Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies

Obesity is reaching epidemic proportions with recent worldwide figures estimated at 1.4 billion and rising year‐on‐year. Obesity affects all socioeconomic backgrounds and ethnicities and is a pre‐requisite for metabolic syndrome. Metabolic syndrome is a clustering of risk factors, such as central obesity, insulin resistance, dyslipidaemia and hypertension that together culminate in the increased risk of type 2 diabetes mellitus and cardiovascular disease. As these conditions are among the leading causes of deaths worldwide and metabolic syndrome increases the risk of type 2 diabetes mellitus fivefold and cardiovascular disease threefold, it is of critical importance that a precise definition is agreed upon by all interested parties. Also of particular interest is the relationship between metabolic syndrome and cancer. Metabolic syndrome has been associated with a plethora of cancers including breast, pancreatic, colon and liver cancer. Furthermore, each individual risk factor for metabolic syndrome has also an association with cancer. Our review collates internationally generated information on metabolic syndrome, its many definitions and its associations with life‐threatening conditions including type 2 diabetes mellitus, cardiovascular disease and cancer, providing a foundation for future advancements on this topic.     

2型糖尿病与恶性肿瘤

2型糖尿病不仅是一个严重的健康问题，还与恶性肿瘤有着密切的联系。近年来流行病学研究证实2型糖尿病与一些常见恶性肿瘤如结、直肠癌、肝癌、胰腺癌、乳腺癌以及子宫内膜癌的发病有关，但其关联的确切机理仍无定论，可能与高血糖、胰岛素及胰岛素样生长因子、内皮素、脂联素、微量元素、激素和药物等诸多因素有关。     

Diabetes Mellitus in Pancreatic Cancer and the Need for Diagnosis of Asymptomatic Disease

Pancreatic cancer is strongly associated with the development of hyperglycemia, peripheral insulin resistance and diabetes mellitus, especially when presented as new-onset diabetes mellitus. Peripheral insulin resistance and hyperinsulinemia have been suggested to promote growth of pancreatic cancer cells, and therefore a relation between longstanding diabetes mellitus type 2 and pancreatic cancer has been implied. Epidemiological studies, though, give incongruent results to this problem. There are data supporting a tumor-derived influence on glucose metabolism, insulin secretion and eventually the development of diabetes mellitus in early stages of pancreatic cancer. The only possibility for curative intent in pancreatic cancer is to diagnose the disease before symptoms occur. Patients with newly diagnosed diabetes mellitus type 2 or hyperglycemia as a risk group have been recommended for primary screening for pancreatic cancer. To date, there is no specific biomarker to identify patients with an asymptomatic pancreatic cancer. The review discuss the relationship between pancreatic cancer and diabetes mellitus and the possibility of secondary screening of patients with newly diagnosed diabetes mellitus type 2 or hyperglycemia in an artificial neural network. PubMed was searched for articles using the Mesh term ‘pancreatic neoplasms’ combined with ‘insulin resistance’ and ‘glucose metabolism disorders’. Additional articles were retrieved through hyperlinks and by manually searching reference lists in original published articles. In total 36 articles were systematically reviewed.     

Diabetes mellitus and the risk of cancer

Although diabetes has been known to increase the risk of cancer for over a century, it was not until recently when this area gained momentum and generated a lot of interest. That is in- part because of the rising global diabetes epidemic and the wide spread use of insulin analogues, metformin and other anti-diabetic agents, providing hypothesis generating data on the cancer risk in the diabetic population. Type 2 diabetes is associated with increased risk of breast, colon, pancreatic and other types of cancer, while type 1 diabetes is associated with increase in stomach, pancreatic, endometrial and cervical cancer. Mechanisms postulated for increased cancer risk in diabetes include hyperglycemia, hyperinsulinemia with stimulation of IGF-1 axis, obesity that serves as a common soil hypothesis for both cancer and diabetes as well as other factors such as increased cytokine production. More recently some antidiabetic agents have been thought to increase cancer risk such as insulin glargine, while metformin appears to lower cancer risk. In this review, we present the evidence for the link between diabetes and cancer highlighting the general mechanisms proposed for such a link as well as specific hypotheses for individual cancer. We will also discuss the role of insulin, metformin and other antidiabetic agents in cancer risk.     

Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients

BACKGROUND & AIMS: Endogenous hyperinsulinemia in the context of type 2 diabetes mellitus is potentially associated with an increased risk of colorectal cancer. We aimed to determine whether insulin therapy might increase the risk of colorectal cancer among type 2 diabetes mellitus patients. METHODS: We conducted a retrospective cohort study among all patients with a diagnosis of type 2 diabetes mellitus in the General Practice Research Database from the United Kingdom. We excluded patients with <3 years of colorectal cancer-free database follow-up after the diabetes diagnosis as well as those insulin users who developed colorectal cancer after <1 year of insulin therapy. The remaining insulin users and the noninsulin-using type 2 diabetic patients were followed for the occurrence of colorectal cancer. Hazard ratios (HR) were determined in Cox proportional hazard analysis. A nested case-control study was conducted to perform multivariable analysis and to determine a duration-response effect. RESULTS: The incidence of colorectal cancer in insulin users (n = 3160) was 197 per 100,000 person-years, compared with 124 per 100,000 person-years in type 2 diabetes mellitus patients not receiving insulin (n = 21,758). The age- and sex-adjusted HR of colorectal cancer associated with > or =1 year of insulin use was 2.1 (95% CI: 1.2-3.4, P = 0.005). The positive association strengthened after adjusting for potential confounders. The multivariable odds ratio associated with each incremental year of insulin therapy was 1.21 (95% CI: 1.03-1.42, P = 0.02). CONCLUSIONS: Chronic insulin therapy significantly increases the risk of colorectal cancer among type 2 diabetes mellitus patients.     

Adipositas, metabolisches Syndrom und Krebsentstehung

Type 2 diabetes mellitus and obesity are pathophysiologically closely related. This is revealed in the complex entity of metabolic syndrome, which describes the simultaneous occurence of glucose intolerance, obesity, arterial hypertension, and dyslipidemia. Patients with type 2 diabetes mellitus show an increased frequency of colorectal, pancreatic, liver, breast and endometrial cancer. Independent of diabetes manifestation, an increase of malignancies has been reported in obesity, and also mortality due to cancer is increased. The underlying pathophysiology is currently under investigation and potential factors under study include hyperinsulinemia, adipokines, sex hormones, chronic inflammation and oxidative stress. Considering the enormous and further accelerating increase of type 2 diabetes mellitus and overweight the potential enhanced risk of cancer needs to be carefully addressed in research and clinical aspects.     

Influence of obesity on the risk of developing colon cancer

Obesity is a risk factor for many diseases. Thirty per cent of Americans are viewed as super obese; therefore, we need to find a solution. We already know about the diseases associated with obesity such as high blood pressure, diabetes, sleep apnoea, etc. Lately, there has been an increased interest in understanding if cancer is related to obesity. In this paper, we review the incidence of colon cancer and obesity. Insulin is the best established biochemical mediator between obesity and colon cancer. Hyperinsulinaemia, such as occurs in type II diabetes, is important in the pathogenesis of colon cancer. All adipose tissue is not equal. Visceral abdominal fat has been identified as the essential fat depot for pathogenetic theories that relate obesity and colon cancer. The genders differ as regards to how the relationship between obesity and colon cancer has been evaluated. Obesity imposes a greater risk of colon cancer for men of all ages and for premenopausal women than it does for postmenopausal women. Regular exercise reduces the risk of developing colon cancer and the risk of death from colon cancer should it develop. We believe that a combination of waist circumference (WC) and body mass index (BMI) measurements is recommended to assess the obesity related risk of developing colon cancer. Radiographic assessments of visceral abdominal fat may eventually prove to be the best means of assessing a patient's obesity related risk of developing colon cancer. Although WC is better established as a measure of obesity than BMI, the evidence for colon cancer risk is not secure on this point; combining BMI and WC measurements would appear, at present, to be the wisest approach for colon cancer risk assessment. Doctors who wish to decrease their patients' risk of dying of colon cancer should advise weight loss and exercise. Conversely, physicians and public health authorities should consider both exercise and obesity when designing colon cancer screening protocols. Morphometric cut offs should be adjusted, if possible, for age, sex, ethnicity, and height.     

Obesity and pancreatic diseases

Obesity is defined as BMI (calculated as weight in kg divided by height in m2) more than 30, and overweight is defined as BMI of 25-29.9. Obesity has been considered as a risk factor for pancreatic diseases, including pancreatitis and pancreatic cancer. Severe acute pancreatitis is significantly more frequent in obese patients. Furthermore, obese patients develop systemic and local complications of acute pancreatitis more frequently. The underlying mechanisms are increased inflammation and necrosis from increased amount of intra- and peri-pancreatic fat. In addition, obesity is a poor prognostic factor in acute pancreatitis, and overweight before disease onset appears to be a risk factor for chronic pancreatitis. Overweight and/or obesity are associated with greater risk of pancreatic cancer and younger age of onset. Physical activity appears to decrease the risk of pancreatic cancer, especially among those who are overweight. Long-standing diabetes increases the risk of pancreatic cancer. The pathogenic mechanism is that obesity and physical inactivity increase insulin resistance. In a state of hypersinulinemia, increased circulating level of insulin-like growth factor-1 induces cellular proliferation of pancreatic cancer. Obesity is associated with negative prognostic factor and increased mortality in pancreatic cancer. However, there are controversies regarding the effects of obesity on long-term post-operative results in the patient with pancreatic cancer.     

2型糖尿病与肺癌的相关性

研究表明2型糖尿病可能增加肺癌发生的风险，但其尚缺乏有力的相关机制研究。本文从2型糖尿病和肺癌间的流行病学特点、2型糖尿病患者的肺癌发病率升高、高血糖、胰岛素抵抗、高胰岛素血症、胰岛素样生长因子、血管内皮生长因子、炎症细胞因子、激素调节功能紊乱、免疫系统功能降低、微量元素及降糖药物等方面综述二者可能的相关性，但2型糖尿病加重肺癌的机制仍需要大量研究证明。     

Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer

Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.     

Diabetes and pancreatic cancer

Epidemiological studies clearly indicate that the risk of pancreatic cancer (PC) is increased in diabetic patients, but most studies focus on overall diabetes or type 2 diabetes mellitus (T2DM), and there are few studies on the risks of type 1 and type 3c (secondary) diabetes. Possible mechanisms for increased cancer risk in diabetes include cellular proliferative effects of hyperglycemia, hyperinsulinemia, and abnormalities in insulin/IGF receptor pathways. Recently, insulin and insulin secretagogues have been observed to increase the PC risk, while metformin treatment reduces the cancer risk in diabetic subjects. In addition, anticancer drugs used to treat PC may either cause diabetes or worsen coexisting diabetes. T3cDM has emerged as a major subset of diabetes and may have the highest risk of pancreatic carcinoma especially in patients with chronic pancreatitis. T3cDM is also a consequence of PC in at least 30% of patients. Distinguishing T3cDM from the more prevalent T2DM among new-onset diabetic patients can be aided by an assessment of clinical features and confirmed by finding a deficiency in postprandial pancreatic polypeptide release. In conclusion, diabetes and PC have a complex relationship that requires more clinical attention. The risk of developing PC can be reduced by aggressive prevention and treatment of T2DM and obesity and the prompt diagnosis of T3cDM may allow detection of a tumor at a potentially curable stage.     

Mechanisms for early microvascular injury in obesity and type II diabetes

Obesity in the absence of hyperglycemia carries a low risk for microvascular disease compared with type II diabetes. The occurrence of hyperglycemia seems to be an important, if not the most important, distinction between obesity and obesity plus diabetes mellitus for microvascular disease. In vitro and in vivo human and animal studies of the early microvascular consequences of hyperglycemia indicate an immediate detrimental suppression of vasodilatory microvascular mechanisms that might be even worse with pre-existing obesity. The overall concept emerging from a very large research base is that hyperglycemia activates protein kinase C, increases oxidant formation, elevates constrictor prostanoid species to the detriment of beneficial prostanoids, and suppresses flow-mediated regulation with the nitric oxide generated by endothelial cells. The end result is decreased blood flow and loss of microvascular reactivity to endothelial-dependent vasodilatory stimuli that persists for 3 to 6 hours.     

Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans

OBJECTIVE: Obesity, defined as a body mass index (BMI) greater than 30 kg/m(2), is now recognised as a risk factor for diabetes mellitus, hyperlipidaemia, colon cancer, sudden death and other cardiovascular diseases. In this study, it is hypothesized that obesity is an independent risk factor for lipid peroxidation and decreased activities of cytoprotective enzymes in humans. SUBJECTS: Fifty normal healthy subjects with healthy BMI (19-25 kg/m(2)) and 250 subjects with different grades of obesity (30-50 kg/m(2)) with no history of smoking or biochemical evidence of diabetes mellitus, hypertension, hyperlipidaemia, renal or liver disease or cancer. MEASUREMENTS: To test this hypothesis, we assessed lipid peroxidation and cytoprotection by measuring the concentrations of plasma malondialdehyde (P-MDA) and the activities of erythrocyte copper zinc-superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GPX). RESULTS: The concentration of P-MDA was significantly lower (P<0.001) in subjects with healthy BMI (2.53+/-0.04 micro mol/l) than in those with BMI above 40 kg/m(2) (4.75+0.05 micro mol/l). Furthermore, there was a significantly positive association (r=0.342, P=0.013) between BMI and P-MDA. On the other hand, subjects with healthy BMI had significantly higher (P<0.001) erythrocyte CUZn-SOD (1464+/-23 units/g Hb) and GPX (98.4+/-3.3 units/g Hb) than those with BMI above 40 kg/m(2) (1005+/-26 units/g Hb) and (84.3+/-6.7 units/g Hb) respectively. Furthermore, erythrocyte CuZn-SOD and GPX activities were negatively associated with BMI (r=-0.566, P=0.005 and r=-0.436, P=0.018) respectively. CONCLUSION: It is concluded from these results that obesity in the absence of smoking, diabetes mellitus, hyperlipidaemia, renal or liver disease causes lipid peroxidation and decreased activities of cytoprotective enzymes, and should therefore receive the same attention as obesity with complications.     

Type 2 diabetes mellitus and the risk of colorectal cancer.

BACKGROUND & AIMS: Type 2 diabetes mellitus might increase the risk of colorectal cancer on the basis of chronic hyperinsulinemia and hyperglycemia. However, epidemiologic evidence for this association is inconclusive. We conducted a population-based study to clarify this association. METHODS: We conducted a case-control study in the United Kingdom General Practice Research Database. Cases included all patients with incident colorectal cancer diagnoses (n = 10,447). Up to 10 control subjects were selected for each case, matching on year of birth, enrollment date, and duration of database follow-up. The exposure of interest was type 2 diabetes mellitus. Odds ratios (ORs) were calculated by using conditional logistic regression. RESULTS: A prior diagnosis of type 2 diabetes mellitus was associated with a modestly increased risk of colorectal cancer (OR, 1.42; 95% confidence interval [CI], 1.25-1.62). The association between type 2 diabetes mellitus and colorectal cancer was observed in both men (OR, 1.36; 95% CI, 1.16-1.61) and women (OR, 1.38; 95% CI, 1.14-1.67). The risk increase was observed in both colon (OR, 1.45; 95% CI, 1.25-1.70) and rectal (OR, 1.34; 95% CI, 1.08-1.68) cancers. CONCLUSIONS: Type 2 diabetes mellitus is associated with an increased risk of colorectal cancer. The risk increase is present in both sexes, as well as in both colonic and rectal cancers.     

Latest insights into the risk of cancer in diabetes

A growing body of evidence from observational studies and meta‐analyses of the data suggest that diabetes mellitus is associated with an increased risk of cancer. Meta‐analyses have shown that diabetes increases the risks of total cancer, and of site‐specific cancers of the breast, endometrium, bladder, liver, colorectum and pancreas, and that it decreases the risk of prostate cancer. Insulin resistance and secondary hyperinsulinemia is the most frequently proposed hypothesis, and hyperglycemia itself might promote carcinogenesis. In addition to several facets of lifestyle including obesity, smoking and lack of exercise, treatment for diabetes might affect the risk of cancer. For instance, metformin, an insulin sensitizer, reportedly has a potential anticancer effect. In light of the exploding global epidemic of diabetes, even a modest increase in the cancer risk will translate into a substantial socioeconomic burden. The current insights underscore the need for clinical attention and better‐designed studies of the complex interactions between diabetes and cancer.     

Evidence-based guideline of the German Nutrition Society: carbohydrate intake and prevention of nutrition-related diseases

The relative contribution of nutrition-related chronic diseases to the total disease burden of the society and the health care costs has risen continuously over the last decades. Thus, there is an urgent necessity to better exploit the potential of dietary prevention of diseases. Carbohydrates play a major role in human nutrition - next to fat, carbohydrates are the second biggest group of energy-yielding nutrients. Obesity, type 2 diabetes mellitus, dyslipoproteinaemia, hypertension, metabolic syndrome, coronary heart disease and cancer are wide-spread diseases, in which carbohydrates could have a pathophysiologic relevance. Correspondingly, modification of carbohydrate intake could have a preventive potential. In the present evidence-based guideline of the German Nutrition Society, the potential role of carbohydrates in the primary prevention of the named diseases was judged systematically. The major findings were: a high carbohydrate intake at the expense of total fat and saturated fatty acids reduces the concentrations of total, LDL and HDL cholesterol. A high carbohydrate consumption at the expense of polyunsaturated fatty acids increases total and LDL cholesterol, but reduces HDL cholesterol. Regardless of the type of fat being replaced, a high carbohydrate intake promotes an increase in the triglyceride concentration. Furthermore, a high consumption of sugar-sweetened beverages increases the risk of obesity and type 2 diabetes mellitus, whereas a high dietary fibre intake, mainly from whole-grain products, reduces the risk of obesity, type 2 diabetes mellitus, dyslipoproteinaemia, cardiovascular disease and colorectal cancer at varying evidence levels. The practical consequences for current dietary recommendations are presented.     

Genetic predisposition to obesity leads to increased risk of type 2 diabetes

Aims/hypothesis  

Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort.     

Antidiabetic actions of estrogen: Insight from human and genetic mouse models

There is increasing evidence both in humans and rodents linking the endogenous estrogen 17β-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic β-cell function/survival and insulin secretion in conditions of oxidative stress.     

Physical activity, body mass index, and risk of type 2 diabetes in patients with normal or impaired glucose regulation

BACKGROUND: Sedentary lifestyle, obesity, and impaired glucose regulation are associated with the risk of type 2 diabetes. However, the joint associations of these risk factors are not known. METHODS: We prospectively followed up 2017 Finnish men and 2352 Finnish women aged between 45 and 64 years without a history of known or newly diagnosed diabetes at baseline. Single and joint associations of physical activity, body mass index (BMI), and blood glucose levels with risk of type 2 diabetes were examined using Cox proportional hazards models. RESULTS: During a mean follow-up of 9.4 years, there were 120 incident cases of type 2 diabetes. After adjustment for confounding factors (age, study year, sex, systolic blood pressure, smoking, and education), physical activity was found to be inversely associated with the risk of type 2 diabetes. This association was persistent in subjects with (1) both obesity and impaired glucose regulation, (2) either obesity or impaired glucose regulation, and (3) a normal BMI and glucose regulation. Similarly, the multivariate-adjusted positive association between BMI and risk of type 2 diabetes was consistently observed. Obesity in subjects who reported being inactive and had normal glucose levels was associated with an increased risk of diabetes compared with a normal BMI in subjects who reported being active and had impaired glucose regulation. CONCLUSIONS: Increasing physical activity can reduce the risk of type 2 diabetes. The protective effect of physical activity was observed in subjects with an excessive BMI and elevated glucose levels. Physical activity and weight control are critical factors in diabetes prevention in subjects with both normal and impaired blood glucose regulation.