UBC scientists have demonstrated for the first time a causal link between high insulin levels and pancreatic cancer.
In a study published today in Cell Metabolism, researchers lowered insulin levels in mice predisposed to developing pancreatic cancer and found that these lower levels protected the mice against developing the disease.
The findings hold promise for early detection and prevention of pancreatic cancer in humans.
“Pancreatic cancer can be tricky to detect and is too often diagnosed at a late stage, making it one of the deadliest cancers,” said James Johnson, senior co-author of the study, a professor and member of the Diabetes Research Group in the Life Sciences Centre at UBC.
“The five-year-survival rate is less than five percent, and incidences of the disease are increasing alongside obesity.”
Hyperinsulinemia, a condition in which the body produces more insulin than it needs to control blood sugar levels, is increasingly common, found in more than one-third of obese adults, and can be modulated by diet and lifestyle factors.
“The link between hyperinsulinemia has actually been found across multiple cancers, including breast cancer, but pancreatic cancer has the strongest link,” said Janel Kopp, senior co-author and associate professor in the department of cellular and physiological sciences.
“Our experiment is the first to directly test that hypothesis, in any cancer, in any animal model.”
For the study, lead author and Ph.D. student Anni Zhang crossed a strain of mice that is genetically incapable of developing a rise in insulin with a strain of mice predisposed to developing pancreatic cancer.
These and the control mice were fed a diet for a year that was known to increase insulin levels and promote pancreatic cancer.
At the end of the yearlong study, the mice with slightly reduced insulin levels were shown to be protected from the start of pancreatic cancer.
“No matter whether you look at the entire pancreas, lesions or tumours, less insulin meant reduced beginnings of cancer in the pancreas,” Johnson said.
“We don’t see a reason why this wouldn’t be generalizable to other cancers,” added Kopp, noting they used the same mutation as 90 percent of pancreatic cancers in people. “Our mouse models are extremely relevant to people.”
In addition to examining the relationship between insulin levels and other cancers, the scientists would like to investigate whether decreasing excess insulin produced by the body could positively influence later stages of pancreatic cancer.
They plan to work with colleagues at BC Cancer on human clinical trials.
Obesity, Chronic Inflammation, and Insulin Resistance
Obesity is a disease characterized by chronic low-grade inflammation and insulin resistance (IR).
Adipose tissue acts as an endocrine organ and secretes a large number of proteins, which regulate metabolism, energy intake, and fat storage such as leptin, adiponectin, interleukin- (IL-) 6, and tumor necrosis factor alpha (TNF-α) [1].
The chronic inflammatory state created by high cytokine levels generates a pro-tumorigenic environment promoting angiogenesis [2].
In addition, proinflammatory cytokines, mainly delivered by macrophages, can induce IR [3].
IR is defined as “the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population” [4].
Another major complication of obesity is the risk of developing the metabolic syndrome defined as the increase in waist circumference, hypertension, glucose intolerance, and dyslipidemia.
Both IR and metabolic syndrome have been shown to be conditions predisposing tumoral development.The link between metabolic alterations and tumors is mainly represented by changes in insulin, inflammation, and insulin-like growth factor (IGF) system [2,3,5].
Obesity and Cancer
Obesity is associated with the development of several cancers. Indeed, at least 12 types of cancer related to obesity have been described in the literature: colorectal, esophageal, gallbladder, gastric cardia, kidney, liver, intrahepatic bile duct, pancreatic, thyroid, uterine corpus, breast and ovarian cancers, and multiple myeloma [6] have been described and an increased risk has been reported.
Different neoplastic forms have different ages of onset, however an early increase in body weight has been shown to be related with the age of onset of some tumors.
An anticipated age of diagnosis has been observed for colorectal, endometrial, pancreatic cancers, and multiple myeloma in patients who developed obesity in childhood [7].
As mentioned above, obesity is characterized by a status of chronic low-grade inflammation, which is also associated with several types of cancer.
The link between inflammation and cancer is mainly represented by oxidative stress and cytokine and adipokine release [2].
Leptin is produced by adipose tissue and its levels are increased in obesity. Leptin acts on the hypothalamus mediating food intake and energy homeostasis.
This hormone also stimulates cell growth, migration, and production of cytokines by macrophages. The promoting action of leptin on tumor development is supposed to be mediated by inducing the activation of proangiogenic factors [3].
Adiponectin, which is also produced by adipocytes and involved in energy homeostasis, is negatively correlated with BMI and inflammatory cytokine levels, and inhibits angiogenesis and inflammation.
In CRC, its level has been shown to be inversely correlated with the risk and stage of cancer [3].CRC can be considered an example of an obesity-related tumor as many studies have shown how environmental factors, such as weight gain, diet, level of physical activity, IR, and smoking increase its incidence [8].
Metabolic alterations also play a role in the development of CRC. Kim et al. observed an increased risk of CRC in obese men with metabolic syndrome in contrast with those obese but without metabolic alterations [9].
Insulin Resistance (IR) and Cancer
Abdominal obesity correlates with alterations in circulating insulin levels. IR and subsequent hyperinsulinemia and type 2 diabetes mellitus (T2D) are conditions with increased risk of cancer, especially CRC, cholangiocarcinoma, and cancers of the endometrium, pancreas, and liver; the latter is the most increased cancer in diabetic patients [10].
The link between IR, hyperinsulinemia, and cancer has been explained by changes in the expression of insulin receptors and IGF system peptides. There is a very strong association indeed among IGF-I, insulin receptors and insulin, IGF-I, and IGF-II [11]. The interaction between IGF-I and its receptor has an important antiapoptotic effect; likewise, insulin has the same action [12].
Furthermore, insulin, which is known to be a growth factor, binds with low affinity to the IGF-I receptor (IGF1R), stimulating cell proliferation.
An IGF-I serum level within the upper part of the normal range has been reported to be associated with an increased risk of cancer in the general population [5].
Fetal isoforms of the insulin receptor have been described in tumor cells, binding both insulin and IGF-II with high affinity. Moreover, some cancer cells locally produce IGF-II, promoting tumor proliferation [13].
Interestingly, the expression of the fetal insulin receptor has been reported to be increased in CRC and liver cancer and would contribute with other genetic and environmental factors to the development of these neoplasias.
Animal models with precancerous colon adenomas have an increased expression of insulin receptors and, in particular, of the fetal isoforms compared with the mature forms further supporting a role in the development of this cancer [13].
In addition, Lu et al. demonstrated that insulin triggered cell proliferation and could induce metastatic effects in human CRC [14].
In this review, we will highlight the role of microRNAs (miRNAs) as a potential link between obesity and cancer focusing on CRC due to its relationship with the early development of obesity and with alterations of the metabolic state, in particular with IR.
More information: Anni M.Y. Zhang et al. Endogenous Hyperinsulinemia Contributes to Pancreatic Cancer Development, Cell Metabolism (2019). DOI: 10.1016/j.cmet.2019.07.003
Journal information: Cell Metabolism
Provided by University of British Columbia
