Metabolic syndrome, hyperinsulinemia, and cancer

Abstract

The term metabolic syndrome describes the association between obesity, insulin resistance, and the risk of several prominent chronic diseases, including cancer. The causal link between many of these components remains unexplained, however. What is clear are the events that precede the development of the syndrome itself. In animal models, a fat-supplemented diet causes 1) lipid deposition in adipose depots, 2) insulin resistance of liver and skeletal muscle, and 3) hyperinsulinemia. One hypothesis relating fat deposition and insulin resistance involves enhanced lipolysis in the visceral depot, which leads to an increase in free fatty acid (FFA) flux. Increased mass of stored lipid and insulin resistance of visceral adipocytes favors lipolysis. Additionally, hypersensitivity of visceral adipose cells to sympathetic nervous system stimulation leads to increased lipolysis in the obese state. However, little evidence is available for enhanced plasma FFA concentrations in the fasting state. We measured FFA concentrations over a 24-h day in obese animals and found that plasma FFAs are elevated in the middle of the night, peaking at 0300. Therefore, it is possible that nocturnal lipolysis increases exposure of liver and muscle to FFAs at night, thus causing insulin resistance, which may play a role in hyperinsulinemic compensation to insulin resistance. Nocturnal lipolysis secondary to sympathetic stimulation may not only cause insulin resistance but also be responsible for hyperinsulinemia by stimulating secretion and reducing clearance of insulin by the liver. The resulting syndrome-elevated nocturnal FFAs and elevated insulin-may synergize and increase the risk of some cancers. This possible scenario needs further study.

Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis

“…Lastly, our study does not address the issue in nondiabetic populations at risk for cancer for different conditions, including personal or family history of cancer or the presence of premalignant lesions, in which the preventive potential of metformin is unknown. However, because diabetes and obesity are emerging risk factors, involving a large fraction of the population of Western countries (1,(4)(5)(6), the findings derived from this metaanalysis may have important public health implications.…”

“…A large proportion of all cancers in Western countries is attributable to Western lifestyle, characterized by physical inactivity and early onset of metabolic syndrome and insulin resistance with diabetes, cardiovascular disease, and cancer (1)(2)(3)(4)(5)(6)(7). Hyperinsulinemia adversely affects prognosis in cancer patients (3,(7)(8)(9)(10)(11) and is an independent risk factor for several types of neoplasms, thus explaining the obesity-cancer association (12).…”

Reduced colorectal cancer incidence in type 2 diabetic patients treated with metformin: a meta-analysis

“…Direct and indirect mechanisms might be associated with CRC occurrence related to metformin treatment. Metabolic syndrome is largely accepted as risk factors for CRC occurrence, including hyperinsulinemia and high glycemic levels (Giovannucci 2007;Hsu et al 2007). Metformin plays anti-diabetic roles through targeting adenosine monophosphate activated protein kinase (AMPK) system and acts as a sensor of cellular energy status (2) Bodmer…”

Cancer Risk Associated with Use of Metformin and Sulfonylurea in Type 2 Diabetes: A Meta-Analysis

“…Hyperinsulinemia was associated with increased cancer risk at many sites including colorectal, liver, gallbladder, pancreas, and endometrial [40 -44]. High glycemic levels are also considered a risk factor for selected cancers including colon and breast [40,41].…”