Systems to Cells Flashcards

Question

What does phosphorylation do?

Answer 1

Phosphorylation may turn an enzyme on/off, It alters the 3D conformation of the target protein because of the high charge density of the protein-bound phosphoryl group, -2 at physiological pH (quite a large charge). These often make salt bridges with nearby Arginine and Lysine residues which are positively charged

Answer 2

Two main classes of kinase: those that phosphorylate Tyrosine residues and those that phosphorylate Serine/Thereonine residues

Answer 3

Glucagon increases glycogen degradation by activating Protein Kinase A which goes on to phosphorylate Glycogen synthase a (active form) into Glycogen synthase b (inactive form). Simultaneously, Glycogen phosphorylase b (inactive form) is phosphorylated into Glycogen phosphorylate a (active form). Conversion of both Glycogen synthase a and Glycogen phosphorylase b into their alternate forms uses one molecule of ATP * ATP + H2O = ADP + Pi + H⁺+ ENERGY

Answer 4

Insulin increases glycogen synthesis by activating Protein phosphotase-1 which goes on to dephosphorylate Glycogen synthase b (inactive form) into Glycogen synthase a (active form). Simultaneously, Glycogen phosphorylase a (active form) is phosphorylated into Glycogen phosphorylate b (inactive form). Conversion of both Glycogen synthase b and Glycogen phosphorylase a into their alternate forms uses a molecule of water and produces a Phosphate ion. ATP + H2O = ADP + Pi + H+ + ENERGY

Answer 5

Gluconeogenesis is the metabolic process by which organisms produce sugars (namely glucose) for catabolic reactions from non-carbohydrate precursors. Glucose is the only energy source used by the brain (with the exception of ketone bodies during times of fasting), testes, erythrocytes, and kidney medulla.

Answer 6

* Biosynthetic and degradative pathways are almost always distinct. this means that both pathways can be thermodynamically favourable. * The rates of metabolic pathways are governed by the activities of key enzymes (and not by mass action). * Glycogen formation/breakdown is a perfect example of this * Specific hormones induce soecific events in cells/tissues. * Allosteric modulation of enzyme activity. Reversible covalent modification is a well-used example. * In cases where the direction of a metabolic pathway has to be reversed, the pathway is controlled at an irreversible step. * Where glycogen needs to be reversed back into Glucose 1-P for example. Glycogen synthase cannot revert glycogen back into Glucose 1-P, Glycogen phospphorylase has to instead.

Answer 7

In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step or rate-limiting step

Answer 8

* Enzymes can be controlled bu allosteric interactions with other molecules * Often some of the other molecules and intermediates in the downstream pathway * Molecules which potentiate one direction (glycolysis) are often negative regulators of the other direction (gluconeogenesis) Allosteric regulation can be used to superimpose other control pathways on top of a metabolic pathway

Answer 9

Both are polypeptide hormones released from the pancreas. Both bind to specific receptors enriched in muscle, liver and fat cells but have opposing actions.

Answer 10

* Macular degeneration - leading cause of non-traumatic blindness * Kidney failure - diabetes is the leading cause of kidney failure * Stroke * Fatty liver - fatal if untreated * Atherosclerosis * Foot ulcers

Answer 11

Exercise and diet component, not enough exercise and overeating And genetics of course

Answer 12

There are two types: Type 2: * 90% of diabetics have type 2 * Insulin resistance * Beta cell dysfunction Type 1: * 10% of diabetics have type 1 * Characterised by beta cell destruction either an auto-immune response or idiopathic - we don't know the cause.

Answer 13

Half of all South Asian, Black African and caribbean people in the UK will develop type 2 diabetes by the age of 80. For Europeans the figure is 20%. South Asian men are typically 5 years younger on diagnosis and have increased risk of all complications compared to other ethnic groups

Answer 14

Insulin is produced by transcription and translation of the Human Insulin Gene. 1. Mature mRNA encodes a complex polypeptide called prepoinsulin 2. mRNA translated into protein inserted into lumen of the endoplasmic reticulum. 3. This preproinsulin undergoes proteolytic sequential cleavage.

Answer 15

1. Ribosome sees mRNA and starts to read along 2. Sees signal sequence - tells ribosomes to pause. Transalational pause signal. 3. Pause point is just as signal sequence is just poking out of ribosome exit tunnel (insulin polypeptide in red) 4. Signal sequence is recognised by SRP (signal recognition peptide. It grabs the signal sequence very tightly. 5. SRP receptor passes ribosome to complex of proteins called Sec61 translocon complex 6. Imagine these to be a gateway into the lumen ER 7. Want to get insulin into the Endoplasmic reticulum lumen. 8. At that point, translation is carried on 9. Insulin peptide is co-translationally passed through membrane and into cystol of ER.

Answer 16

The prepreoinsulin is passed into the lumen is because the peptide needs to have disulphide bonds added to it to make it stable before it's released into the blood

Answer 17

Disulfide bonds play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium. Since most cellular compartments are reducing environments in general, disulphide bonds are unstable in the cystol as it is a reductive environment. The peptide will only be folded and oxidised in the ER lumen. This is also where the S=S bonds are formed which are crucial for the folding of the molecule into its biologically active form.

Answer 18

Once inside, the preproinsulin can fold and the disulphide bonds can form. It is still not biologically active yet, it's now proinsulin.

Answer 19

Proinsulin only becomes active when the connecting peptide is removed.

Answer 20

The pre-sequence is cleaved by signal peptidase

Answer 21

1. Preproinsulin is translated on ribosomes and is inserted across the ER membrane. 2. Inside the ER, the processing begins, the pre-sequence is cleaved by signal peptidase. Disulphide bond A and B chains which stabilises the 3D structure. 3. Proinsulun then traffics to golgi via vesicular transport. 4. Proinsulin traffics through the Golgi, before being packaged into secretory granules. 5. Proinsulin is cleaved into insulin and C-peptide by enzymes called pro hormone convertase PC1/3 and PC2. Carboxypeptidase E removes basic residues at the C-terminus. 6. High levels of insulin are packaged into the secretory vesicles by making crystalline complex with Zn²⁺ ions selectively pumped into the secretory vesicles. 7. The net result = Very high insulin concentrations in specialised packages. 8. In response to a suitable signal, secretory granules fuse with the plasma membrane and release their contents (insulin and C-peptide).

Answer 22

Regulated exocytosis is a process in which the membranes of cytoplasmic organelles fuse with the plasma membrane in response to stimulation.

Answer 23

Increased extracellular glucose is detected in the blood. Glucose moves from outside of the beta cell to inside using the glucose transporter GLUT2. Once inside the cell, it undergoes glycolysis. Phosphates get added to produce ATP. By doing this the ratio of ATP:ADP is increased. The ATP sensitive postassium channel detects this change and allows the movement of potassium out of the cell. It's inhibited by ATP causing it to close, depolarising the beta cell. This is sensed by voltage gated calcium channel causing it to open. The No. of extracellular Ca²⁺ is 2-3 orders of magnitude higher than the intracellular Ca²⁺ and the the ions diffuse into the cell down the diffusion gradient. Leads to increase in intraxcellular calcium ions causing the fusing of the vesicles to membrane, thus the release of insulin.

Answer 24

That extracellular glucose is accurately sensed. * Vital to this mexhanism is the ability of the cell to sense the extracellular conc. of glucose and adjust intracellular metabolism in direct proportion. * The cell needs to proportionally gauge a response to the increase in blood sugar levels. * A key facet of this mechanism is the low-affinity glucose transporter expressed in the beta cell plasma membrane - GLUT2. It is not that effective in its role.

Answer 25

it would be difficult because glucose is a polar molecule so it would no tbe able to interact with the plasma membrane enough to be able to pass through its non-polar hydrophobic layer. However, the way in which the glucose would be transported in this case, the glucose would need to be dehydrated (as it's usually surrounded by water). The molecule becomes rehydrated within the cell. This requires a lot more energy than with a transporter.

Answer 26

The two gradients a substance can diffuse down are either the chemical graident (a region of high conc. to low conc.) or the elctrical gradient (a charged particle would move from a high potential difference to a lower potential difference).

Answer 27

Facilitative diffusion transporters

Answer 28

The principle of which is that the protein switches conformations to present the substrate binding site to alternate sides of the membrane without ever fully opening a channel from one side to the other.

Answer 29

GLUT transporters have a turnover of about 17,000-20,000 glucose molecules per min. Whereas channels open and allow flow of many ions quickly. This may be as high as 10⁶ ions per second. Structures are different to reflect this. There are 12 different GLUTs in the human genome. Even more channels

Answer 30

Membrane channels are a family of biological membrane proteins which allow the passive movement of ions (ion channels), water (aquaporins) or other solutes to passively pass through the membrane down their electrochemical gradient.

Answer 31

The KM in a Michaelis-Menton curve shows the concentration of extracellular glucose at which we see half of the maximum velocity of glucose entry into a cell. The KM is a measure of affinity, how well this protein can trasnport glucose.

Answer 32

The higher the KM of a transporter the lower the affinity for its substrate. As it takes a longer time for the trasnporter to reach its ¹/₂V_max.

Answer 33

We would want GLUT2 to be a low affinity transporter because this means that the velocity of glucose entry per concentration of glucose is inherently more proportional than if it were a high affinity transporter with a low KM. This allows the glucose transporter to respond to increases in extracellular glucose proportionally.

Answer 34

In most cells ATP is relatively invariant, not for Beta cells though. Glucose metabolism in beta cells is inefficient. As a result, beta cells respond to changes in extracellular glucose concentrations by rapidly changing ATP:ADP ratio. Glucose phosphorylation in beta cells use the low affinity (high KM) enzyme glucokinase. This enzyme is not as saturated as physiological glucose concentrations. So the phosphorylation rate is directly proportional to intracellular glucose concentrations. Glycolytic rate therefore depepnds on glucose entry/blood glucose concentrations.

Answer 35

The 3 main targets of insulin are muscle cells, liver cells and adipose tissue which express an inuslin receptor.

Answer 36

The insulin receptor is an alpha₂Beta₂ polypeptide, held together by disulphide bonds. Has two alpha subunits and two beta subunits. Insulin binds to the alpha 2 subunits inducing a conformational change in alpha subunits. This transmits a signal to the Beta subunits activating an intrinsic tyrosinase kinase within the cytosolic domain. The signal has crossed the membrane at this point. The binding is specific - only insulin can bind to the receptor.

Answer 37

Insulin Signalling? 1. Activation of the receptor occurs only upon insulin binding. Imparts specificity of signal to the tissues that express the receptor. 2. Amplification - a single molecule of insulin activates a kinase that cxan phosphorylate many target molecules. 3. Tyrosine kinase receptor phosphorylates specific Tyr resiudes within the receptor - auto-phosphorylation 4. These p-Tyr residues recruit signalling molecules (IRS-1 shown here) tit he receptor which are then themselves phosphorylated. 5. This forms a signalling complex.

Answer 38

Phospho-tyrosine residues are recognised by specific proteins * SH2 domains * PTB domains Recruits specific set of target proteins to the activated receptor to form an active signalling complex. Many of these targets are then phsophorylated by the activated receptors.

Answer 39

When insulin receptor auto-phosphorylates: Phosphorylated residues become docking sites for other signalling molecules Insulin receptor recruits a big adaptor protein: * IRS-1 * (Insulin receptor substrate 1) * IRS-1 is phosphorylated Selectively recruit molecules Signalling comlex

Answer 40

* The autophosphorylation of specific tyrosine residues function to recruit SH2 domain containing proteins to the receptor. * These are then activated. * Signal propagated. * Insulin receptors selectively recruit different SH2-domain containing proteins.

Answer 41

All SH2 domains bind phsophotyosine. All SH2 domains have a pocket into which the P-tyr residue fits. But not all SH2 domains bind all P-Tyr residues; there is specificty dictated by the surrounding sequence in the target (receptor) polypeptide.

Answer 42

* Pocket contains positively charged residues at the bottom to interact with negative phosphate * If tyrosine isn't phosphotylated: affinity for pocket is gone * Second binding pocket: * E.g. hydrophobic pocket which recognises isoleucine. * Confers specificity

Answer 43

A key downstream target ia thw activation of a Ser/Thr kinase known as Akt. Amplification at all steps Insulind change the phosphorylation status of 100s of different proteins. cAkt is an key enzyme which is activsted by insulin. All signalling pathways amplify.

Answer 44

The key action of insulin is to increase glucose transport into muscle and fat cells.

Answer 45

Uses a specialised form of gluvpse transporter, GLUT4, expressed only in fat and muscle. GLUT4 is capable of moving to the cell surface as a response to insulin binding to its receptor. This si triggered by cAkt. Regulated exocytosis.

Answer 46

In the absence of insulin GLUT4 is inside the cells in specialised vesicles - GSVs GLUT4 is the only GLUT isoform that exhibits this trafficking. Glucose transport is low in the absence of insulin.

Answer 47

In adipose cells cAkt activates GLUT4 trafficking to the cell surface. In liver/muscle cells cAkt phosphorylates and activates phosphatase - promoting glycogen storage. Akt us a crucial molecule in insulin signalling. Different tissues express different Akt 'effectors'.

Answer 48

Insulin can upregulate and down regulate gene expression. Upregulated genes are transcribed relatively quickly. However, they have a low sensitivity to insulin and require a higher dose. Downregulated genes are transcribed slowly but have a high sensitivity to insulin sp a low dose is required.

Answer 49

Insulin signals through IRS1 to a variety of transcription factors that control gene expression. Insulin activates the LxR transcription factor (one of many) in liver and fat. In fat, this drives increased expression of SREBP1 transcription factor. SREBP1 controls (among others) fatty acid synthase, AcetylcoA carboxylase the lipid metabolism genes turned on.

Answer 50

* Acetyl Co-A (under the right conditions) enters the lipogenesis pathway. * It then gets converted to triglycerides. The genes for the enzymes involved in lipogenesis are turned on: * Acetyl CoA carboxylase * Fatty Acid Synthase * SCD1 LxR turns on SREBP1 which turns on the lipid metabolism genes. This gives co-ordinate regulation of lipogenesis as multiple enzymes upregulated by a single transcription factor.

Answer 51

A promoter is a sequence of DNA to which proteins bind that initiate transcription of a single RNA from the DNA downstream of it. This RNA may encode a protein, or can have a function in and of itself, such as tRNA, mRNA, or rRNA.

Answer 52

Activators which help general transcription factors and RNA polymerase assemble. This promotes and increases transcription of target gene. There are also repressors which blocks the genral transcription factors and RNA polymerase.

Answer 53

It can change the stability of a molecule and its location

Answer 54

Phosphorylated TFs can travel through nuclear pore while non phosphorylated TFs cannot.

Answer 55

Amplification is a common feature of signalling cascades

Answer 56

Regulate feeding; it signals to the brain (hypothalamus) to control food intake.

Answer 57

* Adipose cells aree more than inert energy store, they secrete diffferent polypeptide hormones. * These hormones act on other tissues to produce biological effects - adipocytokines; adipokines. * Some of these molecukles are constitutively secreted. * Most well-characterised is Leptin, but there are many others and the inter-relationships between these molecules and their targets is complex and as yet poorly understood. * Likely to be the key to understanding obesity/diabetes

Answer 58

* Most people who are obese have increased fat depot and increased circulating leptin levels. So why are they obese? * This suggests that obesity is asssociated with an inability of leptin to counteract feeding this could be due to leptin resistance? * Suggests that key therapies for obesity treatment may need to target complex regulatory networks in the brain, rather than metabolic tissues like liver or fat.

Answer 59

Endocrine cells are responsible for producing and relkeasing hormone molecules into the bloodstream. Endocirne cells are typically grouped together in organs referred to as endocrine glands.

Answer 60

Neuroendocrine cells are cells that recieve neuronal input (neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release message molecules (hormones) to the blood.

Answer 61

Enteroendocrine cells form the basis of the lagest endocrine system in the body. They secrete multiple regulatory molecules which control physiological and hoomeostatic functions, particularly postprandial secretion and motility.

Answer 62

GLP-1 secretion by ileal L cells (entero-endocrine cells) is dependent on the presence of nutrients in the lumen of the small intestine. It is released in response to major nutrients such as carbs and lipids.

Answer 63

Once in circulation, it has a half life of only 2 minutes as it is rapidly degraded by an enzyme called dipeptidyl peptidase-4.

Answer 64

GLP-1 is a major regulator of whole body glucose homeostasis by acting both centrally (brain) and peripherally (pancreas, adipocytes, liver etc.) to regulate metabolic profiles/fucntion of the tissues. It also slows gastric emptying and thus can indirectly regulate appeptite.

Answer 65

Glucagon-like peptide-1 (GLP-1) is a potentn anti-hypoglycaemic hormone. GLP-1 acts (via receptors) on the beta cell to enhance the release of insulin in response to a rise in blood glucose levels (and supresses glucagon secretion from alpha cells). This is important as unregulated release of insulin when plasma glucose is in the normal range can cause hypoglycaemia - a dangerous fall in blood glucose. This does not happen because of GLP-1.

Answer 66

When blood glucose is in the normal acting range, there is no GLP-1, and the beta cells no longer secrete insulin; this is important when blood glucose is in thr normal fasting range as it will prevent catastrophic hypoglycaemic episodes. When you eat a meal, carbohydrates in gut cause a release of GLP-1. 'Switches the pancreas on'.

Answer 67

GLP-1 is an example of homrones called incretins.

Answer 68

GLP-1 has numerous physiological actions, including: potentation of glucose-stimulated insulin secretion, enhancement of beta cell growth and survival, and inhibition of glucagon release, gastric emptying and food intake. These anti-diabetic effects of GLP-1 have led to intense interest in the use of this peptide, and other incretins, for the treatment of patients with T2D.

Answer 69

Incretins are a group of metabolic hormones that promote a reduction in blood glucose. They achieve this by several mechanisms: * They augment glucose-stimulated insulin release from beta cells. * They surpress glucagon release. * They regulate the absoprtion of nutrinets from the gut.

Answer 70

Main incretins are Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Both are rapidly inactivated by the peptidase dipeptidyl peptidase-4 (DPP-4) and have very short half-life in the curculation. Because of this, their therapeutic use is limited. Longer-lasting analogues are in clinical use as insulinotropic agents. Another approach is to inhibit the enzyme that activates GLP-1 and GIP, DPP-4.

Answer 71

* Platypuses lack a functional stomach. * They instead have high circulating levels of GLP-1 because its biology is rather unusual. * There are conflicting functions of GLP-1 in the platypus: in the gut as a regulator of blood glucose, and in venom to fend off other platypus males during mating season.

Answer 72

While the human version of GLP-1 degrades quickly the platypus version appears to have evolved to be long-lasting which makes it desirable for the tratment of T2D.

Answer 73

* Dolphins and humans have co-evolved metabolic processes. reflecting brain size, - high demands for readily available glucose - and red blood cells that can transport glucose. * Studies of populations of dolphins show that animals fasted overnight exhibit blood chemistry akin to T2D. * When dolphins have a dextrose meal, they had an insulin deficient response - sustained post-prandial high blood glucose with no insulin. Akin to T1D. * Dolphins can switch between T2D and T1D easily.

Answer 74

* Hibernating animals store massive amounts of fat each autumn. * These serve as the main source of metabolic fuel over winter. * Fats are rich and have the advantage of generating metabolic waster as they are catabolised. * Fat deposition occurs on an annual basis. * This is correlated to the length of daylight. * Cycles of natural obesity and insulin resistance.

Answer 75

* Annual cycle of body weight fluctuation is intrinsic rhythm entrained by light. * Depends on melatonin secretion from the pineal gland. * Independent of temperature or food availability. * Liver changes metabolic profile from carbohydrate to fat based metabolism.

Answer 76

* Phenotypic flexibility in the digestive system of migrating birds. * Digestive organs (gizzard, liver, smalll intestine) increase in size and capacity to convert more food into energy e.g. pre-migration * Atrophy when demands fall e.g. during migration. * Many other adaptive changes exhibited: * Increased muscle size and capacity for oxidative metabolism * Liver metabolic profile chnages * There is rapid, precise regulation of physiologicaal systems that is often completely reversible. * Coordinate regulation of metabolic processes like change in diet from seeds to nectar to accumalate rapid fat deposits.

Answer 77

Stored ATP lasts about a second. Creatine phosphate lasts for around 4 seconds, The rest of the exercise will be using the fermentaation of glucose.

Answer 78

Genome Wide Association Studies. How genes effect the development of a trait/phenotype

Answer 79

All you need, e.g. for cystic fibrosis: - Trait segregating in (large) families - Behaves as a Mendelian, single gene trait - Genetic differences across the genome

Answer 80

Most traits are not inherited in a simple mendelian fashion. The risk of developing a disease like autism or diabetes do not display a clear pattern of mendelian inheritnce. Quantative traits are traits that can be quantified such as height/IQ. These traits can have multiple genes involved or there could even be no genetic basis at all!

Answer 81

The manner by which genes and traits are passed from parents to their children. The modes of Mendelian inheritance are autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Also known as classical or simple genetics.

Answer 82

If the trait is heritable It would affect the risk of developing the trait Trait is not pre-determined A role for the environment Could be a small number of genes or many genes which cause the trait. * Small effect size (each make a small contribution to risk)

Answer 83

By utilising family history? if a trait runs in a family it may well be tyhe case that the trait is caused by genetics and the heritability of the certain genes, however, it could be due to the shared environment.

Answer 84

twin studies provide insight into heritabiloity of traits identical twins 100% shared genes and shared environment If one twin has multiple sclerosis for example, the odds of the other one having it is 20% In non identical twins 50% sahared genes and shared environment. If one twin has MS the odds of the other one having it is 5% To calculate the heritability from the above (Monozygiotic twins percentage - Dizygotic twins percentage) x 2 = 30

Answer 85

30% heritability means: For population: 30% of risk is attributable to genetics 70% of risk is non-genetic 30% heritability does NOT mean: Each individual: 30% of trhe trait is genetic 70% of the trait is due to environment.

Answer 86

* 99.9% of the human genome is conserved betyween ppl * All variation is from 0.1% * SNPs are the main source of common allele differences

Answer 87

* Cannot use LINKAGE mapping * No clear patterns, too few ppl * Switch in strategy is needed * Study **populations** rather than families Pre-disposing alleles should exist on limited number of haplotypes and we shouldbe ble to detect them without genotyping them i.e. if only nearby SNPs are genotyped. Can find them even if multiple genes contrubute. As each gene contributes a small amount of risk we are esssentially looking for small effects so need huge numbers. In essence, this is what GWAS (Genome Wide Association Studies) are.

Answer 88

* New medicines: Drug targets that are backed by genetic info are approximately twice as likely to become a successful medicine * Better medicines: Understanding how a medicine is working can help us avoid unwanted side-effects and enhance the probability the medicine will be effective.

Answer 89

GWAS analyse small effect sizes, therefore one needs huge numbers of people. The participants need to be separated based on the trait looking to be analysed. Take care to match the groups for age, sex and ethnicity.

Answer 90

Genotyping is the technology that detects small genetic differences that can lead to major changes in phenotype, including both physical differences that make us unique and pathological changes underlying disease. It has a vast range of uses across basic scientific research, medicine, and agriculture.

Answer 91

1. Mating is random 2. No mutations are arising 3. No gene flow 4. No natural selection 5. Population size is infinitely large

Answer 92

MAnhattan plots are used to display GWAS.

Answer 93

Maturity Onset Diabetes of the Young (MODY) is an inherited form of diabetes mellitus. It is caused by a change in one of eleven genes. Up to 5% of all diabetes cases may be due to MODY. Just like other people with diabetes, people with MODY have trouble regulating their blood sugar levels.

Answer 94

This disorder is more like type 1 diabetes than type 2, although it can be confused with either type. In type 1, the pancreas cannot make and release enough insulin. People with type 2 diabetes, on the other hand, usually make enough insulin, but their bodies cannot respond to it effectively (known as insulin resistance). Type 2 diabetes is usually associated with being overweight, but that is not true of type 1 diabetes or MODY. However, obesity does matter. An obese person with a MODY gene mutation may develop symptoms of diabetes sooner than someone of normal weight.

Answer 95

maturity onset diabetes of the young. There are multiple forms (11) which are usually mistaken for T2D or T1D.

Answer 96

* HNF1A * Transcription factor * Drives expression of genes in endoderm, including GLUT1 and GLUT2 * Strong loss of functrion mutations (recessive) * Treatment: low dose sulfonylurea

Answer 97

* GCK= Glucokinase * catalyses first step in glycolysis * “traps” glucose in cells * important for rapid uptake and metabolism of glucose * STRONG loss of function mutations (recessive) * Often asymptomatic requiring no treatment

Answer 98

* ~10% of all diabetes cases * ~0.5% of UK population * Autoimmune condition: destruction of pancreatic beta-cells * Presentation of insulin as ‘self-antigen’ * No strong sex bias * Onset usually between 5 and 20 yrs old; used to be fatal rapidly * Modern therapy – recomb. insulin injection – more or less normal lifespan now; but …. * Some familial clustering - 20% familial cases, 80% sporadic – most familial cases are sib-pairs, not large families hints at complex inheritance

Answer 99

A measure of INCREASED RISK of having condition conferred by GENOTYPE at each locus/gene

Answer 100

Clinical signs are well established •but only evident after development of disease Genotyping could identify; * High-risk subset of children with decent confidence * 2-5 years BEFORE development of disease * Improved clinical management * Stratification: distinguish T1D from other forms of diabetes e.g. MODY

Answer 101

* T2D diabetes is a complex disorder * Multifactorial * Polygenic * Biggest known risk factor is obesity/ high adiposity * Causal pathway involves ectopic liver fat * T2D genes could also affect * Behaviour- food intake * Metabolism, Glycaemic traits * Fat accumulation/ BMI (adiposity genes → T2D genes) * Beta-cell responses and survival

Answer 102

The strongest risk variant is TCF7L2 * Transcription factor 7-like 2 * The gene has 4 common spliced variants; when variant SNP rs7903146 is present in two copies (CT/TT risk genotypes) * Wnt (wingless/integrated) signalling pathway * Pleiotropic effects across tissues and systems * Has been identified across multiple ethnic groups

Answer 103

The majority of T2D risk variants lie in non-coding regions.

Answer 104

Gene promoter or enhancer regions Alter gene expression (Up or Down)

Answer 105

* Let us calculate the increased RISK: the ODDS RATIO: consider TCF7L2 * 100 people carry the risk allele vs 100 who don’t T2D Cases Healthy Total Carriers 7 93 100 No Risk 5 95 100 Odds ratio = ratio of affected/Unaffected Odds for carrier of risk allele getting T2D = 7/93 = 0.075 Odds for non-carrier getting T2D = 5/95 = 0.053 Therefore the odds ratio = 0.075/0.053 = 1.4

Answer 106

* Moderate intensity - unlike healthy individuals, where hepatic glucose production is matched by peripheral glucose uptake; diabetics use more than is produced (reducing blood glucose) * Lasts for between 24 - 72 hrs * High intensity can cause hyperglycemia due to catecholamine induced glycogen production (lasting 1 - 2 hrs) * May be sensitive to duration of intensity?

Answer 107

* Moderate aerobic activity (2-3 times per week) - metabolic impact for up to 72 hrs * Combined with resistance exercise - metabolic impact for up to 24 hrs - increased muscle mass/strength for enhanced insulin independent affect * Compliance? - time, access to facilities, boring…. - novel strategies for HIIT

Answer 108

At rest the preferred substrate for ATP generation are FFAs (Free Fatty Acids). So by default the high carbohydrate content foods increase blood glucose and should be avoided. The amount of carbohydrates is the primary determinant of blood glucose.

Answer 109

* The type of carbohydrates (amylose vs amylopectin) * Preperation (cooking time or method) * Processed foodstuff vs fresh * trans fatty acids in energy dense food

Answer 110

Starch is made up of two components, amylose and amylopectin. Amylose is a straight chain of glucose units connected by alpha 1-4 bonds. These bonds are broken by the enzymes maltase and amylase Amylopectin contains the same chains, but also has "branch points" created by alpha 1-6 bonds, these bonds are broken by the enzyme isomaltase

Answer 111

Steric hindrance at a given atom in a molecule is the congestion caused by the physical presence of the surrounding ligands, which may slow down or prevent reactions at the atom.

Answer 112

* Theoretically, amylose should be easier to digest because it does not require isomaltase, and does not have the steric hindrance caused by the branch points * However, amylose can form a very compact physical structure, which inhibits digestion * Therefore, amylopectin is actually digested better than amylose

Answer 113

“The whole reason that we evolved as humans is because we started cooking our food. When we only had a raw diet, we had to be eating constantly, because our bodies struggled to get the nutrients out of raw food.” - Macciochi There’s a substantial back catalogue of evidence suggesting that human evolution is directly linked to the use of fire.

Answer 114

* When our ancestors cooked and processed their food, they made it easier to extract calories and fat (improving the gap between the amount of energy it took to digest their food and that extracted from it) * Cooking also kills many of the potentially harmful bacteria that can grow in and on food, protecting from bouts of food poisoning

Answer 115

Some health risks include: obesity, heart disease, high blood pressure and diabetes

Answer 116

A low carbohydrate diet is ineffective without calorie restriction to maintain energy balance.

Systems to Cells Flashcards

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