Association of Diabetes Mellitus and Alcohol Abuse with Cancer

The possible biological links between diabetes mellitus or impaired glucose tolerance and cancer comprise hyperinsulinemia, hyperglycemia, and fat-induced chronic inflammation. DM is a known risk factor for several cancers [1], resulting from insulin resistance induced by a paraneoplastic syndrome [2] or pancreatic β-cell dysfunction [3]. Mechanistically, hyperglycemia may cause hyperinsulinemia, providing growth signals to positively stimulate the expansion of cancer [4,5,6]. In addition, it has been demonstrated that moderate alcohol intake had no significant impact, whereas high alcohol intake was associated with an increased risk of breast and gastrointestinal cancer [7,8,9,10].

According to the National Diabetes Statistics Report, a periodical publication by the Centers for Disease Control and Prevention (CDC), during 1999–2016, the age-adjusted prevalence of total diabetes significantly increased among adults aged 18 years or older. Prevalence estimates were 9.5% in 1999–2002 and 12.0% in 2013–2016. Among the overall US population, the crude estimates for 2018 were that 34.2 million people of all ages or 10.5% of the US population had diabetes. Furthermore, 34.1 million adults aged 18 years or older, or 13.0% of all US adults, had diabetes. Age-adjusted data for 2017–2018 indicated that non-Hispanic blacks (8.2 per 1000 persons) and people of Hispanic origin (9.7 per 1000 persons) had a higher incidence of diabetes compared to non-Hispanic whites (5.0 per 1000 persons). According to the National Institute of Diabetes and Digestive and Kidney Diseases, diabetes is the seventh leading cause of death in the United States.

In 2017, the International Agency for Research on Cancer (IARC) concluded that obesity is a risk factor of cancer of 13 anatomic sites [11]. The direct association of diabetes mellitus with pancreatic, liver, breast, endometrium, bladder, and kidney cancer has been demonstrated. In addition to obesity and diabetes, other risk factors of cancer are alcohol abuse, genetics (family history), smoking, and exposure to toxic chemicals (Figure 1). Recent studies have shown an association between the incidence of cancer and anti-diabetic medications. Furthermore, the use of metformin (a drug for type 2 diabetes mellitus) is associated with a reduced risk of cancer [12,13,14,15,16] or cancer mortality [17]. The objective of this review paper is to update and summarize the mechanisms of association of diabetes mellitus and alcohol abuse with major cancer.

Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin (a hormone that regulates blood sugar) or when the body cannot effectively use the insulin it produces. There are three major types of diabetes mellitus (DM)—type 1, type 2, and gestational diabetes. Type 1 diabetes mellitus (T1DM), insulin-dependent diabetes mellitus, or juvenile-onset diabetes may account for about 5% of all cases of diabetes. T1DM is characterized by a genetic predisposition manifested in one of several human leukocyte antigens. Type 2 diabetes mellitus (T2DM), non-insulin-dependent diabetes mellitus, or adult-onset diabetes, account for about 90% (285 million people), and this number is projected to grow to 438 million by 2030. T2DM is a form of diabetes mainly characterized by high blood glucose, insulin resistance, and relatively a weaker insulin-stimulated response under hyperglycemic conditions. In obese individuals with euglycemia, peripheral insulin resistance is present but compensated by increased insulin secretion [18,19,20]. Insulin resistance progressively worsens in predisposed individuals, along with progressive β-cell dysfunction and the reduction of β-cell mass, eventually leading to T2DM [18,19,20]. DM is not only related to retinopathy, neuropathy, nephropathy, and cardiovascular diseases but is also related to several liver diseases such as nonalcoholic fatty liver disease (NAFLD), steatohepatitis, and liver cirrhosis. Long-standing T2DM, insulin resistance, and obesity have been shown to modestly increase the risk of several types of cancers [21,22,23,24,25,26,27,28]. According to the World Health Organization, obesity is defined by the body mass index of more than 30 kg/m², and overweight is 25–30 kg/m². Obesity causes chronic inflammation of the body and is a risk factor for many cancers. There are a number of conditions associated with diabetes, such as thyroid disease, coeliac disease, polycystic ovary syndrome, diabetes insipidus, necrobiosis lipoidica diabeticorum, mastopathy, muscular conditions, dental health complications, and certain types of cancer. Growing evidence suggests that patients with colorectal, breast, liver, endometrial, and gastric cancers and leukemia [29,30] who also have DM are at increased risk of cancer recurrence and mortality [31].

Upon digestion of dietary sugar, glucose is absorbed by the intestine, which results in a rise in the blood glucose level (Figure 2). In the liver, insulin regulates glucose production/utilization. When glucose levels increase in the blood and insulin is secreted by pancreatic β-cells. Intestinal cells secrete DPP4, which inhibits the production of incretins such as GLP-1 and GIP; they act on pancreatic β-cells to regulate insulin production. In physiological states, the combined action of glucagon and insulin allows the precise regulation of hepatic glucose output. Although glucagon induces hepatic glucose production, insulin acts as a potent inhibitor of glucose production when its concentration in the blood rises. In addition to inducing glycogen synthesis, insulin also inhibits hepatic glucose production. In the case of insulin resistance, physiologic levels of circulating insulin are insufficient to elicit the appropriate insulin response in hepatic cells. In the liver, insulin resistance impairs glycogen synthesis, fails to suppress glucose production, enhances lipogenesis, and increases the synthesis of proteins. Insulin resistance occurs due to a decrease in the metabolic response of insulin-responsive cells to insulin or, at a systemic level, an impaired/lower response to circulating insulin by blood glucose levels. In skeletal muscle, insulin resistance is considered to be an important extra-pancreatic factor in the development of T2DM. Under physiological conditions, insulin stimulates muscle glycogen synthesis by enhancing glucose uptake from plasma.

Alcohol has been classified as a human carcinogen for the liver by the International Agency for Research on Cancer (IARC). Ethanol metabolism is shown in Figure 3. Chronic ingestion of alcohol and its metabolite acetaldehyde may initiate and/or promote the development of cancer in the liver, oral cavity, esophagus, stomach, gastrointestinal tract, pancreas, prostate, and female breast. During ethanol metabolism, ethanol is oxidized to acetaldehyde by alcohol dehydrogenases (ADH) in the presence of NAD⁺ [32,33]. Another source of acetaldehyde is bacteria living in the gastrointestinal tract [34,35]. The CYP p450 (CYP2E1) pathway also metabolizes ethanol into acetaldehyde, as well as reactive oxygen species (ROS). However, this pathway is more active when a high alcohol intake is consumed [36]. Acetaldehyde is further metabolized into acetate by aldehyde dehydrogenase (ALDH), in particular, the form encoded by ALDH2 on chromosome 12 [36]. The breakdown of alcohol into acetaldehyde and then acetate mainly takes place in the liver. Some alcohol metabolism also occurs in other tissues, such as the pancreas and the brain. Additionally, small amounts of alcohol are metabolized to acetaldehyde in the gastrointestinal tract. Recently, ALDH2 deficiency has been linked with the risk, pathogenesis, and prognosis of various cancers, and has emerged as a promising therapeutic target [37]. Ethanol and acetaldehyde can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues [38,39]. Disulfiram and calcium carbamide can inhibit ALDH2 activity. Continue.......