A Spatial Model of Hepatic Calcium Signaling and Glucose Metabolism Under Autonomic Control Reveals Functional Consequences of Varying Liver Innervation Patterns Across Species

Rapid breakdown of hepatic glycogen stores into glucose plays an important role during intense physical exercise to maintain systemic euglycemia. Hepatic glycogenolysis is governed by several different liver-intrinsic and systemic factors such as hepatic zonation, circulating catecholamines, hepatocellular calcium signaling, hepatic neuroanatomy, and the central nervous system (CNS). Of the factors regulating hepatic glycogenolysis, the extent of lobular innervation varies significantly between humans and rodents. While rodents display very few autonomic nerve terminals in the liver, nearly every hepatic layer in the human liver receives neural input. In the present study, we developed a multi-scale, multi-organ model of hepatic metabolism incorporating liver zonation, lobular scale calcium signaling, hepatic innervation, and direct and peripheral organ-mediated communication between the liver and the CNS. We evaluated the effect of each of these governing factors on the total hepatic glucose output and zonal glycogenolytic patterns within liver lobules during simulated physical exercise. Our simulations revealed that direct neuronal stimulation of the liver and an increase in circulating catecholamines increases hepatic glucose output mediated by mobilization of intracellular calcium stores and lobular scale calcium waves. Comparing simulated glycogenolysis between human-like and rodent-like hepatic innervation patterns (extensive vs. minimal) suggested that propagation of calcium transients across liver lobules acts as a compensatory mechanism to improve hepatic glucose output in sparsely innervated livers. Interestingly, our simulations suggested that catecholamine-driven glycogenolysis is reduced under portal hypertension. However, increased innervation coupled with strong intercellular communication can improve the total hepatic glucose output under portal hypertension. In summary, our modeling and simulation study reveals a complex interplay of intercellular and multi-organ interactions that can lead to differing calcium dynamics and spatial distributions of glycogenolysis at the lobular scale in the liver.

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Autoregulation of hepatic glucose production

Acta Endocrinologica ◽

10.1530/eje.0.1380240 ◽

1998 ◽

pp. 240-248 ◽

Cited By ~ 77

Author(s):

MC Moore ◽

CC Connolly ◽

AD Cherrington

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glycogen ◽

Neural Pathways ◽

Hepatic Glucose Output ◽

Counterregulatory Hormones ◽

Hepatic Glucose ◽

Glucose Output

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

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Metabolic Effects of Metformin in Humans

Current Diabetes Reviews ◽

10.2174/1573399814666181009125348 ◽

2019 ◽

Vol 15 (4) ◽

pp. 328-339 ◽

Cited By ~ 5

Author(s):

María M. Adeva-Andany ◽

Eva Rañal-Muíño ◽

Carlos Fernández-Fernández ◽

Cristina Pazos-García ◽

Matilde Vila-Altesor

Keyword(s):

Insulin Resistance ◽

Glycogen Synthesis ◽

Metabolic Effects ◽

Hepatic Glycogen ◽

Insulin Deficiency ◽

Indirect Pathway ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Patients With Diabetes ◽

Glucose Output

Background: Both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and postprandial hyperglycemia in patients with diabetes. Introduction: Metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive. Results: Patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from “de novo” synthesized glucose) owing to insulin deficiency and glucagoninduced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves β-cell function in patients with type 2 diabetes. Conclusion: Several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown.

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Early glycogenolysis and late glycogenesis in human liver after intravenous administration of galactose

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.270.1.g14 ◽

1996 ◽

Vol 270 (1) ◽

pp. G14-G19 ◽

Cited By ~ 2

Author(s):

R. Fried ◽

N. Beckmann ◽

U. Keller ◽

R. Ninnis ◽

G. Stalder ◽

...

Keyword(s):

Magnetic Resonance ◽

Competitive Inhibition ◽

Glycogen Synthesis ◽

Liver Volume ◽

Hepatic Glycogen ◽

Resonance Spectroscopy ◽

Hepatic Glucose Output ◽

Glycogen Concentration ◽

Hepatic Glucose ◽

Glucose Output

Galactose is incorporated by a different metabolic pathway than glucose. Its contribution to glycogen synthesis has not been studied in humans. We administered galactose (0.5 g/kg iv) to overnight-fasted normal human volunteers and examined its effects on hepatic glycogen synthesis and hepatic glucose output (HGO). Hepatic glycogenesis was assessed noninvasively, determining glycogen concentration by 13C magnetic resonance spectroscopy (MRS) and liver volume by magnetic resonance imaging. HGO was determined by [6,6-2H2]glucose and gluconeogenesis calculated by adding the amount of hepatic glycogenesis to the HGO. After galactose administration, liver glycogen concentration (baseline 254 +/- 11 mmol/l) decreased in the first 45 min to 207 +/- 15 mmol/l (P < 0.05) and increased thereafter to 313 +/- 7 mmol/l (P < 0.01). Net hepatic glycogenesis was 101 +/- 12 mmol over 150 min. HGO (baseline 14.3 +/- 1.9 mumol.kg-1.min-1) increased threefold in the first 15 min and then returned to baseline. The average rate of gluconeogenesis was 12.3 mumol.kg-1.min-1. Intravenous galactose leads to an increase in hepatic glycogen and hepatic glucose output in normal humans. Competitive inhibition of UDP-glucose pyrophosphorylase by UDP-galactose could explain the apparent glycogenolysis observed early after galactose administration. 13C MRS in combination with a stable isotope tracer is a noninvasive and safe method to study hepatic carbohydrate metabolism in humans.

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