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Sahoo B, Srivastava M, Katiyar A, Ecelbarger C, Tiwari S. Liver or kidney: Who has the oar in the gluconeogenesis boat and when? World J Diabetes 2023; 14:1049-1056. [PMID: 37547592 PMCID: PMC10401452 DOI: 10.4239/wjd.v14.i7.1049] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/20/2023] [Accepted: 04/11/2023] [Indexed: 07/12/2023] Open
Abstract
Gluconeogenesis is an endogenous process of glucose production from non-carbohydrate carbon substrates. Both the liver and kidneys express the key enzymes necessary for endogenous glucose production and its export into circulation. We would be remiss to add that more recently gluconeogenesis has been described in the small intestine, especially under high-protein, low-carbohydrate diets. The contribution of the liver glucose release, the net glucose flux, towards systemic glucose is already well known. The liver is, in most instances, the primary bulk contributor due to the sheer size of the organ (on average, over 1 kg). The contribution of the kidney (at just over 100 g each) to endogenous glucose production is often under-appreciated, especially on a weight basis. Glucose is released from the liver through the process of glycogenolysis and gluconeogenesis. Renal glucose release is almost exclusively due to gluconeogenesis, which occurs in only a fraction of the cells in that organ (proximal tubule cells). Thus, the efficiency of glucose production from other carbon sources may be superior in the kidney relative to the liver or at least on the level. In both these tissues, gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates. Liver and renal gluconeogenesis are differentially regulated under various pathological conditions. The impact of one source vs the other changes, based on post-prandial state, acid-base balance, hormonal status, and other less understood factors. Which organ has the oar (is more influential) in driving systemic glucose homeostasis is still in-conclusive and likely changes with the daily rhythms of life. We reviewed the literature on the differences in gluconeogenesis regulation between the kidneys and the liver to gain an insight into who drives the systemic glucose levels under various physiological and pathological conditions.
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Affiliation(s)
- Biswajit Sahoo
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Medha Srivastava
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Arpit Katiyar
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Carolyn Ecelbarger
- Department of Medicine, Georgetown University, Washington, DC 20057, United States
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Sharma R, Tiwari S. Renal gluconeogenesis in insulin resistance: A culprit for hyperglycemia in diabetes. World J Diabetes 2021; 12:556-568. [PMID: 33995844 PMCID: PMC8107972 DOI: 10.4239/wjd.v12.i5.556] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/27/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Renal gluconeogenesis is one of the major pathways for endogenous glucose production. Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes. We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes. A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up. Insulin-resistant models exhibit reduced insulin receptor (IR) expression and/or post-receptor signaling in their kidney tissue. Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys, which may increase renal gluconeogenesis in the state of insulin resistance. It is now established that the kidney contributes up to 20% of all glucose production via gluconeogenesis in the post-absorptive phase. However, the rate of renal glucose release excessively increases in diabetes. The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels. Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis. Overall, the available literature suggests that impairment in renal gluconeogenesis in an insulin-resistant state may contribute to hyperglycemia in type 2 diabetes.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Abstract
According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although animal and in vitro studies have documented that the kidney is capable of gluconeogenesis, glucose production by the human kidney has been regarded as negligible. This knowledge is based on net balance measurements across the kidney. Recent studies combining isotopic and balance techniques have demonstrated that the human kidney is involved in the regulation of glucose homeostasis by making glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the postabsorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis actually increases by approximately 2-fold. Following meal ingestion, glucose utilization by the kidney increases. Increased glucose uptake into the kidney may be implicated in diabetic nephropathy. Normally each day, ∼ 180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium glucose cotransporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and when plasma glucose concentrations exceed a threshold, glucose begins to appear in the urine. Renal glucose release is stimulated by epinephrine and is inhibited by insulin. Handling of glucose by the kidney is altered in type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the postabsorptive and postprandial states, and renal glucose reabsorption is also increased Since renal glucose release is almost exclusively due to gluconeogenesis, it seems that the kidney is as important gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactae glutamine and glycerol.
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Affiliation(s)
- Asimina Mitrakou
- Department of Clinical Therapeutics, Athens University Medical School, Athens, Greece.
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Abstract
Overproduction of glucose is the major factor responsible for fasting hyperglycemia in type 2 diabetes. Formerly, this had been considered to be solely due to excessive hepatic glucose production because the human kidney was not regarded as an important source of glucose except during acidosis and after prolonged fasting. However, data accumulated over the last 60 years in animal and in vitro studies have provided considerable evidence that the kidney plays an important role in glucose homeostasis in conditions other than acidosis and prolonged fasting. This article summarizes early work in animals and humans, discusses methodologic issues in assessing renal glucose release in vivo, and provides evidence from recent human studies that the kidney substantially contributes to glucose overproduction in type 2 diabetes.
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Affiliation(s)
- Christian Meyer
- Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue, Box MED/CRC, Rochester, NY 14642, USA
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Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest 1998; 102:619-24. [PMID: 9691098 PMCID: PMC508922 DOI: 10.1172/jci2415] [Citation(s) in RCA: 214] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321+/-36 vs. 125+/-15 micromol/min, P < 0.001). Hepatic glucose release was increased approximately 30% (P = 0.03), but increments in hepatic and renal glucose release were comparable (2.60+/-0.70 vs. 2.21+/-0.32, micromol.kg-1.min-1, respectively, P = 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353+/-48 vs. 103+/-10 micromol/min, P < 0.001), resulting in net renal glucose uptake in the diabetic subjects (92+/-50 micromol/ min) versus a net output in the nondiabetic subjects (21+/-14 micromol/min, P = 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake (r = -0.51, P < 0.01), which was reduced by approximately 60% in diabetic subjects (10. 9+/-2.7 vs. 27.0+/-3.3 micromol/min, P < 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney.
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Affiliation(s)
- C Meyer
- Departments of Medicine and Physiology and Pharmacology, University of Rochester School of Medicine, Rochester, New York 14642, USA
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Perriello G, Jorde R, Nurjhan N, Stumvoll M, Dailey G, Jenssen T, Bier DM, Gerich JE. Estimation of glucose-alanine-lactate-glutamine cycles in postabsorptive humans: role of skeletal muscle. THE AMERICAN JOURNAL OF PHYSIOLOGY 1995; 269:E443-50. [PMID: 7573421 DOI: 10.1152/ajpendo.1995.269.3.e443] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
To evaluate transfer of carbon between plasma glucose and plasma alanine (glucose-alanine cycle) and lactate (Cori cycle), to assess the contribution of skeletal muscle to these cycles, and to determine whether a glucose-glutamine cycle exists in postabsorptive humans, we infused 11 normal overnight-fasted volunteers with [2-3H]glucose, [6-14C]glucose, and [3-13C]alanine to isotopic steady state and in 7 of these simultaneously measured forearm net balance, uptake, and release of labeled and unlabeled glucose, lactate, and alanine. We found that 40.9 +/- 3.3, 66.8 +/- 3.2, and 13.4 +/- 1.1%, respectively, of plasma alanine, lactate, and glutamine carbon came from plasma glucose. More plasma glucose was converted to plasma alanine than could be derived from plasma alanine (1.89 +/- 0.20 vs. 1.48 +/- 0.15 mumol.kg-1.min-1, P < 0.001). A similar direction of net carbon flux was found for lactate (8.5 vs. 4.2 mumol.kg-1.min-1), with only glutamine adding more carbon to plasma glucose than was received from it (1.0 vs. 0.75 mumol.kg-1.min-1). Skeletal muscle accounted for 50.2 +/- 3.9 and 45.5 +/- 5.7% of the overall appearance of alanine and lactate in plasma and 54.2 +/- 5.4 and 36.4 +/- 4.2% of their respective origins from plasma glucose. Skeletal muscle release of alanine and lactate that had been formed from plasma glucose accounted for 19.1 +/- 2.1 and 48.4 +/- 4.8%, respectively, of muscle glucose uptake and 42.4 +/- 5.5 and 49.9 +/- 5.8% of the overall release of alanine and lactate from muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- G Perriello
- Division of Endocrinology and Metabolism, Scripps Clinic, La Jolla, California 92037, USA
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Abstract
The factors that sustain postabsorptive glucose concentrations have been analyzed and the adverse effects of various hypoglycemic disorders on these factors examined. The role of alanine has been reviewed and the importance of glycerol as a precursor of glucose and of ketones as a fuel substitute for glucose emphasized. Finally, we have suggested that fasting functional hypoglycemia replace ketotic hypoglycemia as a descriptive term and that we relinquish the concept of leucine-sensitive hypoglycemia as a specific entity.
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Lindblad BS, Rahimtoola RJ, Ahmad SS, Fancy K, Singha L, Hussain SS. Plasma free amino acid levels during the initial rehabilitation of protein-energy malnutrtion with protracted diarrhoea using a free amino acid--glucose diet. ACTA PAEDIATRICA SCANDINAVICA 1978; 67:335-43. [PMID: 418621 DOI: 10.1111/j.1651-2227.1978.tb16331.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This study intends to assess, by ion-exchange chromatography of free amino acid levels of peripheral blood plasma, the amino acid absorption of severely growth retarded infants with protracted diarrhoea, during the initial period of rehabilitation. Eleven infants from a very low socio-economic group of a developing country, with nutritional marasmic growth retardation and prolonged diarrhoea, were treated for a period of 10 days with a commercially available free amino acid--glucose diet (Vivonex, Pfrimmer Co., Erlangen, Germany). Excessive hyperprolinaemia characterized the plasma aminogram before treatment. After initial rehabilitation with this diet, the plasma analyses showed very low branch-chained and cystine levels, and marginally high alanine, glycine, and proline levels. It seemed that the free amino acids could not be absorbed quickly enough to meet with the high supply of glucose. Furthermore, this investigation supports the assumption that cystine is an essential amino acid in malnourished infants. In spite of normal or high human growth hormone levels, somatomedin was not detectable in pooled samples from these severely growth retarded infants.
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Wicklmayr M, Dietze G. On the mechanism of glucose release from the muscle of juvenile diabetics in acute insulin deficiency. Eur J Clin Invest 1978; 8:81-6. [PMID: 417939 DOI: 10.1111/j.1365-2362.1978.tb00816.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In fifty-three healthy subjects and twenty-three juvenile diabetics the measurement of arterial and deep venous glucose concentrations showed that the substrate was taken up by the tissues of the forearm of all the healthy subjects and released from it in all the diabetic ones. In six of the diabetics glucose output was accelerated almost five-fold during the intrabrachial arterial administration of metaproterenol (1.62 nmol/min), indicating that basal glucose release from muscle may result from enhanced glycogenolysis during acute insulin deficiency. In line with this view a reduction of glucose uptake by muscle was observed in six healthy subjects receiving metaproterenol infusion. However, since the production of lactate by the forearm appeared to be smaller in the diabetics, the basal glucose output could also partly be due to impaired glycolysis. These data suggest that the glucose released from muscle during acute insulin deficiency may be of clinical importance, especially when the rate of glycogenolysis is further stimulated by, for example, enhanced catecholamine drive.
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Parrilla R, Goodman MN, Toews CJ. The effect of anoxia on nitrogen metabolism in the isolated perfused rat liver. Pflugers Arch 1977; 369:167-75. [PMID: 560678 DOI: 10.1007/bf00591573] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Munro HN. Absorption and metabolism of amino acids with special emphasis on phenylalanine. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1976; 2:189-206. [PMID: 825655 DOI: 10.1080/15287397609529426] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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13
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Garber AJ, Karl IE, Kipnis DM. Alanine and glutamine synthesis and release from skeletal muscle. II. The precursor role of amino acids in alanine and glutamine synthesis. J Biol Chem 1976. [DOI: 10.1016/s0021-9258(17)33860-7] [Citation(s) in RCA: 137] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Garber AJ, Karl IE, Kipnis DM. Alanine and glutamine synthesis and release from skeletal muscle. I. Glycolysis and amino acid release. J Biol Chem 1976. [DOI: 10.1016/s0021-9258(17)33859-0] [Citation(s) in RCA: 137] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Breuer J, Breuer H. Konzentrationen von Aminosäuren im Blut verschiedener Gefäßabschnitte von Patienten mit Lebercirrhose während und nach Anlegen einer porto-cavalen Anastomose. Clin Chem Lab Med 1975. [DOI: 10.1515/cclm.1975.13.5.191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Garber AJ, Menzel PH, Boden G, Owen OE. Hepatic ketogenesis and gluconeogenesis in humans. J Clin Invest 1974; 54:981-9. [PMID: 4430728 PMCID: PMC301639 DOI: 10.1172/jci107839] [Citation(s) in RCA: 167] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Splanchnic arterio-hepatic venous differences for a variety of substrates associated with carbohydrate and lipid metabolism were determined simultaneously with hepatic blood flow in five patients after 3 days of starvation. Despite the relative predominance of circulating beta-hydroxybutyrate, the splanchnic productions of both beta-hydroxybutyrate and acetoacetate were approximately equal, totaling 115 g/24 h. This rate of hepatic ketogenesis was as great as that noted previously after 5-6 wk of starvation. Since the degree of hyperketonemia was about threefold greater after 5-6 wk of starvation, it seems likely that the rate of ketone-body removal by peripheral tissues is as important in the development of the increased ketone-body concentrations observed after prolonged starvation as increased hepatic ketone-body production rate. Splanchnic glucose release in this study was 123 g/24 h, which was less than that noted previously after an overnight fast, but was considerably more than that noted during prolonged starvation. Hepatic gluconeogenesis was estimated to be 99 g/24 h, calculated as the sum of lactate, pyruvate, glycerol, and amino acid uptake. This was greater than that observed either after an overnight fast or after prolonged starvation. In addition, a direct relationship between the processes of hepatic ketogenesis and gluconeogenesis was observed.
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Hagenfeldt L, Wahren J, Pernow B, Räf L. Uptake of individual free fatty acids by skeletal muscle and liver in man. J Clin Invest 1972; 51:2324-30. [PMID: 4639017 PMCID: PMC292398 DOI: 10.1172/jci107043] [Citation(s) in RCA: 126] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Arterial-venous concentration differences for individual free fatty acids (FFA) were measured across the deep tissues of the forearm, the splanchnic vascular bed, and the kidney in healthy, postabsorptive subjects. In addition, arterial-portal venous FFA differences were determined in five patients undergoing elective cholecystectomy. The differences in fractional uptake among the individual FFA across the forearm were small and not statistically significant. Splanchnic fractional uptake was high for FFA with short chain lengths and rose with increasing degree of unsaturation. Small, negative arterial-portal venous differences for individual FFA were observed, indicating that arterial-hepatic venous FFA differences mainly reflect hepatic uptake. When the arterial FFA concentration was reduced to approximately 25% of the control values by the administration of nicotinic acid, net uptake of total FFA ceased but there was release of stearic acid and uptake of lauric, myristic, and palmitoleic acid to the splanchnic region. Muscle and liver uptakes of individual FFA were both dependent on their arterial concentrations with the exception of the splanchnic uptake of stearic acid. There was no uptake of free arachidonic acid by either muscle or liver, nor was there significant uptake of any of the free fatty acids by the kidney. It is concluded (a) that there are important quantitative differences between the net exchanges of individual FFA across the splanchnic vascular bed, (b) that tracer studies of FFA metabolism require the determination of individual FFA specific activities, (c) that palmitic and oleic acid appear to be suitable tracers for the entire FFA fraction in most instances.
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Wahren J, Felig P, Cerasi E, Luft R. Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus. J Clin Invest 1972; 51:1870-8. [PMID: 5032528 PMCID: PMC292335 DOI: 10.1172/jci106989] [Citation(s) in RCA: 222] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
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.
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Felig P, Kim YJ, Lynch V, Hendler R. Amino acid metabolism during starvation in human pregnancy. J Clin Invest 1972; 51:1195-202. [PMID: 5020432 PMCID: PMC292250 DOI: 10.1172/jci106913] [Citation(s) in RCA: 67] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
To evaluate the factors regulating gluconeogenesis in pregnancy, plasma amino acid levels were determined during the course of an 84-90 hr fast in physically healthy women studied during wk 16-22 of gestation (before undergoing therapeutic abortion), and in nonpregnant controls. The effect of pregnancy on the glycemic response to exogenous alanine administration during starvation was also investigated. In the nonpregnant group fasting resulted in a 2- to 3-fold increase in the levels of plasma valine, leucine, isoleucine, and alpha-aminobutyrate, while the concentration of alanine and glycine fell. In the pregnant group, the levels of most amino acids were significantly reduced in the postabsorptive state. With starvation, the plasma concentration of alanine fell more rapidly in the pregnant group and was significantly below that of the nonpregnant subjects for the first 60 hr of the fast. In contrast, a significant elevation in plasma glycine, serine, and threonine was observed in the pregnant group after 84 hr of fasting, whereas similar increments were not demonstrable until after 10 days of fasting in previously studied nonpregnant obese subjects. Paralleling the changes in maternal plasma, amniotic fluid levels of valine, leucine, and isoleucine increased while that of alanine fell during the fast. Although the plasma glucose concentration was lower in the pregnant group at termination of the fast, intravenous alanine administration (0.15 g/kg), resulted in a prompt, comparable increase (20-25 mg/100 ml) in plasma glucose in both groups of subjects. It is concluded that (a) pregnancy accelerates and exaggerates the hypoalaninemic and hyperglycinemic effects of starvation; (b) lack of key endogenous substrate rather than altered intrahepatic processes may limit hepatic gluconeogenesis in pregnancy and contribute to gestational hypoglycemia; (c) maternal caloric deprivation profoundly alters the levels of amino acids in amniotic fluid.
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Arhammar G, Björnesjö KB, Jagenburg R, Mellander O. Plasma and erythrocyte amino acids during treatment of protein calorie malnutrition. C.N.U. report 56. ACTA PAEDIATRICA SCANDINAVICA 1972; 61:145-8. [PMID: 5010528 DOI: 10.1111/j.1651-2227.1972.tb15918.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Abstract
Arterial concentration and net exchange across the leg and splanchnic bed of 19 amino acids were determined in healthy, postabsorptive subjects in the resting state and after 10 and 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min. Arterio-portal venous differences were measured in five subjects undergoing elective cholecystectomy. In the resting state significant net release from the leg was noted for 13 amino acids, and significant splanchnic uptake was observed for 10 amino acids. Peripheral release and splanchnic uptake of alanine exceeded that of all other amino acids, accounting for 35-40% of total net amino acid exchange. Alanine and other amino acids were released in small amounts (relative to net splanchnic uptake) by the extrahepatic splanchnic tissues drained by the portal vein. During exercise arterial ananine rose 20-25% with mild exertion and 60-96% at the heavier work loads. Both at rest and during exercise a direct correlation was observed between arterial alanine and arterial pyruvate levels. Net amino acid release across the exercising leg was consistently observed at all levels of work intensity only for alanine. Estimated leg alanine output increased above resting levels in proportion to the work load. Splanchnic alanine uptake during exercise exceeded that of all other amino acids and increased by 15-20% during mild and moderate exercise, primarily as a consequence of augmented fractional extraction of alanine. For all other amino acids, there was no change in arterial concentration during mild exercise. At heavier work loads, increases of 8-35% were noted for isoleucine, leucine, methionine, tyrosine, and phenylalanine, which were attributable to altered splanchnic exchange rather than augmented peripheral release. The data suggest that (a) synthesis of alanine in muscle, presumably by transamination of glucose-derived pyruvate, is increased in exercise probably as a consequence of increased availability of pyruvate and amino groups; (b) circulating alanine serves an important carrier function in the transport of amino groups from peripheral muscle to the liver, particularly during exercise; (c) a glucose-alanine cycle exists whereby alanine, synthesized in muscle, is taken up by the liver and its glucose-derived carbon skeleton is reconverted to glucose.
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Bloxam DL. Nutritional aspects of amino acid metabolism. 1. A rat liver perfusion method for the study of amino acid metabolism. Br J Nutr 1971; 26:393-422. [PMID: 5157947 DOI: 10.1079/bjn19710046] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
1. Experiments were done to find whether the rat liver can be maintained in a satisfactory condition when perfused with oxygenated Krebs-Ringer bicarbonate buffer without added protein or red cells.2. The condition and preformance of the liver in this system were assessed from measurements made to ascertain its general condition or viability, its basal characteristics and its response to added substrates.3. It was found that the rapid flow-rate of the medium through the livers and the efficient oxygenation of the medium ensured that enough oxygen was available for the livers to deal with large quantities of added lactate.4. The potassium concentrations in the livers and the rates of alanine aminotransferase (EC2.6.1.6) from the cells during perfusion, and the water content after perfusion showed that the livers were not grossly damaged and that they did not deteriorate measurably for up to 3 h of perfusion.5. Liver oxygen consumption, ATP concentrations, lactate and pyruvate concentrations and ratios, and rates of urea and glucose synthesis and bile secretion, all in perfusions without added substrate, were either similar to measurements by other workers from livers perfused withmedia containingred cells and protein or were reasonable extrapolations from availabledata.6. The rates of glucose production from lactate, and urea and glucose output from amino acids indicated that the liver responds adequately to added substrates.7. Measurements of amino acid concentrations in perfusate indicated that the livers of rats starved for 18–20 h regulated the amino acids to characteristic levels, by overall output or uptake, except for valine, leucine and isoleucine which were continuously given out into the medium. The results suggest that in vivo there is a general flow of most of the amino acids from extrahepatic tissues to the liver during fasting, while valine, leucine and isoleucine flow from liver to extrahepatic tissues.8. When pentobarbitone sodium (Nembutal) was used as the anaesthetic for removal of the liver from the donor rat, the rates of urea and glucose output in perfusions without added substrates were lower than when halothane (Fluothane) was used, indicating that pentobarbitone has an inhibitory effect on these measures of liver function during the subsequent perfusion.
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Marliss EB, Aoki TT, Pozefsky T, Most AS, Cahill GF. Muscle and splanchnic glutmine and glutamate metabolism in postabsorptive andstarved man. J Clin Invest 1971; 50:814-7. [PMID: 5547277 PMCID: PMC291995 DOI: 10.1172/jci106552] [Citation(s) in RCA: 231] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Arterio-venous differences across forearm muscle in man in both prolonged starvation and in the postabsorptive state, show an uptake of glutamate and a relatively greater production of glutamine. Splanchnic arteriovenous differences in the postabsorptive state show a net uptake of glutamine and lesser rate of glutamate production. These data suggest that muscle is a major site of glutamine synthesis in man, and that the splanchnic bed is a site of its removal. The relative roles of liver and other tissues in the splanchnic circuit were not directly assessed, only the net balance. These data in man are in conflict with most previous studies in other species attributing the major proportion of glutamine production to the liver and, pari passu, to the splanchnic bed.
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Bertolini AM, Barbiano di Belgioioso G, Santagostino A, Surian M. [Free plasmatic amino acids in the untreated diabetic]. ACTA DIABETOLOGICA LATINA 1971; 8:295-310. [PMID: 5568107 DOI: 10.1007/bf01550871] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Nitzan M, Groffman H. Hepatic gluconeogenesis and lipogenesis in experimental intrauterine growth retardation in the rat. Am J Obstet Gynecol 1971; 109:623-7. [PMID: 5541461 DOI: 10.1016/0002-9378(71)90638-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Exton JH, Mallette LE, Jefferson LS, Wong EH, Friedmann N, Miller TB, Park CR. The hormonal control of hepatic gluconeogenesis. RECENT PROGRESS IN HORMONE RESEARCH 1970; 26:411-61. [PMID: 4319350 DOI: 10.1016/b978-0-12-571126-5.50014-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Pozefsky T, Felig P, Tobin JD, Soeldner JS, Cahill GF. Amino acid balance across tissues of the forearm in postabsorptive man. Effects of insulin at two dose levels. J Clin Invest 1969; 48:2273-82. [PMID: 5355340 PMCID: PMC297484 DOI: 10.1172/jci106193] [Citation(s) in RCA: 322] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Amino acid balance across skeletal muscle and across subcutaneous adipose tissue plus skin of the forearm has been quantified in postabsorptive man before and after insulin infusion into the brachial artery. Skeletal muscle released significant amounts of alpha amino nitrogen after an overnight fast. Most individual amino acids were released. Alanine output was by far the greatest. The pattern of release probably reflects both the composition of muscle protein undergoing degradation and de novo synthesis of alanine by transamination. A significant correlation was observed between the extent of release of each amino acid and its ambient arterial concentration. Elevation of forearm insulin in eight subjects from postabsorptive (12 muU/ml) to high physiologic levels (157 muU/ml) in addition to stimulating muscle glucose uptake blocked muscle alpha amino nitrogen release by 74%. Consistent declines in output were seen for leucine, isoleucine, tyrosine, phenylalanine, threonine, glycine, and alpha-aminobutyric acid. Alanine output was insignificantly affected. Doubling forearm insulin levels (from 10 to 20 muU/ml) in eight subjects increased muscle glucose uptake in three and blocked alpha amino nitrogen output in two although both effects were seen concurrently in only one subject. Changes in net amino acid balance after insulin could be accounted for by increased transport of amino acids into muscle cells or retardation of their exit. It is likely that ambient arterial amino acid concentrations are established and maintained primarily by the extent of muscle amino acid release. The individual amino acids whose outputs from forearm muscle decline after forearm insulinization correspond well with those whose levels fall systematically after systemic insulinization. This suggests that declines in amino acid levels after systemic insulinization are due to inhibition of muscle release. Doubling basal insulin approaches the threshold both for blockade of muscle amino acid output and stimulation of glucose uptake, effects which appear to occur independently.
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Felig P, Owen OE, Wahren J, Cahill GF. Amino acid metabolism during prolonged starvation. J Clin Invest 1969; 48:584-94. [PMID: 5773094 PMCID: PMC535724 DOI: 10.1172/jci106017] [Citation(s) in RCA: 490] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Plasma concentration, splanchnic and renal exchange, and urinary excretion of 20 amino acids were studied in obese subjects during prolonged (5-6 wk) starvation. Splanchnic amino acid uptake was also investigated in postabsorptive and briefly (36-48 hr) fasted subjects.A transient increase in plasma valine, leucine, isoleucine, methionine, and alpha-aminobutyrate was noted during the 1st wk of starvation. A delayed, progressive increase in glycine, threonine, and serine occurred after the 1st 5 days. 13 of the amino acids ultimately decreased in starvation, but the magnitude of this diminution was greatest for alanine which decreased most rapidly during the 1st week of fasting. In all subjects alanine was extracted by the splanchnic circulation to a greater extent than all other amino acids combined. Brief fasting resulted in an increased arterio-hepatic venous difference for alanine due to increased fractional extraction. After 5-6 wk of starvation, a marked falloff in splanchnic alanine uptake was attributable to the decreased arterial concentration. Prolonged fasting resulted in increased glycine utilization by the kidney and in net renal uptake of alanine. It is concluded that the marked decrease in plasma alanine is due to augmented and preferential splanchnic utilization of this amino acid in early starvation resulting in substrate depletion. Maintenance of the hypoalaninemia ultimately serves to diminish splanchnic uptake of this key glycogenic amino acid and is thus an important component of the regulatory mechanism whereby hepatic gluconeogenesis is diminished and protein catabolism is minimized in prolonged fasting. The altered renal extraction of glycine and alanine is not due to increased urinary excretion but may be secondary to the increased rate of renal gluconeogenesis observed in prolonged starvation.
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Rutenberg HL, Schwartz H, Soloff LA. Norepinephrine- and heparin-induced changes in plasma free fatty acids: a comparison between patients with ischemic heart disease and normal young adults. Am Heart J 1968; 76:183-92. [PMID: 5665416 DOI: 10.1016/0002-8703(68)90193-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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