Jordan D. Tobin

A Model of the Kinetics of Insulin in Man

The design of the present study of the kinetics of insulin in man combines experimental features which obviate two of the major problems in previous insulin studies. (a) The use of radioiodinated insulin as a tracer has been shown to be inappropriate since its metabolism differs markedly from that of the native hormone. Therefore porcine insulin was administered by procedures which raised insulin levels in arterial plasma into the upper physiologic range. Hypoglycemia was prevented by adjusting the rate of an intravenous infusion of glucose in order to control the blood glucose concentration (the glucose-clamp technique). (b) Estimation of a single biological half-time of insulin after pulse injection of the hormone has been shown to be inappropriate since plasma insulin disappearance curves are multiexponential. Therefore the SAAM 25 computer program was used in order to define the parameters of a three compartment insulin model. The combined insulin mass of the three compartments (expressed as plasma equivalent volume) is equal to inulin space (15.7% body wt). Compartment 1 is apparently the plasma space (4.5%). The other two compartments are extra-vascular; compartment 2 is small (1.7%) and equilibrates rapidly with plasma, and compartment 3 is large (9.5%) and equilibrates slowly with plasma. The SAAM 25 program can simulate the buildup and decay of insulin in compartments 2 and 3 which cannot be assayed directly. Insulin in compartment 3 was found to correlate remarkably with the time-course of the servo-controlled glucose infusion. Under conditions of a steady-state arterial glucose level, glucose infusion is a measure of glucose utilization. We conclude that compartment 3 insulin (rather than plasma insulin) is a more direct determinant of glucose utilization. We suggest that the combined use of glucose-clamp and kinetic-modeling techniques should aid in the delineation of pathophysiologic states affecting glucose and insulin metabolism.

Amino acid balance across tissues of the forearm in postabsorptive man. Effects of insulin at two dose levels

Amino acid balance across skeletal muscle and across subcutaneous adipose tissue plus skin of the forearm has been quantified in postabsorptive man before and after insulin infusion into the brachial artery. Skeletal muscle released significant amounts of alpha amino nitrogen after an overnight fast. Most individual amino acids were released. Alanine output was by far the greatest. The pattern of release probably reflects both the composition of muscle protein undergoing degradation and de novo synthesis of alanine by transamination. A significant correlation was observed between the extent of release of each amino acid and its ambient arterial concentration. Elevation of forearm insulin in eight subjects from postabsorptive (12 muU/ml) to high physiologic levels (157 muU/ml) in addition to stimulating muscle glucose uptake blocked muscle alpha amino nitrogen release by 74%. Consistent declines in output were seen for leucine, isoleucine, tyrosine, phenylalanine, threonine, glycine, and alpha-aminobutyric acid. Alanine output was insignificantly affected. Doubling forearm insulin levels (from 10 to 20 muU/ml) in eight subjects increased muscle glucose uptake in three and blocked alpha amino nitrogen output in two although both effects were seen concurrently in only one subject. Changes in net amino acid balance after insulin could be accounted for by increased transport of amino acids into muscle cells or retardation of their exit. It is likely that ambient arterial amino acid concentrations are established and maintained primarily by the extent of muscle amino acid release. The individual amino acids whose outputs from forearm muscle decline after forearm insulinization correspond well with those whose levels fall systematically after systemic insulinization. This suggests that declines in amino acid levels after systemic insulinization are due to inhibition of muscle release. Doubling basal insulin approaches the threshold both for blockade of muscle amino acid output and stimulation of glucose uptake, effects which appear to occur independently.

Aging and ethanol metabolism

The effect of aging on the distribution and elimination of ethanol was studied in a group of 50 healthy subjects ranging in age from 21 to 81 yr (mean, 53.3). Ethanol was administered in a continuous 1‐hr infusion at a mean rate of 375 mg/m2 body surface area/min (equivalent to a mean dose of 0.57 gm/kg body weight). Serial blood samples for the determination of ethanol concentration were obtained at 15‐ to 30‐min intervals for up to 4 hr post irifusion. Ethanol elimination and distribution were evaluated with the aid of a two‐compartment model. Rates of ethanol elimination were not affected by age. Peak ethanol concentration in blood water at the end of the infusion period was correlated with age (r = 0.55, p ‐ 0.001). Lean body mass and total volume of distribution of the ethanol were negatively correlated with age. The smaller volume of distribution, in association with the decreased lean body mass, most likely explains the higher peak ethanol concentration found in the blood after administration of an ethanol dose on the basis of surface area in the old as compared with the young subjects. This study demonstrates that age‐related changes in body composition are important factors in the study of ethanol metabolism and its pharmacologic effects.

Impact of Age on Weight Goals

Although the health hazards due to excessive obesity and excessive leanness are multiple and diverse, weight recommendations for over 40 years have been based solely on the risk of dying. The weight recommendation tables in nearly universal usage have been derived from the experience of the life insurance industry. Those tables have not recommended any weight adjustments for age. An analysis of the actuarial data on which the most recent tables are based shows that minimal mortality occurs at progressively increasing body weight as age advances (20 to 29, through 60 to 69 years). There is, furthermore, no systematic sex difference in those weights. We have prepared height-weight tables that are age-specific and delete sex and body frame type as variables. These weight standards are lower for young adults and higher for older adults than those previously recommended. A review of 23 other reported populations confirms the need to adjust weight standards for age.

Insulin Control of Glucose Metabolism in Man: A New Kinetic Analysis

Analyses of the control of glucose metabolism by insulin have been hampered by changes in bloog glucose concentration induced by insulin administration with resultant activation of hypoglycemic counterregulatory mechanisms. To eliminate such mechanisms, we have employed the glucose clamp technique which allows maintenance of fasting blood glucose concentration during and after the administration of insulin. Analyses of six studies performed in young healthy men in the postabsorptive state utilizing the concurrent administration of [14C]glucose and 1 mU/kg per min (40 mU/m2 per min) porcine insulin led to the development of kinetic models for insulin and for glucose. These models account quantitatively for the control of insulin on glucose utilization and on endogenous glucose production during nonsteady states. The glucose model, a parallel three-compartment model, has a central compartment (mass = 68 +/- 7 mg/kg; space of distribution = blood water volume) in rapid equilibrium with a smaller compartment (50 +/- 17 mg/kg) and in slow equilibrium with a larger compartment (96 +/-21 mg/kg). The total plasma equivalent space for the glucose system averaged 15.8 liters or 20.3% body weight. Two modes of glucose loss are introduced in the model. One is a zero-order loss (insulin and glucose independent) from blood to the central nervous system; its magnitude was estimated from published data. The other is an insulin-dependent loss, occurring from the rapidly equilibrating compartment and, in the basal period, is smaller than the insulin-independent loss. Endogenous glucose production averaged 1.74 mg/kg per min in the basal state and enters the central compartment directly. During the glucose clamp experiments plasma insulin levels reached a plateau of 95 +/-8 microU/ml. Over the entire range of insulin levels studied, glucose losses were best correlated with levels of insulin in a slowly equilibrating insulin compartment of a three-compartment insulin model. A proportional control by this compartment on glucose utilization was adequate to satisfy the observed data. Insulin also rapidly decreased the endogenous glucose production to 33% of its basal level (0.58 mg/kg per min), this suppression being maintained for at least 40 min after exogenous insulin infusion was terminated and after plasma insulin concentrations had returned to basal levels. The change in glucose utilization per unit change in insulin in the slowly equilibrating insulin compartment is proposed as a new measure for insulin sensitivity. This defines insulin effects more precisely than previously used measures, such as plasma glucose/plasma insulin concentration ratios. Glucose clamp studies and the modeling of the coupled kinetics of glucose and insulin offers a new and potentially valuable tool to the study of altered states of carbohydrate metabolism.

Oral glucose augmentation of insulin secretion. Interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels

Gastric inhibitory polypeptide, or GIP, has been postulated as the major enteric hormonal mediator of insulin release. The release of immuno-reactive GIP (IR-GIP) after oral glucose and its role in insulin release was studied in normal men by the glucose clamp technique. In 24 subjects studied with the hyperglycemic clamp, blood glucose was maintained at 125 mg/dl above basal for 2 h via a primed-continuous IV glucose infusion coupled to a servo-controlled negative feedback system. 40 g glucose per m(2) surface area was ingested at 60 min, and the blood glucose was maintained at the steady-state hyperglycemic level. Plasma IR-GIP and insulin (IRI) levels were measured throughout the 2-h period. IR-GIP levels changed little when IV glucose alone was given; the mean basal value was 305+/-34 (SEM) pg/ml. After oral glucose, IR-GIP levels began to rise within 10 min and reached a peak within 40 min of 752+/-105 pg/ml. Plasma IRI responded initially to the square wave of hyperglycemia in the typical biphasic pattern. After oral glucose, plasma IRI levels rose strikingly above the elevated levels produced by hyperglycemia alone, reaching a peak of 170+/-15 muU/ml within 45 min. The time course of the rise in IR-GIP and IRI was nearly identical. To assess whether the maintenance of euglycemia would affect this process, the euglycemic clamp was employed in 11 subjects to maintain basal blood glucose levels during a similar 2-h study. A primed-continuous insulin infusion, with a constant rate of 120 mU/m(2) per min was given together with a servo-controlled glucose infusion. This resulted in hyper-insulinemia of approximately 300 muU/ml. Glucose was ingested by six subjects at 60 min. Plasma IR-GIP responded to oral glucose similarly to the effect seen in the hyperglycemic studies. No increase in endogenous insulin release was seen despite the increase in IR-GIP when euglycemia was maintained. However, in five of seven subjects given insulin whose blood glucose concentration rose by 20 mg/dl or more after oral glucose, there was an increase in plasma insulin concentration associated with the elevation in IR-GIP. Thus, the effect of glucose-released IR-GIP on insulin secretion is dependent upon the presence of some degree of hyper-glycemia and is not inhibited in the presence of marked hyperinsulinemia.

Familial aggregation of osteoarthritis: Data from the Baltimore longitudinal study on aging

OBJECTIVE To evaluate the familial aggregation of osteoarthritis (OA) in a cohort of healthy volunteers drawn from a community setting. METHODS Hand radiographs obtained between 1978 and 1991 and bilateral standing knee radiographs obtained between 1984 and 1991 were read for changes of OA, using Kellgren-Lawrence (K-L) scales. The hand sites were distal interphalangeal (DIP) joints, proximal interphalangeal (PIP) joints, and first carpometacarpal (CMC1) joints. For each joint group, the presence of OA in at least 1 joint in a joint group, the number of affected digits in each joint group, and the sum of the K-L grade across all joints were analyzed. Polyarticular OA was recorded if there were OA findings in 2 of 3 hand joint groups plus 1 or both knees. Data from 167 families with hand radiographs, 157 families with knee radiographs, and 148 families with both hand and knee radiographs were analyzed for sib-sib correlations. RESULTS After adjustment for age, sex, and body mass index, clinically relevant sib-sib common correlations were found for OA of the DIP, PIP, and CMC1 joints, for OA at 2 or 3 hand sites, and for polyarticular OA (r = 0.33-0.81) when OA was defined according to the number of affected joints or as the sum of the K-L grade across all joints. CONCLUSION These results from a cohort of volunteers drawn from a community setting and ascertained without regard to OA status demonstrate familial aggregation of OA and contribute to the evidence for heritability of OA.

Age-Adjusted Standards for Creatinine Clearance

Excerpt Glomerular filtration rate (GFR) has been shown to decline with age after maturity (1). Creatinine clearance finds frequent use as a clinical estimate of GFR, and published criteria for sev...

Vitamin D deficiency in older people.

Because of changes that occur with aging, older people with any other risk factors for vitamin D deficiency are likely to have inadequate stores of this vitamin. The consequences of vitamin D deficiency are likely to be losses in bone, strength, and function and the development of pain. Many questions remain regarding screening, prevention, and treatment of vitamin D deficiency. Supplementation may be unnecessary in most healthy, ambulatory seniors. Excessive supplementation in this group may lead to vitamin D toxicity. There does seem to be a role for supplementation in homebound older people who will not get adequate vitamin D from sunlight exposure. This population is at particular risk of developing vitamin D deficiency. Issues such as inadequate diet, physiologic changes with aging, polypharmacy, and diseases that interfere with vitamin D metabolism contribute to this risk. In such circumstances, a recommendation of 800 IU per day is reasonable. An alternative to daily dosing is a single oral dose of 100,000 IU of vitamin D (ergocalciferol or cholecalciferol) every 3 to 6 months. A simple maneuver is for geriatricians, who see many chronically ill patients with low vitamin D stores (who are likely to be seen in the office every 3 to 6 months), to administer vitamin D during the office visits. These dosing schedules have not been associated with toxicity and can be considered safe in homebound (sunlight-deprived) older adults.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliability of grading scales for individual radiographic features of osteoarthritis of the knee: The Baltimore longitudinal study of aging atlas of knee osteoarthritis

RATIONALE AND OBJECTIVES The authors present an atlas of individual radiographic features of osteoarthritis of the knee and evaluate the inter- and intra-reader reliability of trained readers using this atlas. METHODS Four trained readers graded 30 standing anterior-posterior knee radiographs for eight selected features of osteoarthritis (medial and lateral osteophytes, joint space narrowing, and sclerosis; osteophytes of the tibial spines and chondrocalcinosis) as well as the Kellgren-Lawrence global scale. Inter- and intra-reader reliability were calculated using intraclass correlation coefficients. RESULTS For all features except sclerosis and osteophytes of the tibial spines, inter-reader reliability ranged from 0.63 to 0.83, whereas intra-reader reliability ranged from 0.82 to 0.95. CONCLUSION Using this atlas, trained readers are reliable in measuring the presence and severity of individual radiographic features of osteoarthritis of the knee. This atlas should be useful in clinical and epidemiologic studies of osteoarthritis of the knee.