Diabetes and cancer

The U.S. incidence of both diabetes mellitus and cancer is increasing. Approximately 1.6 million new cases of diabetes mellitus and 1.4 million of cancer are diagnosed every year.

Pankaj Shah, M.D., of the Division of Endocrinology, Diabetes, Metabolism, & Nutrition at Mayo Clinic, says: "Evidence suggests that these 2 common conditions coexist more often than would be expected to occur by chance.

"Large cohort studies show that pancreatic, colorectal, breast, hepatobiliary, bladder, and endometrial cancers occur more frequently in people with type 2 diabetes. Potential reasons behind this association include common causality (shared risk factors), hyperglycemia, and other metabolic abnormalities of type 2 diabetes that cause cancer, and cancer that causes hyperglycemia."

Older age, male sex, obesity, diminished physical activity, a diet high in calories and glycemic index, excessive alcohol intake, and tobacco smoking are associated with increased risk of diabetes, as well as many cancers.

Mechanisms linking cancer and diabetes mellitus

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Dr. Shah explains: "A common thread for many of these risk factors is hyperinsulinemia. Insulin induces cell proliferation. Hyperinsulinemia, insulin resistance, and obesity are associated with increased estrogens, endometrial hyperplasia, and breast and endometrial cancers.

"Obesity is also associated with increased insulinlike growth factor 1 (IGF-1) activity due to reduced levels of insulinlike growth factor binding proteins 1 and 2. Most malignant cells express IGF-1 receptors. Activation of IGF-1 receptors by IGF-1 or insulin, or both, is thought to have an important role in carcinogenesis. Whether exogenously administered insulin used to control hyperglycemia promotes cancer growth in vivo is still an open question."

In 1956, Otto Warburg proposed that cancer cells preferentially use large amounts of glucose through glycolysis to produce lactate, whereas most nonmalignant cells completely oxidize glucose through the citric acid cycle. Potential mechanisms linking cancer and type 2 diabetes include the following:

• Glycolysis upregulation may support carcinogenesis. Cancer cells may have a defective mitochondrial metabolism and may have overexpression of the glucose transporter GLUT-1.
• Hyperglycemia may be responsible for excess glucose supply to these glucose-hungry cells, resistance to apoptosis, oncogenesis, and tumor cell resistance to therapy. However, hyperglycemia associated with type 1 diabetes is not associated with these cancers. Moreover, hyperglycemia correction has yet to show reduction in cancer incidence in people with type 2 diabetes.
• Hyperglycemia and hyperinsulinemia are associated with endothelial proliferation and neovascularization (in the retina). Vascular growth is essential to the fuel supply required for malignancy maintenance. Therefore, it is conceivable that vascular growth is stimulated in people with type 2 diabetes, thus promoting cancers.
• Some cancers (such as pancreatic cancer) are associated with newly diagnosed diabetes.
• Cytokines and other substances released from cancers can cause hyperglycemia by inducing insulin resistance.
• Cancer-related decreased physical activity can reduce insulin sensitivity.
• Cancers are associated with varying degrees of cachexia, and cachexia-associated muscle wasting leads to insulin resistance.

Managing diabetes in patients with cancer

Treating diabetes in a person with active cancer is often complicated by the cancer, cancer therapies, and the adverse effects of treatment (such as anorexia, nausea, weight loss). Acute diabetes complications and the urgency of treating severe hyperglycemia may delay cancer treatment.

Dr. Shah advises: "Tight glycemic control carries clinically important risks without clear benefits in patients with cancer. The goals of therapy should be to prevent marked hyperglycemia (>180 mg/dL) and the adverse effects of treatment (eg, hypoglycemia, anemia, increased risk of fractures).

"Hyperglycemia first recognized during cancer therapy should not be neglected, and the patient and the family should be taught to monitor blood glucose concentrations. Hyperglycemia can and possibly will occur again during subsequent treatment cycles. If hyperglycemia is recognized and appropriately treated, severe acute hyperglycemic complications can be prevented.

"The health care provider must understand the patient's distressing situation. We take special care to share with the patient and the family that we understand their difficult situation. We tell them that we know that they are likely overwhelmed by the complexity of their multiple therapies and the adverse effects emanating from cancer and cancer therapies.

"Usually, this conversation is followed with clarification of the purpose of home glucose monitoring and hyperglycemia therapy. We stress that our goal is to prevent severe acute hyperglycemic and infective complications while avoiding complications from hyperglycemia therapies and ensuring timely optimal cancer therapy. Patients often participate in the decision making about the goals and modes of hyperglycemia therapies."

Choosing antidiabetic agents

Marked hyperglycemia is associated with poor outcomes in cancer patients. Thus, most experts recommend treatment of severe hyperglycemia.

Growing evidence shows that metformin use is associated with lower cancer incidence and lower cancer mortality rate than is treatment with sulfonylureas or insulin. The adenosine monophosphate-activated protein kinase (AMPK) pathway is involved in cancer growth, and metformin activates AMPK.

Currently, 10 studies registered at clinicaltrials.gov are investigating possible benefits of metformin in cancer patients. These studies include patients with advanced cancers and patients with breast, pancreatic, and prostate cancers.

Mutation of peroxisome proliferator-activated receptor g (PPAR-g) is involved in carcinogenesis. Thiazolidinediones are PPAR-g agonists and are being investigated to see whether they enhance outcomes from anticancer therapy in patients with breast, lung, prostate, and head and neck carcinomas; sarcoma; and premalignant conditions.

Clinical use of antidiabetic agents

Dr. Shah recommends: "If tolerated and not contraindicated, metformin is the first line oral agent. Metformin may cause nausea and diarrhea, which can be confused with complications of cancer or its therapies.

"Insulin is usually effective in controlling severe hyperglycemia. In our experience, intensive insulin therapy using multiple insulin injections may be easier, providing the patient with freedom of time and amount of food.

"The so-called sliding scale insulin regimen is associated with the worst glycemic extremes and should be avoided. If diabetes is treated with agents that predispose to hypoglycemia (eg, sulfonylureas, other insulin secretagogues, intermediate-acting or mixed insulin), meals should be timed throughout the day.

"When life expectancy with terminal cancer is brief, blood glucose monitoring is performed only when symptom control requires it, with the sole aim of making the person comfortable."