WILLIAM H. BESTERMANN
“Traditional wisdom can be long on tradition and short on wisdom”
My colleagues have asked me about an article in Diabetes Care that shows roughly a 40% reduction in cancer risk in patients who are on insulin and treated concurrently with metformin. The reduction in cancer risk was attributed to beneficial effects of metformin. This information is not surprising. We have already gone into the metformin and cancer story in this space.
There is much more to this discussion however. High levels of insulin in the circulation may contribute to the development of cancer. Higher doses correlated with increased risk for all insulin types.
There are a number of ways for individuals to be exposed to abnormally high insulin levels. Overweight, insulin-resistant patients have insulin levels that are three times higher than those found in slender healthy young people. Certain medications like glyburide work by causing the pancreas to secrete more insulin. Most endocrinologists use large doses of insulin to treat type 2 diabetic patients that are very insulin resistant with high glucose levels that are hard to control. By using several insulin injections or insulin pumps they may treat these patients with hundreds of units of insulin a day. The risk of developing cancer is correlated with the insulin dose. Slender young patients who are not insulin resistant may only require twenty units of insulin daily.
The higher the insulin level in the circulation, the more likely the patient is to gain weight. This weight gain is not because of non-compliance on the part of the patient. It is instead related to the treatment selected by the physician treating the patient. Increased weight is itself correlated with higher risk of developing cancer.
Basic scientists are giving us the tools to have a better understanding of how this all might tie together. The overweight patient makes multiple hormones and signaling molecules in abdominal fat that are not normally present. These factors have a profound effect on the development of multiple chronic diseases in heavy patients but are especially important to understanding the increased cancer risk in individuals with increased insulin levels. One of these hormones is aldosterone and increased aldosterone is implicated in the development of the metabolic syndrome itself. Blockade of aldosterone effects may lead to reduced insulin and glucose levels. Increased aldosterone levels also activate signaling pathways that are enhance cancer development. (see page F1331) These pathways are oncogenic.
Aldosterone causes increased production of oxidative particles which leads to transactivation of the epidermal growth factor receptor (EGFR). Angiotensin II, another critical signaling molecule in hypertension also increases oxidative particles and activates EGFR. Alterations in EGFR may result in cancer and members of this growth factor family are prominent in breast cancer.
In the diagram above, all of the signaling molecules below EGFR participate in cancer development. They are oncogenic. Any one of several growth factors can be substituted in the EGFR position and these factors are likewise oncogenic. Most importantly, insulin and insulin like growth factor can be substituted in this position and would be expected to favor cancer development.
In fact, all of the growth factors tested, including insulin and IGF-1, activated the Ras/Raf/Erk ½ signaling pathway in a manner that would foster and maintain cancer development. Understanding this segment of cancer science has led for the first time to more targeted and effective treatments for malignant melanoma.
Very recently I attended a meeting of professional people who are very dedicated to the treatment of diabetes. One of the faculty discussed new developments in diabetes and talked about the beneficial effects of metformin and cancer. This person did not believe that insulin contributed to cancer development. I think that statement reflects a much larger problem in diabetic management and the treatment of chronic conditions in general. It really does not matter what we believe. We need to learn this new science. The same pathways are involved in multiple chronic conditions and that fact has tremendous implications for the design of new systems of care. We will need very well trained generalists to understand pathway science to coordinate and integrate the treatment of chronic disease.
We are about to make some big mistakes in diabetic management policy. The leaders in diabetic care are still behaving as if diabetes is a glucose disease. The high glucose that establishes the diagnosis of diabetes is a late manifestation of complex metabolic processes that increase the risk of cancer, heart attack, stroke, cirrhosis etc. The same metabolic processes that cause fatty liver and liver cell death leading to cirrhosis also cause pancreatic cell death, loss of insulin production and diabetes. These pathways foster cellular proliferation and cancer when persistently and abnormally activated.
The ACCORD trial was designed to show that lowering the glucose to near normal by whatever means would reduce cardiovascular events. It did not. 20% more people died and the trial was stopped early by the safety committee. Patients in the ACCORD trial received large amounts of insulin and gained weight. Many of the patients died suddenly and the deaths were blamed on hypoglycemia which was a frequent problem in the trial. Diabetologists are now saying that we should be less aggressive in the treatment of high risk patients. . In other areas of risk management, the sickest and highest risk patients benefit the most from aggressive treatment.
We are taking away the wrong message. The successful management of chronic disease including diabetes will not come without deep understanding of the metabolism that links these conditions. It is how we lower the glucose that makes all the difference. The Steno 2 trial showed reductions in death, heart attack, stroke and dialysis by using a protocol approach. There are many interventions that lower glucose and do not involve insulin. Aldosterone blockers, Angiotensin blockers, metformin, Byetta, Victoza, and Symlin all lower glucose while reducing insulin requirements and/or insulin resistance. Insulin is essential to the successful management of diabetes and we use it early. We are always working to find ways to achieve aggressive control without hypoglycemia or weight gain and while using the least amount of insulin that we can to accomplish good control.
By considering all of these factors we have produced aggressive control of diabetes in high risk patients with minimal hypoglycemia and modest weight loss rather than weight gain. Carefully integrating these treatments in a Steno like protocol will prove to be the better approach. Aggressive management of high risk patients is still important-it is all about how you do it.
Bill Bestermann is a vascular physician at the Holston Medical Group in Kingsport, TN.