trial 4 or more days (n = 78), and use of an efficacy outcome measure (n = 61). Reviewers, "blinded" to manufacturer status, evaluated the narrative interpretation of results and extracted numeric data on efficacy and toxicity. Manufacturer-associated trials were defined as those that acknowledged an association with a pharmaceutical manufacturer. Because of the scarcity of non-manufacturer-associated trials (n = 9), we report only on the manufacturer-associated articles. RESULTS: Fifty-two publications (85.2%) representing 56 trials were associated with a manufacturer. The manufacturer-associated drug was reported as comparable with (71.4%) or superior to (28.6%) the comparison drug in all 56 trials. These narrative claims of superiority were usually justified with trial data. Of the trials identifying one drug as less toxic (n = 22), the manufacturer-associated drug's safety was reported as superior to the comparison drug in 86.4% of cases. Justification for the narrative interpretation of the trial findings regarding less toxicity was provided in only 12 (54.5%) of 22 trials. CONCLUSION: The manufacturer-associated NSAID is almost always reported as being equal or superior in efficacy and toxicity to the comparison drug. These claims of superiority, especially in regard to side effect profiles, are often not supported by trial data. These data raise concerns about selective publication or biased interpretation of results in manufacturer-associated trials.

Effect of age on systemic delivery of oral glucose in men.

This study examined the effect of age on the posthepatic delivery of oral glucose (PHDG) during steady-state conditions. We used an intravenous-oral modification of the euglycemic insulin-clamp technique to assess PHDG in six men aged 24-39 yr (young) and eight men aged 65-83 yr (old). Each subject underwent two studies in which insulin was infused at 120 mU.m-2.min-1 for 3 h, and either oral glucose (45 g) or water was given 60 min after initiating insulin. This level of insulin infusion is known to fully suppress hepatic glucose output. For each subject, PHDG was calculated as the difference between the whole-body glucose disposal rates in the paired studies. The time course of PHDG differed in the two groups (P less than .0001), with an overall delay in PHDG in the older men. During the 1st h, younger men showed a greater PHDG (58.6 +/- 3.8% of the oral load vs. 45.1 +/- 4.2%) than the older group (P = .04). During the 2nd h, PHDG was less in the younger group (20.7 +/- 4.9%) than the older group (36.6 +/- 3.9%, P = .02). Over the 2-h period, total PHDG was comparable in younger (79.3 +/- 7.4%) and older (81.7 +/- 7.9%) men. These results indicate that normal aging is associated with significantly delayed but overall equal PHDG in men, consistent with the greater effect of age on 2-h rather than earlier postprandial glucose levels. It reinforces the role of impaired peripheral utilization as the primary mechanism of the glucose intolerance of aging.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin enhances insulin-mediated glucose disposal in elderly subjects.

Somatostatin (SRIH) infusion has been widely used in metabolic studies of carbohydrate metabolism. While the effects of SRIH itself on various aspects of carbohydrate economy have been assessed in young adults, such studies have not been conducted in the elderly, which represent an increasingly important study group. To examine the effect of SRIH on insulin-mediated glucose disposal in the elderly, we studied 12 (7 men and 5 women) healthy nonobese subjects, aged 65-80 yr. Paired 3-h euglycemic insulin clamp studies were performed in random order employing insulin alone (22 mU/m2.min) or insulin with SRIH (250 micrograms/h) and glucagon (0.4 ng/kg.min) to maintain normal basal plasma glucagon levels. Basal plasma insulin, glucose, glucagon, GH, and glucose production and disappearance were similar on each occasion. Steady state (10-180 min) mean plasma insulin [insulin alone, 298 +/- 12 (+/- SE); insulin; glucagon, and SRIH, 304 +/- 15 pmol/L] and glucagon (insulin alone, 85 +/- 7; insulin, glucagon, and SRIH, 96 +/- 9 ng/L) concentrations were similar. At steady state (150-180 min) glucose production was suppressed to similar levels (insulin alone, 26 +/- 7; insulin, glucagon, and SRIH, 36 +/- 13 mumol/kg.min). However, steady state glucose disposal was significantly higher during the SRIH infusion (insulin alone, 295 +/- 26; insulin, glucagon, and SRIH, 346 +/- 32 mumol/kg.min; P less than 0.02). We conclude that SRIH augments insulin-mediated glucose disposal in healthy older subjects at physiological levels of insulin.

The dawn phenomenon does not occur in normal elderly subjects.

To determine whether the dawn phenomenon occurs in normal elderly subjects and thus contributes to the progressive mild fasting hyperglycemia of aging, we examined the effect of physiological insulin levels on glucose disposal and hepatic glucose production (HGO) between 0530 and 0800 h, and 0930 and 1200 h. Paired euglycemic insulin clamp studies (8 mU/m2 X min) were performed on healthy old subjects (n = 5), employing [3H]glucose methodology to measure glucose production and disposal rates. Basal plasma insulin, GH, glucagon, and cortisol levels, and HGO and glucose disposal rates were similar before each study. Steady state plasma insulin values were slightly, but not significantly, lower during the dawn study [dawn: 20.3 +/- 1.1 (SE); control: 23.5 +/- 2.1 microU/ml, P = 0.08]. Insulin clearance rates were higher during the dawn study (dawn: 523 +/- 16; control: 430 +/- 19 ml/m2 X min, P less than 0.01). Maximum glucose disposal rates (dawn: 3.10 +/- 0.24; control: 3.03 +/- 0.23 mg/kg X min) and minimum HGO levels (dawn: 0.83 +/- 0.09; control: 0.62 +/- 0.03 mg/kg X min) were not significantly different in each part of the study. There was a significant decrease in plasma GH during the dawn (P less than 0.01, analysis of variance) but not the control studies. There was no difference in cortisol levels during the euglycemic clamp between the dawn and control studies. The mean decrement in glucagon during the insulin infusion was similar in each part of the study. We conclude that the dawn phenomenon does not occur in healthy elderly subjects despite an increase in insulin clearance during the dawn period.

Somatostatin does not alter insulin-mediated glucose disposal.

We examined the effect of somatostatin (SRIH) infusion on insulin-mediated glucose disposal (Rd) in normal young subjects (n = 8) to determine the influence of SRIH on insulin action. Paired 3-h euglycemic insulin clamp studies were performed in random order employing insulin alone (25 mU/m2 X min) or insulin with SRIH (250 micrograms/h) and replacement of basal glucagon (0.4 ng/kg X min). Basal plasma glucose, insulin, glucagon (IRG), and GH concentrations, hepatic glucose production, and Rd were similar on each occasion. Steady state (10-180 min) plasma insulin insulin alone, 283 +/- 10 (+/- SEM); insulin, IRG, and SRIH, 284 +/- 10 pmol/L) and glucagon levels (insulin alone, 84 +/- 7; insulin, IRG, and SRIH, 82 +/- 7 ng/L) were similar. Hepatic glucose production (insulin alone, 0.66 +/- 0.12; insulin, IRG, and SRIH, 0.78 +/- 0.48 mg/kg X min) and Rd (insulin alone, 8.16 +/- 0.62; insulin, IRG, and SRIH, 8.17 +/- 0.61 mg/kg X min) were not different at steady state. We conclude that SRIH infusion with glucagon replacement does not augment insulin-mediated glucose disposal in normal young subjects at physiological insulin levels.

Age-related failure of volume-pressure-mediated vasopressin release.

Osmoreceptor sensitivity, as estimated by the plasma vasopressin (AVP) response to hypertonic saline infusion, increases with age. We studied volume-pressure sensitivity, as estimated by the plasma AVP response to orthostasis, in healthy young (19-31 yr old; n = 12) and old (62-80 yr old; n = 15) subjects. After remaining recumbent overnight (minimum of 8 h), subjects stood quietly for 8 min. Cardiovascular changes on standing were not influenced by age. The peak plasma AVP response was greater in the young than in the old (P = 0.02, by rank sum test). When categorized as responders (peak AVP response, greater than or equal to 3 pg/ml) or nonresponders (peak response, less than 3 pg/ml), the young group included 11 responders and 1 nonresponder, while the old group included 8 responders and 7 nonresponders (P = 0.03, by Fisher exact test). There was no difference in the marked increase in plasma norepinephrine on standing between old responders (n = 6) and old nonresponders (n = 4). These studies indicate that failure to release AVP in response to orthostasis is more common in the elderly than in the young. The intact norepinephrine response to orthostatis in the elderly, regardless of the AVP response, suggests that the age-related defect is distal to the vasomotor center in the afferent limb of the baroreceptor reflex arc. Insensitivity to the volume and pressure changes accompanying hypertonic saline infusion may contribute to the previously noted augmented AVP response of the elderly to hyperosmolality.

The effect of age and glycemic level on the response of the beta-cell to glucose-dependent insulinotropic polypeptide and peripheral tissue sensitivity to endogenously released insulin.

Normal aging is characterized by a progressive impairment in glucose tolerance. An important mechanism underlying the glucose intolerance of aging is an impairment in glucose-induced insulin release. These studies were conducted to determine whether the age-related impairment in insulin release was caused by a decreased beta-cell sensitivity to glucose-dependent insulinotropic polypeptide (GIP). Thirty-one Caucasian men were divided into four groups: two young groups (age range: 19-26 yr, n = 15) and two old groups (age range: 67-79 yr, n = 16). Each volunteer participated in three studies (n = 93 clamps). Hyperglycemic clamps were conducted at two doses [basal plasma glucose (G) + 5.4 mmol/L and G + 12.8 mmol/L] for 120 min. In the initial hyperglycemic clamp, only glucose was infused. In subsequent studies, GIP was infused at a final rate of 2 or 4 pmol/ kg(-1) x min(-1) from 60-120 min. Basal plasma insulin and GIP levels were similar in the young (41 +/- 6 and 51 +/- 6 pmol/L) and the old subjects (42 +/- 6 and 66 +/- 12 pmol/L) in all studies. First- and second-phase insulin responses were similar during the control study and during the first 60 min of each GIP infusion study in both groups. The 90-120 min GIP values were similar between groups and between hyperglycemic plateaus during the 2 and 4 pmol/kg(-1) x min(-1) GIP infusion (young: 342 +/- 28 and 601 +/- 44 pmol/L, old: 387 +/- 45 and 568 +/- 49 pmol/L). In response to the GIP infusions, significant increases in insulin occurred in young and old at both glucose levels (P < 0.01). The potentiation of the insulin response caused by GIP was greater in the young subjects than in the old, in the G + 5.4 mmol/L studies (P < 0.05). However, the insulin response to GIP was similar in both young and old during the G + 12.8 mmol/L clamps. The insulinotropic effect of the incretin was higher in the young and in the old, in the G + 12.8 mmol clamps, than in the G + 5.4 mmol/L clamps. We conclude that normal aging is characterized by a decreased beta-cell sensitivity to GIP during modest hyperglycemia, which may explain, in part, the age-related impairment in glucose-induced insulin release. We also find that the insulinotropic effect of GIP is increased with increasing levels of hyperglycemia.

Impairment of noninsulin-mediated glucose disposal in the elderly.

While normal aging is characterized by resistance to insulin-mediated glucose disposal (IMGU), the effect of age on noninsulin-mediated glucose disposal (NIMGU), which is responsible for the majority of basal glucose uptake, has not been completely evaluated. These studies were conducted on healthy nonobese young (n = 10; age, 20-30 yr) and old (n = 10; age, 62-80 yr) men. Each subject underwent two paired studies in random order. In all studies a [3H]glucose infusion was used to measure glucose uptake and production rates, and somatostatin (500 micrograms/h) was infused to suppress endogenous insulin release. In study A, plasma glucose was kept close to fasting levels (approximately 5.6 mmol/L) using an euglycemic clamp protocol for 4 h. Plasma insulin decreased to less than 20 pmol/L within 15 min and remained suppressed thereafter in all studies. Steady state (15-240 min) plasma glucagon levels were slightly greater in the elderly [young, 86 +/- 5 (+/- SE); old, 98 +/- 2 ng/L; P less than .05]. Basal glucose uptake was similar in both groups (young, 877 +/- 21; old, 901 +/- 24 mumol/min). Glucose uptake during the last hour of the study (180-240 min) was used to represent NIMGU, because insulin action was assumed to be absent by this time. NIMGU was less in the elderly (young, 744 +/- 18; old, 632 +/- 32 mumol/min; P less than 0.01). In study B, plasma glucose was kept at about 11 mmol/L for 4 h using a hyperglycemic clamp protocol. Plasma insulin decreased to less than 20 pmol/L within 15 min and remained suppressed thereafter in all studies. Steady state plasma glucagon levels were slightly but not significantly higher in the elderly (young, 88 +/- 6; old, 100 +/- 4 ng/L). Basal glucose uptake (young, 910 +/- 27; old, 883 +/- 25 mumol/min) and NIMGU (young, 933 +/- 36; old, 890 +/- 16 mumol/min; P = NS) were similar in both young and old subjects. We conclude that aging is associated with impairment in NIMGU only in the basal state, which may explain in part the increase in fasting glucose with age.

Counterregulatory responses to insulin-induced glucose reduction in the elderly.

The impact of age on counterregulatory responses to moderate reductions in blood glucose induced by a constant insulin infusion (20 mU/m2 X min) was studied in normal young (n = 7; aged 20-42 yr) and old (n = 7; aged 66-77 yr) nonobese subjects. Insulin was infused until the whole blood glucose level fell to or below 60 mg/dl. This required an infusion time of 39 +/- 3 (+/- SE) min in the young and 36 +/- 3 min in the old. Mean basal glucose [young, 88 +/- 2 (+/- SE); old, 88 +/- 2 mg/dl), minimum glucose (young, 51 +/- 2; old, 54 +/- 1 mg/dl), time to nadir (young, 48 +/- 3; old, 44 +/- 3), and time to recovery were similar in both groups. Maximal (young, 40.3 +/- 2.3; old, 42.1 +/- 3.3 microU/ml) insulin levels were also similar. Basal and maximal levels of glucagon, epinephrine, and GH were similar in the two groups. Although basal norepinephrine values were higher in the old subjects (young, 243 +/- 38; old, 364 +/- 23 pg/ml; P = 0.02), increments above basal during reduction in blood glucose were not affected by age. Basal cortisol values were similar (young, 13.7 +/- 1.4; old, 14.0 +/- 0.7 micrograms/dl), but maximum cortisol responses were slightly greater in the old subjects (young, 14.6 +/- 1.0; old, 17.7 +/- 0.9 micrograms/dl; P = 0.03). These studies indicate that hormonal responses and counterregulatory efficiency during modest reductions in blood glucose are preserved in healthy elderly subjects.

Metabolic response to three years of continuous, basal rate intravenous insulin infusion in type II diabetic patients.

We studied two obese type II diabetic patients before, during, and after 3 yr of continuous iv insulin infusion, delivered by means of totally implanted insulin infusion pumps. Tolerance of the devices was excellent, and no side-effects or episodes of significant hypoglycemia occurred. Glycosuria was eliminated, and mean 24-h plasma glucose and hemoglobin A1c levels decreased in both patients and remained in or near the normal range for 3 yr. Improvements were also noted in serum triglyceride concentrations and vitreous fluorescein concentrations after iv fluorescein injection. Euglycemic insulin clamp studies showed that no significant change in glucose disposal rate occurred after 6 and 12 months of treatment. However, some improvement in insulin secretion during hyperglycemic insulin clamp studies occurred in both patients after 6 months of insulin infusion. Evaluation of the insulin-glycerol mixture used in the pump revealed that moderate degradation of insulin occurred in the pump during the 21-day flow cycle, resulting in 6-12% increases in fasting blood glucose levels; in addition, higher mol wt species of immunoreactive insulin were present in the patients' serum. We conclude that long term continuous iv infusion of insulin using a totally implantable infusion pump is practical in type II diabetic patients, is acceptable to patients, and is capable of providing near-normal glycemic control.

High-carbohydrate, high-fiber diets increase peripheral insulin sensitivity in healthy young and old adults.

To examine extra-alimentary effects of high-carbohydrate, high-fiber (HCF) diets, insulin-mediated glucose disposal employing the euglycemic clamp and hepatic glucose output (HGO) employing [6,6-2H2]glucose were measured in 12 healthy young and old individuals before and after 21-28 d of an HCF diet. Diet lowered fasting concentrations of glucose from 5.3 +/- 0.2 to 5.1 +/- 0.1 mmol/L (p less than 0.01) and insulin from 66.0 +/- 7.9 to 49.5 +/- 5.7 pmol/L (p less than 0.01). Fasting serum cholesterol decreased from 5.17 +/- 0.18 to 3.80 +/- 0.20 mmol/L (p less than 0.01) in young individuals and from 6.15 +/- 0.52 to 4.99 +/- 0.49 mmol/L (p less than 0.01) in elderly individuals. Fasting serum triglyceride concentrations, basal HGO, and insulin suppression of HGO were unchanged by the diet. Glucose disposal rates increased from 18.87 +/- 1.66 before 23.87 +/- 2.78 mumol.kg-1.min-1 after the diet (p less than 0.02). Therefore, HCF diets may improve carbohydrate economy by enhanced peripheral sensitivity to insulin.

Phenytoin-induced improvement in muscle cramping and insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy.

Phenytoin sodium has been used to treat muscle cramps of diverse causes, and is known to increase insulin sensitivity during long-term use. We have previously described a syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy with continual muscle cramping. The effect of 300 mg/d of phenytoin (Dilantin) on muscle cramping and carbohydrate economy was studied in three affected patients and four control subjects. Oral glucose tolerance tests, euglycemic insulin infusion studies, and monocyte insulin binding tests were conducted before and after phenytoin administration. All three patients had notable improvement in muscle cramps. In response to phenytoin, metabolic improvements were variable, with improvement characteristically better in patients with less severe baseline metabolic abnormalities. Patient 1, with the mildest degree of glucose intolerance, had decreased fasting insulin and blood glucose levels, improved glucose tolerance, and insulin-mediated glucose disposal, associated with an increase in monocyte insulin receptors. Patient 2 had reduced fasting plasma glucose and insulin levels and improved oral glucose tolerance, suggesting a beneficial effect on carbohydrate metabolism. Patient 3, with the most severely impaired carbohydrate economy, showed no metabolic improvement despite marked lessening of muscle pain. These clinical characteristics were unaffected in control subjects. We conclude that phenytoin is of value in the therapy of muscle cramps and glucose intolerance in patients with this syndrome.