Pathogenesis of Diabetes: Glucose Homeostasis, Insulin Resistance Flashcards
What 2 hormones regulate glucose?
Insulin and glucagon
While glucagon keeps blood glucose from dropping too low, insulin is produced to keep blood glucose from rising too high. The two hormones counterbalance each other to stabilize blood glucose.
How do pancreatic hormones in the pre- and post-pandrial states change?
- Glucagon signals are high during lack of glucose to ensure adequate supply of energy to the brain energy, once you eat and glucose is readily available, glucagon is inhibited with release of insulin
- With rapid rise in glucose in circulation, beta cells release insulin to activate uptake into cells
Energy homeostasis in the fasting state
Glucagon high (released from alpha cells) activates the transition to utilizing alternative fuels for energy as a means of maintaining glucose homeostasis.
* liver → glycogenolysis, gluconeogenesis, proteolysis, FFA oxidation
* muscle → proteolysis & FFA oxidation (precursers for gluconeogenesis)
* fat → lipolysis
Need to look at 301 notes
What is the primary goal of glucose homeostasis?
Supplying the brain with glucose to maintain normal function
What occurs in the prolonged fasting state?
FFAs are used to generate ketone bodies as a fuel source for the brain
* Usually just extreme situations
glucose from proteolysis
Protein can be broken down to AA and these can be used as precursers for gluconeogenesis
glucose from lipolysis
triacylglycerols (TAGs) break down via hydrolysis into their constituent molecules: glycerol and free fatty acids (FFAs) and the glycerol can be a precurser for gluconeogenesis
Where does glucagon act on in gluconeogenesis?
- PEPCK
- fructose 1,6-bisphosphates
- glycogen phosphorylase
- glucose 6 phosphatase
Glucagon on PEPCK
Phosphoenolpyruvate carboxykinase (PEPCK) is a rate-controlling enzyme in hepatic gluconeogenesis, and it therefore plays a central role in glucose homeostasis. The rate of transcription of the PEPCK gene is increased by glucagon (via cAMP) and glucocorticoids and is inhibited by insulin
glucagon effect on fructose 1,6 bisphosphatase
enhances flux through fructose 1,6-bisphosphates
Glucagon effect on glycogen phosphorylase
increased glycogenolysis and the production of glucose-6-phosphate.
Glucagon effect on glucose 6-phosphatase
G-6-Pase promotes gluconeogenesis by converting G-6-P to glucose, the last step of the pathway, glucagon has been shown to increase G-6-Pase expression and activity
Draw supply of energy in pre-pandrial state
How do AAs enter gluconeogenesis?
Through conversion to lactate or gluconeogenic AA intermediates can enter the CAC at different steps, then gluconeogenesis removes oxaloacetate from CAC
* Leu and Lys are NOT glucogenic
Cori Cycle
Draw it out
If fasting but exercising muscles will use up glucose and produce lactate which can be transported to the liver to make more glucose to be used for energy
Energy homeostasis in the postprandial state
Draw it out
Pancreatic beta cells sense lots of glucose and secret insulin stimulared glucose uptake and regenerating energy stores for all macronutrients
* Brain: glucose uptake and once gets enough glucose, stimulates satiety and extra glucose is put towards storage
* liver: glucose uptake, glycogenesis, protein synthesis
* Lipocytes: glucose uptake, TG uptake (CMs, VLDL) lipid synthesis, FFA storage (esterification)
* muscle: glucose uptake glycogenesis, protein synthesis
What does insulin stimulate/ inhibit?
Stimulates glucose uptake and usage in peripheral tissues
* Glycolysis to generate ATP
* Glycogenesis in liver and muscles
* Lipogenesis in adipose tissue
* Glucose usage for protein synthesis
Inhibits:
* Ketogenesis (b-oxidation)
* Gluconeogenesis
* Glycogenolysis
Where does insulin act in glycolysis?
- stimulates hexokinase
- stimulate phosphofructokinase 1
- stimulate pyruvate dehydrogenase
- stimulate glycogen synthase
Draw supply of energy in post prandrial state
What 2 biological functions does insulin signalling serve?
- apoptosis (survival)
- growth
Insulin effect on GLUT4
Draw it out
Stimulates PI3 Kinase cascase which causes translocation of GLUT4 to the membrane
Detailed description of the PI3K cascade
Insulin resistance definition
Inability of insulin to produce its usual biological actions at circulating concentrations that are effective in normal subjects.
* Insulin does not fully exert its action
What increases insulin resistance?
- Fat mass (linked to BMI)
- pregnancy
- gender (males)
- diet (fat, vitamins)
- alcohol
- hormones
- drugs/medications
- sedentary lifestyle.
Energy homeostasis in insulin resistance
Hyperinsulinemia → Glucose goes up and beta cells senses it so secretes insulin but does not do very good in activating uptake so beta cells secrete more because it still sense it and will do so until it can exert normal action and then glucose will be taken up and beta cells can turn off. So just keeps secreting insulin until desired result.
* a lot of people who have this don’t even know it and probably 70% will go on without developing diabetes or experiencing hyperglycaemia.
What are potential problems with insulin resistance?
- Episodes of hyperlipidemia? →Because insulin does not do its job there is more time for glucose to remain higher so does that contribute to more fat gain?
- Hyperglycemic excursions? → Does glucose go higher and/ or remain elevated for longer and can this damage the body?
Energy homeostasis in diabetes
Lots of glucose → hyperglycemia, hyperlipidemia, ketoacidosis.
Pancreatic beta cells do not secrete enough insulin and cannot evaluate glucose concentration properly so it remains elevated and glucagon continues to be released and the systems are tricked into thinking there is a lack of glucose.
* hepatic glucose output → Glycogenolysis, gluconeogenesis, proteolysis, FFA oxidation
* lipocytes → lipolysis, ketogenesis
* muscle → proteolysis, FFA oxidation
What are some biological outcomes of hyperglycemia?
- neuronal dysfunction → certain threshold of glucose is toxic
- decreased incretins → gut hormones that signal plentiness are not released as well
- glucose reabsorption from kidneys
- decreased insulin → glucose stays elevated
- Increased HGP → keeps making glucose
- increased FFAs → mobilizes fat stores
- inefficient glucose uptake
- increased glucagon
