Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years
OBJECTIVE It was reported that the long-acting insulin analogue glargine induces cell proliferation in a human osteosarcoma cell line and therefore might induce or accelerate tumor growth. Induction of cell proliferation would be particularly relevant for insulin treatment of subjects with diabetes and the potential of bearing tumor cells (e.g., a history of a malignant disease). RESEARCH DESIGN AND METHODS Proliferation, apoptosis, and the expression levels of insulin receptor, IGF-I receptor, and insulin receptor substrate (IRS) 2 were analyzed in human pancreatic cancer cells (Colo-357) after incubation (72 h) with insulin glargine or regular human insulin at 0-100 nmol/l. A total of 125 subjects, after partial or total pancreatectomy due to pancreatic carcinoma, were analyzed over a median follow-up period of 22 months. RESULTS There was no significant difference between glargine and regular human insulin with respect to regulation of proliferation and apoptosis of Colo-357 cells. The expression levels of insulin receptor, IGF-I receptor, and IRS2 as a downstream molecule of both receptor signaling pathways were not altered at any concentration tested. The insulin receptor was downregulated to a similar degree by glargine and regular human insulin at high insulin concentrations (P < 0.0001 for glargine, P = 0.002 for regular human insulin). The median survival time after pancreatic surgery was 15 months. Survival analysis showed that the time-dependent proportion of patients who survived was identical in patients receiving insulin glargine versus insulin treatment without glargine and control subjects without diabetes after surgery (P = 0.4, three-sample comparison). CONCLUSIONS Regular human insulin and insulin glargine may be used to treat diabetes in patients with pancreatic cancer.