White Paper April 2018

Diabetes, Obesity and Metabolic Syndrome in the UAE. The connection between Metabolic Syndrome and Cancer. The preventive effects of Met-

formin, Liraglutide and Molecular Hydrogen.

Department of Translational Medicine Author: Harry Paterakis, Apostolia Alizioti

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• 33 Scheuchzerstrasse 8006 Zurich Switzerland

• url: www.SR21.ch • email: info@SR21.ch

White Paper April 2018

One of the key areas of this white paper is to develop an understanding about the high prevalence of diabetes, obesity and Metabolic Syndrome in the UAE and wider region. Rapid economic growth, sedentary lifestyles and unhealthy diets characteristic to the UAE are all risk factors, leading to the number of people with diabetes expecting to double to 2.2 million by 2040.However, an increasing population and a greater understanding of the condition among the communities have also contributed to the increase in patients diagnosed with diabetes.

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Trends indicate that the prevalence of diabetes in the UAE is rising at

a faster rate than both the MENA region and the rest of the world.

White Paper April 2018

Over two-thirds (67.3%) of adults with diabetes live in urban areas. Fig-ures from the International Diabetes Federation (IDF) revealed that, in 2017, 17.3% of the UAE population between the ages of 20 and 79 have type 2 dia-betes. There are over 1 million people living with diabetes in the UAE, placing the country 15th worldwide for age-adjusted comparative prevalence.

Diabetes is a regional affliction in the G.C.C. where all countries featur-ing in the top twenty in terms of prevalence worldwide. It is important to say that according to the IDF, approximately 38.7 million adults aged 20-79 years were living with diabetes in the MENA region in 2017. Close to half (49.1%) of these cases were undiagnosed.

Obesity is known to increase the risk of developing Type 2 diabetes in adulthood, and with the rise in childhood obesity in recent years, more children are developing Type 2 diabetes. Type 2 diabetes can be prevented, managed and even reversed by eating a healthy, balanced diet, keeping a normal weight and exercising regularly.

Obesity and Cancer: Being overweight and obese has been reported to be responsible for death in 14% of men and 20% of women. Epidemiological stud-ies have demonstrated that an increase in waist circumference and/or body mass index (BMI) has an association with colon, postmenopausal breast, endometri-um, esophagus, liver, gallbladder, gastric (cardia) and kidney cancer develop-ment. In the pathophysiology of obesity and cancer relationship, insulin resis-tance is found to play an essential role.

Type 2 diabetes is mainly brought on by an unhealthy, inactive lifestyle and weight gain. It is associated with decreasing levels of activity and an in-creasing prevalence of obesity. In this type of diabetes, there is insulin in the body, but the body becomes resistant to it so the insulin becomes largely inef-fective. On the other hand, type 1 diabetes is an auto-immune condition where the pan-creas is attacked by auto-antibodies that mistakenly target and damage specific tissues or organs of the body, causing it to fail. Type 1 diabetes usually develops before adulthood and remains with them throughout their life, requiring insulin treatment.

Hyperglycemia and Cancer development are associated independent of Body Mass Index. It was found hyperglycemia to be associated with cancer de-velopment in male and the strongest association was observed with hepatocellu-lar cancer in men.

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White Paper April 2018

Insulin resistance/hyperinsulinemia/ *IGF-1 * Insulin-like growth factor (IGF-1) is a natural human growth hormone instrumental in normal growth during childhood, but in adulthood can promote abnormal growth—the proliferation, spread (metastasis), and invasion of cancer.

It is accepted that hyperinsulinemia/insulin resistance is the primary mechanism responsible for many manifestations of Metabolic Syndrome. The strongest evidence in Metabolic Syndrome and cancer association focuses on obesity and hyperinsulinemia/insulin resistance. Insulin is a major anabolic hormone that stimulates cell proliferation and its effect on cancer cell prolifera-tion is suggested to be with IGF-1 stimulation. Growth hormone is the primary stimulant for IGF-1 production in liver and insulin stimulates IGF-1 production in liver by upregulating growth hormone receptors. Hyperinsulinemia also in-creases IGF-1 bioavailability by decreasing hepatic secretion of IGF-binding protein-1 and 2. IGF receptor is overexpressed in breast and colon cancers and the p21 ras/mitogenactivated protein kinase (MAPK) pathway and phos-phatidylinositol-3 kinase/AKT pathway for cell proliferation.

Among the proliferative and anti-apoptotic characteristics of IGF, its an-giogenetic effect (due to vascular endothelial growth factor (VEGF) is also sug-gested to play an important role in colon, endometrium, breast and prostate can-cer development. On the other hand, it is reported that hyperinsulinemia and IGF-1 inhibit sex-binding globulin synthesis in liver increasing bioavailability of sex hormones and this may have a role in hormone-dependent cancers like breast, endometrium and prostate cancer.

Aromatase Activity

The most important estrogen source after menopause is aromatisation of androgens in adipose tissue with cytochrome p450 enzyme complex. In obese women (especially visceral obesity), an increase of estrogen bioavailability with the effect of insulin and IGF1 and an increase in estrogen synthesis due to aromatization in adipose tissue are considered to be the most important factors in the development of breast and endometrium cancer in postmenopausal women.

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White Paper April 2018

Metabolic syndrome

Metabolic syndrome is a cluster of cardiometabolic risk factors charac-terised with obesity, hypertension, atherogenic dyslipidemia, hyperglycemia, prothrombotic and proinflammatory states. Growing data show the association of metabolic syndrome or its components with cancer development and cancer-related mortality. It is suggested that in Metabolic Syndrome and cancer associ-ation, insulin resistance and insulin-like growth factor 1 system play a key role, especially adipokines secreted from visceral adipocytes, free fatty acids and aromatase activity contribute to this process. It is also reported that Metabolic Syndrome has a link with colorectal, breast, endometrial, pancreas, primary liver and, although controversial, prostate cancer. Despite every component of Meta-bolic Syndrome is known to have an association with cancer development, it is still debated whether the effects of these components are additive or synergistic.

On the other hand, in the association between Metabolic Syndrome and cancer, the role of antidiabetic and antihypertensive treatments is also suggest-ed. The primary approach in Metabolic Syndrome -cancer relation is to prevent risk factors. Life style changes including weight loss and a healthy diet are known to decrease cancer risk in normal population. It is postulated that an in-sulin-sensitizing agent, metformin, has cancer-preventing effects on diabetic pa-tients. Epidemiological studies have revealed that metformin therapy decreased cancer incidence and the risk of cancer-related mortality in diabetics when compared to those treated with sulfonylureas or other therapies.

Possible Mechanisms of Metabolic Syndrome and Cancer Association

It is proposed that obesity, inflammation and insulin resistance are all in-terconnected and this is potentially as a result of adipose tissue hypoxemia. It is also stated that development of insulin resistance in obese individuals is associ-ated with tumor necrosis factor alpha (TNF-α) secreted from adipose tissue im-pairing intracellular insulin signal cascade, elevation in free fatty acid levels, decrease in adiponectin levels and also inhibition of peroxisome proliferator-ac-tivated receptor gamma by TNF-α and interleukin (IL)-1 stimulated with nu-clear factor kappa B (NF-κB).

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Prevention

The basic approach for cancer prevention in patients with Metabolic Syn-drome is to prevent risk factors. Life style changes including weight loss and a healthy diet, especially the Mediterranean diet, are known to decrease cancer risk in normal population. In cases with bariatric surgery, cancer-related mortal-ity was shown to have decreased compared to all cases and matched controls. In patients using sulfonylureas or insulin, cancer-related mortality was found to be higher respectively than metforminusing patients.

Findings have given birth to the opinion that metformin treatment in pa-tients with type 2 diabetes may have a cancer-preventive effect. Today, the in-sulin-sensitizing agent, metformin may have cancer-preventive effects indepen-dent of its hypoglycemic effect. It is postulated that metformin suppresses in vitro and in vivo cancer cell growth and there may be potential mechanisms like liver kinase b1/AMPK pathway activation, induction of apoptosis, inhibition of protein synthesis, decrease in insulin levels, activation of immune system and eradication of cancer stem cell. The benefit of metformin as an adjuvant chemotherapeutic agent and its affect as increased response to chemotherapy is still investigated. Some of the observational studies managed to prove this effect of metformin. Jiralerspong et al. showed that diabetic patients with breast can-cer receiving metformin and neoadjuvant chemotherapy have a higher patholog-ic complete response rate than diabetics not receiving metformin.

The case of Liraglutide

Liraglutide safely and effectively reduces HbA(1c) in patients with type 2 diabetes. The most recent American Diabetes Association guidelines recom-mended a GLP-1 agonist along with metformin as a second-tier therapy for type 2 diabetes. Subcutaneous liraglutide was approved for the treatment of Type 2 diabetes mellitus in Europe in 2009 and in the USA in 2010. In December 2014, liraglutide 3.0 mg was approved by the Food and Drug Administration (FDA) and in March 2015 by the European Medicines Agency (EMA) for the treatment of chronic weight management. Liraglutide causes a glucose-dependent increase in insulin secretion, decreases glucagon secretion and promotes weight loss by inhibiting appetite. Liraglutide probably induces satiety through activation of different areas in the hind brain and possibly by preserving free leptin levels. Recently, liraglutide has been suggested to protect against pre-diabetes and seems to prevent bone loss by increasing bone formation following diet-induced weight loss in obesity.

Liraglutide is a member of a new class of antidiabetic medications called GLP-1 analogues. These mirror the effects of naturally produced glucagon-like

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White Paper April 2018

peptide-1 (GLP-1), which includes glucose-dependent stimulation of insulin se-cretion, suppression of glucagon secretion, reduction of appetite and delay of food absorption. Liraglutide shares 97% structural homology with human GLP-1 and has a half-life of 10–14 hours. The longer half-life is due to a modifica-tion of the peptide with an amino acid substitution and the addition of a fatty acid chain that allows it to bind to circulating plasma proteins, thus slowing ab-sorption and rendering it resistant to degradation.

Drug repurposing of Liraglutide

Liraglutide injection is widely now used to reduce the risk of heart at-tack, stroke, or other life-threatening complications of diabetes, including kid-ney problems, nerve damage, eye problems, blood vessel disease and various other.

Insulin resistance

Insulin resistance promotes Alzheimer disease and its related neurode-generation and dementia. A growing body of clinical and epidemiological re-search suggests that two of the most common diseases of ageing, type 2 Dia-betes Mellitus and Alzheimer disease (AD), are linked. Strong evidence provide that patients with Type 2 Diabetes Mellitus are at a significantly increased risk of developing AD was the Rotterdam study. This cohort study of 6,370 elderly subjects found that the presence of diabetes almost doubled the risk of develop-ing AD.

The risk of AD was even higher among patients treated with insulin, a group that likely had a longer history of diabetes and were refractory to oral agents. Several other large studies have also investigated the relationship be-tween Alzheimer disease and elevated glucose levels, impaired glucose toler-ance, and diabetes, and a systematic review and meta-analysis of these studies reported similar overall findings. More recently, Crane et al.showed that blood glucose level is positively associated with accelerated cognitive decline, even among individuals without clinical diabetes.

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White Paper April 2018

Molecular Hydrogen (H2)

Hydrogen (H2) is the lightest gas molecule. The numerous strains of in-testinal bacteria, primarily in the large intestine, produce H2, and approximately 14% of H2 is absorbed in the colon and released from the lungs. Ohsawa et al recently reported that hydrogen acts as a therapeutic anti-oxidant by selectively reducing hydroxyl radicals. H2 affects ischemia -reperfusion injury, ath-erosclerosis, Parkinson’s disease, acute pancreatitis, and type 1 allergic reaction. H2 therapy may reduce stroke in patients with metabolic syndrome in-volving diabetes mellitus.

Metabolic syndrome is a strong risk factor of stroke. It has been reported that H2 therapy can improve metabolic syndrome in basic and clinical settings. Recent extensive studies have revealed that molecular hydrogen has great po-tential for improving oxidative stress-related diseases. Oxidative stress caused by reactive oxygen species is considered a major mediator of tissue and cell in-juries in various conditions, including neurological emergencies and neurode-generative diseases. Recently, the beneficial effect of H2 has been reported in many other organs, including the brain. Molecular hydrogen is well charac-terised as a scavenger of hydroxyl radicals and peroxynitrite. The neuroprotec-tive effects of treatment with molecular hydrogen have been reported in both basic and clinical settings.

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White Paper April 2018

Selected bibliography:

- Wallace DC. A mitochondrial paradigm of metabolic and degenerative dis-eases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407 - Salganik RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J. Am. Coll. Nutr. 2001;20:464S–72S. - Kawasaki H, Guan J, Tamama K. Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials. Biochem Biophys Res Commun. 2010;397:608–13. - Ohta S, Ohsawa I. Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer’s disease: on defects in the cytochrome c oxidase complex and aldehyde detoxification. J Alzheimers Dis. 2006;9:155–66 - Brambilla D, Mancuso C, Scuderi MR, et al. The role of antioxidant supple-ment in immune system, neoplastic, and neurodegenerative disorders: a point of view for an assessment of the risk/benefit profile. Nutr J. 2008;7:29. - Jaggers JR, Sui X, Hooker SP, LaMonte MJ, Matthews CE, Hand GA, Blair SN. Metabolic syndrome and risk of cancer mortality in men. Eur J Cancer. 2009;45:1831–8. - Pothiwala P, Jain SK, Yaturu S. Metabolic syndrome and cancer. Metab Syndr Relat Disord. 2009;7:279–88. - Gallagher EJ, LeRoith D. Insulin, insulin resistance, obesity, and cancer. Curr Diab Rep. 2010;10:93–100. - Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the

stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:351–60.

- LeRoith D. et al. The role of insulin and insulin-like growth factors in the in-creased risk of cancer in diabetes. RMMJ. 2011;2(2):e0043.

- Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T, Cao Y. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A. 2004;101:2476–81.

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- Monami M, Dicembrini I, Marchionni N, Rotella CM, Mannucci E. Effects of glucagon‐like peptide‐1 receptor agonists on body weight: a meta‐analysis. Exp Diabetes Res 2012; 2012 672658.

- Astrup A, Rossner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double‐blind, placebo‐controlled study. Lancet 2009; 374: 1606–1616.

- Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once‐daily human glucagon‐like peptide 1 analogue, in the treat-ment of type 2 diabetes mellitus. Clin Ther 2009; 31: 2472–2488.

- Moloney AM, Griffin RJ, Timmons S, O'Connor R, Ravid R, O'Neill C. De-fects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease in-dicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31(2):224–243. doi: 10.1016/j.neurobiolaging.2008.04.002.

- Hamilton A, Hölscher C. Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. Neuroreport. 2009;20:1161–1166.

- Matthaei S and Greten H. Evidence that metformin ameliorates cellular in-sulin-resistance by potentiating insulin-induced translocation of glucose trans-porters to the plasma membrane. Diabete Metab. 1991; 17:150-158.

- Schuler KM, Rambally BS, DiFurio MJ, Sampey BP, Gehrig PA, Makowski L, Bae-Jump VL. Antiproliferative and metabolic effects of metformin in a pre-operative window clinical trial for endometrial cancer. Cancer Med. 2015;4:161–173.

- De Celis Ferrari ACR, Pfiffer TEF, Alex AK, Nebuloni DR, Carneiro AQ, Ca-pareli FC, Leite LAS, Braghiroli MIFM, Lobo J, Hoff PM, Riechelmann RP. Phase II trial of metformin and paclitaxel for patients with gemcitabine-refrac-tory advanced adenocarcinoma of the pancreas. ASCO Meeting Abstracts. 2014;32:e15196.

- Joshua AM, Zannella VE, Downes MR, Bowes B, Hersey K, Koritzinsky M, Schwab M, Hofmann U, Evans A, van der Kwast T, Trachtenberg J, Finelli A, Fleshner N, Sweet J, Pollak M. A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer Prostatic Dis. 2014;17:252–258.

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Glossary:

- Adipokines: Adipokines is a generic term for a family of cytokines (proteins involved in cell signaling) and other proteins secreted by adipose tissue (body fat). Some of adipokines have pro-inflammatory properties while others have anti-inflammatory properties or insulin sensitizing properties. Adipokines dys-regulation is related to obesity, metabolic syndrome, Diabetes Mellitus type II, hypertension and cardiovascular disease. - Adiponectin: is a protein hormone involved in the regulation of glucose and the degradation of fatty acids to their metabolites. - Aromatase: also called estrogen synthetase, is an hormone that plays a key role in the process of biosynthesis of estrogen. - Atherogenic dislipidemia: is a clinical condition characterised by elevated lev-els of triglycerides and low-density lipoprotein (LDL) and low levels of high-density lipoprotein cholesterol (HDL-C). - Insulin-like growth factor (IGF-1): is a natural human growth hormone instru-mental in normal growth during childhood, but in adulthood can promote ab-normal growth—the proliferation, spread (metastasis), and invasion of cancer. - Interleukin-1 (IL-1): is a group of pro-inflammatory proteins that play a crucial role in the regulation of inflammatory responses and immunity. - Leptin: is an hormone primarily produced by adipose cells, promotes the sense of satiety/inhibits hunger and the regulation of energy balance. - MAPK pathway: is involved in directing cellular responses to mitogens, osmot-ic stress, heat shock and proinflammatory cytokines and in regulation of cell survival, proliferation, mitosis, apoptosis and gene expression.- Proinflammatory cytokines: are signaling molecules that are involved in the upregulation of inflammatory reaction. Proinflamatory cytokines are excreted from immune cells (helper T cells and macrophages) and cells that promote in-flammation such as interleukin-1, interleukin-12, interleukin-18, tumor necrosis factor (TNF) and interferon gamma (IFN-gamma). - Phosphatidylinositol 3-kinase/AKT pathway: Phosphatidylinositol 3-kinase and Akt are key proteins in the homonymous signal transduction pathway, which plays a primary role in the promotion of cell growth, proliferation, apoptosis and cell survival. Dysregulation of signaling activity is linked to various dis-eases including Diabetes Mellitus type II and cancer.

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- Protein kinase: is an enzyme that by adding phosphate groups to proteins, leads the modification and the function of proteins and with its activity regulates most of the cellular pathways, particularly those involved in signal transduction. - Sulfonylureas: is a class of antidiabetic drugs, widely used for the treatment of Diabetes Mellitus type II. - TNF-a: is a protein that promotes cell signaling and is involved in inflamma-tion. - Upregulation/downregulation: are processes by which cells increase/decrease cellular components

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