Insulin detemir enhances proglucagon gene expression in the intestinal L cells via stimulating β-catenin and CREB activities

Am J Physiol Endocrinol Metab. 2012 Sep 15;303(6):E740-51. doi: 10.1152/ajpendo.00328.2011. Epub 2012 Jul 17.


Insulin therapy using insulin detemir (d-INS) has demonstrated weight-sparing effects compared with other insulin formulations. Mechanisms underlying these effects, however, remain largely unknown. Here we postulate that the intestinal tissues' selective preference allows d-INS to exert enhanced action on proglucagon (Gcg) expression and the production of glucagon-like peptide (GLP)-1, an incretin hormone possessing both glycemia-lowering and weight loss effects. To test this hypothesis, we used obese type 2 diabetic db/db mice and conducted a 14-day intervention with daily injection of a therapeutic dose of d-INS or human insulin (h-INS) in these mice. The body weight of the mice after 14-day daily injection of d-INS (5 IU/kg) was decreased significantly compared with those injected with the same dose of h-INS or saline. The weight-sparing effect of d-INS was associated with significantly elevated circulating levels of total GLP-1 and reduced food intake. Histochemistry analysis demonstrated that d-INS induced rapid phosphorylation of protein kinase B (Akt) in the gut L cells of normal mice. Western blotting showed that d-INS stimulated Akt activation in a more rapid and enhanced fashion in the mouse distal ileum compared with those by h-INS. In vitro investigation in primary fetal rat intestinal cell (FRIC) cultures showed that d-INS increased Gcg mRNA expression as determined by Northern blotting and real-time RT-PCR. Consistent with these in vivo investigations, d-INS significantly increased GLP-1 secretion in FRIC cultures. Consistently, d-INS was also shown to induce rapid phosphorylation of Akt in the clonal gut cell line GLUTag. Furthermore, d-INS increased β-catenin phosphorylation, its nuclear translocation, and enhanced cAMP response element-binding protein (CREB) phosphorylation in a phosphatidylinositol 3-kinase and/or mitogen-activated protein kinase kinase/extracellular signal-regulated kinase-sensitive manner. We suggest that the weight-sparing benefit of d-INS in mice is related to its intestinal tissues preference that leads to profound stimulation of Gcg expression and enhanced GLP-1 secretion in intestinal L cells, potentially involving the activation of insulin/β-catenin/CREB signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / agonists
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Fetus / cytology
  • Gene Expression Regulation / drug effects
  • Glucagon-Like Peptide 1 / blood
  • Glucagon-Like Peptide 1 / metabolism
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Detemir
  • Insulin, Long-Acting / pharmacology
  • Insulin, Long-Acting / therapeutic use*
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • L Cells
  • Mice
  • Mice, Mutant Strains
  • Obesity / complications
  • Obesity / prevention & control
  • Organ Specificity
  • Phosphorylation / drug effects
  • Proglucagon / genetics
  • Proglucagon / metabolism*
  • Protein Processing, Post-Translational / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • beta Catenin / agonists
  • beta Catenin / metabolism*


  • Cyclic AMP Response Element-Binding Protein
  • Hypoglycemic Agents
  • Insulin, Long-Acting
  • RNA, Messenger
  • beta Catenin
  • Insulin Detemir
  • Proglucagon
  • Glucagon-Like Peptide 1