Net Splanchnic Glucose Production Research Articles

Intravenous and subcutaneous administration of a long‐acting somatostatin analogue: effects on glucose metabolism and splanchnic haemodynamics in healthy subjects

The effect of SMS 201-995, a long-acting somatostatin analogue, on splanchnic blood flow and glucose metabolism, was investigated in five groups of healthy subjects. Groups A (n = 4), B (n = 5), C (n = 5) and D (n = 5) were studied before, during and after a 60-min intravenous infusion of SMS (1.7, 0.8, 0.2 and 0.1 micrograms min-1, respectively). Group E (n = 6) was investigated before and for 6 h after a subcutaneous injection of 25 micrograms of SMS. The splanchnic blood flow decreased by 20-25% in all groups in response to SMS and remained low during the entire observation periods. Arterial concentrations of glucose showed a 15-20% decline during SMS infusion in Groups A and B (P less than 0.05-0.01) and a less pronounced decrease in the other groups. Fifteen minutes after the end of infusion the glucose levels started to rise and in group A, the levels were significantly higher than basal (+25%, P less than 0.05-0.01) at 90-180 min after the end of infusion. The net splanchnic glucose production, determined in groups A and B, decreased by 65-75% in response to SMS infusion. Towards the end and immediately after the infusions, however, the net glucose output increased, but decreased again at 30-60 min after the end of infusion. Arterial, insulin and glucagon concentrations decreased significantly during infusion in all groups. This decline was more pronounced for insulin (50%) than for glucagon (20-25%) and insulin concentrations remained low for a longer period after the end of infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of vasoactive intestinal polypeptide (VIP) on splanchnic and central hemodynamics in healthy subjects

The influence of VIP, a potent vasodilator, on central hemodynamics, splanchnic blood flow and glucose metabolism was studied in six healthy subjects. Teflon catheters were inserted into an artery, a femoral vein and a right-sided hepatic vein. A Swan-Ganz catheter was introduced percutaneously and its tip placed in the pulmonary artery. Determinations of cardiac output, systemic, pulmonary arterial and hepatic venous pressures as well as splanchnic blood flow were made in the basal state and at the end of two consecutive 45 min periods of VIP infusion at 5 and 10 ng/kg/min, respectively. Arterial blood samples for analysis of glucose, FFA, insulin and glucagon were drawn at timed intervals. VIP infusion at 5 ng/kg/min resulted in an increase in cardiac output (55%) and heart rate (25%) as well as a reduction in mean systemic arterial pressure (15%) and vascular resistance (45%). With the higher rate of VIP infusion heart rate tended to rise further while cardiac output and arterial pressure remained unchanged. At 15 min after the end of VIP infusion the above variables had returned to basal levels. Splanchnic blood flow and free hepatic venous pressure did not change significantly. Arterial concentrations of glucose, FFA, insulin and glucagon increased during VIP infusion. At 15 min after the end of infusion the glucose levels were still significantly higher than basal (20%). Net splanchnic glucose output did not change in response to VIP infusion. It is concluded that VIP exerts a potent vasodilatory effect resulting in augmented cardiac output and lowered systemic blood pressure and vascular resistance. The increased levels of glucose and FFA, as well as unchanged net splanchnic glucose production, indicate an accelerated lipolysis and diminished glucose uptake by peripheral tissues. The metabolic alterations may be secondary to sympathetic activation, induced by the fall in blood pressure.

Splanchnic metabolism of amino acids in healthy subjects: Effect of 60 hours of fasting

Brief starvation is accompanied by decreased circulating levels of most amino acids, which has been attributed to an increased splanchnic uptake of amino acids, primarily alanine, for gluconeogenesis. However, quantitative data on splanchnic exchange of amino acids and gluconeogenic precursors is lacking. Consequently, arterial concentrations and splanchnic exchange of whole blood amino acids, ketone bodies, glucose, and gluconeogenic precursors were measured in 16 prolonged fasted (60 to 64 hours) and 15 overnight fasted (12 to 14 hours) healthy, nonobese subjects. After the 60-hour fast net splanchnic glucose production decreased by 41% to 0.31 ± 0.02 μmol/L ( P < .001), whereas the splanchnic uptake of gluconeogenic precursors increased and could account for the total glucose output. Net splanchnic uptake of taurine, threonine, serine, glycine, lysine, histidine, and arginine rose significantly in response to fasting ( P < .05 to .01) due to increased splanchnic fractional extraction. Although the splanchnic fractional extraction of alanine was augmented by 40% ( P < .001), net splanchnic uptake was not influenced by fasting. Total net splanchnic uptake of amino acids increased by 68%, from 231 ± 44 μmol/min in the postabsorptive state to 388 ± 63 μmol/min (mean ± SEM) ( P < .05) in the 60-hour fasted state. However, only one half of this rise was accounted for by gluconeogenic amino acids.

Evidence for an augmented glucagon dependence of hepatic glucose production in cirrhosis of the liver.

The role of endogenous glucagon in maintaining hepatic glucose production after an overnight fast in patients with cirrhosis of the liver was studied with arterial-hepatic-venous catheterization and using somatostatin to suppress glucagon secretion. Arterial glucagon levels were elevated in eight cirrhotics to 290 +/- 90 pg/ml (SEM) compared to 100 +/- 10 pg/ml (P less than 0.02) in five normal controls, and they were lowered during administration of somatostatin (SRIF; 250 microgram/h) by a mean of 154 pg/ml and 39 pg/ml in cirrhotics and controls, respectively. Basal net splanchnic glucose production (NSGP) was similar in patients with and without cirrhosis (approximately 100 mg/min) but declined more markedly during 30 min of SRIF in cirrhotics to a net splanchnic uptake of glucose of 30 +/- 20 ml/min, as opposed to a fall of NSGP by 44 +/- 2 mg/min in controls (P less than 0.01). To assure that NSGP declined during SRIF infusion due to the fall of glucagon levels, SRIF was combined with a glucagon infusion at 150 ng/m2 . min in four cirrhotics and in five control subjects. Arterial glucagon levels were elevated to a mean of 650 pg/ml and 559 pg/ml in cirrhotics and controls, respectively. NSGP increased after 40 min of SRIF and glucagon replacement to 179 +/- 33 mg/min in cirrhotics and significantly more, to 412 +/- 68 mg/min, in controls (P less than 0.01). Thus, hepatic glucose production during basal and elevated glucagon levels suggested hepatic resistance to glucagon in cirrhosis. Nevertheless, endogenous glucagon played an augmented stimulatory role in maintaining glucose production in the normal range since there was an exaggerated fall of hepatic glucose output during glucagon suppression.

Possible mechanism by which somatostatin-induced glucagon suppression improves glucose tolerance during insulinopaenia in man.

The present study examines the question of whether lowering the basal plasma glucagon concentration alters the response of the liver to an intravenous glucose load under conditions where insulin is present at near-basal concentrations. Acute hyperglycaemia of 220–240 mg/dl was induced by peripheral venous glucose infusion in two groups of normal men who had undergone hepatic vein catheterization. Somatostatin (0.9 mg/h) was infused in both groups together with an infusion of insulin (0.15 mU/kg/min) to maintain arterial insulin levels at 7–12 μU/ml. Glucagon (1.5 ng/kg/min) was infused in one group resulting in a rise in plasma glucagon levels from 148±37 to 228±25 pg/ml, thus mimicking basal portal glucagon concentrations, whereas in the second group glucagon was not replaced, resulting in a fall in circulating glucagon levels from 132±21 to 74±15 pg/ml. In the glucagon-deprived group, net splanchnic glucose production (NSGP) fell from 143±31 to −72.5±39 mg/ min (p<0.01), indicating that net splanchnic glucose uptake had occurred. By contrast, NSGP did not change significantly (137±20 vs 151±60 mg/min) in the group in which both insulin and glucagon were replaced during hyperglycaemia. These data thus suggest that during hyperglycaemia, when the insulin concentration is fixed at basal levels, glucagon may play an important role in determining whether or not the liver diminishes its output of glucose and stores glucose in response to a glucose load.

HYPERGLYCEMIA PER SE (INSULIN AND GLUCAGON WITHDRAWN) CAN INHIBIT HEPATIC GLUCOSE PRODUCTION IN MAN

We examined the effect of hyperglycemia per se on net splanchnic glucose balance. In 2 groups of normal postabsorptive men who had undergone hepatic vein catheterization, somatostatin was administered to block endogenous insulin and glucagon secretion. Exogenous glucose was infused in both groups to maintain euglycemia for 2 h in one group (n = 7) and to induce hyperglycemia of 220-240 mg/dl after 30 minutes of euglycemia in the second group (n = 4). In both groups the induction of insulinopenia and glucagonopenia with euglycemia maintained resulted in an initial 75% fall in net splanchnic glucose production (NSGP). In the group in which euglycemia was maintained NSGP returned to basal rates (157 +/- 31 mg/min) within 2 h. However, in the group in which hyperglycemia was induced, NSGP did not return to basal rates but remained suppressed (28 +/- 4 mg/min) for the duration of the study. These data in normal man indicate that hyperglycemia per se with insulin and glucagon acutely withdrawn can suppress splanchnic glucose production but does not induce net splanchnic glucose storage.

Effects of Chronic Glucagon Excess on Hepatic Metabolism

To investigate the effect of chronic hyperglucagonemia on hepatic metabolism, we have studied net splanchnic glucose and ketone body production rates in a patient with glucagonoma before and after complete tumor resection. Preoperatively, immunoreactive glucagon (IRG) concentration was high (1,800 pg. per milliliter) and the molar insulin/glucagon (I/G) ratio was low (0.4). Arterial free fatty acid (FFA) concentration (0.74 mM) and net splanchnic FFA uptake (0.27 mmole per minute) were normal. However, 48 per cent of the net splanchnic FFA uptake was utilized for net splanchnic ketone body production, which was four times (0.52 mmole per minute) greater than normal. Postoperatively IRG (40 to 150 pg. per milliliter) and the molar I/G ratio (&amp;gt; 1.0) were both normal. Arterial FFA concentration and net splanchnic FFA uptake were unchanged (0.67 mM and 0.27 mmole per minute, respectively). However, only 19 per cent of the net splanchnic FFA uptake was utilized for net splanchnic ketone body production, which had declined to 0.19 mmole per minute. These data suggest that chronic hyperglucagonemia in this patient had a stimulating effect on ketogenesis. Preoperatively, the net splanchnic glucose production rate was 0.56 mmole per minute and could be accounted for entirely by gluconeogenesis from lactate (83 per cent), pyruvate (9 per cent), glycerol (14 per cent), and alanine, glutamine, and glutamate (8 per cent). The abnormally large contribution of lactate to gluconeogenesis was an effect of inappropriately elevated lactate concentration (0.88 mM) and increased blood flow (2,400 ml. per minute). Postoperatively the net splanchnic glucose production rate was 0.67 mmole per minute, of which 51 per cent could be accounted for by gluconeogenesis. The data provide no evidence for an effect of chronic hyperglucagonemia on splanchnic glucose production. However, they do not exclude a small stimulating glucagon effect on gluconeogenesis from amino acids.

Transient Stimulatory Effect of Sustained Hyperglucagonemia on Splanchnic Glucose Production in Normal and Diabetic Man

Insulin can modulate glucagon-stimulated hepatic glucose production and is considered to be the major factor acting in vivo to exert a couterregulatory action to glucagon. The insulin-dependent diabetic, therefore, might be especially vulnerable to enhanced hepatic glucose production promoted by glucagon. To investigate this hypothesis, low-dose glucagon infusions were administered to normal and diabetic men to compare the effects of glucagon on net splanchnic glucose production (NSGP). Four normal and three insulin-dependent, ketosis-prone, hyperglycemic diabetic men (insulin withheld for 24 hours) underwent brachial-artery-hepatic-vein catheterization. Each received a 90-minute glucagon infusion at 5 ng/kg./min. Glucagon levels rose four-to-fivefold in both groups, plateauing at 300-600 pg./ml. In the normals, NSGP rose from 92+/-12 to 211+/-31 mg./min. at 15 minutes and returned to basal levels by 45 minutes. Insulin measured in the hepatic vein rose from 19+/-6 to 33+/-11 muU/.ml., while plasma glucose rose 17 mg./dl. In the insulin-dependent diabetics, NSGP rose from 78+/-24 to a peak of 221+/-33 mg./min. at 30 minutes and then fell sharply to 113+/-15 mg./min. at 60 minutes despite continuing hyperglucagonemia. Plasma glucose in the diabetics rose 21 mg./dl. These data suggest a mechanism that acts to rapidly diminish glucagon-induced hepatic glucose production in diabetic man but does not appear to be mediated by increased insulin secretion.

Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man.

To investigate the role of glucagon in regulating hepatic glucose production in man, selective glucagon deficiency was produced in four normal men by infusing somatostatin (0.9 mg/h) and regular pork insulin (150-muU/kg per min) for 2 h. Exogenous glucose was infused to maintain euglycemia. Arterial plasma glucagon levels fell by greater than 50% whereas plasma insulin levels were maintained in the range of 10-14 muU/ml. In response to these hormonal changes, net splanchnic glucose production (NSGP) fell by 75% and remained suppressed for the duration of the study. In contrast, when somatostatin alone was administered to normal men, resulting in combined insulin and glucagon deficiency (euglycemia again maintained), NSGP fell markedly but only transiently, reaching its nadir at 15 min. Thereafter, NSGP rose progressively, reaching the basal rate at 105 min. These data indicate that the induction of selective glucagon deficiency in man (with basal insulin levels maintained) is associated with a marked and sustained fall in hepatic glucose production. We conclude, therefore, that basal glucagon plays an important role in the maintenance of basal hepatic glucose production in normal man.

Differential sensitivity of glycogenolysis and gluconeogenesis to insulin infusions in dogs.

The suppressive effect of insulin on hepatic glucose production is generally recognized. Though it is well established that this effect is at least partially due to inhibition of glycogenolysis, controversy still exists about insulin's effect on gluconeogenesis. The present study was undertaken to determine whether insulin could affect gluconeogenesis from alanine in the intact dog and to compare the effect of insulin on glycogenolysis and gluconeogenesis. In anesthetized dogs fasted overnight, blood samples were drawn simultaneously from a femoral artery and hepatic vein. Alanine-U-14C, 10 mu Ci./kg., was infused over 110 minutes. A constant insulin infusion at either 1 or 5 mU./kg./min. was begun at 50 minutes, and blood glucose concentration was maintained by a variable glucose infusion. When insulin was infused at 1 mU./kg./min., resulting in plasma immunoreactive insulin (IRI) levels of 73 +/- 10 muU./ml., the net splanchnic glucose production (NSGP) was suppressed from 2.7 +/- 2 mg./kg./min. to virtually zero. In constrast, this small increment in insulin concentration had no demonstrable effect on the net splanchnic uptake of alanine or on the conversion of plasma alanine to glucose (7.9 +/- 0.3 mu mol/min.). Insulin infused at 5 mU./kg./min. resulted in IRI levels of 240 +/- 25 muU./ml. This higher insulin concentration was associated with a marked suppression of both the NSGP (100 per cent) and the conversion of plasma alanine to glucose (90 per cent) but did not affect the extraction of alanine by the splanchnic bed. Doses of both 1 and 5 mU./kg./min. were associated with a 35 per cent fall in immunoreactive glucagon levels. These data demonstrate that (1) glycogenolysis is more sensitive than gluconeogenesis to the inhibitory effect of small increments in insulin concentrations, (2) gluconeogenesis could be suppressed by insulin but only at higher insulin concentrations, (3) this suppression of gluconeogenesis from alanine by insulin was due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine, and finally, (4) that insulin can suppress glucagon in the absence of hyperglycemia.

Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men.

The effect of glucagon (50 ng/kg/min) on arterial glycerol concentration and net splanchnic production of total ketones and glucose was studied after an overnight fast in four normal and five insulin-dependent diabetic men. Brachial artery and hepatic vein catheters were inserted and splanchnic blood flow determined using indocyanine green. The glucagon infusion resulted in a mean circulating plasma level of 4,420 pg/ml. In the normal subjects, the glucagon infusion resulted in stimulation of insulin secretion indicated by rising levels of immunoreactive insulin and C-peptide immunoreactivity. Arterial glycerol concentration (an index of lipolysis) declined markedly and net splanchnic total ketone production was virtually abolished. In contrast, the diabetic subjects secreted no insulin (no rise in C-peptide immunoreactivity) in response to glucagon. Arterial glycerol and net splanchnic total ketone production in these subjects rose significantly (P=<0.05) when compared with the results in four diabetics who received a saline infusion after undergoing the same catheterization procedure.Net splanchnic glucose production rose markedly during glucagon stimulation in the normals and diabetics despite the marked rise in insulin in the normals. Thus, the same level of circulating insulin which markedly suppressed lipolysis and ketogenesis in the normals failed to inhibit the glucagon-mediated increase in net splanchnic glucose production. It is concluded (a) that glucagon at high concentration is capable of stimulating lipolysis and ketogenesis in insulin-deficient diabetic man; (b) that insulin, mole for mole, has more antilipolytic activity in man than glucagon has lipolytic activity; and (c) that glucagon, on a molar basis, has greater stimulatory activity than insulin has inhibitory activity on hepatic glucose release.

Carbohydrate metabolism of the liver in normal man under varying dietary conditions.

The glucose and urea production and the uptake of gluconeogenic precursors by the liver were measured with the liver vein catheterization technique in two series of healthy subjects after 4 days on a well-defined normo-caloric diet. After a normal mixed diet the net splanchnic glucose production was 0.87 mmol/min. The glucose derived from maximum gluconeogenesis was 0.31 mmol/min. By using a liver biopsy technique in a similar series, the glycogenolysis was found to be 0.54 mmol glucose/min. After a carbohydrate-poor diet the splanchnic glucose production had decreased to 0.30 mmol/min. In this situation the liver was deprived of most of its glycogen, as shown earlier by direct determination of glycogen in liver biopsy specimens. The uptake of gluconeogenic substrates corresponded to the net glucose production. The decreased glucose production during carbohydrate-poor diet did not result in any significant change of the blood glucose level. This indicates a considerable decrease of the peripheral uptake o...

Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus.

Splanchnic and leg exchange of glucose, lactate, pyruvate, and individual plasma amino acids was studied in diabetics 24 hr after withdrawal of insulin and in healthy controls. Measurements were made in the basal postabsorptive state and during the administration of glucose at a rate of 2 mg/kg per min for 45 min. In the basal state, net splanchnic glucose production did not differ significantly between diabetics and controls. However, splanchnic uptake of alanine and other glycogenic amino acids was 1(1/2)-2 times greater in the diabetics, while lactate and pyruvate uptake was increased by 65-115%. Splanchnic uptake of these glucose precursors could account for 32% of hepatic glucose output in the diabetics, as compared to 20% in the controls. This increase in precursor uptake was a consequence of a two- to threefold increment in fractional extraction of these substrates inasmuch as arterial levels of alanine, glycine, and threonine were reduced in the diabetics, while the levels of the remaining substrates were similar in the two groups. Peripheral output of alanine and other glycogenic amino acids as reflected in arterio-femoral venous differences was similar in both groups. An elevation in arterial valine, leucine, and isoleucine was observed in the diabetics, but could not be accounted for on the basis of alterations in splanchnic or peripheral exchange of these amino acids. Administration of glucose (2 mg/kg per min) for 45 min resulted in an 80% reduction in splanchnic glucose output in controls, but failed to inhibit hepatic glucose release in the diabetics despite a twofold greater increment in arterial glucose levels. In both groups no consistent changes in arterial glucagon were observed during the infusion. It is concluded that in nonketotic diabetics (a) total splanchnic output of glucose is comparable to controls, but the relative contribution of gluconeogenesis may be increased by more than 50%; (b) accelerated splanchnic uptake of glucose precursors is a consequence of increased hepatic extraction of available substrates rather than a result of augmented substrate supply; and (c) the failure of glucose infusion to inhibit hepatic glucose output suggests that the exquisite sensitivity of the liver to the infusion of glucose in normal man is a consequence of glucose-induced insulin secretion.