More and more people are living with an increased quantity of fat in the liver (metabolic fatty liver disease). Fatty liver is closely associated with excess weight and is key to the development of metabolic syndrome, including cardiovascular disease and type 2 diabetes.

In a review in the January 2021 Journal of Clinical Medicine, we elucidate the effect of increased liver fat on the liver’s glucose- and insulin metabolism, and the possible underlying molecular mechanisms.

Our conclusion is that fatty liver is strongly associated with reduced insulin-mediated suppression of hepatic glucose production and reduced insulin clearance, causing increased peripheral insulin concentrations, which affects the body’s glucose metabolism and may ultimately be contributory to the development of type 2 diabetes.

Background to the research
When the amount of liver fat increases, independently of body weight, the suppressant effect of insulin on the liver’s glucose production is reduced. This causes the liver to produce greater quantities of glucose, both during fasting and after a meal. The molecular basis of this is an increased formation of glucose from substrates such as lactate and amino acids and, to a lesser extent, an increased breakdown of the liver’s glycogen deposits. Insulin, which is secreted from the pancreas is transported to the liver via the portal vain   and approximately 60-70% is cleared in the liver before it reaches the systemic circuit. When fat is accumulated in the liver, the liver’s ability to clear insulin is impaired, so that greater quantities of insulin reaches the systemic circuit and peripheral tissues such as fat and muscles. It was previously thought that this increased insulin concentration was the body’s attempt to compensate for reduced insulin sensitivity in fat and muscle, but in fact it is unknown whether the high insulin concentration might be an aggravating factor in the peripheral tissue becoming less sensitive to insulin.

It is known that weight loss reduces the quantity of liver fat and simultaneously normalize the liver’s glucose production and insulin clearance. What is particularly interesting is that the effect on the liver seems to happen within few days of dietary changes, before significant weight loss has occurred. Hence beneficial effects on the liver’s glucose metabolism and insulin clearance are observed within days after gastric bypass surgery before major weight loss has occurred. Recent research indicates that a reduction in the carbohydrate content of the diet has especially beneficial effects on liver fat content, glucose metabolism and insulin clearance after just a few days. The liver is therefore a highly dynamic organ that can alter the quantity of liver fat after few days of changes in dietary composition or calorie availability, resulting in changes in the liver’s insulin sensitivity and insulin clearance.

As stated, our conclusion is therefore that fatty liver is strongly associated with reduced insulin-mediated suppression of hepatic glucose production and reduced insulin clearance. This raises peripheral insulin concentration, which affects the body’s glucose metabolism and may – ultimately – be contributory to the development of type 2 diabetes.

The review was written by Amalie London (MD, PhD student), Anne-Marie Lundsgaard (PhD, postdoc), Bente Kiens (Professor) and Kirstine Nyvold Bojsen-Møller (MD, PhD)

CONTACT
Amalie London, MD and PhD student Department of Endocrinology Hvidovre Hospital
amalie.london@regionh.dk

READ THE ARTICLE HERE
London, A. et al. (2021) ‘The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis — Dysregulation by the Liver’ // https://www.mdpi.com/2077-0383/10/3/390
Published: 20 January 2021