watson - diabetes Flashcards by Megan Maloney

diabetes leads to wasting of tissue and excessive urine production T/F

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how is insulin produced

by the pancreatic beta cells

synthesised as preproinsulin and is then cleaved

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what is the difference between the onset of type 1 and type 2 diabetes

type 1 diabetes is typically adolescent onset whereas type 2 is mature onset

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what is different about the insulin requirement of type 1 and type 2 diabetes

type 1 has an absolute requirement for insulin whereas type 2 may not require insulin

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what is different about the outcome of type 1 and 2

type 1 can be fatal without treatment - regular injections of insulin. type 2 can be modified by exercise

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what are the key tissues that control glucose homeostasis

pancreas
muscle
liver
adipose tissue

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what molecule do pancreatic alpha cells produce

glucagon - has opposite effects to insulin

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pancreatic beta cells produce insulin and this acts in an endocrine manner. what does this mean

the insulin hormone is released and diffused through tissues

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what molecules are important in determining when pancreatic beta cells produce insulin

kir 6.2 - ATP gated inward rectifying K+ channel
L-type Ca channel
GLUT-2 - glucose transporter
hexokinase

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glucose enters the cell via what

GLUT2

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when glucose enters the cell it is phosphorylated by what to prevent it leaving the cell

hexokinase IV

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after phosphorylation G-6-P is metabolised by mitochondria which alters levels of what to act as a sensor for circulating glucose levels

ATP

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As the ATP levels in the cell increase the KIR6.2 potasssium channel shuts what does this cause

a negative potential and the calcium channel to open and calcium influx into cell

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what does the influx of calcium into the cell cause

catalyses the membrane fusion of secretory granules and release of insulin

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the specific receptor for insulin is in which family

receptor tyrosine kinase

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when insulin binds to receptor the phosphorylation of the receptor leads to the activation of serine/threonine kinases which leads to phosphorylation of a series of what

insulin-receptor subtrates (IRS-1 to IRS-4)

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which pathway does the phosphorylation of IRS-1/IRs-2 activate

phosphoinositol

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what does activation of the phosphoinositol pathway lead to

activation of Akt which is the main mediator od metabolic actions of insulin

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what does Akt signalling drive

cytoskeleton rearrangements that lead to insertion/activation of GLUT4 - increases uptake of glucose 20 fold

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what does the uptake of glucose but GLUT-4 stimulated by insul-Aktcause

reduces blood glucose levels

what is the effect of insulin/akt in the liver

decreases gluconeogenesis
increase glycogenesis
downregulates glycogenolysis
increases lipogenesis

what is the effect of insulin/akt in the muscles

glucose transport increases via GLUT4

stimulates glycogenesis

what is the effect of insulin/akt in adipocytes

Increase in glucose transport via GLUT4
Increase in lipogenesis
Decrease in lipolysis (breakdown of fats)

what are the 2 main stages of the evolution of type 2 diabetes

loss of insulin sensitivity

loss of insulin production by pancreatic b cells

describe the stages of the evolution of type 2 diabetes

go through a period where glucose levels in blood rise B cells sense this and produce more insulin to drive it down to normal levels cells no longer respond to insulin glucose levels steadily increase B cells cant keep producing insulin at this high output - go into decline blood glucose continurs to rise and gets out of control as insulin production falls

in type 2, diagnosis occurs after insulin production has fallen sufficiently that blood glucose levels rise to symptoms of hyperglycaemia T/F

type 2 causes an increase in fatty acids in circulation, why

lipolysis is not inhibited by insulin

what are the effects of hyperglycaemia which are common to both type 1 and type 2

``` polyuria neuropathy macrovascuar damage microvascular damage infection increased ```

what is the functional unit of the kidney

nephron

how does diabetes lad to polyuria

filtrate contains glucose and now has osmotic pressure - cant transport all water back out of filtrate

how does diabetes lead to microvascular complications

high glucose concs are toxic to endothelial cells lining the capillaries induce expression of fibrogenic growth factor increased deposition of matrix in basement membrane thickening of vessel wall loss of circulation

how does diabetes lead to macrovascular complications

prolonged high levels of glucose increases permeability of endothelial cells lining the arteries can lead to deposits of lipids in supportive layer of vessels - atheroma

how does diabetes lead to neuropathy

prgressive loss of nerve function associated with prolonged exposure to glucose

how does diabetes lead to infection

high levels of tissue glucose provides good habitat for microorgansims • Reduced microvascular function changes the nature of normal inflammatory response • Reduced diffusion of inflammatory mediators • Reduced migration of immune cells • Peripheral neuropathy can reduce awareness of damage

T2D has a stronger genetic basis than T1D BUT

depends on the environment

what are the genes involved with T2D

calpain10 glucokinase GLUT2

what are sulfonureas

intervention for T2D

how do sulfonureas work

target SUR1 subunit of ATP gated potassium channel blocks it | triggers Ca influx and increased insulin secretion

how does metaformin work as an intervention for T2D

increases insulin receptor signalling sensitivity

what is the differences between T1 and T2

T2 doesnt require insulin in early stages T1 does Type 2 has a mature onset T1 has adolescent T2 can be managed by diet T1 cant Type 1 is an autoimmune disease

A number of high affinity autoantibodies against beta cell proteins are detected in patientswith T1D

what are the autoantibodies in T1D patients usually against

- Glutamic acid decarboxylase - Insulin - Zinc transporter 8 - Insulin associated antigen 2

HLA alleles account fr around % of Type 1 risk

40-50%

how were the risk alleles of T1D identified

Using NOD mouse

what is Idd-2 and how is it associated with T1D

polymorphism in region upstream from insulin | causes decreased levels of expression of insulin in thymus - T cells that react to it are not all destroyed

how is IL-2 associated with T1D

necessary for generation of Tregs | if theres not enough Tregs this leads to autoimmunity

how is idd-4 associated with T1D

locus associated with aberrant overexpression of IFN response to viral infection in the NOD mouse

how is CTLA-4 associated with T1D

acts to dampen down TCR response | if defective may lead to aberrant response

how is PTPN22 associated with T1D

reverses the action of tyrosine kinases | important in shutting down tyrosine kinase pathways