Proliferation of Colo-357 Pancreatic Carcinoma Cells and Survival of Patients With Pancreatic Carcinoma Are Not Altered by Insulin Glargine

Abstract

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 Ͻ 0.0001 for glargine, P ϭ 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 ϭ 0.4, threesample comparison).CONCLUSIONS -Regular human insulin and insulin glargine may be used to treat diabetes in patients with pancreatic cancer.

Does diabetes therapy influence the risk of cancer?

“…A pancreatic cancer cell line responded similarly to insulin glargine and human insulin, and survival of insulin glargine-treated patients following treatment for pancreatic cancer did not differ from that of patients on insulin or controls [34]. In another study, colorectal, breast and prostate cell lines showed proliferative changes and increased resistance to apoptosis in response to exposure to pharmacological doses of insulin glargine, insulin detemir and insulin lispro, but not to human insulin [35].…”

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“…This fi nding was supported by a 5-year prospective randomized controlled trial, which showed comparably low rates of DR progression (and other assessments of retinopathy) with insulin glargine and NPH insulin [61] . Finally, the turnover of human pancreatic cancer cells was unaff ected by insulin glargine, and survival of patients with pancreatic cancer after pancreatectomy surgery was not determined by the type of insulin used to treat Type 1 diabetes [47] .…”

“…The authors extended these in vitro fi ndings into a clinical context by following over 22 months the clinical progress of patients undergoing total or partial pancreatectomy intended to resect pancreatic carcinoma. The median survival time was 15 months; survival was not altered in patients with diabetes receiving insulin glargine compared with patients receiving regular human insulin, or in patients who had pancreatic cancer but no diabetes [47] . In terms of the use of insulin glargine and possible associations with cancer, several registry studies have proposed an increased risk of cancer in patients treated with insulin glargine [1,3,4] .…”

“…A study has linked intensive insulin therapy with pancreatic carcinoma, through altered IGF-1 signaling [62] . However, in another study by Erbel et al [47] , use of insulin glargine, or regular human insulin at low physiological concentrations (0.01 -1 nM) and at supraphysiological conditions (10 -100 nM), was not associated with increased proliferation or apoptosis of Colo-357 cells (human pancreatic carcinoma cells). The authors extended these in vitro fi ndings into a clinical context by following over 22 months the clinical progress of patients undergoing total or partial pancreatectomy intended to resect pancreatic carcinoma.…”

The insulin glargine dilemma: an opportunity for the diabetes community?

“…The number of hypoglycaemic episodes for a given level of HbA 1c , for example, is clearly an important issue, but only one among many. It is worthy of note that a head-to-head study comparing the effect of insulin glargine vs conventional insulin on the prognosis of patients following surgery for pancreatic cancer was sponsored by the German Research Foundation and a private charity organisation, not by the company [7]. The prospective study that addressed the possibility of deterioration of diabetic retinopathy with insulin glargine treatment [8] has been presented as evidence that the agent does not promote cancer development [9], but was neither designed nor powered to resolve this issue.…”