Folate treatment partially reverses gestational low-protein diet-induced glucose intolerance and the magnitude of reversal is age and sex dependent

Nutrition. 2018 May;49:81-89. doi: 10.1016/j.nut.2017.10.014. Epub 2017 Nov 13.


Objectives: Gestational low-protein (LP) programming causes glucose intolerance (GI) and insulin resistance (IR) in adult offspring. Folate supplementation has been shown to rescue the offspring from various programming effects. The aim of this study was to investigate whether folate supplementation during pregnancy reverses LP-induced GI and IR.

Methods: Pregnant rats were fed control (20% protein), isocaloric low-protein (LP, 6%) or LP with 5 mg/kg folate (LPF) diets from gestational day 4 to delivery. The control diet was given during lactation and to pups after weaning. Glucose tolerance test was done at 1, 2, and 3 mo of age followed by euglycemic-hyperinsulinemic clamp at 4 mo. Rats were sacrificed at 4 mo and their gonadal, renal, inguinal, brown fat, and pancreas were weighed and expressed relative to their body weight.

Results: LP- and LPF-fed dams showed similar weight loss during late pregnancy after decreased feed intake. Both LP and LPF pups were smaller at birth but their weights caught up like that of controls by 3 mo. In males, folate supplementation reduced LP-induced GI at 2 mo (glucose area under the curve [AUC]: 1940 mmol/L × 180 min in LP, 1629 mmol/L × 180 min in LPF, and 1653 mmol/L × 180 min in controls; P <0.05, LP versus control and P <0.01, LP versus LPF) but the effect diminished at 3 mo. In females, folate reduced GI at 1 mo (glucose AUC: 1406 mmol/L × 180 min in LP, 1264 mmol/L × 180 min in LPF, and 1281 mmol/L × 180 min in controls; P <0.05, LP versus control and LP versus LPF) but had no effect at 2 and 3 mo. Interestingly, the LPF group had higher pancreatic weights than other groups, suggesting that folate helps in pancreatic development enabling the LPF rats to produce/secrete more insulin to maintain euglycemia. Euglycemic-hyperinsulinemic clamp shows both LP and LPF are insulin resistant compared with controls by 4 mo with LPF more severe than LP in males. Interestingly, females were more insulin resistant than males.

Conclusions: Folate treatment partially reverses LP-induced GI and the magnitude of reversal is age and sex dependent. Furthermore, folate treatment does not reverse IR in either sex but makes it worse in males at 4 mo. The present study demonstrated that folate treatment is not sufficient to rescue the LP programming effects.

Keywords: Developmental programming; Folate; Glucose intolerance; Insulin resistance; Protein restriction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • Diet, Protein-Restricted / adverse effects*
  • Female
  • Folic Acid / administration & dosage*
  • Glucose Intolerance / etiology
  • Glucose Intolerance / physiopathology
  • Glucose Intolerance / therapy*
  • Glucose Tolerance Test
  • Humans
  • Insulin Resistance
  • Male
  • Maternal Nutritional Physiological Phenomena
  • Pregnancy
  • Pregnancy Complications / etiology
  • Pregnancy Complications / physiopathology
  • Pregnancy Complications / therapy
  • Prenatal Exposure Delayed Effects / etiology
  • Prenatal Exposure Delayed Effects / physiopathology
  • Prenatal Exposure Delayed Effects / therapy*
  • Rats
  • Rats, Wistar
  • Sex Factors
  • Treatment Outcome
  • Vitamin B Complex / administration & dosage*


  • Vitamin B Complex
  • Folic Acid