Physiology of the Pancreas and Blood Glucose Regulation Flashcards
What factors determine the plasma glucose concentration?
Dietary intake - eating stimulates insulin release from pancreas
The rate of entry into cells of muscle and adipose tissue (and to a lesser extent other tissues)
Whether the liver is taking up glucose from the plasma (high insulin/glucagon ratio) or adding glucose to the plasma (low insulin/glucagon ratio)
What takes up the largest quantity of glucose following a carb-containing meal? Why?
Muscle, due to its large mass
Muscle and adipose tissue depend on insulin for enhanced uptake of glucose from plasma
What tissues can take up glucose without depending on insulin?
Brain and nervous system, kidneys, and many other tissues
How does the liver play a central role in determining the plasma glucose level?
During fasting (low insulin/glucagon ratio), liver glycogen is broken down and the liver adds glucose to the bloodstream
With more prolonged fasting, glycogen is depleted, and there is increased gluconeogenesis from amino acids and glycerol in the liver
Describe Insuline Release Following a Meal
Parasympathetic vagal signals (ACh) of pancreatic islet stimulate secretion of insulin from beta cells
- both glucose and certain amino acids stimulate insulin secretion
- certain FAs can acutely stimulate insulin secretion, but prolonged exposure of beta-cells to FAs can impair their ability to secrete insulin (lipotoxicity)
- prolonged exposure of beta-cells to hyperglycemia can impair their ability to respond as a stimulus for insulin secretion (glucotoxicity)
Describe C-peptide and what is Amylin?
within secretory vesicles of the beta cells, proinsulin is converted to insulin and C-peptide (connecting peptide) by proteolytic enzymes
Insulin and C-peptide are stored in secretory granules and are secreted from beta cells in equimolar amounts
Amylin is a peptide that is synthesized by beta cells and co-secreted with insulin & C-peptide - acts to slow gastric emptying and may inhibit glucagon secretion
Draw out Glucose-Induced Insulin Release from Beta-Cells
Describe Glucose-Induced Insulin Release from beta-cells
To stimulate insulin secretion, glucose must enter beta cells via GLUT1 glucose transporters and be metabolized
Glucose metabolism increases the ratio of ATP to ADP, which closes K+ ATP channels, causing depolarization, opening of Ca2+ channels, and insulin secretion from storage granules
C-peptide and amylin are stored in secretory granules together with insulin and co-secreted together with insulin
2-deoxy glucose (analog of glucose taken up by beta cell, but cannot be metabolized) inhibits insulin secretion because it competes with glucose for uptake into the beta cell
Describe the effects of sulfonylureas and meglitinides on the beta cell K+ ATP channel
Sulfonylureas and meglitinides force the K+ ATP channel to close even if plasma glucose concentration is low and beta cells have not metabolized much glucose -> depolarization of plasma membrane, opening of Ca2+ channels, and insulin secretion
* can be used to treat some patients with diabetes, but can cause hypoglycemia
Describe the effects of diazoxide on the beta cell K+ ATP channels.
Forces the beta cell K+ ATP channels to stay open, thereby opposing insulin secretion
Can be administered to try to reverse hypoglycemia, but other available therapies (admin of glucose or admin of extra glucagon) are used more commonly for acute episodes
Incretin Hormones - GLP-1 and GIP
Glucagon-Like Peptide 1 (GLP-1) and Glucose-dependent insulinotropic peptide (GIP) are synthesized and secreted by cells in the gut
Circulate to the pancreas, bind to receptors on pancreatic beta cells, and act to enhance glucose-dependent insulin secretion
‘incretin’ -> increase insulin secretion
Due to increased insulin secretion, there is paracrine inhibition of glucagon secretion, which exaggerates the rise in insulin to glucagon ratio following meals
Compare the effects of glucose administered orally and IV.
If glucose admin orally, there is a rise in glucose and a corresponding rise in secretion of insulin
If instead glucose is infused by IV to raise the blood glucose to the same peak leve, the insulin response will not be as great
* demonstrate the importance of gut hormones for enhancing the insulin response when carbs are ingested orally
Describe GLP-1 Agonists
GLP-1 important in regulating insulin to glucagon ratio following meals, so patients with type 2 diabetes are often treated with GLP-1R agonists (incretin mimetics)
Exenatide commonly used to tx patients with type 2 diabetes
Because GLP-1 enhances glucose-stimulated insulin secretion, treatment with a GLP-1 receptor agonist does not produce hypoglycemia
Describe the effect of islet blood flow on glucose-induced insulin secretion.
If more glucose brought to beta cells, they are capable of taking up more glucose via GLUT1
Increased uptake and metabolism of glucose by beta cells -> more insulin secretion
Factors that influence vasodilation/vasoconstriction can alter insuline secretion via this mechanism
Describe the nervous system regulation of insulin secretion.
Major effect of catecholamines (epinephrine, norepinephrine) to inhibit insulin secretion by binding to alpha-adrenergic receptors on beta cells and/or constricting blood vessels that supply the islets of Langerhans
- minor effect: stimulate insulin secretion via binding to beta-adrenergic receptors on beta cells (or by dilating blood vessels supplying the islets to allow more glucose to reach the beta cells)
If drug given to competitively inhibit alpha-adrenergic activity, one could demonstrate a stimulatory effect of catecholamines on insulin secretion (via catecholamine binding to beta-adrenergic receptors on pancreatic beta cells and/or their blood vessels)
Draw out the adrenergic modulators of insulin secretion in beta-cells
Modulators of Insulin Secretion in Beta-cells
Stimulators of Insulin Secretion bind to what receptors?
SUR = sulfonylurea receptor (sulfonylureas can force insulin secretion even if glucose concentration is low; they can cause hypoglycemia)
M1R = muscarinic receptor (ACh potentiates glucose-induced insulin secretion)
GLP-1R = glucagon-like peptide 1 receptor (agonists potentiate glucose-induced insulin secretion)
GIPR = glucose-dependent insulinotropic peptide receptor (potentiates glucose-induced insulin secretion)
Beta-adrenergic R = beta adrenergic receptor
What are the major effects of catecholamines?
Epinephrine & Norepinephrine
Inhibit insulin secretion by binding to alpha-adrenergic receptors on beta cells and/or constricting blood vessels that supply the islets of Langerhans
Minor effect: stimulate insulin secretion via binding to beta-adrenergic receptors on beta cells (or by dilating blood vessels supplying the islets to allow more glucose to reach the beta cells)
If alpha-adrenergic competitive inhibotr administered, stimulatory effect of catecholamines on insulin secretion can be deomonstrated
What does somatostatin do?
Inhibits insulin release by binding to the somatostatin receptor
What are the cell types in pancreatic islets of langerhans? What do they do?
Alpha cells -> glucagon
Beta cells -> insulin (and amylin)
Delta cells -> somatostatin
F cells -> pancreatic polypeptide
facilitate paracrine communicatoin among cell types, including a very important inhibitory effect of insulin on glucagon secretion, thereby exaggerating the increase in the insulin to glucagon ratio following meals
Describe somatostatin.
A peptide hormone secreted by D cells of the pancreas
Expressed in many areas of the braina nd GI tract, where it inhibits secretion of hormones and various physiologic functions
In pancreatic islets, it inhibits both insulin and glucagon secretion
Infusions used to suppress endogenous secretion of pancreatic insulin and glucagon - one can determine precise amt of exogenous insulin needed to stimulate the uptake of a certain amt of glucose into the cells of the body
Rapid clearance from plasma limits effectiveness, but long-acting analogs of somatostatin (octreotide) used successfully to tx pancreatic tumors secreting excess insulin (insulinomas), gut neuroendocrine tumors secreting serotonin or vasoactive intestinal peptide (VIP), and pituitary adenomas secreting excess growth hormone (GH)
Describe what happens following insulin and C-peptide are secreted.
Secreted into pancreatic veins in equimolar quantities, travel through the hepatic portal vessels to the liver
Most C-peptide passes through the liver and is eventually excreted in the urine
In patients with renal impairment, less C-peptide is excreted in the urine and more remains in the plasma
Describe insulin in the peripheral circulation, including its half life.
t1/2 = 5mins
Endogenous insulin travels from pancreas -> hepatic portal vessels -> liver
50% of insulin reaching liver is degraded & the remainder escapes the liver to act on other tissues
Liver exposed to higher concentrations of insulin than other tissues
If exogenous insulin admin via subcut. inj to patients with diabetes, similar conc of insulin reach the muscle, adipose tissue, and liver
Describe how to figure out how much insulin is endogenous or exogenous in origin in patients with diabetes.
C-peptide plasma measurement can be obtained to figure out how much endogenous insulin is being secreted
Since C-peptide is secreted from beta cells with insulin in equimolar quantities, a C-peptide level is directly proportional to the amount of insulin being secreted
Describe the actions of insulin
Meal-induced increases in insulin: promote glucose uptake into muscle and adipose tissue, increase hepatic utilization of glucose, which eventually cause a drop in plasma glucose
All cells express one or more types of GLUT for glucose transport across plasma membranes (facilitated diffusion)
In kidneys & intestines, glucose can also enter cells by secondary active transport with sodium
In certain tissues (muscles and adipose tissue), efficient glucose transport into cells requires insulin (GLUT4 = insulin-dependent glucose transporter)
Describe GLUT4
GLUT4 is regulated by insulin and is expressed in muscle and adipose tissue
- insulin increases glucose uptake by causing translocation of intracellular GLUT4 glucose transporters to the plasma membrane
Liver does not express GLUT4 - instead, insulin enhances hepatocyte glucose uptake by stimulating metabolic pathways of glucose utilization, such as glycolysis and glycogen synthesis
Describe the effects of exercise on GLUT4
increase glucose uptake by increasing translocation of intracellular GLUT4 to the plasma membrane
- this effect is independent of insulin
- considered an increase in insulin sensitivity
After exercise is finished, muscle may continue to take up more glucose via this mechanism for several hours to replenish muscle glycogen supply
*Some patients with diabetes may experience hypoglycemia during or after exercise
What happens after glucose enters cells and how does growth hormone and cortisol affect this?
Glucose is phosphorylated.
Growth Hormone (GH) and cortisol inhibit phosphorylation of glucose, which reduces the amount of glucose available for metabolism in these tissues and part of ‘anti-insulin’ effects of GH and cortisol
What does insulin do in muscle and adipose tissues? (think effects on receptors)
Insulin stimulates Na+/K+ ATPase, which increases movement of K+ into cells
Insulin stimulates the muscle Na+/K+/Cl- co-transporter (NKCC), which also moves K+ into cells
Insulin also enhances uptake of phosphate and magnesium ions into insulin-sensitive cells and exerts anabolic effects on muscle by stimulating amino acid uptake and protein synthesis
How does insulin favor anabolism and energy storage?
Promotes:
Synthesis and deposition of glycogen in liver and muscle
Synthesis of lipids in liver and adipose tissue
Uptake and storage of lipids in adipose tissue (increases lipoprotein lipase activity)
Uptake of amino acids and protein synthesis in muscle
*Effects of insulin promote tissue uptake and sequestration of glucose, fatty acids, and amino acids, with a resultant decrease in their plasma concentrations
Describe the major metabolic actions of glucagon.
Increases glycogen breakdown (glycogenolysis)
Increases hepatic gluconeogenesis
Increases lipolysis
Promotes hepatic ketone body synthesis
*Glucagon interacts with G protein coupled cell membrane receptors that promote increased cAMP generation via stimulation of adenylyl cyclase or increased cytosolic calcium as a result of IP3 formation
Diagram the reciprocal relationship of insulin and glucagon.
Glucagon Secretion - Stimulated by? Inhibited by?
Stimulated by: Hypoglycemia, Amino Acids, Parasympathetic Nerves (ACh, Vagal), Sympathetic nerves (NE), Epinephrine
Inhibited by: Hyperglycemia, somatostatin, GLP-1
Diagram regulation of the endocrine pancreas.
Compare Insulin:Glucagon Ratios at specific points of food - basal (overnight fast), prolonged fast (3d), large carb meal, IV glucose, protein meal (or arginine infusion), meal containing both carb & protein
Basal (overnight fast) = 0.15; ↓ insulin, ↑ glucagon
Prolonged fast (3d) = 0.05; ⇊ insulin, ⇈ glucagon
Large carb meal = 0.5; ↑ insulin, ↓ glucagon
IV glucose = 0.25; ↑ insulin, ↓ glucagon
Protein meal = 0.15; ↑ insulin, ↑ glucagon
*ingestion of amino acids stim secretion of both insulin & glucagon bc glucagon stim uptake of aa in liver for gluconeogenesis
Meal w/ both carb and protein = 0.5; ⇈ insulin, ⇵ glucagon
What are the signs and symptoms of hypoglycemia?
Tachycardia
Perspiration
Tremor
Hunger
Irritability
Headache
Loss of concentration
Behavioral abnormalities
Seizures
Coma
When are counter-regulatory hormones released and what do they do?
Released in response to insulin-induced hypoglycemia
Hormones have anti-insulin effects that attempt to counteract the hypoglycemic effects of insulin
Also enhance fat breakdown (lipolysis) in an attempt to provide an alternative fuel source (fatty acids)
What does epinephrine do as a counter-regulatory hormone?
From adrenal medulla
- suppresses pancreatic insulin release
- increases pancreatic glucagon release
- increases lipolysis
- increases glycogen breakdown (glycogenolysis)
- enhances hepatic gluconeogenesis
- decreases glucose uptake by muscle and adipose tissue (making more glucose available to brain)
- epinephrine is responsible for many of the clinical symptoms and signs associated with hypoglycemia: tachycardia, widened pulse pressure, tremor, sweating
What does glucagon do as a counter-regulatory hormone?
from alpha cells of the pancreas
- increases glycogen breakdown (glycogenolysis)
- increases hepatic gluconeogenesis
- increases lipolysis
- promotes ketone body synthesis by the liver
What does cortisol do as a counter-regulatory hormone?
from the adrenal cortex
- decreases glucose uptake by muscle and adipose tissue (making more glucose available to brain)
- serves a permissive role for lipolysis
- serves a permissive role for gluconeogenesis
- when present in excess, can stimulate protein breakdown
What does growth hormone do as a counter-regulatory hormone?
from anterior pituitary
- decreases glucose uptake by muscle and adipose tissue (makes more glucose available for brain)
- increases hepatic gluconeogenesis
- increases lipolysis
- promotes ketone body synthesis by the liver
When will hypoglycemia present in a healthy person?
blood glucose rarely drops below 70mg/dL because this is usually the threshold for activation of counter-regulatory hormone systems
- symptoms do not develop until below 60mg/dL
When will hypoglycemia present in a patient with diabetes?
If treated with insulin or insulin secratagogues (sulfonylureas or meglitinides) may develop symptoms of hypoglycemia if blood glucose drops at a rapid rate due to increased insulin
- hypoglycemic risk is increased in pt with type 1 diabetes who are tx with intensive insulin regimen in an effort to achieve near-normal blood glucose
What happens to signs up hypoglycemia if a patient is taking beta-adrenergic antagonists?
Symptoms are blunted and may find it more difficult to perceive that they are developing hypoglycemia
What can a patient do if they recognize hypoglycemia?
Treat by consuming carbohydrates
Patients with diabetes find it more helpful/convenient to carry hard candy or glucose tablets (1tab = 15g glucose)
if hypoglycemia is severe and pt unable to swallow, an injection of glucagon can be given, which increases plasma glucagon conc above the patient’s endogenous glucagon response to hypoglycemia
What is hypoglycemia-associated autonomic failure (HAAF)?
In patients with type 1 diabetes, frequent episodes of hypoglycemia can dampen usual counter-regulatory adrenomedullary epinephrine response during a subsequent hypoglycemic episode
HAAF is a specific defect in sympathetic nervous system and adrenomedullary catecholamine responses to hypoglycemia
without epinephrine’s effects to increase blood glucose, patient’s may experience an increased rate of fall in blood glucose and increased severity of hypoglycemia
What is hypoglycemia unawareness and how does it relate to HAAF?
because HAAF have fewer catecholamine-mediated symptoms (palpitations, tremor), these patients may not recognize hypoglycemia
hypoglycemia unawareness - patients may need to rely on others to help them recognize symptoms associated with neuroglycopenia (confusion, loss of concentration)
HAAF and resultant hypoglycemia unawareness can be improved if patients can avoid hypoglycemia - it worsens if hypoglycemia becomes a frequent occurrence
Describe how the kidney handles glucose via filtration.
the kidney glomeruli filter small molecules such as glucose
amount of glucose filtered = ‘filtered load’ of glucose
as plasma glucose increases, mroe glucose molecules pass through the glomeruli and into the renal tubular fluid
Filtered load of glucose is directly proportional to the plasma glucose concentration
Any glucose molecules that are not reabsorbed from the renal tubules will be excreted in the urine (glucosuria = glucose in the urine)
Describe how the kidney handles glucose via reabsorption
The rate of glucose reabsorption depends on the number of functioning glucose transport carrier proteins (sodium-dependent glucose symporters/sodium glucose cotransporters = SGLT protein family)
SGLT moves 1 glucose molecule with 1 or 2 molecules of sodium across the apical membrane of the proximal tubule epithelial cells (apical membrane faces the tubular lumen)
- example of secondary active transport: the energy used to transport glucose into the cell comes from transporting Na+ down its conc gradient
Glucose then exits basolateral membrane to opposite side of tubule cells and enters interstitial space via facilitated diffusion - driven by the glucose concentration gradient
renal glucose reabsorptive process prevents loss of glucose energy in the urine at normal blood glucose concentrations
in healthy individuals, the kidney reabsorbes ~180g glucose/day
Describe how the kidneys handle glucose when concentrations are high.
the filtered load of glucose is so high that most of the glucose carrier proteins become saturated and glucose reabsorption reaches a constant maximal rate (tubular transport maximum Tm)
Additional glucose cannot be reabsorbed, so it is ‘spilled’ into the urine
glucosuria causes an osmotic diuresis (high urine volume), which explains the symptoms of polyuria and nocturia in patients with poorly controlled diabetes
Describe what happens if SGLT is pharmacologically inhibited.
Reduces the quantity of glucose reabsorbed, causing more glucose to be lost in the urine
Lowers the plasma glucose concentration, improving hyperglycemia
SGLT2 inhibition (using drugs such as empagliflozin, canagliflozin, or dapagliflozin) is a potential therapeutic modality for lowering plasma glucose in patients with diabetes
Caution must be used to avoid worsening of diabetes symptoms related to osmotic diuresis
