Effect of continuous subcutaneous insulin infusion with lispro on hepatic responsiveness to glucagon in type 1 diabetes

OBJECTIVE: People with type 1 diabetes frequently develop a blunted counterregulatory hormone response to hypoglycemia coupled with a decreased hepatic response to glucagon, and consequently, they have an increased risk of severe hypoglycemia. We have evaluated the effect of insulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabetic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: Ten subjects on CSII were treated for 3 months with lispro and 3 months with regular insulin in a double-blind randomized crossover study After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was measured in each subject. The test consisted of a 4-h simultaneous infusion of somatostatin (450 microg/h) to suppress endogenous glucagon, regular insulin (0.15 mU x kg(-1) x min(-1)), glucose at a variable rate to maintain plasma glucose near 5 mmol/l, and D-[6,6-2H2]glucose to measure HGP During the last 2 h, glucagon was infused at 1.5 ng x kg(-1) x min(-1). Eight nondiabetic people served as control subjects. RESULTS: During the glucagon infusion period, free plasma insulin levels in the diabetic subjects were 71.7+/-1.6 vs. 74.8+/-0.5 pmol/l after lispro and regular insulin treatment, with plasma glucagon levels of 88.3+/-1.8 and 83.7+/-1.5 ng/l for insulin:glucagon ratios of 2.8 and 3.0. respectively (NS). However, plasma glucose increased to 9.2+/-1.1 mmo/l after lispro insulin compared with 7.1+/-0.9 mmol/l after regular insulin (P < 0.01), and the rise in HGP was 5.7 +/-2.8 micromol x kg(-1) x min(-1) after lispro insulin versus 3.1+/-2.9 micromol x kg(-1) x min(-1) after regular insulin treatment (P=0.02). In the control subjects, HGP increased by 10.7+/-4.2 micromol x kg(-1) x min(-1) under glucagon infusion. CONCLUSIONS: Insulin lispro treatment by CSII was associated with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensitivity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.     

Effect of respiration, exercise, and food intake on hepatic vein circulation

Since the effects of respiration, nutrition, and exercise on blood flow in the hepatic vein are not well understood, the objective of this study was to determine the hemodynamic influence of these factors on hepatic venous circulation using Doppler ultrasonographic tracings. The venous blood flow of the middle hepatic vein was determined during arrested full inspiration, midinspiration, and expiration in 25 healthy subjects. The maximum velocity and the systolic-to-diastolic ratio of the blood flow were measured. The portal vein blood flow velocity was measured in 20 volunteers before and after food intake. The portal vein blood flow and the hepatic vein flow velocity were examined in eight volunteers after exercise. During inspiration, maximum blood flow velocity of the hepatic veins decreased compared to midinspiration (P < 0.001). With expiration the maximum velocity increased (P < 0.001). After food consumption, there was no change in the velocity of the hepatic veins, but the portal vein blood flow increased (P = 0.041). After physical exercises, the maximum velocity of the hepatic venous flow increased, on average, about 148% (P = 0.01), and the portal vein blood flow decreased about 44% (P = 0.027). To achieve standard measurements of hepatic venous blood flow, the state of respiration and physical exertion should be established. The nutritional status had only a minor influence on hepatic vein measurements.     

The role of growth hormone, somatostatin and glucagon in hepatic resection

BACKGROUND/AIMS: The aim of this study was to clarify the roles of growth hormone, somatostatin, and glucagon in vital reactions against surgical stress as well as in hepatic regeneration. METHODOLOGY: Eleven consecutive patients, who underwent hepatic resection, were included in this study. Changes in intrinsic hormones, specifically growth hormone, somatostatin, and glucagon, were investigated. Furthermore, a comparison was made between major (more than 2 segments) and minor (less than 1 segment) hepatectomies. RESULTS: Growth hormone was observed to increase four-fold during hepatectomy and thereafter remained at relatively high levels. Somatostatin reached its lowest level on postoperative day 1 and then returned to near the preoperative level on postoperative day 7, while glucagon gradually increased and reached a peak around postoperative day 3. The concentrations of both somatostatin and glucagon in the portal vein were higher than those in the peripheral vein. No significant differences between major and minor hepatectomies were found throughout the perioperative course. CONCLUSIONS: Growth hormone is considered to be a sensitive parameter in terms of surgical stress and can also act as a trigger as well as a promoter of hepatic regeneration, while a dissociation between somatostatin and glucagon in the early postoperative period indicates the promotion of hepatic regeneration. Furthermore, portal blood, which contains higher concentrations of these substances, plays an important role in regulating hepatic regeneration. However, the absence of a correlation between the extent of the hepatectomy and these parameters suggests that some other, as yet unidentified mechanism, may also be related to the regulation of hepatic regeneration.     

Effect of glucagon on pinocytosis by the yolk sac of the rat

The uptake of macromolecular markers by fluid pinocytosis in the rat yolk sac was inhibited by glucagon, with half-maximal effect at a hormone concentration of approximately 3 X 10(-8) M. Glucagon had no effect on the cellular distribution of the marker subsequent to its uptake. Rates of uptake promptly returned to normal when the yolk sacs were transferred from a glucagon-containing to a glucagon-free medium. Epinephrine also inhibited, but only at much higher concentrations. The effect of the latter was augmented by theophylline. Insulin (10(-6) M) had no effect when added alone or with an inhibitory level of glucagon (10(-7) M). The presumption that the hormone effect was mediated by cyclic AMP was supported by the findings that the cellular levels of cyclic AMP were elevated in the presence of glucagon and that dibutyryl cyclic AMP could replace glucagon as an effective inhibitor. The conclusion that the hormone effect was on uptake rather than on subsequent regurgitation was based on the linearity of accumulation in both the presence and absence of glucagon and the inability of glucagon to stimulate loss of invertase from preloaded cells. Colchicine and vinblastine also inhibited uptake. This finding and those of others which are discussed suggest the possibility that effects of cyclic nucleotides on certain cell functions may involve their regulation of microtubular status.     

Insulin, glucagon, portal systemic shunting, and hepatic failure in the dog

The cerebrospinal fluid (CSF) composition was studied in 54 premature infants. The pregnancy was normal and the delivery normal and non traumatic in all of them, and the 5 minutes Apgar score ranged from 6 to 9. No abnormalities were found on physical examination including neurological examination. Blood cell countings and blood gasometry were normal. CSF composition was studied as to: total cell count and total protein, glucose, bilirrubin and hemoglobin concentrations. Data found permit to stablish as physiologic the following values: leucocytes, until 16 per cumm; erithrocytes, until 1,280 per cumm; total protein content until 300 mgm/100 ml; bilirrubin until 80 micrometer/1; hemoglobin until 8 micrometer/1; glucose, two thirds of the concentration found in the blood. Protein, bilirrubin and hemoglobin are significantly increased as compared to values found for the CSF of 79 fullterm normal newborn babies evaluated previously. Hemoglobin was not detected in the CSF of any full term newborn baby. The differences found are probably due to a less efficient blood-CSF barrier in premature infants as compared to full-term newborn babies.     

Acute liver failure due to temporary hepatic ischemia in the pig

The model of temporary complete liver ischemia was investigated in 60 pigs in order to produce a disease which resembles liver failure in man. The interval of time leading to death in every animal differed in a wide range. A number of biochemical alterations was of no value as for the prognosis of the animal under investigation. The ammonium in the peripheral blood is elevated during shunting of portal blood around the liver only. Microscopic examinations demonstrated that the damage produced is limited to the hepatic tissue. The lesions were less when ischemia was produced after a longer interval after the operation. The role of processes of regeneration and reparation of liver tissue is discussed.     

Changes in plasma insulin and growth hormone after intravenous glucagon in hepatic cirrhosis

Decreased increases in blood sugar by comparison with control subjects was noted in patients with cirrhosis of the liver after i.v. administration of 1 mg glucagon. Insulin secretion was similar to that observed in the controls. Basal GH values were higher in the liver patients, whereas after glucagon they displayed a gradual and progressive increase with a peak at 60'. No significant differences in GH pattern were noted in the two groups, however.     

Effect of ticlopidine on the cutaneous circulation in peripheral vascular disease

To assess the effect of ticlopidine on the cutaneous circulation, 25 patients with lower limb ischemia were investigated just before and at two hours after being given a 200 mg oral dose of ticlopidine. The transcutaneous partial pressure of oxygen (PtcO2) and the skin temperature were determined at 35 limb sites and 9 chest walls sites. Both the PtcO2 and the skin temperature were significantly increased at two hours after the administration of ticlopidine (p < 0.01). The findings suggest that ticlopidine can improve the cutaneous microcirculation in patients with peripheral vascular disease.     

Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans

The effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose production and peripheral glucose utilization was investigated with or without infusion of somatostatin to inhibit insulin and glucagon secretion in 13 healthy, non-diabetic women aged 59 years. After 120 min 3-(3)H-glucose infusion, GLP-1 was added (4.5 pmol kg(-1) bolus + 1.5 pmol kg(-1) min(-1)). Without somatostatin (n = 6), GLP-1 decreased plasma glucose (from 4.8 +/- 0.2 to 4.2 +/- 0.3 mmol L(-1), P = 0.007). Insulin levels were increased (48 +/- 3 vs. 243 +/- 67 pmol L(-1), P = 0.032), as was the insulin to glucagon ratio (P = 0.044). The rate of glucose appearance (Ra) was decreased (P = 0.003) and the metabolic clearance rate of glucose (MCR) was increased during the GLP-1 infusion (P = 0.024 vs. saline). Also, the rate of glucose disappearance (Rd) was reduced during the GLP-1 infusion (P = 0.004). Since Ra was reduced more than Rd, the net glucose flow was negative, which reduced plasma glucose. Somatostatin infusion (500 microg h(-1), n = 7) abolished the effects of GLP-1 on plasma glucose, serum insulin, insulin to glucagon ratio, Ra, Rd, MCR and net glucose flow. The results suggest that GLP-1 reduces plasma glucose levels mainly by reducing hepatic glucose production and increasing the metabolic clearance rate of glucose through indirectly increasing the insulin to glucagon ratio in healthy subjects.     

Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement

BACKGROUND & AIMS: Hepatic involvement in hereditary hemorrhagic telangiectasia is common but often asymptomatic. However, in some cases, the vascular lesions that involve the liver may lead to high-output cardiac failure and pulmonary hypertension that is predominant over hepatobiliary manifestations. Liver transplantation and treatment of these complications are described and discussed in this article. METHODS: Three patients with hereditary hemorrhagic telangiectasia and hepatic involvement received transplants. They had pulmonary hypertension and chronic right-sided heart failure caused by disseminated intrahepatic telangiectasias with shunts between the hepatic artery and hepatic veins or portal vein. Left-to-right intrahepatic shunt output was estimated to range between 51% and 57.5% of cardiac output. RESULTS: Hyperdynamic circulation disappeared after liver transplantation in all patients. Results of computed tomography and right-sided heart catheterization performed 6 months later were normal. Follow-up periods currently are 65, 53, and 29 months, and each patient continues to be asymptomatic. CONCLUSIONS: This report suggests that liver transplantation can be considered as an alternative and successful curative treatment that may prevent the irreversible evolution of cardiopulmonary disease.     

In vivo and in vitro regulation of hepatic glucagon receptor mRNA concentration by glucose metabolism

We have recently cloned the murine glucagon receptor (GR) gene and shown that it is expressed mainly in liver. In this organ, the glucagon-GR system is involved in the control of glucose metabolism as it initiates a cascade of events leading to release of glucose into the blood stream, which is a main feature in several physiological and pathological conditions. To better define the metabolic regulators of GR expression in liver we analyzed GR mRNA concentration in physiological conditions associating various glucose metabolic pathways in vivo and in vitro in the rat and in the mouse. First, we report that the concentration of the GR mRNA progressively increased from the first day of life to the adult stage. This effect was abolished when newborn rodents were fasted. Second, under conditions where intrahepatic glucose metabolism was active such as during fasting, diabetes, and hyperglycemic clamp, the concentration of GR mRNA increased independent of the origin of the pathway that generated the glucose flux. These effects were blunted when hyperglycemia was corrected by phlorizin treatment of diabetic rats or not sustained during euglycemic clamp. In accordance with these observations, we demonstrated that the glycolytic substrates glucose, mannose, and fructose, as well as the gluconeognic substrates glycerol and dihydroxyacetone, increased the concentration of GR mRNA in primary cultures of hepatocytes from fed rats. Glucagon blunted the effect of glucose without being dominant. The stimulatory effect of those substrates was not mimicked by the nonmetabolizable carbohydrate L-glucose or the glucokinase inhibitor glucosamine or when hepatocytes were isolated from starved rats. In addition, inhibitors of gluconeogenesis and lipolysis could decrease the concentration of GR mRNA from hepatocytes of starved rats. Combined, these data strongly suggest that glucose flux in the glycolytic and gluconeogenic pathways at the level of triose intermediates could control expression of GR mRNA and participate in controlling its own metabolism.     

Influences of cardiopulmonary bypass and fentanyl anesthesia on hepatic circulation and oxygen metabolism in beagles

Decreases in hepatic blood flow (HBF) have been reported in patients and in animal experiments during cardiopulmonary bypass (CPB). We examined changes in HBF and hepatic oxygen metabolism during CPB in 16 beagles anesthetized with fentanyl. Hepatic arterial blood flow (HABF) and portal venous blood flow (PVBF) were measured by using an electromagnetic flowmeter before and during normothermic and hypothermic CPB with 10 microg x kg(-1) x h(-1) (F-10 group; n = 8) or 50 microg x kg(-1) x h(-1) (F-50 group; n = 8) of fentanyl anesthesia. CPB was conducted with membrane oxygenation and a nonpulsatile pump flow of 2.4 L x m(-2) x min(-1). Hepatic oxygen delivery (HDO2) and consumption (HVO2) were calculated from HBF and oxygen content in arterial, portal venous, and hepatic venous blood. HABF did not change during normothermic CPB in the F-10 group, but it decreased significantly during hypothermic CPB in both groups, especially the F-50 group. During CPB, PVBF and total HBF decreased significantly in both groups-more so with the larger dose of fentanyl--whereas HDO2 decreased significantly because the arterial and portal venous blood oxygen levels decreased. The HVO2 was stable in the F-10 group but was significantly depressed during CPB in the F-50 group. Our results indicate that during hypothermic nonpulsatile CPB larger doses of fentanyl are associated with reduced HBF and impaired HDO2 and HVO2. Implications: Hepatic dysfunction after cardiopulmonary bypass (CPB) has been frequently reported and could be partly attributed to hepatic circulatory disturbance during CPB. We found that, in beagles, large doses of fentanyl were associated with greater decreases in hepatic blood flow and hepatic oxygen metabolism during hypothermic CPB than smaller doses of fentanyl.     

Effect of nitroglycerin on regulation of cerebral circulation

Investigations carried out with the use of radioisotopic, electromagnetic and resistographic methods showed that nitroglycerine increased the cerebral circulation diminishing the tone of the intracranial vessels. The drug also markedly depressed the central regulation of the cerebral circulation; it suppressed the reflex reaction of the intracranial vessels and prevented the development of experimental disturbances of the cerebral circulation of adrenergic origin.