Lecture 5 - Glucose Control in Health and Disease Flashcards Preview

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Flashcards in Lecture 5 - Glucose Control in Health and Disease Deck (48):

Normal blood glucose level



Parts of a meal that are soluble in the blood

Glucose, amino acids


Parts of a meal that are insoluble in blood



How do lipids enter the blood?

Packaged into chylomicrons. Enter blood via lymphatics


Insulin release after a meal stimulates:

Glucose uptake Amino acid uptake into muscles, protein synthesis


Insulin precursor activation into insulin 1) 2) 3)

1) Prepro insulin has A, B, C subunits, curled into a paperclip shape 2) NH3-terminal signal sequence is cleaved, two disulphide bonds form between A and B subunits, one disulphide bond forms on B subunit. This forms pro insulin. 3) C subunit is removed. Insulin formed.


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A image thumb

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Stages of insulin formation (picture)

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What are GLUT proteins?

Membrane-bound proteins that mediate glucose movement across animal cell plasma membranes


How can GLUT isoforms differ? 1) 2) 3) 4)

1) Tissue expression 2) Substrate specificity 3) Kinetic characteristics 4) Functions


Generic shape of a GLUT protein 1) 2) 3) 4) 5)

1) Single polypeptide. 2) 12-pass transmembrane. 3) Both C and N termini are in the cytoplasm. 4) ~500aa 5) Mostly hydrophobic residues in transmembrane regions. Polar residues in the membrane form a polar pore


Where are GLUT4 found?



GLUT4 regulation in myocytes 1) 2) 3) 4) 5) 6)

1) Regulated exocytosis 2) GLUT4 stored in cytoplasmic vesicles 3) When insulin binds insulin receptor, vesicle fuses with plasma membrane, depositing GLUT on cell surface 4) When insulin levels drop, GLUT are removed from the plasma membrane by endocytosis 5) Smaller vesicles fuse with endosome 6) Small, GLUT-rich parts of endosome bud off to form GLUT vesicles


What is the rate-limiting step in glucose use by a cell?

Glucose uptake


Proportion of insulin-stimulated glucose uptake that occurs in muscle



Early feature of insulin resistance

Failure of GLUT4 transport


How are pancreatic beta cells induced to release insulin? 1) 2) 3) 4)

1) Increased extracellular glucose leads to increased glucose uptake through GLUT2 into beta cell 2) This increases intracellular ATP levels 3) ATP inhibits ATP-gated K+ channel, which depolarises plasma membrane 4) Voltage-gated Ca2+ channel brings Ca2+ into cell. This leads to insulin release from vesicles into extracellular environment


Primary targets of insulin (organs)

Liver Adipose tissue Muscle


Broad outcomes of insulin release 1) 2) 3) 4)

1) Increased glucose uptake from blood into tissues 2) Increased glucose storage as glycogen 3) Increased metabolism of glucose for energy 4) Increased synthesis of triacyl glycerides (TAGs)


Product of glucose metabolism that leads to TAG synthesis

Acetyl coenzyme A (from pyruvate)



Very low density lipoprotein


How is glucagon release stimulated? 1) 2) 3)

1) Hypothalamus monitors blood glucose 2) When blood glucose drops too low, K+-gated ATP channels depolarise cell. 3) Autonomic nerve signalling stimulates alpha cells to release glucagon


Targets of glucagon

Mainly the liver Adipose tissue


Enzymes upregulated by glucagon 1) 2) 3)

1) Glycogen phosphorylase 2) Fructose 1,6-bisphosphatase 3) Triacylglycerol lipase


Enzymes downregulated by glucagon 1) 2) 3)

1) Glycogen synthase 2) Pyruvate kinase 3) Phosphofructokinase 1


Effect of downregulating glycogen synthase

Reduction in liver synthesis of glycogen


Effect of increasing glycogen phosphorylase

Increased liver breakdown of glycogen


Effect of reducing pyruvate kinase

Increased gluconeogenesis in liver.

Stops glycolysis.


Effect of increasing fructose 1,6-bisphosphatase

Increased gluconeogenesis in liver


Effect of decreasing phosphofructokinase 1

Reduced glycolysis


Effect of increasing triacylglycerol lipase

Increased mobilisation of fatty acids


Symptoms of uncontrolled type 1 diabetes 1) 2) 3) 4) 5) 6)

1) Frequent urination 2) Extreme thirst, dry mouth 3) Hunger 4) Sudden weight loss 5) Lack of energy 6) Blurred vision


Mechanism behind type 1 diabetes

Autoimmune destruction of beta cells in pancreas. Particularly inflammatory cytokines


Relative loss of beta cells in type 1 and 2 diabetes

Greater loss of beta cells in type 1


Characteristics of type 2 diabetes 1) 2) 3) 4)

1) Heterogenous levels of insulin production and release 2) Varying levels of insulin resistance in tissue 3) Increasing levels of beta cell destruction as disease progresses 4) Symptoms are similar to type 1 diabetes


Effect of type 1 diabetes on muscle glucose uptake 1) 2) 3) 4)

1) Lack of insulin binding to insulin receptor leads to little GLUT4 transport to cell surface 2) This limits the amount of glucose entering a cell 3) Glycogen synthesis is inhibited 4) Glycogen stores are depleted


Effect of type 1 diabetes on muscle

1) Uptake of amino acids and muscle synthesis is inhibited 2) Normal inhibition of protein degradation is lost 3) Muscle degradation


Consequence of muscle degradation in type 1 diabetes

Increased transport of nitrogen to the liver in the form of alanine. This leads to gluconeogenesis, worsening hyperglycaemia


Effect of type 1 diabetes on adipose tissue 1) 2) 3) 4) 5)

1) Glucose uptake failure by GLUTs 2) Increased lipolysis of TAGs leads to increased levels of circulating free fatty acids 3) Transfer of lipids to liver for metabolism 4) Fatty acid oxidation leads to excess ketone body formation 5) Excess ketone bodies lead to diabetic ketoacidosis


Why is glycogenolysis favoured in type 1 diabetes?

Loss of activation of glycogen synthase by insulin Loss of inhibition of glycogen phosphorylase


What leads to diabetic ketoacidosis? 1) 2) 3) 4)

1) Lack of insulin leads to excess glucagon, stress hormone release. 2) Muscle broken down into amino acids, TAGs in adipose tissue lipolysed into fatty acids 3) Blood glucose exceeds ability of kidneys to remove glucose. Urine becomes hypertonic, drawing more water out of the body. Increased urination. 4) Liver produces increased numbers of ketone bodies


What might lead to insulin resistance?

Defective insulin receptor


When does type 2 diabetes occur?

When there is both insulin resistance in target tissues, and death of beta cells in pancreas


Stages of type 2 diabetes 1) 2) 3)

1) Insulin resistance in tissues. Pancreas releases more insulin to compensate (hyperinsulinaemia) 2) Hyperglycaemia despite elevated insulin. Glucose tolerance impaired 3) Insulin secretion declines from death of beta cells. High fasting blood glucose (diabetes)


Lipotoxicity model of insulin resistance 1) 2) 3) 4)

1) With positive caloric balance, adipocytes enlarge (store TAGs). Excessively large adipocytes release MCP-1 (macrophage chemotaxis protein). 2) MCP-1 attracts macrophages, which release TNFa 3) TNFa favours TAG export. Adipocytes export TAGs, which deposit on muscle cells 4) Ectopic lipids form on muscles, which interfere with GLUT4 transport.


Structure of insulin receptor

Preformed heterotetrameric receptor Alpha and beta subunits. Insulin binds alpha subunit, beta subunit is transmembrane, autophosphorylates in response to insulin binding. Alpha and beta are joined by disulphide bridges


Protein tyrosine kinases

1) Transfer gamma-phosphate of ATP to target tyrosine residue on substrate