title: Insulin glargine and NPH insulin increase to a similar degree epithelial cell proliferation and aberrant crypt foci formation in colons of diabetic mice.
abstract: The insulin analog glargine has a higher binding affinity than regular insulin for the insulin-like growth factor 1 receptor in vitro, raising questions about increased mitogenicity in vivo. Observational studies in humans have recently reported a potential differential association between insulin glargine and malignancies, but available evidence remains inconclusive. We directly compared glargine vs. neutral protamine Hagedorn (NPH) insulin's effects on cell proliferation in colonic mucosa and on formation of aberrant crypt foci in diabetic mice, i.e., early stages of colorectal cancer development. Mice (BKS.Cg-+Lepr(db)/+Lepr(db)/OlaHsd) were treated with insulin glargine (G), NPH insulin (NPH), or saline (NaCl). We assessed epithelial proliferation after long-term insulin treatment (18 weeks) by 5-bromo-2'-deoxyuridine and Ki67 staining and analyzed the formation of aberrant crypt foci (ACF) in mice treated with insulin glargine or NPH insulin or 10 weeks after initiation with 1,2-dimethylhydrazine. Insulin glargine treatment did not result in significantly different epithelial colonic proliferation compared to NPH insulin (G, 137 ± 22; NPH, 136 ± 15; NaCl, 100 ± 20 (relative proliferation index)), but both insulin-treated groups of mice had a higher proliferation index compared to the NaCl control group (p<0.001). Similarly, we observed no difference in ACF formation between glargine- and NPH-insulin-treated mice (G, 132 ± 12; NPH, 138 ± 9; NaCl, 100 ± 7 (relative number of ACF)), but ACF formation was significantly higher in insulin-treated mice than in NaCl-treated control mice (p=0.001). Chronic insulin treatment results in higher colonic epithelial proliferation and ACF formation, but the use of insulin glargine vs. NPH insulin is not associated with increased risk.
authors.affiliation: Department of Medicine II, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, 81377 Munich, Germany. jnagel@bidmc.harvard.edu
authors.forename: Jutta M
authors.initials: JM
authors.lastname: Nagel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Staffa
authors.forename: Ingrid
authors.initials: I
authors.lastname: Renner-Müller
authors.forename: David
authors.initials: D
authors.lastname: Horst
authors.forename: Michael
authors.initials: M
authors.lastname: Vogeser
authors.forename: Markus
authors.initials: M
authors.lastname: Langkamp
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeflich
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Frank T
authors.initials: FT
authors.lastname: Kolligs
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D000069036:Insulin Glargine; D007336:Insulin, Isophane / Q000009:adverse effects*; D049528:Insulin, Long-Acting / Q000009:adverse effects*; D051379:Mice
chemical_list: D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D007336:Insulin, Isophane