Emily Jane Gallagher

Minireview: IGF, Insulin, and Cancer

In recent years, the influence of the IGF system and insulin on cancer growth has been widely studied. Observational human studies have reported increased cancer mortality in those with obesity and type 2 diabetes, which may be attributable to hyperinsulinemia, elevated IGF-I, or potentially both factors. Conversely, those with low insulin, IGF-I and IGF-II levels appear to be relatively protected from cancer development. Initial attention focused on the role of IGF-I in tumor development. The results of these investigations allowed for the development of therapies targeting the IGF-I receptor signaling pathway. However, after in vitro and in vivo studies demonstrating that insulin may also play a significant and independent role in tumorigenesis, insulin is now receiving more attention in this regard. Some studies suggest that targeting insulin receptor signaling may be an important alternative or adjunct to targeting IGF-I receptor signaling. In this minireview, we discuss some of the recent in vitro, animal, and clinical studies that have elaborated our understanding of the influence of IGF and insulin on tumorigenesis. These studies have shed more light on the interaction between insulin and IGF signaling in cancer cells. They have made possible the development of novel targeted therapies and highlighted some of the potential future directions for research and therapeutics.

The proliferating role of insulin and insulin-like growth factors in cancer

Epidemiological studies have reported an increased risk of cancer in people with type 2 diabetes (T2DM) and obesity, related in part to hyperinsulinemia, secondary to insulin resistance. Hyperinsulinemia leads to increased expression of insulin-like growth factor (IGF)-I expression. In fact, increased insulin, IGF-I and IGF-II levels are associated with tumor growth in vitro, in animal models, and in epidemiological studies in humans. In this paper, we discuss the roles of insulin, IGF-I and IGF-II, their interaction with the insulin receptor (IR) and IGF-I receptor (IGF-IR), and their signaling pathways and regulation as these pertain to tumor growth. We explain how these pathways have been deciphered by in vitro and in vivo studies, and how they are being exploited in the development of targeted cancer therapies.

Insulin Resistance in Obesity as the Underlying Cause for the Metabolic Syndrome

The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and β cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic syndrome.

Diabetes, cancer, and metformin: connections of metabolism and cell proliferation

Diabetes is associated with an increased risk of developing and dying from cancer. This increased risk may be due to hyperglycemia, hyperinsulinemia, and insulin resistance or other factors. Metformin has recently gained much attention as it appears to reduce cancer incidence and improve prognosis of patients with diabetes. In vitro data and animal studies support these findings from human epidemiological studies. Metformin has multiple potential mechanisms by which it inhibits cancer development and growth. For example, metaformin inhibits hepatic gluconeogenesis, thus decreasing circulating glucose levels, and it increases insulin sensitivity, thus reducing circulating insulin levels. Intracellularly, metformin activates AMPK, which decreases protein synthesis and cell proliferation. Metaformin also reduces aromatase activity in the stromal cells of the mammary gland. Finally, metformin may diminish the recurrence and aggressiveness of tumors by reducing the stem cell population and inhibiting epithelial to mesenchymal transition. Here, we discuss the metabolic abnormalities that occur in tumor development and some of the mechanisms through which metformin may alter these pathways and reduce tumor growth.

OBESITY AND DIABETES: THE INCREASED RISK OF CANCER AND CANCER-RELATED MORTALITY

Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes.

Review of hemoglobin A1c in the management of diabetes

Hemoglobin HbA1c (A1c) has been used clinically since the 1980s as a test of glycemic control in individuals with diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that tight glycemic control, quantified by lower blood glucose and A1c levels, reduced the risk of the development of complications from diabetes. Subsequently, standardization of A1c measurement was introduced in different countries to ensure accuracy in A1c results. Recently, the International Federation of Clinical Chemists (IFCC) introduced a more precise measurement of A1c, which has gained international acceptance. However, if the IFCC A1c result is expressed as a percentage, it is lower than the current DCCT‐aligned A1c result, which may lead to confusion and deterioration in diabetic control. Alternative methods of reporting have been proposed, including A1c‐derived average glucose (ADAG), which derives an average glucose from the A1c result. Herein, we review A1c, the components involved in A1c formation, and the interindividual and assay variations that can lead to differences in A1c results, despite comparable glycemic control. We discuss the proposed introduction of ADAG as a surrogate for A1c reporting, review imprecisions that may result, and suggest alternative clinical approaches.

Obesity and type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence.

Both obesity and Type 2 diabetes are independently associated with an increased risk of developing cancer and an increased mortality. The etiology is yet to be determined but insulin resistance and hyperinsulinemia maybe important factors. Hyperglycemia, hyperlipidemia and inflammatory cytokines in addition to the insulin-like growth factors are also possible factors involved in the process.

The Metabolic Syndrome—from Insulin Resistance to Obesity and Diabetes

In todays society with the escalating levels of obesity, diabetes, and cardiovascular disease, the metabolic syndrome is receiving considerable attention and is the subject of much controversy. Greater insight into the mechanism(s) behind the syndrome may improve our understanding of how to prevent and best manage this complex condition.

Epidemiology and molecular mechanisms tying obesity, diabetes, and the metabolic syndrome with cancer.

It is well recognized that the world is witnessing an epidemic of obesity and type 2 diabetes (T2D). Numerous studies have shown that both obesity and T2D are associated with an increased risk for developing many of the common epithelial cancers as well as an increased risk of cancer-related mortality. There are many factors that are commonly associated with obesity, T2D, and the metabolic syndrome; these include lifestyle factors such as diet and physical inactivity and biological factors such as abdominal obesity, increased inflammation, dyslipidemia, hyperglycemia, and altered hormone and adipokine levels. Human, animal, and in vitro cell studies have examined the potential contribution of many of these factors to the development and growth of multiple cancers. In this review, we will present the epidemiological evidence for this association and then discuss the multiple factors that may play a role in the increased cancer risk and mortality in individuals with obesity, T2D, and the metabolic syndrome. ### Obesity and cancer The World Health Organization classifies weight in adults based on BMI, and many studies examine the link between obesity and cancer using BMI as a measure of obesity. The Cancer Prevention Study II (CPS II) examined the risk of cancer mortality in obese men and women in the U.S. They reported that obesity is associated with a significant increase in mortality from multiple cancers, including esophageal, colorectal, liver, gallbladder, pancreatic, breast, endometrial, cervical, ovarian, renal, brain, kidney, and prostate cancer; non-Hodgkin lymphoma; and multiple myeloma (1). A subsequent meta-analysis of 221 datasets revealed an increased incidence of many similar tumors associated with increased BMI, as well as thyroid cancer in both men and women and malignant melanoma in men (2). It has been estimated that overall overweight and obesity cause ~20% of all cancer cases (3). The highest association is between obesity and endometrial …

Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model.

Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE−/−), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE−/− and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE−/− mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE−/− mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE−/− mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased AktS473 phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated AktS473 phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE−/− mice is a favorable setting for mammary tumor growth and metastasis.