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Biomedical subjects

K L Minaker

Publications and source records attributed to K L Minaker.

70 records · Page 4Linked to original sources
PubMed1986

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.

Aged↗
PubMed1985

Intra-individual variability in postural blood pressure in the elderly.

Orthostatic hypotension, an age-related phenomenon, has been associated with hypertension and body weight variability. To evaluate the relative contributions of blood pressure elevation and abnormalities in extracellular volume regulation to orthostatic hypotension, elderly institutionalized subjects (mean age = 87 +/- 7 years), taking no cardiovascular medications, underwent measurement of body weight (n = 15) and first morning supine and standing blood pressures (n = 19), 12-13 times per subject over a 2-4 week period. There was a wide day-to-day variability in postural systolic blood pressure change (coefficient of variation = 533%) and a strong negative correlation between each day's postural change in systolic blood pressure and basal supine blood pressure (r = -0.55, P less than 0.0001). There was no association between postural blood pressure change and heart rate response or body weight changes, which were very small over the duration of the study (coefficient of variation = 0.6%). Elderly individuals have intact homeostatic mechanisms for the control of standing pressure when basal blood pressure is normal. Postural hypotension in the elderly is a variable phenomenon related to elevations in basal blood pressure.

Age Factors↗
PubMed1985

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.

Adult↗
PubMed1985

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.

Adult↗
PubMed1985

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.

Blood Glucose↗
PubMed1985

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)

Acanthosis Nigricans↗
PubMed1985

Health and disease among the oldest old: a clinical perspective.

Interactions of aging and disease are poorly understood by both clinicians and the aged themselves. The altered expressions of illness in the oldest old--in severity, presentation, and perception--provide a clinical challenge to treatment as well as to the formulation of health policy. A progressively diverse population, the oldest old will require new strategies for individualized care (acute and long-term), case-finding, research and training, and health promotion.

Aged↗
PubMed1984

Whole body insulin resistance in myotonic dystrophy.

To quantitate the degree of whole body insulin resistance in patients with myotonic dystrophy, three separate euglycemic insulin infusions were given to ambulatory patients and the results compared with findings in normal control subjects. Basal glucose and insulin values were similar for the two groups. There was no significant difference in insulin clearance rates between normal subjects and patients at the three insulin infusion rates used. A highly significant decrease in the whole body glucose disposal rate was seen during the 120-minute insulin infusion in the patients with myotonic dystrophy compared with normal subjects at all three insulin dosages (20 mU/m2/min: 2.18 +/- 0.29 [standard error] versus 5.49 +/- 1.72 mg/kg/min, p less than 0.0001; 80 mU/m2/min: 4.16 +/- 0.34 versus 8.49 +/- 0.45 mg/kg/min, p less than 0.0001; 200 mU/m2/min: 5.22 +/- 0.53 versus 10.06 +/- 0.50 mg/kg/min, p less than 0.0001). These marked decreases in glucose disposal rates for the patients were adjusted in accordance with their 24-hour urinary creatinine excretion rate to correct for the difference in muscle mass between patients and controls. This adjusted glucose disposal rate was 15 to 25% lower (p less than 0.02) in the patients with myotonic dystrophy at insulin infusion rates of 20 and 80 mU. During the 200 mU insulin infusions, the adjusted glucose disposal rate remained lower than that in normal subjects but was of borderline statistical significance. These studies suggest that moderately severe whole body insulin resistance is responsible for the postprandial hyperinsulinemia typically seen in patients with myotonic dystrophy.

Adult↗
PubMed1984

Effect of exogenous vasopressin on vasopressin release.

To characterize the influence of extracellular volume status on vasopressin pharmacokinetics, eleven young (aged 19-31 yr) and four old (aged 62-80 yr) subjects received bolus injections of 1 mU/kg Pitressin or synthetic arginine vasopressin following 6 days of sodium depletion (10 meq Na/day) or sodium loading (250 meq Na/day). In six young subjects the rapid decline in plasma vasopressin (pAVP) following the initial peak was interrupted by a second peak 5-30 pg/ml in magnitude 7.5-20 min after injection. In four of these subjects the second peak was larger following sodium depletion as compared with sodium loading. In the elderly a small (4 pg/ml) second peak was present in one sodium-depleted subject. Of five sodium-depleted subjects with central diabetes insipidus, none showed a secondary rise in pAVP. These results indicate that exogenous vasopressin may stimulate the release of endogenous AVP, an effect that appears to be enhanced by sodium depletion and is virtually absent in the elderly. There was no effect of age, volume status, or diabetes insipidus on AVP pharmacokinetics.

Adult↗
PubMed1983

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.

Adult↗
PubMed1982

Effect of age on insulin stimulation of sympathetic nervous system activity in man.

Previous studies have shown that oral glucose increases plasma norepinephrine (NE) in man, an effect which is more pronounced in the elderly. Recently we have shown that hyperinsulinemia results in a dose-dependent increase in sympathetic nervous system (SNS) activity in young men independent of changes in blood glucose. We now report studies of the influence of hyperinsulinemia on SNS activity in healthy elderly. Euglycemic glucose clamp studies were performed at 2 insulin infusion rates, 2 mU/kg/min (young 22-37 yr, n = 7; old 63-77 yr, n = 9) and 5 mU/kg/min (young 22-36 yr, n = 7; old 64-75 yr, n = 5) nonobese men. Control studies were performed in 5 young and 3 old subjects. In control studies there were no significant changes in NE or cardiovascular measures in either group. Insulin infusion at 2 mU/kg/min in young subjects were associated with significant increases in NE, (p less than 0.001) pulse (p less than 0.05), pulse pressure (p less than 0.005) and double product (pulse x systolic pressure) (p less than 0.01). In contrast 2 mU/kg/min insulin infusion in the elderly did not result in an increase in NE, and cardiovascular changes were limited to an increase in pulse pressure (p less than 0.01). The changes in NE at this insulin infusion dose were greater in the young than in the old (p less than 0.005). Insulin infusion at 5 mU/kg/min in young subjects were associated with significant increases in NE, (p less than 0.001) mean arterial blood pressure (MABP) (p less than 0.001), pulse pressure (p less than 0.001) and double product (p less than 0.001). In contrast 5 mU/kg/min insulin infusion in the elderly did not result in an increase in NE, and cardiovascular changes were limited to a decrease in MABP (p less than 0.001) only. The change in NE and MABP at this insulin infusion dose were greater in the young than in the old (p less than 0.001) for each). In the young group the increases in NE were greater during the 2 mU/kg/min studies than in the control studies (p less than 0.001) and the increases in NE during the 5 mU/kg/min studies were greater than during the 2 mU/kg/min studies (p less than 0.001). In the old group there were no differences in NE or cardiovascular measures between the control, 2 mU or 5 mU insulin infusions. These studies indicate diminished insulin-induced SNS activation in the elderly. The disparity in the elderly between the enhanced SNS response to oral glucose and the blunted response to intravenous insulin and glucose suggests that splanchnic factors may mediate the SNS activation after oral glucose.

Adult↗
PubMed1982

Potassium homeostasis during hyperinsulinemia: effect of insulin level, beta-blockade, and age.

The euglycemic glucose clamp technique was used to evaluate the influence of level and duration of hyperinsulinemia, presence of beta-adrenergic blockade, and subject age on insulin-mediated changes in plasma potassium. In 16 young subjects, 2-h insulin infusions at 20 (n = 6), 80 (n = 13), and 200 (n = 8) mU.m-2.min-1 resulted in dose-dependent declines in plasma potassium (P less than 0.001 at all doses) during the 1st h. During the 2nd h plasma potassium declined during the 20 mU.m-2.m-1 infusions, was stable during the 80 mU.m-2.m-1 infusions, and rose slightly during the 200 mU.m-2.min-1 infusions. There was a significant reciprocal relationship between the changes in plasma potassium during the 1st and 2nd h of study (r = 0.99, P less than 0.01). During 4-h infusions (80 mU.m-2.min-1, n = 6) plasma potassium declined during the first 90 min (p less than 0.001) and rose thereafter until the end of the infusion (P less than 0.05). Studies with and without propranolol infusion at two insulin dose levels (20 and 80 mU.m-2.min-1) in six young subjects showed no effect of beta-blockade, and studies at three insulin dose levels [20 (n = 5), 80 (n = 6), and 200 (n = 6) mU.m-2.min-1 in 10 older males (63-77 yr] showed no effect of age on the changes in plasma potassium during hyperinsulinemia. These results suggest the presence of a regulatory mechanism influencing insulin-mediated alterations in plasma potassium. This mechanism appears uninfluenced by age or beta-adrenergic blockade.

Adrenergic beta-Antagonists↗
PubMed1982

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.

Adult↗
PubMed1982

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.

Adult↗
PubMed1982

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.

Adult↗