Changting Xiao, Satya Dash, Cecilia Morgantini, Khajag Koulajian, and Gary F. Lewis Evaluation of the Effect of Enteral Lipid Sensing on Endogenous Glucose Production in Humans Diabetes 2015;64:2939–2943 | DOI: 10.2337/db15-0148 Administration of lipids into the upper intestine of rats has been shown to acutely decrease endogenous glucose production (EGP) in the preabsorptive state, postulated to act through a gut-brain-liver axis involving accumulation of long-chain fatty acyl-CoA, release of cholecystokinin, and subsequent neuronal signaling. It remains unknown, however, whether a similar gut- brain-liver axis is operative in humans. Here, we infused 20% Intralipid (a synthetic lipid emulsion) or saline intraduodenally for 90 min at 30 mL/h, 4 to 6 weeks apart, in random order, in nine healthy men. EGP was assessed under pancreatic clamp conditions with stable isotope enrichment techniques. Under these experi- mental conditions, intraduodenal infusion of Intralipid, compared with saline, did not affect plasma glucose concentration or EGP throughout the study period. We conclude that Intralipid infusion into the duodenum at this rate does not elicit detectable effects on glucose homeostasis or EGP in healthy men, which may reflect important interspecies differences between rodents and humans with respect to the putative gut-brain-liver axis. Endogenous glucose production (EGP), mainly by the liver, plays an important role in regulating glucose homeostasis. In patients with type 2 diabetes, impaired insulin action in insulin-sensitive tissues such as the liver, skeletal muscle, and adipose tissue contributes to hyperglycemia. Hepatic glucose production is inappropriately elevated and is a major determinant of fasting hyperglycemia in this condition (1). Studies in rodents suggest that EGP is subject to neuronal regulation involving nutrient sensing in the hypothalamus (2,3) and in the small intestine (4). Intraduodenal administration of lipids, particularly long- chain fatty acids (LCFAs), has been shown to reduce food intake in both rodents and humans (5,6) and to suppress EGP profoundly and rapidly in rats under experimental conditions. EGP was suppressed by .50% during a 50-min intraduodenal infusion of Intralipid under con- ditions of a pancreatic insulin clamp, and plasma glucose concentration was lowered by ;20% 15 min after intra- duodenal infusion of Intralipid in nonclamped conditions (4). This effect occurred prior to significant absorption of the lipids, as evidenced by the absence of elevations in plasma free fatty acid (FFA) or triglyceride (TG) levels (4). Based on studies in rats, upper intestinal lipid sensing lowers EGP via a gut-brain-liver axis (4,7,8). Since this occurred at a time when insulin levels at the liver were lower than would be present during a meal, the physio- logical role of this pathway in regulating glucose homeo- stasis during food consumption remains unclear. The role of upper intestinal lipid sensing and the potential existence of a gut-brain-liver axis in the reg- ulation of glucose homeostasis have not previously been investigated in humans, hence the aim of the current study. We assessed EGP during infusion of either normal saline or Intralipid into the duodenum in healthy men. Intralipid is an emulsion consisting of predominantly long-chain polyunsaturated fatty acids that has been used to demonstrate a gut-brain-liver axis in rats (4). The choice of infusion rate could not easily be extrapolated from previous rat studies. We chose to infuse Intralipid at a rate that has been demonstrated in humans to inhibit food intake and induce cholecystokinin (CCK) release (9), which is believed to mediate the gut-brain signaling effect in the regulation of satiety in humans (10,11). Higher Division of Endocrinology & Metabolism, Departments of Medicine and Physiology, University of Toronto, Toronto, Canada, and Banting & Best Diabetes Centre, University of Toronto, Toronto, Canada Corresponding author: Gary F. Lewis, gary.lewis@uhn.ca. Received 30 January 2015 and accepted 4 March 2015. C.X. and S.D. contributed equally to this work. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Diabetes Volume 64, August 2015 2939 PATHOPHYSIOLOGY Downloaded from http://diabetesjournals.org/diabetes/article-pdf/64/8/2939/581275/db150148.pdf by guest on 29 September 2023