Resolution of glucose intolerance in long-term high-fat, high-sucrose-fed mice

J Endocrinol. 2017 Jun;233(3):269-279. doi: 10.1530/JOE-17-0004. Epub 2017 Mar 30.


The high-fat, high-sucrose diet (HFSD)-fed C57Bl/6 mouse is a widely used model of prediabetes. However, studies typically implement a relatively short dietary intervention lasting between 4 and 16 weeks; as a result, little is known about how a long-term HFSD influences the metabolic profile of these mice. Therefore, the aim of this investigation was to examine the effects of consuming a HFSD for 42 weeks on the development of hyperinsulinaemia and glucose intolerance in male C57Bl/6 mice. Two cohorts of HFSD mice were studied at independent institutes and they underwent an oral glucose tolerance test (OGTT) with measures of plasma insulin and free fatty acids (FFA). Age-matched chow-fed control mice were also studied. The HFSD-fed mice were hyperinsulinaemic and grossly obese, being over 25 g heavier than chow-fed mice, which was due to a marked expansion of subcutaneous adipose tissue. This was associated with a 3-fold increase in liver lipid content. Glucose tolerance, however, was either the same or better than control mice due to the preservation of glucose disposal as revealed by a dynamic stable isotope-labelled OGTT. In addition, plasma FFAs were suppressed to lower levels in HFSD mice during the OGTT. In conclusion, we have made the paradoxical observation that long-term HFSD feeding results in the resolution of glucose intolerance in the C57Bl/6 mouse. Mechanistically, we propose that the gross expansion of subcutaneous adipose tissue increases the glucose disposal capacity of the HFSD-fed mouse, which overcomes the prevailing insulin resistance to improve glucose tolerance.

Keywords: diet-induced obesity; glucose tolerance; high-fat; high-sucrose diet; insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diet, High-Fat / adverse effects*
  • Dietary Carbohydrates / administration & dosage
  • Dietary Carbohydrates / adverse effects*
  • Drug Administration Schedule
  • Glucose / metabolism
  • Glucose Intolerance*
  • Hyperinsulinism / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / chemically induced
  • Sucrose / administration & dosage
  • Sucrose / adverse effects*
  • Time Factors


  • Blood Glucose
  • Dietary Carbohydrates
  • Sucrose
  • Glucose