Leff Flashcards
What is the primary function of insulin?
increased plasma glucose stimulates beta cells to produce insulin;
insulin functions to: 1. stop the liver from making glucose 2. cause the body to take up glucose (skeletal muscle/adipose)
-Anabolic hormone (signals storage of energy)
What is the primary function of glucagon?
released from alpha cells in response to decreased blood glucose; primarily targets the liver to cause it to produce glucose and release it into circulation
What are the primary theories behind type II diabetes?
- too many fat stores in the body challenges the limits of safely storing fat; fat leaks out to be stored in tissues that don’t normally store fat (ie: liver and muscle) leading to insulin resistance
- TNF and otther inflammatory cytokines, are released from adipocytes and act on tissues in the body, resulting in insulin resistance
Describe the nutrient metabolism after a meal
under the influence of insulin;
Stimulates the skeletal muscle and adipocytes to take up insulin (GLUT 4); brain and liver do NOT require insulin to take up glucose;
glucose production in the liver is decreased and storage is increased
Describe nutrient metabolism during fasting
under the influence of glucago;
causes the breakdown of glycogen in the liver (short fast); eventually causes gluconeogenesis in the liver (gets progressively more important in longer fasts as glycogen stores are used up)
Describe the composition of the pancreas (ie: cells, blood flow, endocrine/exocrine)
Mostly an EXOCRINE organ (digestive enzymes); 1.2% is an endocrine organ (islets of langerhaans)
ISLETS: alpha cells (10-15%); mainly in the periphery, produce glucagon beta cells (80%): mainly in the center of the islet; produce insulin gamma cells (5-10%) mainly in the periphery; produce somatostatin
Blood flows: from the CENTER to the PERIPHERY; thus alpha cells are exposed to insulin, but beta cells are not exposed to glucagon
Describe how Insulin is synthesized and processed
Beta cells in islets sense glucose levels and synthesize insulin accordingly (it is stored in vesicles/secretory granules)
Gene for insulin is transcribed to give pre-pro-insulin (signal peptide + C peptide + mature insulin)
signal peptide = cleaved to give proinsulin in the ER
C protein = cleaved from pro-insulin in the GOLGI to get the active insulin peptide
C protein and mature insulin are released together; C protein is not degraded as fast as insulin and is thus a good marker of insulin in the blood
Describe the insulin receptor
TYROSINE KINASE RECEPTOR;
tetramer (2 alpha, 2 beta domains) that dimerizes upon ligand (insulin) binding;
the alpha domain = ligand binding
beta domain = transmembrane and cytoplasmic portion
cystein rich domain (on alpha) binds insulin
Describe the insulin signal cascade
insulin binds (to alpha part of ) receptor; dimerizes, causes autophosphorylation of cytoplasmic domain of receptor which induces a conformational change to activate the tyrosine kinase which gets phosphorylated and then acts as a phosphorylator; (docking site for signalling proteins)
What are IRS proteins?
Central Docking System;
phosphorylated by insulin receptor on multiple sites that serve as binding for signaling molecules;
activates PKB, which phosphorylates and INACTIVATES GSK-3 (which normally inactivates glycogen synthase) therefore GSK -3 is inactive and so glycogen synthase is ACTIVE and causes glycogen synthesis and storage
Describe the MAPK pathway
MAPK activates another kinase that phosphorylates and activates a protein phosphatase, which dephosphorylates and activates Gycogen Synthase, causing glycogen synthesis and storage
Describe the effect of insulin on GLUT4 expression
PKB also activates a series of proteins that leads to the expression of GLUT4 on the cell surface
Mechanism similar to AQP2 expression
Describe the effect of insulin on HEPATOCYTES
stimulates glycogen synthesis and inhibits gluconeogenesis:
1. Inhibits PEPCK:
PEP CK = catalyzes the committed step of gluconeogenesis; insulin receptor binds insulin, activates IRS2 which activates PKB(AKT) which phosphorylates Foxo, a transcription factor needed for the transcription of PEP CK gene; as a result phosphorylation, Foxo leaves nucleus and trascription of PEP CK goes down (OCCURS FAST!!)
- Inhibits glucose - 6 phosphatase (keeps glucose phosphorylateds as GDP so it cannot leave the cell)
Describe the effect of Insulin on Myocytes:
- Insulin promotes the uptake of glucose into the cell (GLUT4 expression)
Either stored as glycogen or used for energy (glycolysis)
Note: ¾ or more of the glucose after a meal goes to skeletal muscle under normal conditions; in diabetes this process is defective (not as much glucose can be taken up by muscle)
- Insulin also increases the uptake of AA and synthesis of protein (minor role)
Describe the effect of Insulin on Adipocytes:
1.Action similar to in skeletal muscle (GLUT4 expression)
Difference: most of the glucose undergoes glycolysis; some is used for energy but most of it is converted to glycerol and acetate for TAG synthesis and storage of fat
- Inhibits Hormone Sensitive Lipase: (catabolic)
Normally active during fasting for TAG break down - Activates Lipoprotein Lipase: (anabolic)
Secreted from the cell and resides in vessel wall
Liberates free FA from VLDL and chylomicron which are then take up into the adipocytes
What are the stimulators of Insulin Secretion:
Nutrients: Glucose, Amino acids,Ketone bodies
Hormones: Incretins (produced in gut), Glucagon* (because it stimulates glucose release which then
goes to stimulate insulin), Growth hormone
Neurotransmitters: ACh (PS) or BETA SS ADRENERGIC
Drugs: cholinergic drugs, sulfonylureas, cAMP
Electrolytic: increase in calcium, sodium, postassium
What are the Inhibitors of Insulin Secretion
Hormones: Somatostatin
Neurotransmitters: Epi, NE (SS; ALPHA ADRENERGIC) ;
Drugs: atropine (cholinergic (ACh) blocker)
Electrolytic: Mg2+
Describe the bi-phasic insulin RELEASE
Phase I : insulin release is due to vesicles that are close to the plasma membrane (very rapid response; 2-5 minutes
Phase II: (delayed response) due to vesicles that are further away from the plasma membrane
An early symptom of type II diabetes is the loss of PHASE I (EARLY) insulin secretion
Describe the regulation of secretion by the beta cells
Glucose from circulation enters beta cell via GLUT 2 channel and is used for glycolysis, increasing the energy charge charge (ATP:ADP or NADH:NAD+ ratios) of the cell ** GLUT 2 lets the inside of the B-cell see the same [glucose] as theoutside of the B-cell which is linked to plasma [glucose]
The increase in energy charge causes closure of a ATP sensitive K+ channel that normally maintains membrane potential; closure causes the cell to depolarize (because K+ builds up inside the cell ) and Vm to increase;
then the voltage gated Ca2+ channel is opened, causing Ca2+ to enter the cell (**this is all localized to one area of the cell) ; the Ca2+ influx also induces Ca2+ release from the ER leading the docking and fusion of secretory granules, resulting in the release of insulin
What are sulfonylureas?
drugs used in early stages of diabetes that inhibit the K+ channel, which allows for small canges in ATP levels to stimulate insulin release (cell is better at releasing insulin in response to glucose)
What are the three phases of insulin secretion?
- Cephalic
release of insulin that precedes food ingestion (due to sight/pscyhe/smell of food)
stimulated by the PS (PARASYMPATHETIC)/ACh
not a huge amount of insulin is released, but it primes the body to respond faster after food intake - Early Postprandial .
immediately after food is ingested, but before the nutrients reach the blood stream;
Insulin release is stimulated by gut-derived incretetin hormones, GLP1 (glucagon like peptide-1) and GIP; effects overlap with phase 3 - Postprandial
AFTER meal-derived nutrients reach the blood stream;
Insulin released due to elevated blood glucose and amino acid levels (sensed IN circulation)
Describe the neural regulation of insulin secretion
- Parasympathetic: stimulates insulin secretion
- mediated by ventral-lateral hypothalamus via vagus nerve and release of ACh
- mediates the CEPHALIC PHASE of insulin secretion - Sympathetic: INHIBITS insulin secretion
- mediated by ALPHA adrenergic signalling (epi/NE) **BETA adrenergic has opposite effect
- important in regulating insulin secretion during exercise (want to turn off insulin so that you expend energy on catabolism not anabolism)
Describe the regulation of insulin secretion by gut hormones
= incretins
gut produces GIP and GLP, which are incretins that stimulate insulin release BEFORE blood glucose levels change (secreted by intestinal L-cells)
if you give glucose ORALLY: causes a LARGE INSULIN SPIKE
if you give glucose IV (bypasses the gut): there will only be a small release of insulin
therefore conclusion: something (GIP and GLP-1) enhance the effect of blood glucose
Describe the effect of GLP-1 on early postprandial insulin secretion
After a meal, (before the blood glucose levels change) gut secretes GLP-1 into circulation, which causes:
- insulin secretion–> causing increased glucose disposal in adipose tissue and muscle (leading to decreased plasma glucose)
- decreased glucagon section –> decreased hepatic glucose output (gluconeogen) leading to decreased plasma glucose
Describe the paracrine feedback of the islets of langerhans
Glucagon = stimulates insulin secretion (even though the alpha cells are located in the periphery of the islet and blood flows from central to periphery)
insulin = inhibits glucagon secretion (enhances counter regulatory effects)
somatostatin = inhibits both insulin and glucagon secretion
Insulin: activates beta cells and inhibits alpha cells
Glucagon: activates alpha cells which activates beta cells and delta cells
Somatostatin: inhibits alpha cells and beta cells
Describe the structure and processing of glucagon
= derived from a larger precursor protein called “proglucagon” which also gives rise to other hormones;
undergoes different processing in pancreatic alpha cells compared to intestinal L cells:
pancrease: cleaved into GRPP, glucagon, and roglucagon fragment
Lcells = cleaved into glicentin, GLP-1 and GLP-2 (incretins) and IP-2 (unknown function)
Describe the regulation of glucagon secretion:
Nutrients: glucose, fatty acids = inhibit; amino acids = stimulate release
Neuronal signals: SS (via alpha2 or Beta1 adrenergic receptors and PS both stimulate)
Hormones: GLP-1 inhibits release, cortisol stimulates
what tissues does glucagon primarily act on? insulin?
glucagon = liver mainly (stim glycogenolysis and gluconeogenesis)
insulin = liver, muscle, adipose (stim glycogenosis and glycolysis)
What is the effect of protein rich meals on glucagon/insulin/metabolism?
stimulates both insulin and glucagon; results in VERY LITTLE CHANGE IN BLOOD GLUCOSE!
because there is no real storage form of amino acids in the body (because skel muscle has a \fixed rate of protein cat/anabolism) and as a result most is converted to glucose, some is used for protein synthesis but not a lot is needed;
glucagon effects = dominant in the liver to stim gluconeogen (aa used as substrates to make glucose, and glucose tops off glycogen stores in the liver and then the rest is released into circulation)
insulin effects = dominant in periphery, where it stimulates uptake of excess glucose into muscle and adipocytes
What is the effect of glucagon on hepatocytes?
downstream effect = synthesis of glucose (gluconeogen/glycogenolysis) and release of glucose into circulation
- Activates PEP CK (catalyzes rate limiting step in gluconeogen)
glucagon binds receptor to activate PKA pathway, PKA phosphorylates CREB which causes:
a). stimulation of transcription of TFs that stimulate PEP CK transcription
b). stimulates transcription of PEPCK itself - Activates glucose -6 phosphatase
promotes dephosphorylation of glucose and release from the cell
Describe the metabolic stages that occurs in type II diabetes
Normal: does not take a lot of insulin to bring glucose levels back to normal
Insulin resistance: takes more insulin to achieve the same level of glucose tolerance (but glucose tolerance is not yet impaired; no clinical manifestations, you are able to reduce the blood glucose after elevated insulin)
Glucose intolerance: not able to maintain glucose tolerance regardless of increase in insulin release (early stage of diabetes, you are still able to treat it, but blood glucose is elevated regardless of the large increase in insulin secretion)
Diabetes: failure of the endocrine pancreas results in uncontrollable blood glucose levels because of total lack of insulin
Explain the progession of type II diabetes
initially, although a person is becoming more insulin resistant, they can maintain normal blood glucose by compensatory increase in insulin release; however eventually the endocrine pancreas fails as insulin resistance continues to increase and glucose levels skyrocket due to lack of insulin
Describe the incretin based diabetes therapies
inject GLP-1 mimetics to increase insulin concentration;
or DPP4 usually breaks down GLP-1, so inhibit DPP4 to cause prolongation of GLP-1 half life
Describe the structure of growth hormone
2 forms (resulting from differential splicing producing 2 different mRNAs) 20 kDa (176 aa) and 22 kDa (191 aa; primary hormone) differ by 14 aa; no clear understanding why
What does the growth hormone (GH) gene encode?
GH is a part of a gene cluster of closely related genes on Chromosome 17;
encodes for:
1. Human GH (191aa)
other stuff: relating to fetal growth and placenta function:
2. pvGH (191 aa; 93% homologous to GH); regulators of fetal growth (hGH doesnt); has same affinity for GH receptor as hGH
3.Human CS1 and CS2 (191 aa each, 84% homologous to GH)
= human chorionic somtomammotropin; relevant only in embryonic development (produced by placenta)
4. Human PRL (199 aa; 16% homologous)
Describe how GH is synthesized
gene is differentially spliced, resulting in the pre-22 kDA or pre-20 kDA growth hormone mRNA (in the nucleus);
-mRNA enters the RER where it is transcribed to the pre-prohormone and then it is transported to the golgi for processing into prohormone;
eventually, active hormone is stored in secretory granules in the somatotrophic cells of the ANTERIOR PITUITARY, awaiting signal (GHRH) for release
How is GH production episodic?
higher GH levels exist at night during NON-REM SLEEP; (occurs more earlier in the night; = slow wave/deep sleep);
in treatment, therapeutic GH is administered at night when endogenous GH is normally produced
during the day it is still pulsatile, but the amplitude of secretion is no where near as high as it is at night (still pulsatile, just higher amp/more secreted)
What are some of the factors increase GH production?
- Fasting (hypoglycemia, low circulating free FAs.. ie: daily fasting at night, not starvation)
- High protein diet (elevated circulating amino acids, especially arginine; if there is available material for growth then there is an increase in GH)
- Exercise
- Deep sleep (later stages of non-REM)
What factor(s) decrease GH production?
stress/anxiety: short term stress causes an increase in epi/NE and actually causes an increase in GH, but chronic stress = release of glucocorticoids which suppresses downstream GH effects causing inhibition of growth (not due to a decrease in GH production)
