Physiology of the Pancreas and Blood Glucose Regulation

Question 1

What factors determine the plasma glucose concentration?

Answer 1

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)

Question 2

What takes up the largest quantity of glucose following a carb-containing meal? Why?

Answer 2

Muscle, due to its large mass

Muscle and adipose tissue depend on insulin for enhanced uptake of glucose from plasma

Question 3

What tissues can take up glucose without depending on insulin?

Answer 3

Brain and nervous system, kidneys, and many other tissues

Question 4

How does the liver play a central role in determining the plasma glucose level?

Answer 4

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

Question 5

Describe Insuline Release Following a Meal

Answer 5

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)

Question 6

Describe C-peptide and what is Amylin?

Answer 6

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

Question 7

Draw out Glucose-Induced Insulin Release from Beta-Cells

Question 8

Describe Glucose-Induced Insulin Release from beta-cells

Answer 8

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

Question 9

Describe the effects of sulfonylureas and meglitinides on the beta cell K+ ATP channel

Answer 9

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

Question 10

Describe the effects of diazoxide on the beta cell K+ ATP channels.

Answer 10

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

Question 11

Incretin Hormones - GLP-1 and GIP

Answer 11

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

Question 12

Compare the effects of glucose administered orally and IV.

Answer 12

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

Question 13

Describe GLP-1 Agonists

Answer 13

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

Question 14

Describe the effect of islet blood flow on glucose-induced insulin secretion.

Answer 14

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

Question 15

Describe the nervous system regulation of insulin secretion.

Answer 15

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)

Question 16

Draw out the adrenergic modulators of insulin secretion in beta-cells

Question 17

Modulators of Insulin Secretion in Beta-cells

Question 18

Stimulators of Insulin Secretion bind to what receptors?

Answer 18

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

Question 19

What are the major effects of catecholamines?

Answer 19

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

Question 20

What does somatostatin do?

Answer 20

Inhibits insulin release by binding to the somatostatin receptor

Question 21

What are the cell types in pancreatic islets of langerhans? What do they do?

Answer 21

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

Question 22

Describe somatostatin.

Answer 22

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)

Question 23

Describe what happens following insulin and C-peptide are secreted.

Answer 23

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

Question 24

Describe insulin in the peripheral circulation, including its half life.

Answer 24

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

Question 25

Describe how to figure out how much insulin is endogenous or exogenous in origin in patients with diabetes.

Answer 25

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

Question 26

Describe the actions of insulin

Answer 26

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)

Question 27

Describe GLUT4

Answer 27

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

Question 28

Describe the effects of exercise on GLUT4

Answer 28

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

Question 29

What happens after glucose enters cells and how does growth hormone and cortisol affect this?

Answer 29

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

Question 30

What does insulin do in muscle and adipose tissues? (think effects on receptors)

Answer 30

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

Question 31

How does insulin favor anabolism and energy storage?

Answer 31

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

Question 32

Describe the major metabolic actions of glucagon.

Answer 32

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

Question 33

Diagram the reciprocal relationship of insulin and glucagon.

Answer 33

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Question 34

Glucagon Secretion - Stimulated by? Inhibited by?

Answer 34

Stimulated by: Hypoglycemia, Amino Acids, Parasympathetic Nerves (ACh, Vagal), Sympathetic nerves (NE), Epinephrine Inhibited by: Hyperglycemia, somatostatin, GLP-1

Question 35

Diagram regulation of the endocrine pancreas.

Answer 35

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Question 36

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

Answer 36

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

Question 37

What are the signs and symptoms of hypoglycemia?

Answer 37

Tachycardia Perspiration Tremor Hunger Irritability Headache Loss of concentration Behavioral abnormalities Seizures Coma

Question 38

When are counter-regulatory hormones released and what do they do?

Answer 38

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)

Question 39

What does epinephrine do as a counter-regulatory hormone?

Answer 39

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

Question 40

What does glucagon do as a counter-regulatory hormone?

Answer 40

from alpha cells of the pancreas - increases glycogen breakdown (glycogenolysis) - increases hepatic gluconeogenesis - increases lipolysis - promotes ketone body synthesis by the liver

Question 41

What does cortisol do as a counter-regulatory hormone?

Answer 41

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

Question 42

What does growth hormone do as a counter-regulatory hormone?

Answer 42

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

Question 43

When will hypoglycemia present in a healthy person?

Answer 43

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

Question 44

When will hypoglycemia present in a patient with diabetes?

Answer 44

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

Question 45

What happens to signs up hypoglycemia if a patient is taking beta-adrenergic antagonists?

Answer 45

Symptoms are blunted and may find it more difficult to perceive that they are developing hypoglycemia

Question 46

What can a patient do if they recognize hypoglycemia?

Answer 46

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

Question 47

What is hypoglycemia-associated autonomic failure (HAAF)?

Answer 47

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

Question 48

What is hypoglycemia unawareness and how does it relate to HAAF?

Answer 48

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

Question 49

Describe how the kidney handles glucose via filtration.

Answer 49

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)

Question 50

Describe how the kidney handles glucose via reabsorption

Answer 50

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

Question 51

Describe how the kidneys handle glucose when concentrations are high.

Answer 51

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

Question 52

Describe what happens if SGLT is pharmacologically inhibited.

Answer 52

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