Regulation of splanchnic and renal substrate supply by insulin in humans

doi:10.1016/S0026-0495(00)80048-7

Metabolism

Volume 49, Issue 5, May 2000, Pages 676-683

https://doi.org/10.1016/S0026-0495(00)80048-7 Get rights and content

To determine the effects of peripheral insulin infusion on total, hepatic, and renal glucose production and on the percent contribution to glucose production of gluconeogenesis versus glycogenolysis, 10 healthy subjects had arterialized hand and hepatic vein catheterization after an overnight fast and the results were compared with data from 12 age- and weight-matched subjects with renal vein catheterization during a 180-minute infusion of either insulin (0.25 mU/kg · min) with dextrose, or saline. Endogenous, hepatic, and renal glucose production was measured with [6,6-²H₂]glucose, regional lactate, alanine, and glycerol balance by arteriovenous difference; hepatic blood flow by indocyanine green clearance; and renal blood flow by p-aminohippurate clearance, before and every 30 minutes during each infusion period. Insulin increased from about 42 to 98 pmol/L and blood glucose remained constant in all studies (3.8 ± 0.2 v 4.4 ± 0.1 μmol/ml, hepatic v renal vein). In response to insulin infusion, endogenous, hepatic, and renal glucose production decreased immediately (30 minutes) and reached a lower plateau value (10.8 ± 0.8 v 6.4 ± 0.7, 10.4 ± 1.1 v 7.8 ± 1.0, and 2.8 ± 0.6 v 1.5 ± 0.6 μmol/kg · min, respectively) between 120 and 180 minutes (all P < .05). Net renal uptake of lactate (2.4 ± 0.4 v 0.9 ± 0.6) decreased earlier [30 minutes] and returned to baseline between 120 and 180 minutes (2.4 ± 0.5 μmol/kg · min), whereas net splanchnic uptake of lactate (5.7 ± 0.7 v 0.7 ± 0.6) and alanine (1.8 ± 0.1 v 1.0 ± 0.5 μmol/kg · min) decreased later (120 to 180 minutes). Net renal (0.3 ± 0.1 v 0.1 ± 0.1) and splanchnic (0.7 ± 0.3 v 0.4 ± 0.2 μmol/kg · min) glycerol uptake decreased 90 to 180 minutes after insulin and increased (P < .05) with saline infusion (0.4 ± 0.1 v 0.6 ± 0.3 and 1.0 ± 0.5 v 1.8 ± 0.4 μmol/kg · min, respectively). These data indicate that the rapid suppression of endogenous glucose production by insulin reflects primarily a decrease in hepatic glucose release, most likely due to inhibition of net glycogenolysis, combined with suppression of renal gluconeogenesis. Inhibition of hepatic gluconeogenesis presumably occurs later during hyperinsulinemia. We conclude that peripheral insulin, in addition to its inhibition of glycogen degradation, regulates endogenous glucose production, in part, by modifying the splanchnic and renal substrate supply.

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Primary substrates for renal and hepatic gluconeogenesis are glutamine and alanine, respectively [10]. Renal gluconeogenesis is more sensitive to insulin inhibitory effects and less sensitive to glucagon stimulatory effects than hepatic gluconeogenesis [12,13]. Increased renal gluconeogenesis has been reported in rats [14–17] and humans [16,18] with T2D and is associated with increased expression of gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), fructose 1,6-bisphosphatase (FBPase), and pyruvate carboxykinase (PC).
Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D.
T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study.
Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D.
The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.
Insulin promotes sodium transport but suppresses gluconeogenesis via distinct cellular pathways in human and rat renal proximal tubules
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Insulin is known to promote sodium transport and regulate gluconeogenesis in renal proximal tubules. Although protein kinase B (also known as Akt) and mammalian target of rapamycin complexes (mTORC) have been established as key regulators in the insulin signaling pathway, their roles in proximal tubules are poorly understood. To help define this, we examined the components of insulin signaling in sodium transport and gluconeogenesis in isolated human and rat proximal tubules, and also investigated the role of insulin in sodium handling and mTORC1 in insulin signaling in vivo. In isolated human and rat proximal tubules, Akt and mTORC1/2 inhibition suppressed insulin-stimulated sodium-bicarbonate co-transporter 1 (NBCe1) activity, whereas mTORC1 inhibition had no effect. Akt2 and mTORC2 gene silencing largely inhibited insulin-stimulated NBCe1 activity, whereas silencing of Akt1 and mTORC1 had no effect. Furthermore, insulin decreased sodium excretion, and this effect depended on phosphoinositide 3 kinase in vivo. Moreover, insulin reduced glucose production in rat proximal tubules and the expression of gluconeogenic genes in human and rat proximal tubules. Akt and mTORC1 inhibition largely abolished the observed insulin-mediated inhibitory effects. Gene silencing of insulin receptor substrate 1 (IRS1), Akt2, mTORC1, and mTORC2 also abolished insulin-mediated inhibition of gluconeogenesis. Additionally, in vivo, mTORC1 inhibition abolished insulin-mediated inhibitory effects in rat proximal tubules, although not in liver. These results indicate that insulin-stimulated proximal tubule sodium transport is mediated via the Akt2/mTORC2 pathway, whereas insulin-suppressed proximal tubule gluconeogenesis is mediated via the IRS1/Akt2/mTORC1/2 pathway. Thus, distinct pathways may play important roles in hypertension and hyperglycemia in metabolic syndrome and diabetes.
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Insulin is a potent inhibitor of hepatic glucose production (Brown et al., 1978,Rizza et al., 1981, Peak et al., 1998), although the effects of insulin on direct hepatic regulation of glucose output are dependent to a large extent on relative glucagon levels (Unger and Cherrington, 2012, Cherrington et al., 1998). The transition from glycogen utilization to glycogen synthesis is rapidly stimulated by insulin (Cersosimo et al., 2000, Chiasson et al., 1980), and glucokinase levels elevate quickly (Nouspikel and Iynedjian, 1992). Many of the other effects of insulin on hepatocytes are less rapid and involve altered transcription patterns, such as the down-regulation of genes that promote gluconeogenesis and hepatic glucose release.
Insulin acts as the major regulator of the fasting-to-fed metabolic transition by altering substrate metabolism, promoting energy storage, and helping activate protein synthesis. In addition to its glucoregulatory and other metabolic properties, insulin can also act as a growth factor. The metabolic and mitogenic responses to insulin are regulated by divergent post-receptor signaling mechanisms downstream from the activated insulin receptor (IR). However, the anabolic and growth-promoting properties of insulin require tissue-specific inter-relationships between the two pathways, and the nature and scope of insulin-regulated processes vary greatly across tissues. Understanding the nuances of this interplay between metabolic and growth-regulating properties of insulin would have important implications for development of novel insulin and IR modulator therapies that stimulate insulin receptor activation in both pathway- and tissue-specific manners. This review will provide a unique perspective focusing on the roles of “metabolic” and “mitogenic” actions of insulin signaling in various tissues, and how these networks should be considered when evaluating selective pharmacologic approaches to prevent or treat metabolic disease.
Severe catabolic state after an overnight fast in patients with chronic renal failure
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The kidney contains a gluconeogenic enzyme, glucose-6-phosphatase, and has gluconeogenic activity similar to that of the liver [1]. Gluconeogenesis is linked closely to energy supply and blood glucose levels in postabsorptive states [2–7]. In the fasting state, gluconeogenic regulation of blood glucose levels and energy supplies from the liver and kidney become more important [5].
Starvation causes more rapid development of a catabolic state in patients with liver cirrhosis than in normal subjects. Because the kidneys have a gluconeogenic activity similar to that of the liver, we tested whether patients with chronic renal failure develop a catabolic state after an overnight fast.
The effect of an overnight fast on diurnal changes in respiratory quotient (RQ) was studied in 12 normal subjects and 12 patients with stable chronic renal failure. Changes in RQ in the early morning after an overnight fast were also studied in 27 patients with chronic renal failure not on dialysis. We also examined the effect on RQ of consuming a light snack in the evening before the measurements.
The RQ before breakfast, but not at other times, was significantly lower in patients with renal failure than in normal subjects (0.824 ± 0.051 versus 0.868 ± 0.038, P < 0.05). This indicated that patients with renal failure had higher fat use and developed a catabolic state early in the morning. The RQ before breakfast showed significant inverse correlations with creatinine levels (r = −0.604, P < 0.001). Supplementation with a carbohydrate-rich snack in the evening resulted in a significant increase of 0.07 ± 0.04 (P < 0.05) in mean RQ in the early morning. This suggested that a late evening snack is useful for improving the catabolic state of patients with renal failure.
Starvation involving an overnight fast facilitates catabolism of visceral and muscle proteins in renal failure. This suggests that nutritional management of renal failure should focus not only on the contents of a meal, but also on the timing of the meal.
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The role of renal glucose production after an overnight fast and in response to different hormonal conditions has been debated. The aim of this study was to determine whether hyperglycemia, glucagon, or epinephrine can affect renal glucose production. In 18-hour fasted conscious dogs a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which 1 of 4 protocols was instituted. In G+E glucagon (1.5 ng · kg⁻¹ · min⁻¹; portally) and epinephrine (50 ng · kg⁻¹ · min⁻¹; peripherally) were increased, in G glucagon was increased alone, in E epinephrine was increased alone, and in C neither were increased. In G, E, and C, glucose was infused to match the hyperglycemia in G+E (∼250 mg/dL). The average net renal glucose output during the last 2 hours was not different from the basal values in any group. Furthermore, the changes in unidirectional renal glucose production were not significantly different among groups. Therefore, after an overnight fast in the conscious dog, the kidneys do not significantly contribute to overall glucose production or respond to glucagon or epinephrine.

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: Supported in part by grants from the American Diabetes Association and National Institutes of Health (DK49861) and General Clinical Research Center NIH Grant No. M01-RR10710.

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Regulation of splanchnic and renal substrate supply by insulin in humans

J Lipid Res

The relationship between gluconeogenic substrate supply and glucose production in humans

Am J Physiol

Contribution of net hepatic glycogenolysis to glucose production during early postprandial period

Am J Physiol

Hormones and substrates in the regulation of gluconeogenesis in fasting man

Adv Enzyme Regul

Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus

J Clin Invest

Differential time-course of glucagon's effect on glycogenolysis and gluconeogenesis in the conscious dog

Diabetes

Glucose clamp technique: A method for quantifying insulin secretion and resistance

Am J Physiol

Enhanced hepatic insulin sensitivity but peripheral insulin resistance in patients with type I (insulin-dependent) diabetes

Diabetologia

In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese subjects

J Clin Invest

Dose-response characteristics for effects of insulin on production and utilization of glucose in man

Am J Physiol

Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans

Diabetes

Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans

Am J Physiol

Peripheral effects of insulin dominate suppression of fasting hepatic glucose production

Am J Physiol

Renal gluconeogenesis. IV. Gluconeogenesis from substrate combinations

Acta Biol Med Ger

Renal glucose production during insulin-induced hypoglycemia in humans

Diabetes

Uptake and release of glucose by the human kidney: Postabsorptive rates and responses to epinephrine

J Clin Invest