Metabolism, Disease and Cancer Flashcards Preview

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Flashcards in Metabolism, Disease and Cancer Deck (19)
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What are the types of diabetes mellitus and long term risks

- Type 1: Insufficient production of insulin, autoimmune destruction of b cells, weight loss, increased urination / thirst, ketoacidosis, altered breathing
- Type 2: Insulin resistance, associated with obesity, cells don’t respond to insulin, obesity, high BP / BG, inflammation
- Increases the risk of cardiovascular disease, renal failure, and damage to small blood vessels and nerves


What is metabolic disease

- Syndrome X
- Cluster of disorders of metabolism
- Including, high BP, elevated insulin levels, obesity and abnormal cholesterol levels
- Each of these disorders is by itself a risk factor for other diseases
- In combination, these disorders dramatically boost the chances of developing potentially life-threatening illnesses (diabetes, heart disease, stroke)


What is obesity, what is it influenced by and what cells are affected

- Obesity: Metabolic Syndrome largely linked to obesity, energy storage issue, regulated by hormones
- Influenced by appetite and eating behaviour, exercise, metabolic processing of fuel
- Adipocytes: Influence brain’s decision making about food intake and energy expenditure via the protein hormone leptin
- Adipose Tissue: Fat stored in the adipose tissue, endocrine organ, releases peptide adipokines
- Adipokines: Carry information about fuel stores to brain key ones are leptin & adiponectin


What is adiponectin

- Made by adipose tissue, receptors in brain
- Makes other organs sensitive to insulin
- Works via AMP-activated kinase pathway, bottom up
- AMPK phosphorylates and inactivates acetyl-CoA carboxylase
- Enzyme normally makes malonyl-CoA
- Malonyl-CoA inhibits fatty acid import into mitochondria
- Reduced acetyl-CoA carboxylase means that fatty acids are free to enter the mitochondria for oxidation
- AMPK pathway also inhibits cholesterol synthesis


What is leptin

- Appetite suppressant, sent from adipose tissue to the brain (reduces appetite)
- Inhibits synthesis of fat and causes b oxidation of fat to energy / heat
- Inhibits neuropeptide Y (appetite stimulating)
- Stimulates release of a-MSH (appetite suppressant)
- Stimulate release of norepinephrine and increase transcription of UCP1 gene
- UCP1 increases thermogenesis, heat released without energy, increased fat loss


What is ghrelin

- Short term orexigenic peptide secreted into stomach
- Receptors in brain, heart and adipose tissue
- Works via GPCRs to increase sensation of hunger
- Prader-Willi syndrome associated with high levels of ghrelin and insatiable appetite


What occurs when adipocytes are overloaded

- Lean: TAG diet = TAG catabolised
- Overweight: TAG diet > TAG catabolised
- Pro-Inflammatory: Enlarged adipocyte produce MCP-1, increased FFAs enter glycolysis
- Chronic Inflammation: Macrophages infiltrate adipose tissue, produce TNF-a, increases FFAs export, ectopic lipid deposits build up in muscle, lipids interfere with GLUT4 leading to insulin resistance


How is type 2 diabetes treated

- Diet and exercise to reduce obesity, manage BG, increase insulin sensitivity of muscles
- PPAR activators to increase adiponectin
- Stimulation of insulin by binding ATP gated K channels
- Prevent proteolytic degradation of GLP1 (promotes insulin secretion)


Describe normal cellular development

- Intricate genetic control systems regulate the balance between cell birth and cell death in response to growth signals, growth-inhibiting signals, and death signals
- Normal cell proliferation is modulated by regulation of the cell cycle, apoptosis eliminates damaged cells
- Normal cell numbers are tightly regulated


Describe tumour cell development

- Mechanisms that maintain normal proliferation rates malfunction to cause excess cell division
- Genome changes (point mutations, deletions, amplification)
- Solid tumours (complex, different cell types, interact with environment to obtain a maximal growth advantage)
- Metastatic tumour cells (invade surrounding tissues)
- Highly abnormal karyotypes, genetic makeup dramatically altered, individual chromosome number is altered


What is carcinogenesis

- Sustain proliferative signalling
- Evade growth suppressors
- Resist cell death
- Activate invasion and metastasis
- Enable replicative immortality
- Induce angiogenesis


What are metastatic cancer cells

- Invade surrounding tissues
- Migrate on extracellular matrix (ECM) fibres away from the primary tumour to reach BV
- Attracted by signals such as epidermal growth factor (EGF), which can be secreted by macrophages
- Penetrate BV endothelial cell layer that forms the vessel walls and enter the bloodstream
- Example: Carcinoma cells


Describe the genetic basis of cancer

- Cancer Promoting Mutations: Increase ability of cell to proliferate, decrease susceptibility of cell to apoptosis, increase general mutation rate in cell or its longevity, increase in cell longevity
- Dominant Gain-of-Function: Mutations in protooncogenes, encode growth-promoting signalling proteins and their receptors, signal-transducing proteins, TFs, and anti-apoptotic proteins
- Recessive Loss-of-Function: Mutations in tumour-suppressor genes contribute to cancer, tumour-suppressor genes encode proteins that directly or indirectly control cell-cycle progression


What 7 mutagens in protein types cause cancer

- Oncogenes: Proteins that normally promote cell growth, extracellular signalling molecules (1), signal receptors (2), signal-transducing proteins (3), transcription factors (4)
- Tumour-Suppressor Gene Mutations: Cell-cycle control proteins which function to restrain cell proliferation (5), DNA-repair proteins (6)
- Oncogenes and Tumour-Suppressor Genes: Apoptotic proteins (7)


What is PYY3-36

- Hormone secreted from the small intestine and colon, appetite-suppressing hormone
- Named because 36 aa peptide with two Tyr (Y) residues at end
- Secreted in response to food entering stomach, transported to hypothalamus
- Inhibits release of orexigenic NPY, result is reduced hunger


What is the multi hit model

- Multiple mutations required to cause cancer, predicts increase in incidence with age
- First mutation gives a slight growth advantage
- Second mutation causes cells to grow more uncontrollably and form a small benign tumour
- Third mutation allows cells to outgrow the others to form a mass of cells
- Fourth mutation allows cells to escape into the bloodstream and metastasise


What are direct acting vs indirect acting cancers

- Direct: Carcinogens, reactive electrophiles that react with DNA nitrogen and oxygen atoms to modify DNA bases and introduce mutations
- In-Direct: Carcinogens, generally unreactive, water-insoluble compounds, can act as potent cancer inducers only after introduction of electrophilic centres, modified by cellular enzymes eg P-450


What is p53

- DNA damage sensor
- When DNA is damaged (UV-induced thymine-thymine dimers / double strand breaks) p53 protein (activity) is induced
- Cancer inhibits activity of p53 / cell cycle inhibition (high p21)
- Cell death via Bcl-2-pathway (high puma and noxa) and inhibition of angiogenesis (high thombospondin) does not occur when DNA damage is present


What is the set point model

- Body maintains its weight and body composition through internal regulatory controls
- The nervous system controls the production of specific hormones via the hypothalamus-pituitary system
- The pituitary hormones stimulate other hormone-synthesising glands or act directly on target tissues
- Tissues sense metabolic states and mobilise hormones to other tissues, including blood and the brain, to respond