Lecture 17 Glucose metabolism Flashcards
What are the steps that lead to insulin secretion from the B cell after eating a meal- elevated blood glucose
- Enters the cell through GLUT2 transport - NIMGU
- Glucose undergoes glycolysis to form ATP
- Increased ATP causes closure of voltage gated K+ channels which lead to depolarisation
- Causes opening of v-gated Ca2+ channels
- Influx of Ca2+ triggers insulin translocation and exocytosis from the cell
Where does the insulin produced by the pancreas drain to and what can this cause
Drains to the liver via portal vein. Excess insulin can cause increased fat storage in the liver–> fatty liver –> cirrhosis
Where is the insulin mediated glucose uptake and non insulin mediated glucose uptake (NIMGU) by transporters
NIMGU- RBC, brain, kidney, colon + (Glut 1), pancreas and liver (Glut2)
Glut-4 in muscle and fat is important transporter sensitive to insulin
How do you tell the difference between an endogenous or exogenous increase in insulin causing hypoglycaemia
measure blood insulin and c-peptide- if this is endogenous there should be equal amounts of c peptide and insulin as insulin is created from cleaving pro-insulin + c protein
What is action of Insulin on cell receptor tissues and how does this differ between fat, muscle and liver tissue
- Increase and Decrease
- Insulin binds to the cell surface receptor which leads to autophosphorylation of the tyrosine residues which leads to an enzyme cascade resulting in GLUT4 translocation to the membrane and increases glucose entry for muscle and adipose tissue.
In muscle also increases
- glycogen synthesis,
- amino acid uptake= protein synthesis,
- ketone uptake
In fat
-increases lipogenesis and inhibits lipolysis
In liver
- decreases ketogenesis and gluconeogenesis
- increases glycolysis (ATP making),
- increases glycogen, lipid and protein synthesis,
What are the main signals that promote or inhibit insulin release
Promote
- Increased blood glucose, glucagon, vagus nerve stim, incretin hormones GLP1
Inhibit
-Decreased blood glucose, symp nerve stim, somatostatin,
- adrenaline, growth hormone and cortisol also reduce insulin receptor number and affinity, resulting in a degree of insulin resistance
What is the “Incretin effect” on the observed secretion of insulin and what are the steps leading to that
- Insulin secretion is greater when glucose given orally vs IV to get the same rise in blood glucose
- This is bc ingestion of food triggers release of incretin GLP-1 from gut which acts on
a) beta cells to increase glucose dependent Insulin secretion -> increased peripheral uptake
b) alpha cells to decrease glucose dependent glucagon release–> increase insulin and reduced hepatic glucose output
Therefore leading to decreased Blood glucose after a meal - high spike of insulin in phase 1
What are the two phases of insulin secretion after a meal and how does that change in type 2 diabetes
- Acute phase of insulin spike - this is gone in type 2
2. Sustained 2nd phase - longer lower peak of insulin in type 2- doesn’t return to resting level of glucose.
How is glucose stored in the liver, fat and muscle and what type of need is it for
Glucose can enter the krebs cycle (undergoing glycolysis to become pyruvate) immediately or be stored as
- Liver: Carbs-> Glycogen for immediate needs
- Muscle: Carbs-> Glycogen for immediate needs. Protein in muscle can also be hydrolysed to ATP/ undergo gluconeogenesis
- Fat (the rest) for slower needs store in adipocytes.
How does ketogenesis progress to Diabetic Ketoacidosis in what type of Diabetes
Liver and muscle can oxidise FFA to make ketones (acetoacetate, acetone, b-hydroxybutyrate) as a fuel source, but RBCs and the Brain cannot.
In Type 1 where there is prolonged, profound insulin deficiency, it loses its suppression of:
- hormone sensitive lipase, so is very active - increasing fat lipolysis and formation of ketones which are acidic.
- protein hydrolysis, so is unchecked and amino acids enter krebs to do gluconeogenesis
- glycogenolysis (glycogen-> g6p), so is uncontrolled, increasing glucose production and hepatic glucose output
As a result of increase glucose but inactive GLUT4 : Diabetic Ketoacidosis
What happens to glycolysis in muscle in sepsis or hypoxic conditions
Lactic acidosis through increased glycolysis anaerobically to make ATP via Pyruvate –>Lactate
What are the causes of hypoglycaemia - low blood glucose from common to rare
- Too much insulin in patients undergoing treatment for diabetes
- Sulphonylurea treatment: increase insulin
Rare
3.insulinoma: islet cell tumour - Severe hormone deficiency- autoimmune disease
What counter mechanisms happen after hypoglycaemia, for a diabetics (mainly type 1 - different for normal people) and what 2 symptom groups present because of this
- Low blood glucose cause inhibits insulin secretion from b cells and increased secretion of glucagon, adrenaline, growth hormone, cortisol.
- This stimulates release of glucose from the liver however due to low insulin/sensitivity in Diabetics this is not taken up by the cells like in a normal person
- First symptoms are Neuroendocrine: hunger, sweating, shaking, HR increase
- If it drops more then Neuroglycopenic symptoms
Confusion, aggression, misjudgement, progressive impairment until loss of consciousness.
What is the danger with keeping at a low blood glucose for extended period of time
The body adapts to the new homeostatic mean so that Neuroendocrine symptoms don’t show up, only Neuroglycopenic as the first symptoms which is dangerous as they can impair the ability to seek help.
This is common presentation in undiagnosed type 1 diabetics
How does diabetic ketoacidosis present
As a result of increase glucose but inactive GLUT4 : Diabetic Ketoacidosis
- Hyperglycaemia, Nausea, Vomiting, fruity breath, reduced consciousness, glucosuria, hypovoluaemic due to increased urine output
