Lecture 17: Glucose Homeostasis Flashcards
Where does glucose come from in the body?
- Ingestion
- Gluconeogenesis (AA)
- Glycogenolysis
Write some notes on the islets of langerhan:
1-2% of pancreas mass but receive 20% blood flow
Neurovascular bundle enters each islet through beta cell core
Venous effluent to portal vein and liver
How is glucose transported?
GLUT (facilitated)
SGLT 1 & 2 transporters (Na dependent)
Where is a drug target to alter blood gucose?
Kidneys SGLT1-2 transporters. Blocks Na and glucose uptake
Where are GLUT 1 transporters located? and why is this important?
GLUT1 = RBC and Brain
Non-insulin mediated glucose uptake
What are GLUT 2,3,4 located?
GLUT 2 = Pancreas and liver
GLUT 3 = Neurons (Placenta)
GLUT 4 = Fat and Muscle (Insulin mediated and present in vesicles, also exercise induced - reduces glucose)
What happens to glucose once it enters the cell?
Glucose -> Glycolysis -> ATP
How does rising glucose cause insulin release?
Rising blood glucose influxes into islet cells via GLUT2. They are then broken down via glycolysis and produce ATP which drives a K pump. This depolarises the cell and causes Ca to influx. Ca causes insulin vesicle binding release
How does glucose in the gut result in insulin release?
The gut releases GLP-1 and other factors which influence insulin release
What are the possible drugs targets for influence insulin release?
GLP-1 agonist. DPP4 inhibitors (enzyme for GLP-1)
Sulphonylureas that influence K ATPase and islet cell depolarisation
Describe the structure of insulin in beta cells and what happens as it is released:
- Pro-insulin in the beta cells is cleaved to release insulin and C-peptide
What can c peptide be used for?
- C-peptide measurement can be used to assess endogenous insulin secretory capacity
If hypoglyceamic case presents can measure to see if they need insulin or not.
Describe the signalling mechanism of insulin:
Insulin signalling pathway: Insulin binds to its receptor results in autophosphorylation of the insulin receptor beta sub units on tyrosine amino acids
Insulin receptor autophosphorylation activates the insulin receptor substrates (IRS 1/2) and phosphatidylinositol (PI3) kinases leading to a cascade of events that ultimately leads to GLUT-4 translocation and glucose uptake into tissues.
Describe the time course released of insulin at basal levels and after a meal:
What factors regulate insulin release?
What are insulins generics effects?
Basal: Pulsatile 9-14 mins.
Major regulator is glucose - Acute phase then slower second phase.
Other regulators: AA, glucagon, incretins i.e GLP1 (all increase insulin)
Somatostatin - Decreases insulin release
Effect: Anabolic increasing storage of glucose, fatty and amino acids.
Describe glucagon and its effects:
Catabolic mobilising glucose, fatty and amino acids from stores
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What is often lost in the insulin phase response to glucose challenge?
1st acute phase is often lost in diabetes
What are GIP and GLP1?
GIP = Glucose dependent insulintropic polypeptide
GLP-1 = Glucose like peptide 1
Describes what happens following the consumption of food with incretins and their effects:
GI tract : releases incretins (gut hormones) i.e GLP1 and GIP
-> Act on beta and alpha cells:
Glucose dependent: Increase insulin from beta cells (GLP1 and GIP) = Insulin increased peripheral glucose uptake i.e muscle and fat.
Decrease glucagon (alpha cells) GLP-1, glucose dependent = Increased insulin and decreased glucagon reduce hepatic glucose output
= Blood glucose control
What happens to incretins in a diabetic patient?
Incretin effect is deminished
What does sitagliptin do?
Inhibits DPP-4 enzyme responsible for GIP and GLP1 breakdown thus prolonging their effect
What does insulin do to carbs?
- Liver - inhibits glycogenolysis and gluconeogensis
- Muscle - increase glucose transport and glycolysis
- Adipose tissue - same as muscle
What does insulin do to fat?
Increase TG storage and inhibits lipolysis (dec. hormone sensitive lipase) and FFA production
Inhibits ketone production
Describe the action of insulin on protein:
Anabolic by increasing transport of AA into liver and muscle
Fat represents 20-30% of bw and 70-80% stored energy. Whats it broken down into and what does that enter to produce energy?
Lipolysis -> FFA and Ketones -> Glycerol -> Krebs cycle
How much energy stores are in carbs and protein?
Protein ~20%, hydolysed to AA
Carbs ~1-2% but are readily available
What cells dont have mitochondira?
RBC, thus dont have krebs cycle
In a nutshell what does the krebs cycle do?
Oxidizes acetyle CoA for Energy (ATP)
Interconnects carbohydrate, protein and fat metabolism
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What is ketogenesis?
When FFA are oxidated in the krebs cycle they produce ketones i.e Aceto acetate, acetone, beta hydroxybutyrate
Fuel for muscle and liver but not acutely for brain or RBC
How does ketogenesis occur in the setting of insulin deficiency and what are the implications of this?
Insulin deficiency - Uncontrolled gluconeogenesis and protein hydrolysis - GLUT 4 inactive - Overall net result: Diabetic ketoacidosis
Compensatory resp. alkalosis = Hyperventiliate to blow off CO2
What is normal fasting glucose?
3.5-5.5 mmol/l
As hypoglycemia occurs, what are the symptoms and how do they change?
Level 1-2: Neuroendocrine symtpoms i.e FFF response, insulin secretion inhibited, glucose released from liver.
Level 2-3: Neuroglycopenic symptoms i.e severe cognitive impairment requiring external assistance for recovery
Sustained hypoglyceamia can lower BG set point and thus have no early symptoms before severe hypoglyceamia
What causes hypoglycaemia?
Insulin in patients with diabetes Sulphonyurea therapy (enhanced GLP and GIP effect)
Insulinoma (rare)
Severe horone deficiency i.e addinsons disease
