Insulin, Glucagon, and DM Flashcards
Where is glucagon and insulin produced?
In the islet of Langerhans in the pancreas
Beta cells = insulin
Alpha cells = glucagon
How is insulin synthesize and stored?
It’s synthesized as a preprohormone, cleaved to prohormone in ER, and packaged into vesicles by the Golgi apparatus as insulin and connecting C peptide
Are insulin and glucagon protein bound in circulation?
No, therefore they have a relatively short half life (5-10min)
Generally speaking, what stimulates insulin secretion?
an abundance of nutrients, as insulin promote nutrient uptake by the body
What are some examples of rapid, intermediate, and delayed effects of insulin?
Rapid: glucose, amino acid, and K+ uptake
Intermediate: protein anabolism, inhibition of protein catabolism
Delayed: gene transcription
Describe the insulin receptor
It’s a tetramer.
Has 2 alpha subunits that are extracellular and 2 beta subunits in the phospholipid bilayer. Insulin binds to the alpha subunits –> leads to tyrosine activation of the beta subunits –> autophosphorylation of the intracellular components –> further phosphorylation of activating enzymes
What are the effects of insulin on carbohydrate metabolism in the muscles?
- promotes muscle glucose uptake by GLUT4
- GLUT4 otherwise stored in vesicle in the cytoplasm
- glucose into muscle –> glycolysis & oxidation –> stored as glycogen
- exercise can also translocate GLUT4 independent of insulin
What are the effects of insulin on hepatic carbohydrate metabolism?
- increase glucose uptake via glucokinase induction
- increased phosphorylation of glucose to glucose-6-phosphate
- increased glycogen synthesis by activating glycogen synthase
- decrease hepatic output of glucose: 1. inhibits glycogenolysis by inhibition glycogen phosphorylase, 2. decrease exit of glucose by inhitibting glucose-6-phosphatase, and 3. inhibits gluconeogenesis by inhibiting amino acid uptake by the liver & by decreasing key enzymes in gluoneogenesis
- enhances synthesis of fatty acids: 1. increase glucose flow to pyruvate –> acetyl Co-A, and 2. converts acetyl Co-A to Malonyl-CoA, a rate limiting step in fatty acid synthesis
What are the effects of insulin on carbohydrate metabolism in adipose tissue?
- facilitate glucose uptake
- metabolize glucose to alpha-glycerol phosphate
- provides glycerol for esterification to triglycerides for storage
What are the effects of insulin on carbohydrate metabolism in the brain?
very little effect!
What are the effects of insulin on fat metabolims?
- inhibits hormone sensitive lipase: decrease rate of lipolysis and release for fatty acids in the blood stream
- increase glucose transport into fatty tissue –> metabolize glucose to alpha-glycerol phosphate –> stored as triglyceride
- inhibits lipoprotein lipase: this enzyme is present in the capillary walls, therefore prevents splitting of triglycerides into fatty acids
What are the effects of insulin on hepatic lipid metabolism?
- promotes synthesis and inhibits oxidation of fatty acids
- conversion of acetyl-CoA to malonyl-CoA inhibits carnitine acyltransferase, which is responsible for taking fatty acids from cytoplasm to the mitochondria for beta oxidation and conversion into ketones
- insulin in anti-ketogenic
What’s the effect of insulin on protein?
- anabolic
- increases protein synthesis by increasing gene transcription and translation
- also inhibits protein catabolism
How is insulin secretion controlled?
- major one = glucose feedback to beta cells
Other than blood sugar level, what else can increase insulin secretion?
- amino acids
- GI hormones, esp gastric inhibitory polypeptide and glucagon-like polypeptide
- other hormones, like growth hormone and cortisol –> they antagonize insulin
- autonomic nervous system: sympathetic (alpha-adrenergic) inhibits insulin secretion; parasympathetic increases insulin secretion
Where is glucagon produced?
In the alpha cells in the pancreas - islet of Langerhans
What’s the main action of glucagon?
increase blood sugar concentration when it’s low in the bloodstream
How is the action of glucagon achieved?
Upon binding to the hepatic glucagon receptors –> activation of adenylyl cyclase –> generation of 2nd messenger cAMP –> activates protein kinas A activation –> downstream effects
How does glucagon increase blood sugar level?
- promote glycogenolysis –> activation of glycogen phosphorylase, and simultaneous inhibition of glycogen synthase
- inhibits glycolysis in the liver –> glucose-6-phosphate rises –> more released from the liver
- promote gluconeogenesis. Increases amino acid uptake by the liver and increases activities of key gluconeogenic enzymes –> delayed and protracted actions to promote glucose output by the liver
Glucagon also inhibits acety-CoA carboxylase (so no Malonyl-CoA production), and also inhibits carnitine acyltransferase –> therefore, more beta oxidation of fat in the mitochondria –> ketogenic
- promote fatty acid beta oxidation
What’s the most important controller of glucagon secretion?
blood sugar level
- hypoglycemia will stimulate glucagon secretion
What are some other factors that can increase glucagon secretion?
- amino acids: both glucagon and insulin secretion are increased after a protein meal, but less so for glucagon if there is also glucose ingestion. Simultaneous secretin minimizes the risk of hypoglycemia
- fasting
- exercise
Secretion is stimulated by Beta adrenergic stimulation and inhibited by alpha adrenergic stimulation. It’s secreted when the sympathetic system is activated (opposite of insulin)
What’s the role of somatostatin?
It inhibits both glucagon and insulin secretion
- decreases GI motility, secretion, and absorption
- delays assimilation of nutrients by GI, and utilization of absorbed nutrients
What are the two types of diabetes?
Type 1 = insulin dependent
Type 2 = insulin independent
What’s the cause of type I diabetes mellitus?
- impaired secretion of insulin
- autoimmune against the beta cells, or due to viral destruction
What are the 3 major effects of insulin deficiency?
- hyperglycemia
- Depletion of proteins
- depletion of fat stores and increased ketogenesis
What are the results of the fundamental derangement caused by type I diabetes?
- glucosuria, diuresis, hypovolemia, hypotension
- hyperosmolality, dehydration, PD
- hyperphagia with weight loss, lethargy
- acidosis –> diabetic coma
- hypercholesterolemia
What are the results of the fundamental derangement caused by type II diabetes?
- hyperglycemia
- accelerated lipolysis and ketogenesis don’t usually occur
How does glucose stimulate insulin release?
Glucose from bloodstream goes through the GLUT2 transport of the beta cell –> becomes glucose-6-phophate via glucokinase (rate limiting step) –> turns into ATP –> closes Na/K ATPase –> depolarization of the cell –> opening of the Ca2+ channel –> influx of Ca2+ –> exocytosis of insulin
