Week 5:Endocrinology 3 Glucose levels Flashcards by Elizabeth McCabe

What are the main cell types that depend on glucose for their energy?

Red blood cells
Brain
Renal Medulla

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What are the main regulators or blood glucose?
Why?

INsulin
Glucagon
Respond directly to levels of blood glucose

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What are the consequences on the brain of long term starvation?

Reduced blood glucose
No blood glucose available
Relatiant on ketone bodies for alternative source of energy
Can result in permanent and grave brain damage

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What is the average level of bloodstream glucose?

4.5 to 7 mM

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What is the basic role on insulin?

Promote glucose uptake in muscle and adipose tissue
Glucose usage in glycolysis
Glycogen synthesis
Protein synthesis
Uptake of ions (k+ and phosphate)
Prevents hyperglycemia

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What is the basic role of glucagon?

Promote glycogenolysis
Gluconeogenesis
Lipolysis
Glycogenolysis
Ketogenesis
Proteolysis
Prevents hypoglycemia

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What is the role of the endocrine pancreas?

Structure = islets of Langerhans
Alpha cells - secrete glucagon
beta cells - secrete insuline
D cellls - secrete somatostatin - inhibits insulin and glucagon release
F cell/PP cell - release Pancreatic polypetide

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What cell types are most abundant in the islet of langerhan?

Beta cells
Alpha cells
D cells
Level of PP cells varies.

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What is the structure of insulin?

Made of two polypetide chains - a shorter alpha chain and a longer beta chain
These chains are crosslinked by two disulfide bonds
The alpha chain also has an intrachain disulfide bond

Produces alongside a C-peptide but this is cleaved in active insulin.
In total consists of 51 amino acids.

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What is the half life on insulin and C-peptide?
Why is this important for clinical investigations?

Insulin - 4-6 minutes
C-peptide - 30 minutes
C-peptide preferred in clinical measurements to estimate levels of insulin when trying to differentiate between type 1 and type 2 diabetes - less random and more accurate of an average
High in type 2, low in type 1

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Describe how insulin is formed

Preproinsulin - consists of a signal sequence, beta chain, C-peptide and an alpha chain
Signal sequence is cleaved by an enzyme in the endoplasmic reticulum - forms proinsulin
C-peptide is cleaved and disulfide bonds form in the golgiapparatus - forms insulin.

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How does high blood glucose lead to insulin release?

Beta cells in the islet of langerhans take up glucose, convert to glucose 6 phosphate by action of glucokinase, which is then used in oxidative phosphorylation to produce ATP
ATP : AMP ratio increases to high level at blood glucose greater than 5mM. THis causes ATP-sensitive K+ channels to close
K+ build up inside the cytoplasm causing membrane depolarisations
THis opens voltage gated calcium ion channels - influx of calcium
High levels intracellular calcium results in release of stored granules containing insulin and C-peptide. (1;1 ratio)

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Where are GLUT4 receptors found and what is their role?

Are insulin dependent
In skeletal muscle - cause inc glucose uptake, glycogen synthesis and protein synthesis
In adipose tissue - cause inc glucose uptake, inc lipogenesis and decreased lipolysis

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Where are GLUT 2 receptors found and what is their role?

Are insulin independent
Found in liver - increase lipogenesis + glycogen synthesis and decrease gluconeogenesis
Found in basolateral enterocytes - absorption of monosaccharides from GIT

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What factors cause insulin secretion from beta cells?

Blood glucose conc above 5mM - main factor
Can also be enhanced by
1. amino acids - arginine, leucine and glutamine
2. Gut hormones - incretin (GLP and GIP)
3. Neural output - parasympathetic ACh after a meal

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What factors inhibit insulin release?

Sympathetic - adrenaline and noradrenaline

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What is the detailed version of insulin production and secretion?

Stimulated by high blood glucose
Genes encoding for insulin are transcribed to mRNA in the nucleus
Translation occurs when bound to ribosome, forms an N-terminal hydrophobic signal sequence that aids in the transport of mRNA and ribosomes to RER
N-terminal sequence - penetrates the RER resulting in preproinsulin production and continues to elongate into RER
Signal sequences is cleaved in RER forming proinsulin
Transport to golgi -cleaved to insulin and C-peptide that are stored in secretory granules
Released by excytosis

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What type of receptor is the insulin receptor?
How does it bring about its effects?

Is a tyrosine kinase - binding of insulin triggers a conformational change that results in autophosphorylation
Activates MAP kinase signalling pathway
Activates PI-3K pathway

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What are the consequences of the activation of the MAP kinase signalling pathway by insulin?

Cell growth
Cell proliferation
Gene expression

What are the consequences of the activation of the Pi-3K signalling pathway by insulin?

Synthesis of lipids, protein and glycogen
Cell survival and proliferation
Fusion of vesicles containing GLUT 4 within cell membrane - increases amount of functional GLUT 4 on membrane

What is meant by the fasted and the fed state?

Fed - 2 hours after a meal
Fasted - 5-6 hours after a meal

What are the conditions of glucose metabolism in the fasted state?

Low glucose levels
Glycogen stores are depleted to supply more glucose
Muscles and adipose tissue switch to an alternative supply - mainly Fatty acids and ketons

What are the conditions of glucose metabolism in the fed state?

High glucose levels
Hepatic gluose production is no longer required
Alternative fuels not required
Excess glucose is diverted to energy storage.

What are some common pathologies of insulin?

Diabetes Mellitus
Maturity-onset diabetes of the young
Secondary diabetes
Gestational diabetes

What are the different types and causes of diabetes mellitus?

TYpe 1 - normally autoimmune or viral in cause - atrophy or destruction of beta cells - no insulin production Type 2 - insulin resistance - more insulin than normal needed to give response - leads to subsequent failure of beta cells.

What is maturity onset diabetes in the young?

Syndrome of genetic mutations that leads to impaired insulin production or elevated blood glucose (unable to recognise high glucose levels)

What are some common causes of secondary diabetes?

Acromegaly - increased GH Cushing syndrome - increased cortisol Haemochromatosis - excess iron damaged pancrease Pancreatitis - low insulin production

What is the common cause, treatment and presentation of type 1 diabetes?

10% of all diabetes cases Autoimmune destruction of beta cells Insulin levels are very low or absent Starts in childhood or adolescence Short history of osmlar symptoms - thirsy, polyuria, weight loss and lethargy Common complication: diabetic ketoacidosis (more than type 2) Treatment is lifelong insulin

What are the common features, treatment and presentation of type 2 diabets?

Around 90% of diabets cases Risks - obseity, sedentary lifestyle, strong familial tendency and ageing Gradual onset - so often has incidental finding Cause: target tissues resistant to insulin and insulin secretion may also decrease in later disease due to pancreas damage Treatment: lifestyle, medications, insulin

What are the classic triad of diabets symptoms?

Polyphagia Polydipsia Polyuria * these are more common in type 1

What symptoms may appear in diabetes mellitus?

Extreme fatigue Blurry vision Repeated infection Slow wound healing Weight loss Numbness in hands and feet.

What are the major microvascular complications in diabetes mellitus?

Eye - retinopathy, cataracts and glucoma due to high BG and BP damaging BV Kidney - high BP and BG overwork kidnet - nephropathy Neuropathy - High BG damages peripheral nerves - pain or numbness - feet wounds go undetected - can become infected or gangrenous

What are the major macrovascular complications in diabetes mellitus?

Brain - increased risk of stroke, TIA and cognitive impairment Heart - increase risk of coronary artery disease Extermities - peripheral vascular disease resulting in narrowing of blood vessels - reduced blood flow to the lefs, slow healing feet wounds

What vitamin supplement might be given in T2D?

VitB12 - prevent neurovascular complications

What tests can be used to diagnose a patient with T2D?

Fasting plasma glucose - 8 hours after meal - above 7 mmol/L Random plasma glucose - above 11.1 mmol/L and symptomatic Elevated HbA1c 48mmol/mol Oral glucose tolerance test

What is the golden standard test for diagnosing diabetes mellitus?

Oral glucose tolerance test positive result in 2 hours plasma glucose above 200mg/dL after 75 gms of glucose Shows how well able to regulate glucose metabolism Can identify prediabetes and diabetes.

Why is HbA1c important in diabetes mellitus patients?

Is an indicator of long-term glucose control (over 3 to 4 months) Is a Non-enzymatic glycation of hemoglobin (depends on blood glucose levels) Hig HbA1c indicates poor blood glucose control and higher risk of complications Greater than 6.5% is a positive result for T2D

What is the structure of glucagon?

Peptide hormone with 29 amino acids in a single polypeptide chain Proglucagon is first formed - this is a large protein precurso that is tissue specifically modified Converted to glucagon in alpha cells of pancreas by selective proteolytic cleavage in the secretory granules

What factors increase glucagon secretion?

Main - low blood glucose Enhanced by: amino acids - argininge and alanine Stress hormones - nor(adrenaline) and long term cortisol neural input - sympathetic stimulation during stress

What factors inhibit glucagon secretion?

Insulin Glucose

Where are glucagon receptors mainly found?

Liver hepatocytes Renal cortex cells

What are the effects of glucagon at its receptor?

Glucagon binds to GPCR on plasma membrane Activates adenylyl cyclase Converts ATP to cAMP cAMP binds to and activates regulatory subunits of cAMP dependent protein Kinase A This frees the catalytic portion of protein Kinase A to phsopharylate target enzymes brining about effects.

What are the effects of glucagon in the liver?

Activate - glycogenolysis, gluconeogenesis, lipolysis, beta oxidation adn ketone body synthesis Inhibit - glycogenesis, lipogenesis and glycolysis

What are the effects of glucagon in the renal cortex?

Activation of gluconeogenesis and inhibition of glycolysis

What are the effects of glucagon in fat cells?

Indirect action via low serum insulin: glucagon ration Activation of TAG/triglyceride degradation (together with epinephrine)

Where does insulin have receptors that glucagon does not?

Skeletal muscle