Chronic intake of 4-Methylimidazole induces Hyperinsulinemia and Hypoglycaemia via Pancreatic Beta Cell Hyperplasia and Glucose Dyshomeostasis

Sci Rep. 2018 Nov 19;8(1):17037. doi: 10.1038/s41598-018-35071-6.


Caramel colours are the preferential food colouring agent globally, reaches wide age groups through eatables. Colas, a sweetened carbonated drink are most common caramel coloured beverage and its consumption is linked with diabetes, obesity, pancreatic cancer and other endocrine disorders. A major by-product produced during caramelization is 4-methylimidazole (4-MEI) that is detected in noteworthy concentrations in colas and other beverages. Previous studies revealed the neurotoxic and carcinogenic potential of 4-MEI in animals at higher doses but the effect of 4-MEI at theoretical maximum daily intake dose on glucose homeostasis is unexplored. Here, mice treated with 4-MEI (32 µg/kg bodyweight/day) for seven weeks exhibited severe hypoglycaemia and hyperinsulinemia mediated by hyperplasia of pancreatic beta cells and induces metabolic alterations. On combinatorial treatment, 4-MEI suppressed the glucogenic potential of non-artificial sweeteners and promotes lipogenesis. Furthermore, increased levels of C-peptide, LDL-cholesterol and triglycerides were observed in the humans with regular intake of 4-MEI containing beverages. In summary, 4-MEI induced pancreatic beta cell hyperplasia and leads to disruption of glucose and lipid homeostasis. This study suggests the need for further assessment and reconsideration of the wide usage of 4-MEI containing caramels as food additives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blood Glucose / metabolism*
  • Female
  • Food Coloring Agents / administration & dosage
  • Food Coloring Agents / toxicity
  • Homeostasis / drug effects*
  • Humans
  • Hyperinsulinism / chemically induced*
  • Hyperplasia / pathology
  • Hypoglycemia / chemically induced*
  • Imidazoles / administration & dosage*
  • Imidazoles / toxicity*
  • Insulin / blood
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Lipid Metabolism / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Oxidative Stress / drug effects


  • Blood Glucose
  • Food Coloring Agents
  • Imidazoles
  • Insulin
  • 4-methylimidazole