Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance

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 GNG × EGP. 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.NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.

Keywords: energy expenditure; gluconeogenesis; insulin resistance.

Figure 1.

Energy expenditure attributable to gluconeogenesis (GNG) and fat-free mass (FFM). A: FFM correlated with resting energy expenditure (REE); however, there were no between-group differences in FFM-adjusted REE (B). C: there was a trend toward significant correlation between FFM and GNG. D: after adjusting for age and FFM, absolute GNG correlated with REE among patients with insulin receptor pathogenic variants (INSR, squares), lipodystrophy (LD, circles), type 2 diabetes (T2DM, triangles, diamonds), and obesity (x-sign). P < 0.05 represented statistical significance.

Figure 2.

Measures of gluconeogenesis (GNG) and energy expenditure. Absolute GNG (A) adjusted for fat-free mass was the highest in patients with severe insulin resistance [insulin receptor pathogenic variants (INSR, squares) and lipodystrophy (LD, circles)] vs. mild insulin resistance [type 2 diabetes (T2DM, triangles and diamonds) and obesity (x-sign)]. Estimated GNG energy expenditure (EE; B) was higher in INSR vs. obesity. Predicted GNG EE (product of the EE attributable to GNG and published GNG rates in lean nondiabetic adults) (C) was the lowest in INSR vs. all other groups. Mean excess GNG EE (D) equaled 12% of REE and mean GNG EE (E) equaled 29% of REE. These results suggest that the higher the rates of GNG, the more significant the proportion of resting EE accounted for by GNG. The Mifflin St. Jeor equation (F) underestimated REE. Between-group comparisons between GNG rates, GNG EE, predicted GNG EE, and excess GNG EE were made using analysis of variance (ANOVA), with post hoc pairwise by Tukey’s test. Difference in mean REE between measured (indirect calorimetry) and Mifflin St. Jeor equation [Men: 10 × weight (kg) + 6.25 × height (cm) − 5 × age (yr) + 5; Women: 10 × weight (kg) + 6.25 × height (cm) − 5 × age (yr) − 161] was made using paired t test. P < 0.05 represented statistical significance. P values are two sided. *Indicates statistical significance.