Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion-Induced Insulin Resistance

Diabetes. 2017 Jul;66(7):1871-1878. doi: 10.2337/db16-1475. Epub 2017 May 4.


Systemic hyperaminoacidemia, induced by either intravenous amino acid infusion or protein ingestion, reduces insulin-stimulated glucose disposal. Studies of mice suggest that the valine metabolite 3-hydroxyisobutyrate (3-HIB), fibroblast growth factor 21 (FGF21), adiponectin, and nonesterified fatty acids (NEFAs) may be involved in amino acid-mediated insulin resistance. We therefore measured in 30 women the rate of glucose disposal, and plasma 3-HIB, FGF21, adiponectin, and NEFA concentrations, under basal conditions and during a hyperinsulinemic-euglycemic clamp procedure (HECP), with and without concomitant ingestion of protein (n = 15) or an amount of leucine that matched the amount of protein (n = 15). We found that during the HECP without protein or leucine ingestion, the grand mean ± SEM plasma 3-HIB concentration decreased (from 35 ± 2 to 14 ± 1 µmol/L) and the grand median [quartiles] FGF21 concentration increased (from 178 [116, 217] to 509 [340, 648] pg/mL). Ingestion of protein, but not leucine, decreased insulin-stimulated glucose disposal (P < 0.05) and prevented both the HECP-mediated decrease in 3-HIB and increase in FGF21 concentration in plasma. Neither protein nor leucine ingestion altered plasma adiponectin or NEFA concentrations. These findings suggest that 3-HIB and FGF21 might be involved in protein-mediated insulin resistance in humans.

Trial registration: NCT01538836 NCT01757340.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / metabolism*
  • Aged
  • Amino Acids
  • Blood Glucose / metabolism*
  • Dietary Proteins / pharmacology*
  • Eating
  • Fatty Acids, Nonesterified / metabolism*
  • Female
  • Fibroblast Growth Factors / drug effects
  • Fibroblast Growth Factors / metabolism*
  • Glucose Clamp Technique
  • Humans
  • Hydroxybutyrates / metabolism*
  • Hypoglycemic Agents / pharmacology*
  • Insulin / pharmacology*
  • Insulin Resistance*
  • Leucine / pharmacology*
  • Middle Aged


  • Adiponectin
  • Amino Acids
  • Blood Glucose
  • Dietary Proteins
  • Fatty Acids, Nonesterified
  • Hydroxybutyrates
  • Hypoglycemic Agents
  • Insulin
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Leucine
  • 3-hydroxyisobutyric acid

Associated data