Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance

Authors: QUAYE, EMMANUEL - National Institute Of Diabetes And Digestive And Kidney Diseases; CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); CHUNG, STEPHANIE - National Institute Of Diabetes And Digestive And Kidney Diseases; BRYCHTA, ROBERT - National Institute Of Diabetes And Digestive And Kidney Diseases; CHEN, KONG - National Institute Of Diabetes And Digestive And Kidney Diseases; BROWN, REBECCA - National Institute Of Diabetes And Digestive And Kidney Diseases

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/17/2021
Publication Date: 10/25/2021
Citation: Quaye, E., Chacko, S., Chung, S.T., Brychta, R.J., Chen, K.Y., Brown, R.J. 2021. Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance. American Journal of Physiology - Endocrinology and Metabolism. 321:E795-E801. https://doi.org/10.1152/ajpendo.00281.2021.
DOI: https://doi.org/10.1152/ajpendo.00281.2021

Interpretive Summary: Insulin resistance is a condition when cells in muscles, fat, and liver don't respond well to insulin and are unable to easily take up glucose from circulation. In patients with insulin resistance, insulin-mediated suppression of glucose production from the liver is impaired and high, contributing to high blood glucose. Glucose production is energetically costly and that may contribute to increased energy expenditure. No studies have directly measured the energy expenditure attributable to glucose production from the liver in humans. The objective of this research was to determine energy expenditure attributable to glucose production from the liver in patients with different types of insulin resistance conditions and high glucose production rates, and obesity without diabetes. Scientists in Houston, Texas demonstrated that glucose production from the liver is a major contributor to energy expenditure in humans with insulin resistance. The findings from this study indicate that treatments for diabetes that reduce glucose production from the liver can therefore be expected to decrease energy expenditure, promoting weight gain.

Technical Abstract: Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6-2H2]glucose, and total GNG as fractional GNGxEGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may Underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance.