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How the Liver Affects Insulin and Vice Versa: Part 1 Carbohydrate Metabolism

The human body is able to maintain tight control of blood glucose despite varying glucose consumption, production, and utilization. Two key players involved in maintaining glucose homeostasis are the liver and the hormone insulin which affect each other through various direct and indirect mechanisms….

Insulin Physiology and Metabolism by the Liver

Insulin is produced by the β-cells of the pancreas in response to elevated blood glucose concentrations. The GLUT2 transporter on the β-cellplasma membrane allows free movement of glucose.1 Once inside the cell, glucose becomes phosphorylated by glucokinase to glucose-6-phosphate, which effectively traps the glucose within the cell. Then the process of glycolysis produces an increase in adenosine triphosphate (ATP), which blocks ATP-dependent K+ channels in the β-cell membrane. The resulting cell depolarization allows Ca2+ to enter the cell which triggers exocytosis of the insulin-containing granules.2 Insulin then makes its way to target tissues to affect anabolic and catabolic processes before it undergoes metabolism.

The two main organs that predominantly clear insulin from circulation are the liver and kidney. In a non-diabetic patient the liver clears about 60% of endogenous insulin via the hepatic portal vein while the kidney removes about 35-40%. In diabetic patients who rely on subcutaneous insulin injections this ratio is flipped; the kidney clears as much as 60% of exogenous insulin and the liver removes no more than 30-40%.3

Insulin Stimulates Glycogen Storage in the Liver

The major glucose transporter in the muscle, adipose and other target tissues is the GLUT4 transporter. When insulin binds to the insulin receptors on the surface of target cells, it stimulates translocation of GLUT4 transporters from storage vesicles to the plasma membrane. When glucose concentrations become lower and the amount of circulating insulin decreases, the GLUT4 transporters shift back to the storage vesicles from the plasma membrane to wait for future insulin signaling. Unlike these other tissues, glucose transport into the liver is not dependent on the GLUT4 transporter.4 Instead; the liver relies on another transporter that is not dependent on insulin.
Once glucose is transported inside the hepatocytes, insulin stimulates glycogen synthesis by the following mechanism:

  • Activation of the enzyme hexokinase = phosphorylation of glucose to glucose-6-phosphate
  • Activation of glycogen synthase = lengthening of glycogen chain5
Insulin Inhibits Glucose Production by the Liver

Glucose synthesis from the liver is complex and depends on availability of gluconeogenic precursors, nutritional status, and hormonal influence. Insulin exerts inhibitory actions on the following key enzymes:

  • Phosphoenolpyruvate carboxykinase (PEPCK) = catalyzes rate-limiting step of gluconeogenesis
  • Glucose-6-Phosphatase (G-6-Pase) = final step of gluconeogenesis (production of free glucose)

Another key element is insulin’s inhibitory effects on glycogenolysis.5 Although the exact mechanisms have not been fully elucidated, insulin directly inhibits glycogenolysis, especially at low concentrations. In addition, insulin profoundly decreases glucagon secretion by the alpha cells of the pancreas.5 This decrease in glucagon secretion decreases activation of glycogenolysis (as well as gluconeogenesis).

These actions result in lowered glucose production from the liver and highlight the importance of insulin’s regulatory effects on hepatic glucose production. It’s easy to see how insulin resistance in the liver is a major cause of fasting hyperglycemia in which case, the liver essentially dumps glucose into the bloodstream unregulated.

Ethanol-Induced Hypoglycemia in Patients taking Insulin or Insulin Secretagogues

The metabolism of alcohol occurs mainly in the liver and begins with the enzyme alcohol dehydrogenase which converts ethanol into acetaldehyde, which is then converted to acetic acid.This process occurs, however, not without trade-offs. The metabolism of alcohol suppresses the oxidation of other key nutrients and impacts glucose metabolism in the following ways7:

  • inhibits gluconeogenesis and glycogenolysis
  • suppresses metabolism of insulin
  • inhibits the beta-oxidation of fatty acids

Most studies in type II diabetic patients who acutely consume alcohol in a non-fasted state show no increased risk of hypoglycemia. However, in type II diabetic subjects treated with oral anti-diabetic medications that target insulin secretion (eg, sulfonylurea) a higher risk of hypoglycemia seems to be present.7 Furthermore, in type II diabetics that use insulin injections the same results are likely but currently there are not enough studies to confirm these effects. In type I diabetic patients who consume alcohol most studies confirm the well-known effects of hypoglycemia are due to the impairment of counter-regulatory hormones involved in the early responses to detect hypoglycemia.8

These effects may not be problematic in healthy individuals as the body is still able to compensate and maintain stable plasma glucose. However, in certain patients the risk of hypoglycemia may be increased due to factors such as amount of alcohol consumed and use of insulin or insulin secretagogues (eg, meglitinides & sulfonylureas).

Stay tuned for How the Liver affects Insulin and vice versa – part 2 Obesity and Lipid Metabolism

References:

1. McCall RH, Wiesenthal SR, Shi ZQ, et al: Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogsAm J Physiol 1998; 274:E346-E356

2. Lewis GF, Vranic M, Giacca A: Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humansAm J Physiol 1997; 272:E371-E378.

3.Nolte Kennedy M.S. Chapter 41: Pancreatic Hormones & Antidiabetic Drugs. In B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Clinical Pharmacology, 12e. Retrieved November 20, 2012 from http://www.accessmedicine.com.lp.hscl.ufl.edu/content.aspx?aID=55828662.

4. Petersen KT, Laurent D, et al: Mechanism by which Glucose and Insulin Inhibit Net Hepatic Glycogenolysis in Humans. J Clin Invest1998;101:1203-1209.

5. Barthel, Andreas and Dieter SchmollNovel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 285: E685–E692, 2003; 10.1152/ajpendo.00253.2003

6. Howard AA, Arnsten JH, Goureenvitch MN. Effect of alcohol consumption on diabetes mellitus: a systematic review. Ann Intern Med 2004; 140: 211–219.

7. Pietraszek A, Gregersen S, Hermansen K: Alcohol and type 2 diabetes. A review. Nutrition, Metabolism & Cardiovascular Diseases (2010) 20, 366e375

8. Richardson T, Weiss M, Thomas P, Kerr D. Day after the night before: influence of evening alcohol on risk of hypoglycemia in patients with type1 diabetes. DiabetesCare2005Jul;28(7): 1801e2.

Andre McMahon, Ben Mitrano, PharmD Candidates, University of Florida College of Pharmacy also contributed to this article