The assessment of hepatic and peripheral insulin sensitivity in hypertriglyceridemia

Peripheral insulin resistance is a common finding in hypertriglyceridemia. However, hepatic insulin sensitivity has rarely been investigated. We measured hepatic and peripheral insulin sensitivity in eight nondiabetic, nonobese hypertriglyceridemic subjects (HT) with raised triglyceride concentrations (4.3 +/- 0.6 mmol.L-1, mean +/- SEM) and eight age-, sex-, and weight-matched control subjects (C) with normal triglyceride concentrations (1.2 +/- 0.2 mmol.L-1). Insulin secretion was assessed during a 75-g oral glucose tolerance test (OGTT). Glucose turnover was determined using 3(3H) glucose in the postabsorptive state and during euglycemic glucose clamps at insulin infusion rates of 0.25 and 1.0 mU.kg-1.min-1. At identical fasting glucose concentrations (HT, 5.2 +/- 0.2; C, 5.2 +/- 0.2 mmol.L-1), the glucose responses to OGTT were similar in both groups. Fasting plasma insulin (HT, 8.3 +/- 1.2; C, 4.6 +/- 0.4 mU.L-1; P = .02), and C-peptide (HT, 1.7 +/- 0.2; C, 1.1 +/- 0.1 microgram.L-1; P = .006) concentrations were higher in hypertriglyceridemic subjects. The insulin and C-peptide responses to OGTT were greater in hypertriglyceridemic subjects (insulin, P = .005; C-peptide; P = .01). Hepatic glucose appearance in the postabsorptive state was similar (HT, 11.4 +/- 0.3; C, 10.9 +/- 0.7 mumol.kg-1.min-1; NS). At low insulin concentrations (HT, 20.7 +/- 1.4; C, 20.5 +/- 1.4 mU.L-1), hepatic glucose appearance was equally suppressed (HT, 9.6 +/- 0.9; C, 10.5 +/- 1.3 mumol.kg-1.min-1; NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans

To determine the effect of insulin and glucagon on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB), we measured simultaneously in normal subjects NEFA and KB kinetics at different NEFA levels in the presence of basal (control test) or increasing insulin concentrations with glucagopenia (somatostatin + insulin infusion, insulin test) and without glucagopenia (somatostatin + insulin + glucagon infusion, glucagon test). NEFA levels were controlled during these tests by an intravenous (IV) infusion of a triglyceride emulsion. During the control test, a moderate increase of NEFA (464 +/- 30 to 715 +/- 56 mumol/L) increased the percentage of NEFA converted into KB (13.3% +/- 1.4% to 26.4% +/- 2.1%, P less than .05), and there was a linear relationship between this percentage and NEFA levels (r = .788, P less than .01). During the insulin and glucagon tests, the progressive increase in NEFA induced by the triglyceride emulsion infusion was associated, despite the increase of insulinemia, with an increase in KB production rate (P less than .05) and in the proportion of NEFA used for ketogenesis in the presence (8.1% +/- 1.2% to 14.2% +/- 6.3%, P less than .05) and absence (15.7% +/- 2.8% to 25.2% +/- 3.99%, P less than 0.05) of glucagopenia. In both tests, this percentage was always linearly related with NEFA levels (P less than .05) and the slopes of these relationships were comparable to that observed in the control test. However, the fraction of NEFA used for ketogenesis was always higher (P less than .05) during glucagon substitution than in its absence.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin action and hepatic glucose cycling in essential hypertension.

Peripheral insulin resistance is a feature of essential hypertension, but there is little information about hepatic insulin sensitivity. To investigate peripheral and hepatic insulin sensitivity and activity of the hepatic glucose/glucose 6-phosphate (G/G6P) substrate cycle in essential hypertension, euglycemic glucose clamps were performed in eight untreated patients and eight matched controls at insulin infusion rates of 0.2 and 1.0 mU.kg-1.min-1. A simultaneous infusion of (2(3)H)- and (6(3)H)glucose, combined with a selective detritiation procedure, was used to determine glucose turnover, the difference being G/G6P cycle activity. Endogenous hepatic glucose production (EGP) determined with (6(3)H)glucose was similar in hypertensive and control groups in the postabsorptive state (11.0 +/- 0.3 v 10.9 +/- 0.3 mumol.kg-1.min-1) and with the 0.2 mU insulin infusion (4.9 +/- 0.5 v 4.0 +/- 0.8 mumol.kg-1.min-1). With the 1.0 mU insulin infusion, glucose disappearance determined with (6(3)H)glucose was lower in the hypertensive group (21.8 +/- 2.4 v 29.9 +/- 2.4 mumol.kg-1.min-1, P less than .001). G/G6P cycle activity was similar both in the postabsorptive state (2.2 +/- 0.4 v 2.7 +/- 0.4 mumol.kg-1.min-1) and during insulin infusion (0.2 mU, 2.5 +/- 0.3 v 2.9 +/- 0.4; 1.0 mU, 4.7 +/- 0.3 v 5.3 +/- 1.1 mumol.kg-1.min-1 for hypertensive and control groups, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic studies in lipoatrophic diabetes: mechanism of hyperglycemia and evidence of resistance to insulin of lipid metabolism

We determined in 5 control subjects and in one patient with total congenital lipoatrophy (LA) the effect of insulin infusion on glucose flux and some aspects of lipid metabolism. In the post-absorptive state LA had moderate hyperglycemia (9.2 versus 3.80 +/- 0.07 mmol.l-1) and hyperinsulinemia (19 vs 12 +/- 3 mU.l-1) and a massive increase in glucose production (7.51 mg.kg.-1.min-1) and disappearance (7.40 mg.kg-1.min-1) rates (control subjects: 2.29 +/- 0.14 mg.kg-1 min-1). Raising peripheral insulin levels to 28 +/- 3 mU.l-1 suppressed endogenous glucose production in the control subjects whereas in LA significant (2.01 mg.kg-1.min-1) production persisted even when peripheral insulinemia was raised to 58 mU.l-1. Insulin infusion in control subjects increased progressively glucose utilization to a final value of 15.7 +/- 0.7 mg.kg-1.min-1 (corresponding plasma insulin: 482 +/- 44 mU.l-1). Insulin infusion in LA initially lowered glucose level near to normal values and exogenous glucose was infused for an insulin infusion rate of 10 mU.kg-1.min-1; at this insulin infusion rate glucose utilization rate (6.52 mg.kg-1.min-1) was decreased relative to control subjects in spite of higher insulin levels (750 mU.l-1). NEFA, glycerol and ketone bodies (KB) levels were decreased to undetectable levels by insulin infusion in the normal subjects whereas NEFA and glycerol were decreased only in part and KB were not modified in LA. In addition glycerol and KB appearance rates determined in LA were not suppressed by insulin infusion as expected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular filtration rate is increased in man by the infusion of both D,L-3-hydroxybutyric acid and sodium D,L-3-hydroxybutyrate

A high glomerular filtration rate (GFR) is often found early in insulin-dependent diabetes mellitus (IDDM). It has been suggested that high circulating glucose, glucagon, and GH levels could play a role in this increase in GFR. On the other hand, patients with IDDM in poor metabolic control also have high circulating ketone body levels. This study was undertaken to determine whether exogenous D,L-3-hydroxybutyric acid at two infusion rates (40 and 30 mumol kg-1 min-1) for 180 min altered renal plasma flow (RPF), GFR, and the excretion rate of total protein, beta 2-microglobulin, and albumin in 11 normal (N) subjects and 11 IDDM patients in whom euglycemia was achieved and maintained using the insulin-glucose clamp technique. RPF and GFR were measured by a priming-continuous infusion of [125I]hippurate and [51Cr]EDTA, respectively. The 40 mumol kg-1 min-1 D,L-3-hydroxybutyric acid infusion increased RPF and GFR in both N and IDDM subjects. Mean RPF increased from 588 +/- 78 (+/- SD) to 706 +/- 129 mL min-1 1.73 m-2 in N and from 671 +/- 101 to 781 +/- 99 in IDDM. GFR increased from 121 +/- 11 to 151 +/- 15 ml min-1 1.73 m-2 in N and from 136 +/- 11 to 191 +/- 16 in IDDM. The filtration fraction also was significantly higher in IDDM than in N during the D,L-3-hydroxybutyric acid infusion. The 30 mumol kg-1 min-1 D,L-3-hydroxybutyric acid infusion increased RPF and GFR to a somewhat lesser extent in both groups. D,L-3-hydroxybutyric acid infusions increased the tubular reabsorption rate of ketone bodies and sodium. The increase in tubular sodium reabsorption rate was correlated significantly to that in the tubular ketone body reabsorption rate. A significant decrease in urinary pH was found during the D,L-3-hydroxybutyric acid infusion. D,L-3-Hydroxybutyrate sodium salt (30 mumol kg-1 min-1) also was infused in 5 of the 11 diabetic patients. A similar increase in GFR and RPF occurred. Both total protein and beta 2-microglobulin, but not albumin, excretion rates increased during D,L-3-hydroxybutyric acid (40 mumol kg-1 min-1) infusion in N and IDDM subjects. D,L-3-Hydroxybutyric acid infusion did not change plasma glucagon, GH, or renin activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of ketone bodies on basal and insulin-stimulated glucose utilization in man

Using the euglycemic clamp technique, we investigated the effects of high ketone body levels on basal and insulin-stimulated glucose utilization in normal subjects. Infusion of sodium acetoacetate in the postabsorptive state raised ketone body levels from 150 +/- 20 (+/- SE) mumol/liter to more than 1 mmol/liter. Endogenous glucose production declined from 2.71 +/- 0.20 mg kg-1 min-1 to 1.75 + 0.26 (P less than 0.01) and glucose utilization from 2.71 +/- 0.20 to 1.98 +/- 0.17 mg kg-1 min-1 (P less than 0.01), while blood glucose was maintained at the initial level by the infusion of glucose. There were no changes in plasma glucagon, insulin, or C-peptide. Plasma nonesterified fatty acids (P less than 0.01) and blood glycerol (P less than 0.01) and alanine (P less than 0.05) decreased, while blood lactate increased (P less than 0.01). Infusion of sodium bicarbonate had no effect on glucose kinetics. The decreases in glucose utilization and endogenous glucose production during the infusion of acetoacetate were not modified when the fall of plasma nonesterified fatty acids was prevented by iv heparin injection. During control euglycemic hyperinsulinemic clamps (1 and 10 mU kg-1 min-1 insulin infusion), endogenous glucose production was suppressed at the lowest insulin infusion rate; glucose utilization increased first to 7.32 +/- 0.96 mg kg-1 min-1 and then to 16.5 +/- 1.27 mg kg-1 min-1. During euglycemic hyperinsulinemic clamps with simultaneous sodium acetoacetate infusion, similar insulin levels were attained; endogenous glucose production was also suppressed at the lowest insulin infusion rate, and insulin-stimulated glucose utilization rates (7.93 +/- 1.70 and 15.80 +/- 1.30 mg kg-1 min-1) were not modified. In conclusion, acetoacetate infusion decreased basal, but not insulin-stimulated, glucose utilization. The increase in lactate during acetoacetate infusion in the postabsorptive state suggests that ketone body acted by decreasing pyruvate oxidation.     

Interactions of glucagon and free fatty acids with insulin in control of glucose metabolism

To study the interactions of physiological glucagon and free fatty acids (FFA) concentrations with insulin in the control of glucose metabolism, we determined in normal subjects the response of endogenous glucose production (EGP) and glucose utilization (Rd) to a progressive and moderate increase of insulinemia in the presence of glucagon and FFA levels either decreased (somatostatin [SRIF] and insulin infusion, C test) or maintained to normal postabsorptive values isolated (SRIF + insulin + glucagon infusion, G test; SRIF + insulin + Intralipid infusion, IL test) or in association (SRIF + insulin + glucagon + Intralipid infusion, IL + G test). Compared with the C test, maintenance of glucagon level had only small and inconsistent effects on glucose Rd, but induced a shift to the right of the dose-response curve to insulin of EGP (apparent ED50: C test, 10.9 mU.L-1; G test, 15.2 mU.L-1). Intralipid infusion resulted, whether glucagon was substituted or not, in a near total suppression of the insulin-induced increase of glucose Rd (Rd at the end of the tests: C test, 6.13 +/- 0.85 mg.kg-1.min-1; G test, 7.29 +/- 0.87 mg.kg-1.min-1; IL test, 3.30 +/- 0.65 mg.kg-1.min-1; IL + G test, 3.57 +/- 0.42 mg.kg-1.min-1). In the absence of glucagon, substitution Intralipid infusion also antagonized the action of insulin on EGP. However, this effect was no longer apparent when glucagon was replaced (dose-response curve to insulin of EGP during the G and the IL + G test were comparable).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of epinephrine on glucose-mediated and insulin-mediated glucose disposal in insulin-dependent diabetes.

The aim of this study was to determine the relative roles of changes in glucose-mediated glucose disposal (SG) and insulin sensitivity (SI) on the impairment of glucose disposal caused by epinephrine (EPI) infusion in type I (insulin-dependent) diabetes mellitus (IDDM). Seven non-obese young adult diabetics with minimal endogenous insulin secretion had EPI infusions at 25 ng/kg/min for 5.5 hours, after a basal overnight insulin infusion (12 mU/kg/h), and glucose infusion as required to maintain euglycemia. The EPI infusion produced approximately an eightfold increase in plasma EPI. At 2.5 hours, an intravenous glucose tolerance test (IVGTT) was performed with supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. In random order, each subject also had a control (CTR) infusion of basal insulin before the IVGTT. The results were analyzed according to a modification of the minimal model of Bergman et al. EPI infusion was associated with (1) elevated basal plasma glucose (EPI v CTR, 9.8 +/- 0.3 SE v 7.7 +/- 0.7 mmol/L, P less than .05); (2) elevated plasma nonesterified fatty acids (NEFA, 0.9 +/- 0.1 v 0.3 +/- 0.1 mmol/L, P less than .05); and (3) profoundly reduced glucose disposal (KG 0.59 +/- 0.1 v 1.91 +/- 0.33 min-1 x 10(2), P less than .02). Further analysis showed that the reduced glucose disposal was attributable to a marked decrease in SI (EPI 0.9 +/- 0.5 v CTR 7.03 +/- 3.2 min-1.mU-1.L x 10(4), P less than .05) with no significant change in SG (EPI 2.5 +/- 0.2 v CTR 3.1 +/- 0.5 min-1 x 10(2), NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between glucose oxidation and FFA concentration in septic cancer-bearing patients

Glucose oxidation is inhibited in severely ill patients. The present investigation was designed to study the relationship between glucose tissue uptake, glucose oxidation, and FFA concentration in septic cancer-bearing patients. The influence of glucose infusion alone (3.9 mg x kg-1 x min-1), followed by a euglycemic clamp with the same glucose load, on oxidation of glucose, plasma FFA concentration, and lipid oxidation were measured in eight septic cancer-bearing patients. During infusion of 3.9 mg glucose x kg-1 x min-1 glucose tissue uptake was 4.6 +/- 0.3 mg x kg-1 x min-1, glucose oxidation 0.5 +/- 0.2 mg x kg-1 x min-1, FFA concentration 377 +/- 52 mumol x L-1, and lipid oxidation 2.0 +/- 0.2 mumol x kg-1 x min-1. During the euglycemic clamp glucose tissue uptake was 4.4 +/- 0.3 mg x kg-1 x min-1, glucose oxidation rose to 1.8 mg x kg-1 x min-1 (.001 less than P less than .01), FFA concentration dropped to 202 +/- 23 mumol x L-1 (P less than .001), and lipid oxidation to 1.2 +/- 0.2 mumol x kg-1 x min-1 (.001 less than P less than .01). Nonprotein respiratory quotient rose from 0.73 +/- 0.02 to 0.85 +/- 0.02 (.001 less than P less than .01); 11% +/- 5% of the total amount of glucose taken up by the tissues was oxidized during infusion of glucose alone and increased to 42% +/- 6% during the euglycemic glucose clamp. It is concluded that in septic cancer-bearing patients glucose oxidation is inhibited during infusion of 3.9 mg glucose x kg-1 x min-1, even when expressed as percentage of glucose tissue uptake. With insulin, glucose tissue uptake was not influenced, but glucose oxidation expressed as percentage of glucose tissue uptake was normalized.     

Epinephrine directly antagonizes insulin-mediated activation of glucose uptake and inhibition of free fatty acid release in forearm tissues.

To determine whether the anti-insulin effect of epinephrine is due to a direct antagonism on target tissues or is mediated by indirect mechanisms (systemic substrate and/or hormone changes), insulin and epinephrine were infused intrabrachially in five normal volunteers using the forearm perfusion technique. Insulin (2.5 mU/min) was infused alone for 90 minutes and in combination with epinephrine (25 ng/min) for an additional 90 minutes, so as to increase the local concentrations of these hormones to physiological levels (60 to 75 microU/mL and 200 to 250 pg/mL for insulin and epinephrine, respectively). Systemic plasma glucose and free fatty acids (FFA) concentrations remained stable at their basal values during local hormone infusion. Forearm glucose uptake (FGU) increased in response to insulin alone from 0.8 +/- 0.2 mg.L-1.min-1 to 4.3 +/- 0.8. Addition of epinephrine completely abolished the insulin effect on FGU, which returned to its preinfusion value (0.7 +/- 0.2). Forearm lactate release was slightly increased by insulin alone, but rose markedly on addition of epinephrine (from 5.2 +/- 0.8 mumol.L-1.min-1 to 17 +/- 2; P less than .02). During infusion of insulin alone, forearm FFA release (FFR) decreased significantly from the postabsorptive value of 1.76 +/- 0.25 mumol.L-1.min-1 to 1.05 +/- 0.11 (P less than .01). Epinephrine addition reverted insulin suppression of FFR, which returned to values slightly above baseline (2.06 +/- 0.47 mumol.L-1.min-1; P less than .05 v insulin alone). The data demonstrate that epinephrine is able to antagonize directly insulin action on forearm tissues with respect to both stimulation of glucose uptake and inhibition of FFA mobilization.     

Lipolytic and ketogenic fluxes in human hyperthyroidism

The effect of hyperthyroidism on lipolytic and ketogenic fluxes was determined by measuring simultaneously (stable isotope methodology) glycerol, nonesterified fatty acids (NEFA), and ketone body (KB) kinetics in euthyroid and hyperthyroid subjects. In the postabsorptive state hyperthyroid patients had normal concentrations of insulin and glucagon, but increased concentrations (P less than 0.01) and turnover rates (P less than 0.01) of glycerol, NEFA, and KB. The ratio of NEFA appearance rate to glycerol appearance rate was decreased in hyperthyroid subjects (2.34 +/- 0.23 vs. 3.15 +/- 0.22; P less than 0.05), indicating that intracellular cycling between triglycerides and fatty acids was increased. The percentage of NEFA flux used for KB production, calculated from NEFA disappearance rates and KB appearance rates, was increased in hyperthyroid patients (21.20 +/- 2.75% vs. 13.37 +/- 0.63%; P less than 0.05), suggesting a diversion during hyperthyroidism of hepatic fatty acid metabolism toward ketogenesis. However, when the plasma NEFA levels of control subjects were raised by the infusion of a triglyceride emulsion to levels comparable to those observed in hyperthyroid patients their percentage of NEFA flux used for ketogenesis rose to values slightly higher (26.30%) than those of hyperthyroid subjects. In conclusion, 1) hyperthyroidism results not only in increased lipolysis, but also in enhanced triglyceride-fatty acid cycling, which could contribute to the excessive energy expenditure; and 2) the increased KB production of hyperthyroid patients results more from an increase in NEFA availability than from a direct stimulation of hepatic ketogenesis.     

Interaction of lipid and carbohydrate metabolism after infusions of lipids or of lipid lowering agents: lack of a direct relationship between free fatty acid concentrations and glucose disposal.

The present work was planned to study the effects of changes in lipid metabolism irrespective of FFA concentrations (FFA) on the regulation of oxidative and nonoxidative disposal of a glucose infusion during hyperinsulinaemia. Fifteen normal volunteers participated in the 3 protocols, in which 1) Intralipid 2) beta-pyridylcarbinol or 3) isotonic saline were infused during 2 hours. Thereafter, these infusions were discontinued and a two-hour euglycaemic hyperinsulinaemic clamp was performed. All three studies were carried out in combination with indirect calorimetry to measure glucose uptake, and oxidative and nonoxidative glucose disposal (corresponding essentially to glucose storage). Plasma FFA concentrations were 508 +/- 34, 601 +/- 43 and 546 +/- 45 mumol/l in the basal state during the Intralipid, beta-pyridylcarbinol and control protocols. It increased to 960 +/- 71 mumol/l after the Intralipid infusion, fell to 246 +/- 17 mumol/l after the beta-pyridylcarbinol infusion, vs 600 +/- 48 mumol/l in the control. At the end of the glucose-insulin clamp the values were low in the 3 protocols: 263 +/- 17, 233 +/- 19 and 204 +/- 14 mumol/l. Intralipid infusion prior to the clamp protocol induced a suppression of both insulin-mediated glucose uptake (4.91 +/- 0.46 (Intralipid) vs 6.83 +/- 0.63 mg.kg-1.min-1 (saline)) and storage (1.61 +/- 0.34 vs 2.99 +/- 0.53 mg.kg-1.min-1) while beta-pyridylcarbinol infusion induced an increased insulin-mediated glucose uptake (8.58 +/- 0.37 mg.kg-1.min-1) and in glucose storage (4.29 +/- 0.31 mg.kg-1.min-1) (p less than 0.5 vs Intralipid). These changes occurred even though FFA plasma concentrations were similar in the 3 experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phenylalanine flux in adult men: estimates with different tracers and route of administration

The kinetics of three different tracers of phenylalanine were studied when continuously infused together either by an intravenous (IV) or intragastric (IG) route in six young healthy men during a fasting state. During IV infusion, mean flux values were 39.2 +/- 1.8, 40 +/- 3, 41.8 +/- 3.6 mumol.kg-1.h-1 for L-[ring-2H5], [15N], and L-[1-13C]phenylalanine, respectively (differences not significant). Fluxes were higher (P less than .001) during IG than IV infusion, indicating a disappearance of tracer during the first pass through the splanchnic area. Also, higher fluxes were found for [ring-2H5]phenylalanine (74 +/- 6.23 mumol.kg-1.h-1) compared with [15N] and L-[1-13C]phenylalanine (54.24 +/- 4.7 and 61.15 +/- 5.3 mumol.kg-1.h-1) during IG infusion. Proton exchange might explain this difference, possibly limiting in vivo use of this label when the tracer is to be administered by the IG route.     

Stable isotope model for estimating colonic acetate production in premature infants.

In premature infants, a nutritionally significant proportion of lactose is apparently fermented in the colon to acetate. To estimate the rate of entry of acetate into the peripheral circulation, a model that takes into account extraction of gut-derived acetate by splanchnic and hepatic tissues was developed. Using a [1-13C]acetate orogastric infusion technique, six studies were carried out on five premature infants during constant orogastric feeding. Ranges in gestational age, postnatal age, and breath H2 concentration (corrected for CO2 content) were 28-32 weeks, 16-29 days, and 45-252 microL/L, respectively. The estimated rate of entry of acetic acid (mean +/- SD) was 63.7 +/- 33.8 mumol.kg-1.min-1 (range, 22.9-123.2 mumol.kg-1.min-1), which corresponded to 64.3% +/- 38.6% (24%-136%) of the potential two carbon units from dietary lactose. Thus, a substantial fraction of dietary lactose in premature infants may be converted to acetic acid; this conversion could have a significant effect on protein as well as energy requirements.     

Effects of fasting on blood plasma levels, metabolism and metabolic effects of epinephrine and norepinephrine in steers

Experiments were designed to study effects of 3 days of fasting on blood plasma levels, metabolic clearance rates (MCR) and effects of norepinephrine (NE) and epinephrine (E) on levels of glucose, nonesterified fatty acids (NEFA) and immunoreactive insulin (IRI) in 12 steers. During fasting, levels of E, NE and protein did not change, whereas IRI, T3 and glucose decreased and NEFA, acetoacetate and beta-hydroxybutyrate increased. Before and at the end of fasting, NE or E were iv infused for 120 min. NE and E were elevated after 15 min and to the end of the infusion. The increase in E, but not in NE, was significantly greater after 3 days of fasting than before fasting (P less than 0.05). MCR for E was lower after fasting (299 +/- 17 vs 204 +/- 10 ml.kg-0.75.min-1; P less than 0.001), whereas MCR for NE was not significantly different (455 +/- 37 vs 400 +/- 27 ml.kg-0.75.min-1). MCR was higher for NE than for E, both before and after fasting (P less than 0.05). After the infusion, E and NE decreased within minutes to pre-infusion concentrations. During E infusions, NEFA increased significantly more, whereas glucose increased less in fasted than in fed animals. During NE infusions, NEFA increased in fasted, but not in fed animals, and glucose increased less at the end than before fasting. IRI decreased during E infusions only in fed animals, and transiently increased after the infusion, except after NE infusion in fasted steers.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of epinephrine on ketogenesis in the dog after a prolonged fast

The effects of a selective increase in epinephrine on ketogenesis and lipolysis were determined in the conscious dog following a prolonged fast (7 days). Plasma insulin and glucagon were fixed at basal levels by infusion of somatostatin (0.8 micrograms/kg/min) and basal intraportal replacement amounts of insulin (210 +/- 20 microU/kg/min) and glucagon (0.65 ng/kg/min). Following a 40-minute control period, saline or epinephrine (0.04 microgram/kg/min) was infused for 3 hours. Plasma insulin, glucagon, and norepinephrine levels did not change during saline (6 +/- 1 microU/mL, 83 +/- 17 pg/mL, and 137 +/- 38 pg/mL, respectively) or epinephrine (10 +/- 1 microU/mL, 73 +/- 18 pg/ml, 98 +/- 13 pg/mL, respectively) infusion. Plasma epinephrine levels increased from 80 +/- 26 to 440 +/- 47 pg/mL in response to infusion of the catecholamine, but remained unchanged during saline infusion. Glycerol levels (93 +/- 10 mumol/L) remained unchanged during saline infusion, but increased in response to epinephrine (108 +/- 9 to 170 +/- 18 mumol/L by 30 minutes). The glycerol level had returned to baseline and to the value apparent in saline controls by 60 minutes. The nonesterified fatty acid (NEFA) level declined slowly during the 3-hour saline infusion, but was elevated in response to epinephrine infusion (1.27 +/- 0.16 to 1.97 +/- 0.25 mmol/L at 30 minutes). After the initial epinephrine-induced increase, the NEFA level declined so that by 3 hours it was not significantly different from the basal or saline values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct assessment of splanchnic uptake and metabolic effects of human and porcine insulin

The hepatic vein catheterization technique was used to quantitate the splanchnic uptake and the metabolic effects of biosynthetic human insulin (BHI) and porcine insulin (PI) in normal man. BHI and PI were infused into a peripheral vein (0.9-1.3 mU kg-1 min-1) for 60 min together with SRIH (0.6 mg/h) to inhibit endogenous insulin secretion and glucose to induce moderate hyperglycemia (9-10 mmol/liter). During the infusion period, arterial-hepatic venous difference of plasma C-peptide as well as splanchnic C-peptide output fell by more than 98% indicating virtually complete cessation of endogenous insulin release. Under these conditions, the arterial-hepatic venous differences in plasma insulin concentrations represent a valid and direct measurement of splanchnic insulin uptake. During BHI infusion, arterial insulin levels rose to 82 +/- 11 (SE) microU/ml (range: 33-105 microU/ml). Splanchnic insulin uptake paralleled the rise of arterial insulin, reaching 430 +/- 72 microU kg-1 min-1 at 60 min. No appreciable difference between BHI and PI was demonstrable. A highly significant correlation between arterial insulin concentrations and splanchnic insulin uptake was found (r = 0.816; P less than 0.001). Accordingly, both fractional splanchnic insulin extraction and splanchnic insulin clearance remained unchanged throughout insulin infusion and averaged 70 +/- 4% and 5.3 +/- 2 ml kg-1 min-1, respectively. With BHI infusion, splanchnic glucose balance (-8.5 +/- 0.9 mumol kg-1 min-1, basal) became positive (7.3 +/- 1 mumol kg-1 min-1). In contrast, basal splanchnic lactate uptake was inhibited by BHI and there was lactate production (from 3.4 +/- 0.9 to -1.7 +/- 1.4 mumol kg-1 min-1). Similar changes in splanchnic glucose and lactate metabolism occurred during PI infusion. These studies indicate that: 1) A considerable amount of insulin (70 +/- 4%) is extracted by the splanchnic bed on a single passage, after exogenous administration of either human insulin or PI; 2) over a physiological range of insulin concentrations (33-105 microU/ml) a linear relationship exists between arterial insulin concentrations and splanchnic insulin removal; and 3) BHI and PI do not differ appreciably with respect to their uptake and metabolic effects at the splanchnic level.     

Insulin resistance in alloxan-diabetic dogs: Evidence for reversal following insulin therapy

Hepatic glucose production and peripheral glucose utilization were measured basally and during infusion of insulin (25 and 40 m U X kg-1 X h-1) in normal dogs and in insulin-deficient diabetic dogs, before and after a 10-14 day period of insulin treatment. Basal hepatic glucose production was significantly raised in the diabetic dogs (21.4 +/- 2.5 mumol X kg-1. min-1; p less than 0.005) compared with normal dogs (11.9 +/- 2.5 mumol X kg-1 X min-1) and fell by 20% in diabetic dogs following insulin treatment (17.4 +/- 3.0 mumol X kg-1 X min-1). However, in all groups, hepatic glucose production suppressed equally well during the low dose insulin infusions, suggesting that the raised hepatic glucose production of diabetes is due to insulin deficiency and not hepatic insulin resistance. In addition, a marked defect of glucose utilization was found in the diabetic dogs (25 +/- 5 mumol X kg-1 X min-1; p less than 0.001) compared with normal dogs (99 +/- 15 mumol X kg-1 X min-1) during matched hyperinsulinaemia and hyperglycaemia. This defect of glucose utilization, as defined by euglycaemic insulin dose-response curves employing insulin infusion rates between 40-600 mU X kg-1 X h-1, demonstrated a marked reduction of glucose disposal in diabetic dogs. The severity of the insulin resistance closely paralleled the degree of hyperglycaemia. In contrast, following 10-14 days of insulin treatment, an improvement of glucose disposal was seen in all diabetic dogs. It is concluded that insulin deficiency leads to (a) increased hepatic glucose production, and (b) the development of marked peripheral insulin resistance, which is reversed by insulin treatment.     

Effects of morbid obesity on insulin clearance and insulin sensitivity in several aspects of metabolism as assessed by low-dose insulin infusion.

Obesity is associated with impaired insulin action in glucose disposal, but not necessarily in other aspects of intermediary metabolism or insulin clearance. Sixteen morbidly obese and 14 normal-weight subjects (body mass index, 51.2 +/- 11.5 v 22.1 +/- 2.2 kg.m-2; mean +/- SD) were studied with sequential, low-dose, incremental insulin infusion with estimation of glucose turnover. In obese patients, basal plasma insulin was higher (10.5 +/- 3.8 v 2.4 +/- 3.0 mU.L-1, P less than .001) and remained elevated throughout infusion (F = 492, P less than .001), as did C-peptide (F = 22.7, P less than .001). Metabolic clearance rate for insulin (MCRI) at the highest infusion rate was similar (1,048 +/- 425 v 1,018 +/- 357 mL.m-2.min-1, NS). Basal hepatic glucose production in obese subjects was less than in normal-weight subjects (270 +/- 108 v 444 +/- 68 mumol.m-2.min-1, P less than .01), as was the basal metabolic clearance rate for glucose (MCRG, 77 +/- 26 v 108 +/- 31 mL.m-2.min-1, P less than .05). Insulin infusion caused blood glucose to decrease less in the obese patients (1.4 +/- 0.5 v 1.9 +/- 0.5 mmol.L-1, P less than .05); hepatic glucose production was appropriately suppressed in them by hyperinsulinemia, but their insulin-mediated glucose disposal was reduced (1.67 [0.79] v 4.45 [2.13] mL.m-2.min-1/mU.L-1, P less than .01). Concentrations of nonesterified fatty acids (NEFA), glycerol, and ketones were elevated throughout the insulin infusions in obese patients, despite the higher insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma proline kinetics and the regulation of proline synthesis in man

A quantitative exploration of the regulation of plasma proline concentration, proline oxidation, and proline endogenous biosynthesis was undertaken utilizing a 360-minute primed continuous infusion of L-[1-13C]proline and L-[methyl-2H3]leucine in healthy, postabsorptive young men. The response of proline metabolism to the intravenous administration of two physiologic rates of L-proline, as well as the withdrawal of an L-proline infusion, were examined. The administration of L-proline at 20 mumol.kg-1.h-1 after an overnight fast resulted in a higher steady state plasma proline concentration, attained within 100 minutes, and this was associated with an increase in proline oxidation, from a baseline value of 10.9 to 16.1 mumol.kg-1.h-1 (P less than .01). Additionally, there was a decrease in proline endogenous synthesis from 15.8 (baseline) to 5.3 mumol.kg-1.h-1 (P less than .01). Administration of L-proline at 40 mumol.kg-1.h-1 after an overnight fast resulted again in a higher plasma steady state proline concentration, attained within 100 minutes and with an associated increase in proline oxidation from 13.1 to 20.0 mumol.kg-1.h-1 (P less than .01) and with a decrease in proline endogenous synthesis from 12.2 to -0.6 mumol.kg-1.h-1 (P less than 0.01). The withdrawal of L-proline after a 20 mumol.kg-1.h-1 infusion resulted in a lower plasma steady state proline level and this was accompanied by a decrease in proline oxidation from 21.2 to 18.2 mumol.kg-1.h-1 (P less than .05) and an increase in endogenous synthesis from 22.2 to 29.7 mumol.kg-1.h-1 (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)