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Biomedical subjects

J W Rowe

Publications and source records attributed to J W Rowe.

At least 55 records · Page 3Linked to original sources
PubMed1989

Escape of hepatic glucose production during hyperglycemic clamp.

The role of the pattern of insulin secretion on hepatic glucose production (HGP) was evaluated with hyperglycemic and euglycemic clamp studies in six normal young nonobese subjects. In the hyperglycemic studies, glucose levels were raised and maintained at 98 mg/dl above basal for 150 min. Each subject responded with a biphasic pattern of immunoreactive insulin (IRI) release. HGP was completely suppressed by 20 min, coincident with the first-phase insulin release. HGP then rose steadily, surpassing the basal rate by 100 min when IRI had reached the peak levels of the first phase. By 130 min, when IRI had surpassed the peak first-phase levels, HGP began to fall. In the euglycemic studies with a square wave of hyperinsulinemia (approximately 25 microU/ml), HGP was suppressed to approximately 60% of basal and remained at that rate. We next repeated the hyperglycemic studies with somatostatin, glucagon, and insulin infusions. In these studies with a square wave of hyperinsulinemia (approximately 40 microU/ml, the level observed during the first phase IRI of the previous hyperglycemic clamps), HGP was suppressed to approximately 43% of basal rate and remained at that rate. These studies indicate insulin regulation of HGP is not only dependent on insulin level but may be strongly influenced by the pattern, over time, of insulin secretion.

Adult↗
PubMed1989

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.

Adult↗
PubMed1989

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)

Adult↗
PubMed1988

Insulin-mediated hypokalemia and paralysis in familial hypokalemic periodic paralysis.

To elucidate a potential role for insulin-mediated extra-renal potassium disposal in the clinical syndrome of hypokalemic periodic paralysis, an obese affected man was studied using the euglycemic insulin clamp, which, in normal and obese subjects, produces predictable, insulin dose-dependent declines in plasma potassium levels. During a 20 mU/m2/minute euglycemic clamp (insulin level, 88 microU/ml) procedure, while the patient with hypokalemic periodic paralysis demonstrated severe resistance to insulin-mediated glucose uptake (glucose uptake 50 percent of that of normal control subjects, n = 17), his plasma potassium declined to a degree similar to that seen in normal subjects. During a subsequent higher dose, 200 mU/m2/minute insulin infusion (insulin level, 914 microU/ml), plasma potassium declined to 2.5 meq/liter, a value significantly below that seen in normal (n = 19) (3.3 +/- 0.1 meq/liter) and obese (n = 6) (3.2 +/- 0.1 meq/liter) subjects. During this study, paralysis began in the patient's hand and forearm at the potassium nadir and lasted three hours, despite restoration of normokalemia 30 minutes after paralysis began. Glucose disposal rates during this high-dose insulin infusion were one-half that seen in lean control subjects (n = 19) and similar to those in obese control subjects. If these findings are representative of hypokalemic periodic paralysis and can be generalized to larger numbers of patients, they indicate several new features of this syndrome. The ability of insulin to induce hypokalemia is enhanced in this syndrome even in the presence of marked coexistent obesity-related resistance to the action of insulin to promote glucose utilization. Enhanced sensitivity of potassium uptake systems to activation by insulin (and other factors) may be a central feature of this syndrome. Additionally, paralytic hypokalemia can be induced during a euglycemic insulin clamp procedure, which could be utilized as a diagnostic test for this syndrome.

Adult↗
PubMed1988

Somatostatin infusion enhances hepatic glucose production during hyperglucagonemia.

Somatostatin (SRIH) is widely employed in metabolic studies to permit quantitation of glucose production and disposal rates while the endocrine pancreas is suppressed and the hormonal milieu is under the investigator's control. In these studies it is assumed that if peripheral levels of insulin and glucagon are the same during SRIH infusion as during control studies, the effects of these hormones on glucose metabolism are equivalent. If the effect of glucagon is influenced by SRIH infusion, then these techniques may be unsuitable for the study of the regulation of hepatic glucose output. To assess the influence of SRIH on glucagon-stimulated hepatic glucose production (Ra), we determined Ra during paired studies in ten healthy (five younger and five older) subjects. In each study an insulin infusion designed to yield physiologic systemic insulin levels of 20 to 30 microU/mL was given from 0 to 210 minutes. In addition, from 60 to 210 minutes either glucagon alone (3.5 ng/kg/min) (I + IRG) or glucagon (3.5 ng/kg/min) and SRIH (250 micrograms/h) (I + IRG + SRIH) was infused. Since results for plasma levels of insulin, C-peptide, glucagon, and Ra were similar in young and old subjects, the two age groups were combined for analysis. Basal plasma insulin, glucagon, C-peptide, glucose, and Ra were similar in each arm of the study. Insulin values were nearly identical from 60 to 210 minutes (I + IRG, 23.8 +/- 1.1; I + IRG + SRIH, 24.0 +/- 1.0 microU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Glucose and amino acid metabolism in aging man: differential effects of insulin.

Insulin is a major regulator of glucose and body protein homeostasis, both of which demonstrate age-related changes. To clarify insulin's role in these age-related changes and to compare age-related glucose and protein homeostatic responses, insulin-mediated aspects of glucose and amino acid metabolism were simultaneously examined in healthy postabsorptive young (n = 5, mean age, 25 years) and elderly (n = 5, mean age, 76 years) men. Primed constant infusions of L-[1-13C]leucine and L-[15N]alanine were administered during a basal period (0 to 180 minutes) and during four separate single rate euglycemic insulin infusions (180 to 360 minutes). Steady state insulin concentrations were 16 +/- 1, 29 +/- 3, 75 +/- 5, and 2407 +/- 56 microU/mL in the young and 23 +/- 4, 37 +/- 8, 96 +/- 11 and 3,357 +/- 249 microU/mL in the elderly at the different insulin infusion rates of 6, 10, 30, and 400 mU mU.m-2.min-1, respectively. For the 6 and 10 mU insulin infusion rates, a primed, constant infusion of [6,6 - 2H2]glucose permitted quantitation of hepatic glucose production. Glucose disposal rates adjusted for lean body mass (LBM) were lower in the elderly than in the young at the 6, 10, and 30 mU insulin infusion rates and similar in the two age groups in the 400 mU studies. Insulin dose-dependent reductions occurred in eight of ten plasma amino acids and were not influenced by age. There was an insulin dose-dependent reduction in plasma leucine flux which was similar in both age groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.

Aging in men and rodents is associated with a marked decline in glucose stimulated insulin secretion by pancreatic beta cells (B cells). Secreted insulin is the end result of a series of steps along the biosynthetic protein-secretion pathway, including insulin gene transcription, processing of transcripts to preproinsulin mRNA, translation of mRNA, segregation and processing of newly made proinsulin in secretory vesicles, proinsulin to insulin conversion, transport of vesicles to the plasma membrane, and exocytosis. We have examined the influence of age at three stages along this pathway: preproinsulin mRNA levels, proinsulin synthesis, and secretion of newly made and preformed insulin, using Fischer rats, a widely studied rodent model of aging. Pancreatic weights and total insulin contents, islet sizes, and mean insulin content per islet were the same in young adult (4-5 mo) and senescent (21-22 mo) animals. There was no effect of age on preproinsulin mRNA levels in whole pancreata of fed animals, or in isolated islets cultured for 16 h in 5.5 mM glucose. Proinsulin biosynthesis and the secretion of newly made insulin were compared in isolated islets preincubated in 5.5 mM glucose. After a pulse label at 16.7 mM glucose, proinsulin synthesis, assayed by immunoprecipitation, was decreased 16% in 7 mo islets and 39% in 21-22 mo islets, compared with 4-5 mo islets, though total protein synthesis was not reduced. When chased at 2.8 mM glucose, 4-5 month and 21-22 mo islets showed no difference in release of preformed or newly made insulin. When chased at 16.7 mM glucose, there was a significant decrease in the secretion of newly made insulin in the old islets compared with the young islets. There was preferential release of newly made insulin over preformed insulin in both young and old islets. However, since secretion of preformed insulin was decreased much more than secretion of newly made insulin in senescent islets, these displayed a two- to threefold increase in the proportion of newly made insulin relative to total immunoreactive insulin released compared with young adult islets. The differential effects of aging on these steps in the insulin synthesis-secretion pathway may be due to varying impairments in signals transducing the glucose stimulus into the wide range of B cell responses to glucose.

Aging↗
PubMed1988

Age-related impairment in the short term regulation of insulin biosynthesis by glucose in rat pancreatic islets.

The pancreatic beta-cell is differentiated to express the insulin biosynthetic secretory pathway and to regulate this pathway principally by sensing the extracellular glucose concentration. With aging, glucose stimulation of both insulin synthesis and secretion is significantly impaired. The mechanism of the 40-50% decrease in the short term stimulation of insulin synthesis by glucose in rat pancreatic islets was studied in an effort to elucidate the specific stage at which the impairment occurs. In isolated islets from both young (4- to 5-month-old) and old (18- to 28-month-old) rats at normal (5.5 mM) and elevated (11 mM) glucose concentrations, insulin I was the predominant mature insulin species that accumulated during a 4-h labeling period. After preincubation of islets for 16 h in Minimum Essential Medium (with 5.5 mM glucose), total preproinsulin mRNA levels were similar in old and young islets; after preincubation in an enriched medium, RPMI-1640 (with 11 mM glucose), old and young levels were still similar, although preproinsulin mRNA levels were 6-fold higher. Proinsulin synthesis during a 30-min pulse label period was stimulated 10-fold in young islets and 7-fold in old islets at 16.7 mM glucose compared with synthesis at 2.8 mM glucose and was not affected by 5 micrograms/ml actinomycin-D. Furthermore, stimulation of the two major known intracellular second messenger systems in beta-cells, the cAMP system and the protein kinase-C system, with 8-bromo-cAMP, 3-isobutyl-1-methylxanthine, or a phorbol ester did not further increase proinsulin synthesis over a 30-min pulse label period in islets already stimulated by 16.7 mM glucose. Thus, the impairments in the short term effects of glucose on proinsulin synthesis in old islets are posttranscription of preproinsulin mRNA and likely to lie at the level of enhancement of translation of preexisting preproinsulin mRNA by factors activated or inhibited by the ambient glucose concentration. These age-impaired factors are not modulated through the cAMP or protein kinase-C system.

1-Methyl-3-isobutylxanthine↗
PubMed1988

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.

Age Factors↗
PubMed1987

Clinical consequences of age-related impairments in vascular compliance.

Advancing age is associated with progressive reductions in the vascular distensibility of major vessels. Two clinically relevant consequences of physiologically impaired arterial compliance of aging, increased systolic blood pressure and decreased carotid arterial baroreflex sensitivity, are discussed. While arterial thickening and stiffening with age are associated with increased systolic blood pressure, diastolic blood pressure is generally stable or even decreases slightly with advancing age. Thus, the prevalence of isolated systolic hypertension increases dramatically with age. This long-neglected abnormality has recently attracted attention, and the view that systolic hypertension is harmless and its treatment fraught with a high incidence of serious adverse effects has now been shown to be myth. Several studies indicate substantial risk associated with isolated systolic hypertension, especially with regard to increasing prevalence of stroke. A recent multicenter trial has shown that systolic blood pressure can be safely lowered with low doses of thiazide diuretics. Currently, a National Institutes of Health sponsored multicenter trial aims to determine whether treatment of isolated systolic hypertension is associated with reduced risk. Age-related impairments in baroreflex sensitivity reduce the capacity of normal elderly persons to increase the heart rate in response to hypotensive stress and contribute to the increased prevalence with advancing age of orthostatic hypotension. This must be taken into account in the design of pharmacologic treatment regimens in older persons.

Aged↗
PubMed1987

Human aging: usual and successful.

Research in aging has emphasized average age-related losses and neglected the substantial heterogeneity of older persons. The effects of the aging process itself have been exaggerated, and the modifying effects of diet, exercise, personal habits, and psychosocial factors underestimated. Within the category of normal aging, a distinction can be made between usual aging, in which extrinsic factors heighten the effects of aging alone, and successful aging, in which extrinsic factors play a neutral or positive role. Research on the risks associated with usual aging and strategies to modify them should help elucidate how a transition from usual to successful aging can be facilitated.

Aged↗
PubMed1987

Identification of a protease inhibitor produced by astrocytes that is structurally and functionally homologous to human protease nexin-I.

In the present studies we have compared the structural and biochemical properties of human protease nexin-I (PN-I) and a protease inhibitor present in the serum-free culture fluid of normal rat brain astrocytes. The inhibitor binds to and forms covalent complexes with human urokinase and thrombin. The inhibitor has an approximate Mr = 43,000 based on the size of the complexes (deduced from SDS-PAGE) and mediates the cellular binding and uptake of the proteases to which it links. Binding is heparin sensitive and occurs on a cell surface receptor that also binds complexes formed between proteases and a well-characterized cell-secreted protease inhibitor, human PN-I. In addition, the inhibitor co-migrates with PN-I on SDS-PAGE and cross-reacts with anti-PN-I antibody on immunoblots. A similar molecule, designated NPF, is produced by C6 glioma cells in culture and has neurite promoting activity on a neuroblastoma cell line.

Amyloid beta-Protein Precursor↗
PubMed1987

Plasma tryptophan and total neutral amino acid levels in men: influence of hyperinsulinemia and age.

Because of the well-recognized age-related changes in peripheral tissue sensitivity to insulin and the demonstrated impact of insulin on blood amino acid profiles in young individuals, we evaluated the influence of insulin level and age on the concentrations of tryptophan and its ratio to the sum of the large neutral amino acids (LNAA). The ratio of the plasma concentrations of tryptophan and the LNAA (leucine, isoleucine, valine, tyrosine, and phenylalanine), may be an important determinant of the rate at which tissues synthesize neurotransmitters, such as catecholamines and serotonin. Each of five healthy young (21 to 34 yr) and five healthy old subjects (67 to 85 yr) received, on separate occasions, euglycemic insulin infusions at rates of 6, 10, 30, and 400 mU X m-2 X min-1. Basal plasma tryptophan concentrations and LNAA levels were similar in young and old. Both tryptophan and LNAA levels decreased in an insulin dose-dependent manner (P less than .02). The dose-response effect of insulin on tryptophan levels in the elderly was less than in the young (P less than .03), while the response of the LNAA was similar in both age groups. The ratio of tryptophan to LNAA was less in the old when compared to the young (P less than .03) but increased in the two age groups in an insulin-dose-dependent fashion (P less than .02). Maximal plasma tryptophan decrements were 39% and 32%, and maximal LNAA declines were 58% and 61% in young and old, respectively, during the 400 mU X m-2 X min-1 studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Insulin action in aging man: evidence for tissue-specific differences at low physiologic insulin levels.

This study examined the effect of age on insulin action in several tissues. Euglycemic insulin clamp studies were performed on healthy young (n = 7, 20 to 35 years, 10 and 20 mU/m2 X min insulin infusions) and old (n = 7, 66 to 80 years, 8 and 16 mU/m2 X min insulin infusions) adults. Insulin values were similar during both the lower (young, 24 +/- 1.6, old, 24 +/- 2.1 microU/ml) and higher (young, 40 +/- 3.3; old, 39 +/- 3.8 microU/ml) insulin infusion rates. Although suppression of hepatic glucose output (HGO) was more rapid (p less than .05) in the elderly group at each dose, HGO was eventually suppressed to similar levels in both age groups (low dose: young, 34.4 +/- 10.8, old, 25.3 +/- 1.8 mg/m2 X min; higher dose: young, 22.8 +/- 10.2, old, 6.2 +/- 2.1 mg/m2 X min). Glucose disposal was less (p less than .01) in the aged group at both insulin infusion rates. Suppression of C-peptide was slower in the elderly participants (p less than .05) in the low dose study. Suppression of free fatty acid and glucagon levels was the same in each age group. We concluded that the insulin resistance of aging is not generalized to all tissues.

Adult↗