BIOM30001 Lecture 6: 6 Glucose control in health and disease 2
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The uptake of amino acids and protein synthesis is inhibited
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The normal inhibition of protein degradation is lost, so there is net degradation of
muscle (normally happens in fasting periods for gluconeogenesis)
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Consequence: increase in transport of nitrogen from muscle to the liver as alanine ->
gluconeogenesis -> Worsening of hyperglycaemia
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Muscle protein metabolism
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Failure of glucose uptake by the GLUTs
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Increased lipolysis of triacylglycerols (TAGs), leading to increased levels of circulating
free fatty acids
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Transfer of free fatty acids to the liver for use as fuel (instead of glucose)
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Adipose tissue metabolism
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loss of activation of glycogen synthase by insulin
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loss of inhibition of glycogen phosphorylase
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Glycogenolysis is favoured due to:
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Glycogenolysis contributes to increased blood glucose levels
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Fatty acids broken down and go to liver
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Increased fatty acid oxidation -> ketone body formation (acetoacetate and beta-hydroxy
butyrate) in the liver from Acetyl-CoA -> diabetic ketoacidosis
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Liver glucose metabolism
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Increased production of the ketone bodies (acids)
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Leads to acidosis
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Diabetic ketoacidosis
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Frontiers Page 7
Affects the insulin’s target tissues: liver, adipose tissue and skeletal muscle
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Less glucose disposal in muscle
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Less suppression of endogenous glucose production in the liver
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Insulin effects are ‘subnormal’
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It is thought that disruption of insulin receptor signalling pathways could contribute to insulin
resistance
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insulin resistance in insulin target tissues PLUS
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death and/or dysfunction of pancreatic β cells
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T2DM occurs when there is:
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Insulin resistance
*defined as glucose levels of 7.8 to 11.0 mM 2 h after a 75-g oral glucose tolerance test
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When early insulin resistance starts to develop, the body must produce higher amounts of
insulin to keep glucose levels normal
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Glucose begins to build up, due to a failure of production of insulin in high enough levels
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Stage 3 looks like T1DM
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3 phases in the development of T2DM
When caloric intake is excessive, adipocytes store increasing amounts of TAG until they can
store no more
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Lipotoxicity model of insulin resistance
Frontiers Page 8
Document Summary
The uptake of amino acids and protein synthesis is inhibited. The normal inhibition of protein degradation is lost, so there is net degradation of muscle (normally happens in fasting periods for gluconeogenesis) Consequence: increase in transport of nitrogen from muscle to the liver as alanine -> gluconeogenesis -> worsening of hyperglycaemia. Increased lipolysis of triacylglycerols (tags), leading to increased levels of circulating free fatty acids. Transfer of free fatty acids to the liver for use as fuel (instead of glucose) Glycogenolysis is favoured due to: loss of activation of glycogen synthase by insulin loss of inhibition of glycogen phosphorylase. Fatty acids broken down and go to liver. Increased fatty acid oxidation -> ketone body formation (acetoacetate and beta-hydroxy butyrate) in the liver from acetyl-coa -> diabetic ketoacidosis. Affe(cid:272)ts the i(cid:374)suli(cid:374)(cid:859)s target tissues: li(cid:448)er, adipose tissue a(cid:374)d skeletal (cid:373)us(cid:272)le. Less suppression of endogenous glucose production in the liver.