Biomedical subjects

J N Clore

Publications and source records attributed to J N Clore.

At least 37 records · Page 2Linked to original sources

PubMed1992

Evidence for increased liver glycogen in patients with noninsulin-dependent diabetes mellitus after a 3-day fast.

In order to assess hepatic glycogen stores in patients with noninsulin dependent diabetes mellitus (NIDDM) after a 3-day fast, the incremental glucose response to 1.0 mg iv glucagon (glucose area under the curve, glucoseAUC) was assessed in 19 obese diabetic subjects after an overnight (14 h) fast and again after a 3-day (64 h) fast. Results were compared to those of lean (n = 6) and obese (n = 15) nondiabetic subjects. During the fast, plasma glucose fell significantly in the lean (4.9 +/- 0.2 to 3.9 +/- 0.2 mmol/L), obese (5.1 +/- 0.1 to 4.2 +/- 0.2 mmol/L), and diabetic (14.7 +/- 0.7 to 10.3 +/- 1.0 mmol/L) subjects. However, in contrast to the fall in glucoseAUC observed in the lean (92.4 +/- 15.4 to 39.9 +/- 8.1 mmol min-1 L-1, P less than 0.02) and obese (64.4 +/- 11.1 to 48.4 +/- 9.4 mmol min-1 L-1) subjects, the glucoseAUC increased in diabetic subjects from 81.6 +/- 8.6 to 103.9 +/- 8.8 mmol min-1 L-1 during the fast, and was significantly greater than that of either the lean (P less than 0.001) or obese (P less than 0.001) nondiabetic subjects after the 64-h fast. Evidence that the glucose response to glucagon after a 64-h fast represents glycogenolysis and not gluconeogenesis was provided by studies in 10 additional subjects (5 obese nondiabetic subjects and 5 patients with NIDDM). Overall hepatic glucose output calculated from glucose kinetic data [( 3-3H]glucose) increased in diabetic and nondiabetic subjects during the first 30 min after glucagon administration and fell progressively thereafter. However, no increase in alanine gluconeogenesis (14C-alanine incorporation into glucose) was observed after glucagon administration in either subject group. The paradoxical accumulation of glycogen in the patients with NIDDM during the fast occurred despite basal rates of hepatic glucose output on the third day of the fast which were greater than those of obese nondiabetic subjects (9.0 +/- 1.2 vs. 5.6 +/- 0.5 mumol kg-1 min-1, P less than 0.05). A glycogen sparing action of increased gluconeogenesis is proposed as the explanation for the preservation of liver glycogen in patients with NIDDM.

Adult↗

PubMed1991

Metabolism and actions of dehydroepiandrosterone in humans.

Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHA) and DHA-sulfate are abundantly produced adrenal steroids, whose serum concentrations exceed those of other adrenal steroids. Serum concentrations of DHA and DHA-sulfate, in contrast to other adrenal steroids, exhibit a progressive age-related decline. The mechanism(s) for this selective decline in serum DHA and DHA-sulfate levels and the biologic function of these steroids remain unknown. Studies examining insulin's regulation of adrenal androgens are reviewed. These studies show that experimentally-induced hyperinsulinemia lowers serum DHA and DHA-sulfate levels, and suggest that insulin reduces serum concentrations of these steroids by inhibiting production rather than by increasing clearance. Studies examining the actions of short-term pharmacologic DHA administration to young nonobese and obese men are also reviewed. These studies suggest that DHA may possess hypolipidemic and, possibly, anti-obesity properties. They have failed, however, to demonstrate any effect of DHA on tissue insulin sensitivity.

Apolipoproteins B↗

PubMed1991

In vivo evidence for hepatic autoregulation during FFA-stimulated gluconeogenesis in normal humans.

To examine the effect of increased gluconeogenesis [by increasing free fatty acids (FFA)] on hepatic glucose output (HGO) and on the first substrate (glucose) cycle, a primed continuous infusion of [2-3H]- and [6-14C]glucose was infused to isotopic steady state in 12 normal male volunteers after an overnight fast. Blood samples for the determination of glucose specific activity were obtained before and after an infusion of saline (n = 6) or 10% Intralipid and heparin (90 mU.kg-1.min-1, n = 6). Plasma FFA (593.3 +/- 74.5 to 971.1 +/- 127.1 mumol/l, P = 0.007) and glycerol (68.0 +/- 5.9 vs. 222.4 +/- 32.0 mumol/l, P = 0.002) increased during the lipid infusion, and beta-hydroxybutyrate levels rose from 0.24 +/- 0.12 to 0.50 +/- 0.17 mmol/l (P = 0.01). No change in plasma glucose, insulin, or glucagon levels was observed during the study, and levels of the gluconeogenic substrates alanine and lactate were also unchanged. Baseline rates of glucose cycling (rate of appearance of [2-3H]glucose minus rate of appearance of [6-14C]glucose) were similar in the two groups [1.44 +/- 0.33 vs. 1.33 +/- 0.44 mumol.kg-1.min-1, not significant (NS)] and did not change during either saline or lipid infusion, respectively. However, Cori cycle activity (the conversion of [6-14C]- to [1-14C]glucose) increased significantly from 0.59 +/- 0.19 to 1.28 +/- 0.19 mumol.kg-1.min-1 (P = 0.002) after FFA and glycerol levels had been increased, in marked contrast to the saline control (0.51 +/- 0.18 to 0.39 +/- 0.18 mumol.kg-1.min-1, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome.

To determine whether hyperinsulinemia can directly reduce serum sex hormone-binding globulin (SHBG) levels in obese women with the polycystic ovary syndrome, six obese women with this disorder were studied. Before study, ovarian steroid production was suppressed in each woman by the administration of 7.5 mg of a long-acting GnRH agonist, leuprolide depot, im, on days -56, -28, and 0. This resulted in substantial reductions in serum concentrations of testosterone (from 1.72 +/- 0.29 nmol/L on day -56 to 0.32 +/- 0.09 nmol/L on day 0), non-SHBG-bound testosterone (from 104 +/- 16 pmol/L on day -56 to 19 +/- 5 pmol/L on day 0), androstenedione (from 7.25 +/- 1.65 nmol/L on day -56 to 2.78 +/- 0.94 nmol/L on day 0), estrone (from 371 +/- 71 pmol/L on day -56 to 156 +/- 29 pmol/L on day 0), estradiol (from 235 +/- 26 pmol/L on day -56 to 90 +/- 24 pmol/L on day 0), and progesterone (from 0.28 +/- 0.12 nmol/L on day -56 to 0.08 +/- 0.02 nmol/L on day 0). Serum SHBG levels, however, did not change (18.8 +/- 2.8 nmol/L on day -56 vs. 17.8 +/- 2.6 nmol/L on day 0). While continuing leuprolide treatment, the women were administered oral diazoxide (300 mg/day) for 10 days to suppress serum insulin levels. Diazoxide treatment resulted in suppressed insulin release during a 100-g oral glucose tolerance test (insulin area under the curve, 262 +/- 55 nmol/min.L on day 0 vs. 102 +/- 33 nmol/min.L on day 10; P less than 0.05) and deterioration of glucose tolerance. Serum testosterone, androstenedione, estrone, estradiol, and progesterone levels did not change during combined diazoxide and leuprolide treatment. In contrast, serum SHBG levels rose by 32% from 17.8 +/- 2.6 nmol/L on day 0 to 23.5 +/- 2.0 nmol/L on day 10 (P less than 0.003). Due primarily to the rise in serum SHBG levels, serum non-SHBG-bound testosterone levels fell by 43% from 19 +/- 5 pmol/L on day 0 to 11 +/- 4 pmol/L on day 10 (P = 0.05). These observations suggest that hyperinsulinemia directly reduces serum SHBG levels in obese women with the polycystic ovary syndrome independently of any effect on serum sex steroids.

Adult↗

PubMed1991

Evidence that high dose cortisol-induced Na+ retention in man is not mediated by the mineralocorticoid receptor.

We have previously shown that high dose cortisol (F; 240 mg/day)-induced Na+ retention and systolic blood pressure (BP) increases are not inhibited by the glucocorticoid (type II) receptor antagonist RU486. Adequacy of type II receptor blockade with RU486 was clearly demonstrated, indicating that the Na+ retention was not mediated through the glucocorticoid receptor. Spironolactone (Sp: 400 mg/day), in a preliminary assessment, also did not inhibit F-induced Na+ retention. The purpose of this study was to determine whether the Na+ retention produced by F administration is mediated by the type I receptor by comparing the effects of F to a potent type I agonist [9 alpha-fludrohydrocortisone (9 alpha FF)] with and without Sp administration. The effects of the two agonists and Sp on urinary K excretion and BP were also compared. Normal male volunteers, on a constant daily diet for 10 days, received either F (240 mg/day) or 9 alpha FF (3.0 mg/day) with or without Sp (400 mg/day) for the last 5 days. The mean cumulative reductions in Na+ excretion during the 5 days compared to baseline values before hormone administration were 255 +/- 38 and 494 +/- 81 mmol/5 days for F (n = 9) and 9 alpha FF (n = 5), respectively (P = 0.01). Sp (n = 5) completely inhibited 9 alpha FF-induced Na+ retention (494 +/- 81 vs. -37 +/- 130 mmol/5 days; P less than 0.01), but had no effect (n = 5) on F-induced Na+ retention (255 +/- 38 vs. 193 +/- 50 mmol/5 days; P = NS). After the expected first day kaliuresis, the effects of both steroids on net cumulative urinary K+ excretion were minimal. Systolic BP was increased by F, but not 9 alpha FF, and Sp did not inhibit this increase. A 2-fold greater Sp-inhibitable Na(+)-retaining effect of the mineralocorticoid demonstrates that the failure of Sp to block F-induced Na+ retention is not due to inadequate type I receptor blockade. Based on these findings and earlier studies, we conclude that high dose (stress level) F-induced Na+ retention and systolic BP increase are not mediated by either the mineralo- or glucocorticoid receptor in normal man.

Adult↗

PubMed1991

Evidence for dual control mechanism regulating hepatic glucose output in nondiabetic men.

We previously reported a fall in hepatic glucose output (HGO) during sleep accompanied by reductions in glucose utilization (Rd) and free fatty acids (FFAs). This study was undertaken to determine the potential role of changes in Rd and FFA on HGO in nondiabetic men. To determine if the fall in HGO during sleep could be reversed by FFA elevation, seven nondiabetic men underwent [3-3H]glucose infusions from 2200 to 0800, with heparin (90 mU.kg-1.min-1) added at 0200. Glucose appearance (Ra) fell from 11.7 +/- 1.1 at 2430 to 8.9 +/- 0.8 mumol.kg-1.min-1 (P less than 0.05) at 0200. The fall in Ra was associated with decreases in FFA (0.57 +/- 0.10 to 0.48 +/- 0.07 mM) and glycerol (0.08 +/- 0.01 to 0.06 +/- 0.01 mM). Infusion of heparin significantly increased FFA and glycerol (1.09 +/- 0.21 and 0.11 +/- 0.01 mM, respectively, P less than 0.01) and resulted in a significant fall in plasma alanine, suggesting that gluconeogenesis had been increased. However, rates of glucose turnover were indistinguishable from overnight studies without heparin. In additional studies (n = 6), intralipid and heparin-induced FFA elevation (from 0.61 +/- 0.07 to 0.95 +/- 0.05 mM, P less than 0.01) stimulated gluconeogenesis ([U-14C]alanine to glucose) twofold (188 +/- 22% increase compared to 114 +/- 6% in saline control studies, P less than 0.01). However, despite increasing gluconeogenesis, overall HGO did not change (10.6 +/- 0.5 vs. 10.7 +/- 0.6 mumol.kg-1.min-1) during lipid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

PubMed1990

Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women.

Suppression of serum insulin levels with diazoxide is associated with a decrease in serum testosterone and an increase in serum sex hormone-binding globulin in obese women with the polycystic ovary syndrome. To determine whether physiologic insulin levels play a regulatory role in the androgen status of nonobese women with normal menses, the androgen status of five nonobese normal women was assessed on two occasions: during a control study and after 10 days of oral diazoxide (100 mg, three times daily) administration. Insulin release in response to 100 gm oral glucose administration decreased from 108.0 +/- 28.2 to 49.3 +/- 5.2 nmol.min/L (p = 0.05) after diazoxide administration. However, despite suppression of insulin release, diazoxide administration did not affect serum total testosterone (diazoxide, 0.73 +/- 0.10; control, 0.69 +/- 0.11 nmol/L; p = NS) or sex hormone-binding globulin (diazoxide, 79.7 +/- 16.6; control, 70.2 +/- 12.6 nmol/L; p = NS) concentrations. These observations suggest that physiologic insulin levels in nonobese healthy women do not regulate testosterone metabolism and that diazoxide does not exert a direct or independent effect on serum testosterone or sex hormone-binding globulin levels.

Administration, Oral↗

PubMed1990

A stimulatory effect of FFA on glycolysis unmasked in cells with impaired oxidative capacity.

The physiological importance of the glucose fatty acid cycle has been controversial. Many studies have failed to demonstrate an inhibitory effect of free fatty acids (FFA) on glucose utilization. Using both hepatoma cells (Hep G2) and human erythrocytes, which have poor oxidative capacity and metabolize glucose primarily anaerobically, we have demonstrated a unique stimulatory effect of FFA on glycolysis. Fructose 2,6-bisphosphate (F-2,6-P2) concentrations also increased significantly in Hep G2 cells incubated with palmitic acid. In contrast, F-2,6-P2 concentrations fell in primary cultured hepatocytes incubated with palmitic acid in association with increased oxidation of FFA and accumulation of beta-hydroxybutyrate. We propose that a stimulatory effect of FFA on glycolysis reported here for the first time may have been masked in previous studies performed in tissues in which the oxidation of FFA and the accumulation of intermediates such as citrate may have decreased F-2,6-P2 concentrations. We conclude that the spectrum of FFA effects in glycolysis probably depends on tissue oxidative capacity.

Animals↗

PubMed1990

Impaired modulation of hepatic glucose output overnight after a 72-h fast in normal man.

We have previously reported a 25% fall in glucose utilization (Rd) and glucose production (Ra) in normal volunteers during an overnight fast, when glycogenolysis accounts for approximately 70% of hepatic glucose output (HGO). This reduction in Ra and Rd was positively correlated with reductions in glycerol and FFA. To determine if a similar fall in HGO occurs after a prolonged fast when HGO depends solely upon gluconeogenesis, seven normal male volunteers were fasted for 72 h. Glucose kinetics were then assessed overnight using a [3-3H]glucose infusion from 2200-0800 h. Plasma glucose (3.6 +/- 0.1 mM), immunoreactive insulin (2.7 +/- 0.4 mU/L), C-peptide (0.22 +/- 0.03 nmol/l), Rd (1.30 +/- 0.03 mg/kg.min), and Ra (1.28 +/- 0.03 mg/kg.min) were suppressed, and plasma glucagon (98.8 +/- 13.2 pmol/L) was elevated compared to values obtained during the overnight fast, but none of these parameters changed overnight after the 3-day fast. Plasma lactate (0.98 +/- 0.09 mmol/L) and alanine (0.18 +/- 0.03 mmol/L) levels were also unchanged throughout the night. Plasma glycerol (0.14 +/- 0.03 mmol/L) and FFA (0.98 +/- 0.07 mmol/L) were significantly elevated compared to values during the overnight fast, but failed to fall during the study as had been observed during a 14-h fast. We conclude that the modulation of HGO observed during an overnight fast does not occur during prolonged fasting. The lack of nocturnal modulation of HGO when plasma FFA and glycerol levels are fixed at elevated concentrations supports a role of FFA and/or glycerol in the modulation of HGO during an overnight fast.

Adult↗

PubMed1990

Increased transcapillary escape rate of albumin in nondiabetic men in response to hyperinsulinemia.

Diabetic patients manifest increased vascular permeability. To determine whether insulin per se might increase vascular permeability, five nondiabetic men were studied by the hyperinsulinemic-euglycemic clamp technique. Each subject received a 0.72-nmol/kg body wt i.v. insulin bolus, followed by a 72-pmol.kg-1.min-1 insulin infusion for 4 h. Euglycemia was maintained by the Biostator glucose controller. At 7 h of study, 10 microCi i.v. 125I-labeled albumin was injected as bolus dose. Frequent blood samples were drawn during the next 70 min for determination of the transcapillary escape rate (TER) of albumin. Subjects returned 1-2 wk later for a control study, during which 0.45% saline was infused at a rate identical to the dextrose and insulin infusion rates during the hyperinsulinemic clamp. The mean +/- SE serum insulin levels during the hyperinsulinemic clamp and saline infusion were 9786 +/- 126 and 46 +/- 4 pM, respectively, whereas serum glucose during the two sessions was similar (5.0 +/- 0.2 vs. 4.8 +/- 0.1 mM, NS). Identical fluid volumes were infused during the two sessions (1767 +/- 197 ml/7 h), and urine outputs did not differ significantly (1615 +/- 309 vs. 1035 +/- 248 ml/7 h). The TER of albumin was greater in all five men after hyperinsulinemia than after saline infusion (18.3 +/- 2.7 vs. -2.8 +/- 2.3%/h, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Lack of effect of dehydroepiandrosterone in obese men.

To assess the effects of dehydroepiandrosterone (DHEA) on weight and body fat mass in young obese men, six obese (body mass index, 31.5 +/- 2.9 (s.e.] men were studied at baseline, after 28 days of placebo administration, and again after 28 days of DHEA (1600 mg/day) administration. Body fat mass was assessed on each occasion by three separate methods: hydrostatic weighing, impedance plethysmography, and skinfold measurements at four body sites. Waist-to-hip ratios were recorded. In addition, tissue sensitivity to insulin was determined using the modified minimal model technique, and serum lipids were assayed. Serum DHEA-sulfate levels rose from 7.4 +/- 1.7 mumol/l at baseline to 39.8 +/- 11.9 mumol/l after DHEA administration (P less than 0.05). Although body fat mass was reduced in two of the six men following DHEA administration, for the group as a whole neither total body weight, body fat mass, or waist-to-hip ratio changed significantly during the study. No change in either tissue insulin sensitivity or serum lipids was observed. These observations suggest that, at a daily dose of 13.4-19.7 mg/kg, short-term DHEA administration does not affect the total weight, body fat mass, fat distribution, insulin sensitivity, or lipid status of obese young men.

Adipose Tissue↗

PubMed1989

The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome.

Insulin resistance and hyperinsulinemia appear to be almost universal features of the polycystic ovary syndrome. We propose that obesity permits full phenotypic expression of the polycystic ovary syndrome in women predisposed to develop this condition by generating an insulin-resistant, and consequently hyperinsulinemic, state. The resultant hyperinsulinemia may produce hyperandrogenism by affecting multiple facets of androgen metabolism.

Androgens↗

PubMed1989

Accelerated decline in hepatic glucose production during fasting in normal women compared with men.

Plasma glucose values have been reported to be lower in women than in men after a 72-hour fast. However, a comparison of glucose kinetics in fasting men and women has not been described. Therefore, five normal men and five normal women underwent sequential 3-3H-glucose infusions after both a 14- and a 64-hour fast. Plasma glucose levels fell similarly during the fast in men (5.23 +/- 0.03 v 3.96 +/- 0.14 mmol/L, P less than .01) and women (4.84 +/- 0.14 v 3.65 +/- 0.25 mmol/L, P less than .01). The fall in plasma glucose was associated with a significantly greater fall in glucose appearance (Ra) in women compared with men (P less than .05). Ra fell 15.8% +/- 3.0% in men (2.11 +/- 0.24 to 1.79 +/- 0.24 mg.kg-1.min-1, P less than .01) and 24.6% +/- 1.4% in women (2.22 +/- 0.17 to 1.67 +/- 0.12 mg.kg-1.min-1, P less than .001). During the fast, plasma glycerol, free fatty acids (FFA), and beta-hydroxybutyrate levels rose significantly and plasma alanine fell significantly in both sexes. Plasma glycerol levels were significantly higher in women compared with men after fasting (0.16 +/- 0.01 v 0.11 +/- 0.02 mmol/L, P less than .05). In addition, the transition from ambulation to bed rest demonstrated unexpected sex-related differences in glucose homeostasis after the 64-hour fast. During the two-hour equilibration period required for glucose kinetic studies (subjects reclining), significant decrements in glucose, FFA, and lactate were observed in the 64-hour fasted women but not in the men.(ABSTRACT TRUNCATED AT 250 WORDS)

Bed Rest↗

PubMed1989

Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome.

To test the hypothesis that insulin plays a role in the hyperandrogenism of obese women with polycystic ovary syndrome, we conducted a prospective study in which the androgen status of five obese women with polycystic ovary syndrome was assessed on two occasions: before and after 10 days of oral diazoxide (100 mg, three times daily) administration. Fasting serum insulin levels decreased from 177 +/- 45 (+/- SE) to 123 +/- 43 pmol/L (P less than 0.01) and insulin release in response to 100 g oral glucose administration decreased from 223.0 +/- 29.2 to 55.6 +/- 7.9 nmol.min/L (P less than 0.002) after diazoxide administration. At the same time, serum total testosterone fell from 2.5 +/- 0.4 to 2.1 +/- 0.3 nmol/L (P less than 0.007), serum testosterone not bound to sex hormone-binding globulin fell from 1.9 +/- 0.3 to 1.4 +/- 0.2 nmol/L (P less than 0.01), and the molar ratio of serum androstenedione to serum estrone fell from 25.7 +/- 7.7 to 16.6 +/- 5.5 (P less than 0.04). Serum sex hormone-binding globulin levels increased slightly but not significantly from 13.2 +/- 1.0 to 21.7 +/- 4.1 nmol/L. Serum androstenedione, dehydroepiandrosterone sulfate, estradiol, estrone, and progesterone concentrations did not change, nor did basal or GnRH-stimulated serum LH and FSH concentrations. These results suggest that hyperinsulinemia in obese women with polycystic ovary syndrome may directly increase serum testosterone levels.

Blood Glucose↗

PubMed1989

Suppression of serum dehydroepiandrosterone sulfate levels by insulin: an evaluation of possible mechanisms.

We previously demonstrated a progressive decline in serum dehydroepiandrosterone sulfate (DHEA-S) levels in women during a hyperinsulinemic-euglycemic clamp. To determine whether this fall in serum DHEA-S levels might have been due to insulin-stimulated 1) hydrolysis of DHEA-S to dehydroepiandrosterone (DHEA), 2) conversion of DHEA-S/DHEA to androstenedione, and/or 3) urinary excretion of these steroids, 10 additional men were studied by the hyperinsulinemic-euglycemic clamp technique. Each man received a 0.1 U/kg (0.72 nmol/kg) insulin bolus dose, followed by a 10 mU/kg.min (72 pmol/kg.min) insulin infusion for 4 h. An average insulin level of 12,390 +/- 259 (+/- SE) pmol/L (1,726.8 +/- 36 microU/mL) was achieved; serum glucose was maintained at 5.0 +/- 0.1 mmol/L (90.5 +/- 2.3 mg/dL). During the hyperinsulinemia, serum DHEA-S levels fell progressively and were significantly lower than baseline at 4 and 6 h of study (85.5 +/- 5.9% and 79.1 +/- 3.2% of baseline values, respectively; P less than 0.05). Serum DHEA levels fell concurrently and were significantly lower than baseline at 2, 4, and 6 h of study (66.2 +/- 12.3%, 61.6 +/- 11.2%, and 52.9 +/- 10.2% of baseline values, respectively; P less than 0.05). The percent fall in serum DHEA levels correlated positively with the percent fall in serum DHEA-S levels (r = 0.44; P less than 0.02). Serum androstenedione levels also fell progressively during hyperinsulinemia and were significantly lower than baseline at 2, 4, and 6 h of study (71.5 +/- 4.1%, 71.0 +/- 7.2%, and 48.1 +/- 3.3% of baseline values, respectively; P less than 0.05). No change in serum DHEA-S, DHEA, or androstenedione levels occurred in paired control studies, during which 0.45% saline was infused at rates matched exactly to the rates of the dextrose and insulin infusions during the hyperinsulinemic clamp studies. Despite decreasing serum DHEA-S and DHEA levels during hyperinsulinemia, urinary DHEA-S and DHEA glucuronide excretions were increased by 50% (P less than 0.05) and 86% (P = 0.05), respectively, compared to urinary excretion of these steroids during control studies. In contrast, urinary excretion of unconjugated DHEA was unchanged. Quantitatively, however, increased urinary excretion of conjugated DHEA during hyperinsulinemia accounted for only about 5% of the concomitant fall in serum DHEA-S concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1989

Sleep-associated fall in glucose disposal and hepatic glucose output in normal humans. Putative signaling mechanism linking peripheral and hepatic events.

Values reported for basal hepatic glucose production and glucose utilization do not reflect metabolic changes occurring during sleep. To determine the effect of sleep with its associated lowered metabolic rate and thermogenesis on glucose kinetics and gluconeogenic substrate availability, 11 normal volunteers underwent an overnight study in which [3-3H]glucose was infused. Despite decreased insulin secretion, a fall in hepatic glucose output was observed with sleep that was synchronous with a reduction in glucose utilization and lipolysis (decreased plasma glycerol and free fatty acids). When activity was increased, these parameters rose toward previously reported basal levels. Prevention of sleep in 6 additional subjects attenuated the fall in glucose utilization and production as well as the fall in glycerol and free fatty acids despite similar insulin and counterregulatory hormone profiles. We suggest that sleep-associated metabolic changes produce a peripheral signal(s) that modulates hepatic glucose production in humans.

Adult↗

PubMed1989

Morning insulin requirements. Critique of dawn and meal phenomena.

Morning insulin resistance has frequently been invoked to explain early-morning increases in both basal and breakfast-associated insulin requirements in diabetic patients. This increase in insulin requirements and plasma glucose from 0600 to 0900, when compared with midnight to 0600, has been termed the dawn phenomenon. We believe that the increased need for insulin in the morning has been misinterpreted. Data are reviewed that suggest the major perturbation overnight is a sleep-associated fall in hepatic glucose output, with a return to basal production rates on arousal in the morning. Moreover, the apparent increased insulin requirement for breakfast compared with lunch or supper (meal phenomenon) appears to be related more to lack of residual insulin effect from a preceding meal than to any putative morning insulin resistance. Thus, we found little evidence to support morning insulin resistance as a cause of either the dawn phenomenon (more appropriately designated the sleep phenomenon) or the meal phenomenon. A proper understanding of these phenomena is essential to the management of diabetic patients receiving insulin.

Blood Glucose↗

PubMed1988

Model to examine pathways of carbon flux from lactate to glucose at the first branch point in gluconeogenesis.

The first branch point in gluconeogenesis occurs at the conversion of pyruvate to oxaloacetate. To determine the amount of lactate carbon reaching glucose via the direct pyruvate carboxylase pathway versus the tricarboxylic acid cycle, adult rat hepatocytes in primary culture were incubated for 2 h with one of the following isotopic substrates: [1-14C]lactate, [U-14C]lactate, or [1,2-14C]acetate. Production of 14CO2 and [14C]glucose from each substrate was assessed. The amount of lactate carbon 2 and 3 incorporated into glucose or oxidized to CO2 was determined by subtracting values using [1-14C]lactate from those using [U-14C]lactate. After quantitation of CO2 formed from carbons 2 and 3 of lactate, the amount of these carbons incorporated into glucose via the tricarboxylic acid cycle can be determined by simple proportionality from the ratio of label incorporated into glucose or CO2 from [1,2-14C]acetate. The remaining carbons 2 and 3 of lactate incorporated into glucose are derived from the pyruvate carboxylase pathway directly. Ethanol which on oxidation provides NADH and acetate decreased lactate oxidation and enhanced the pyruvate carboxylase pathway. Glucagon increased carbon flux through both pathways but primarily through the pyruvate carboxylase pathway. In summary, a simple model is presented to examine carbon flux from lactate via the pyruvate carboxylase and tricarboxylic acid pathways during gluconeogenesis.

Animals↗