In inviting me to summarize the Workshop on Insulin and Cancer he intended to organize in Düsseldorf with his colleagues Chantelau and Eckel, Professor Zvi Laron wrote to me that he considered that I had the “honest Weltanschauung” needed to deal with this task. Before accepting, I had to refer to my German Dictionary to find the meaning of the word Weltanschauung. After discovering that it meant some kind of “honest philosophy or view of the world”, how could I have refused?
At first look, the words “insulin” and “cancer” appear antinomic. “Insulin” is the perfect lifesaving drug and “cancer” is still today often associated with suffering and premature death. It remains, however, that the mitogenic properties of insulin and the carcinogenicity of some insulin analogues that did not reach clinical development raise questions that may worry health care professionals and patients. It was the intent of the Workshop to answer some of these questions. The papers selected for this issue of the Archives should help the reader to formulate an opinion on this critical issue.
Insulin over the years
Before 1922, what we call today Type 1 diabetes was a lethal condition. After the discovery of insulin, hope for a normal life expectancy has been given to millions of diabetic patients. For the last 85 years, the production of insulin has changed dramatically. The pancreatic extract injected into Leonard Thompson on 11 January 1922 consisted of 15 ml of “thick brown muck” that was poorly tolerated at the injection site. Over the years, the pancreatic extracts have been purified and the duration of action of insulin prolonged by the addition of protamine, a salmon protein, or by zinc. Nevertheless the content of the vials injected to the patients up to the 1970s was contaminated by numerous proteins and peptides, including proinsulin, proinsulin derivatives, C-peptide, glucagon, VIP, somatostatin and others, to the point, at that time, that the word “dirty insulin” has been used. Consequently, the industry started to produce purified insulin that was still extracted from beef or pork pancreases. The next step has been to produce insulin that was chemically identical to the human hormone either by “humanisation” of porcine insulin (substitution of the porcine B-30 alanine by the human B-30 threonine) or by genetic engineering in micro-organisms. Today that is the insulin most largely used throughout the world, but some still argue that this is really “human insulin” since it is not extracted from human pancreases. As reviewed in the article by Rossetti et al., the industry is now producing and marketing various rapid-acting or long-acting insulin analogues. Their properties and safety will be considered below. It remains that insulin replacement today is far from reproducing the exquisite regulation of insulin release by the healthy B-cell of the islets of Langerhans. The insulin is injected in the wrong site (subcutaneously instead of intraportally), in shots (instead of a continuous low secretion associated with a prompt release in response to a meal, with a total lack of the physiological pulsatile secretion). Recent attempts to use “exotic” routes of insulin administration have failed (oral, rectal, transdermal…) or have been disappointing (nasal or pulmonary).
Insulin: A hormone that comes out of ages and interacts with closely related receptors
Having been found in most primitive organisms, insulin appears early in the ontogenesis and goes deep in the phylogeny. As recalled by Zvi Laron, insulin is not only a hormone affecting metabolic pathways, it is also a real “growth hormone”. To exert its effects, insulin reacts with membrane receptors that are closely related to receptors of the insulin-like growth factor (IGF) family. The papers by Werner et al., Frasca et al. and Mayer et al. deal with these issues.
The system is extremely complex: three ligands (insulin, IGF-1, IGF-2), three corresponding primary receptors, numerous hybrid receptors, various isoforms of those, interference of several binding proteins, etc. Furthermore, the expression of the above mentioned receptors has been shown to vary from individual to individual, from tissue to tissue, even possibly from cell to cell.
As discussed in the papers cited above, there is evidence that the insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) play a role in malignant transformation, progression, protection from apoptosis and metastasis. Some of the signalling events classically assigned to IGF-1 and 2 may well be also mediated by insulin. In that respect and as reviewed by Eckardt & Eckel and by Chantelau et al., some insulin analogues may show greater binding affinities to the insulin receptor or the IGF receptors and potentially have increased mitogenic properties. The finding reported by Mayer et al., that insulin glargine shows a significantly higher proliferative effect on MCF-7 breast cancer cells compared with several other insulin preparations clinically available, is of concern and certainly requires further investigations.
Epidemiological data
Accumulating epidemiological evidence show that excess body weight and the related insulin resistance/hyperinsulinemia are associated with a risk of several common adult cancers. As reviewed by Pisani and by Renehan et al. these include endometrium, post-menopausal breast, colon and kidney cancers. The mechanisms involved are still poorly understood.
Of particular interest, and discussed by Berster and Göke, is the colorectal cancer. The risk for this cancer is particularly high in Type 2 diabetes and seems to be even higher if patients are treated with sulfonylureas or insulin while metformin may have a protective effect. There is some evidence that elevated levels of insulin and free IGF-1promote proliferation of colon cells and lead to a “survival benefit” of transformed cells, ultimately resulting in colorectal cancer. Evidence is sufficiently strong to lead Berster and Göke to propose that all patients with Type 2 diabetes mellitus should be recommended to undergo colonoscopy before starting insulin therapy, and that screening intervals in these patients should not exceed five years.
What next?
Type 1 diabetes is a lethal condition if insulin is not administered and sadly this is confirmed every day in some developing countries where children, adolescents, young adults die because insulin is unavailable or because when it is available it is sometimes not affordable. In Type 2 diabetes, insulin may be required to ensure metabolic control and avoid, or at least delay, the devastative complications of the disease leading to disability and premature death.
It is the role of the industry to manufacture and distribute the best insulin preparations at the most reasonable cost. The industry should also take into consideration the expectations of the patients when these are based on solid evidence. Insulin analogues are welcome when they meet these criteria. They should be properly screened for potential mitogenic and oncogenic properties. Pharmacovigilance of patients receiving new insulin preparations should be established and maintained. Medicine in the 21st century should be based on evidence. An honest weltanschauung on the issue of “Insulin and Cancer” would lead me to conclude that there should not be unwarranted fears, only vigilance and more studies.