Glen Gross
The Endocrine Pancrease
3/12/2014
Objectives:
• Fed-state and Fasted-state metabolism
• Circulating glucose levels are regulated by pancreatic islet hormones
b cell: Insulin is dominant following feeding
a cell: Glucagon is dominant with fasting
Somatostatin, amylin and ghrelin are participants
• Negative feedback involves glucose sensing by a and b pancreatic islet cells
• Hormone properties
• Insulin Secretion Phases
Cephalic Phase
Oral Phase
GI Phase
Blood Glucose Phase
• Net Hormone Regulation
• Glucose Transporters
SGCT (sodium glucose co-transporters)
GLUT (glucose transporters)
GLUT4 is insulin signaling dependent
• Summary
Fed-state and fasted-state metabolism
Glycogen stores:
1. in liver and muscle:
a. stores last 12 hours
2. triglyceride:
a. stores in adipose tissue are unlimited
3. brain:
a. has no energy stores
In the fed state:
1. glucose is stored as:
a. glycogen
b. triglycerides
2. lipogenesis:
a. glucose  2 pyruvates  citrate  2 free fatty acids + glycerol = triglycerides
3. gluconeogenesis:
a. glucose production from non-carbohydrate sources:
i. glycerol
ii. lactate
iii. amino acids
In the fasted state:
1. brain:
a. still uses glucose as the primary energy source
i. ketones are the back-up energy source
2. first:
a. glycogen breakdown in the liver and muscle  produces glucose
b. reserves are depleted in 24 hours
2. next:
a. adipose triglycerides are broken down
i. glycerol from triglycerides  gluconeogenesis  glucose
ii. free fatty acids  used by muscle or converted to ketone bodies
3. eventually:
a. muscle wasting
b. proteins in muscle is broken down into amino acids
i. amino acids  liver  gluconeogenesis  glucose
Insulin:
1. inhibits:
a. lipolysis by inhibiting intracellular lipases
i. net result = no release of fatty acids or glycerol
2. promotes:
a. accumulation of triglycerides in fat cells by allowing entry of glucose into adipocytes
and liver
i. in adipocytes, glucose  used to make glycerol
ii. in liver, glucose is converted into fatty acids after glycogen stores are optimal
b. fatty acids are packaged into lipoporteins and secreted into the blood  become free
fatty acids
c. adipocytes pick up free fatty acids (FFAs)  combines them with glycerol  makes
triglyceride
3. Glycerol = FFA = triglyceride
glucos
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glucos
e
Circulating glucose levels are regulated by pancreatic islet hormones
Beta cell: Insulin is dominant following feeding
Alpha cell: Glucagon is dominant with fasting
Somatostatin, amylin and ghrelin are participants
In the fed state:
1. insulin dominates:
a. increased glucose oxidation
b. increased glycogen synthesis
c. increased fat synthesis
d. increased protein synthesis
In the fasted state:
1. increased glycogenolysis
2. increased gluconeogenesis
3. increased ketogenesis
Homeostatic control: glucose, glucagon, and insulin over a 24 hour period
Circulating Glucose Levels are Tightly Regulated:
1. normal blood glucose:
a. 70-120mg/dL
2. normal fasting glucose:
a. less than 100mg/dL
3. hyperglycemia:
a. over 130mg/dL
4. hypoglycemia:
a. under 60mg/dL
Endocrine Pancreas Regulation of Glucose:
1. hormones of the islets of Langerhans
a. alpha cells: glucagon (20%)
b. delta cells: somatostatin (5%)
c. beta cells: insulin and amylin (70%)
d. epsilon cells: ghrelin (less than 1%)
Innervation of the Islet of the Langerhans:
1. sympathetic nerves:
a. inhibit insulin and amylin secretion
i. during flight-or-fight
2. parasympathetic nerves:
a. vagus nerve
b. promotes cephalic phases of insulin secretion
Negative Feedback Involves Glucose Sensing by alpha and beta pancreatic islet cells
Glucose regulation by insulin
Glucose Regulation by Glucagon
Hormone Properties
Proinsulin, Insulin and C-Chain
1. Chemistry of insulin:
a. proinsulin is the initial form
b. insulin is the mature polypeptide
2. insulin is composed of two chains:
a. alpha chain
i. is acidic
ii. 21 amino acids
b. beta chain
i. is basic
ii. 30 amino acids
c. two disulfide bridges connect the two chains
i. an additional sulfide bridge is found in the alpha chain
d. the sequence 22-26 in the beta chain is essential for biologic activity
3. C-chain:
a. can be measured as an indicator of endogenous insulin production in diabetic
patients
Insulin continued:
1. distribution and metabolism:
a. insulin circulates free in the plasma
2. half life:
a. is less than 10 minutes
3. insulin metabolism:
a. broken down by kidney and the liver
i. 50% in the first pass to the liver
ii. proteolytic enzymes break it down
iii. glutathione-insulin transhydrogenase is located in liver/kidney microsomes
4. insulin receptor:
a. is a tyrosine kinase
5. actions of insulin receptor:
a. promotes glucose uptake into cells
b. glucose goes into storage molecules, glycogen or triglycerides
Amyline is Insulin’s Co-Conspirator:
1. amylin:
a. is a peptide hormone
2. is co-packaged and co-secreted with insulin from B-cells in a 1:1 ratio
3. C-3 receptors:
a. place where amylin binds
b. composed of calcitonin receptor + RAMP (receptor activity-modifying protein)
i. transports the calcitonin receptor to the cell surface
4. half life of amylin:
a. minutes
5. actions of amylin:
a. inhibits glucagon secretion at the level of the alpha cells
b. induces satiety
6. other GI actions of amylin:
a. reduces food intake
b. delays gastric emptying
c. inhibits secretion of digestive enzymes
d. inhibits stomach acid secretion
e. inhibits bile ejection
Glucagon:
1. features:
a. a peptide hormone
2. produced in alpha cells
3. immature form:
a. is pro-glucoagon
4. factors that promote its release:
a. hypoglycemia
b. high levels of amino acids (to prevent hypoglycemia after a high protien meal)
c, sympathetic activity (fight-or-flight)
d. vagal stimulation
5. factors that inhibit its release:
a. hyperglycemia
b. high levels of GLP-1 (glucagon-like-peptide 1)
c. high levels of amylin
Pro-glucagon:
1. the pro-glucagon gene is spliced into glucagon in pancreatic beta cells
2. pro-glucagon is spliced into GLP-1 and GLP-2 in:
a. intestinal cells
Delta cells:
1. somatostatin:
a. inhibits local production of pancreatic hormones
2. somatostain is triggered by:
a. increased insulin
3. somatostatin inhibits secretion of:
a. insulin
b. glucagon
c. ghrelin
4. actions of somatostat in the GI system:
a. reduces the rate of food absorption
5. somatostatin is inhibited by:
a. ghrelin
i. a general signal of hunger
In the fasted state:
1. Ghrelin:
a. is increased
2. actions of ghrelin:
a. promotes glucagon secretion
b. inhibits insulin and somatostatin
GIP and GLP1:
1. are called the incretins
2. actions:
a. promote beta cells release of insulin after eating
b. reduce the rate of absorption of nutrients into the bloodstream
i. by reducing gastric emptying
ii. may directly reduce food intake  cause satiety
3. act as mediators of the intesitnal phase of insulin secretion
GLP-1: Glucagon like peptide 1
1. produced by:
a. L cells of the lower small intestine and colon
2. is the product of alternative splicing of:
a. the pro-glucagon gene
3. actions of GLP-1:
a. stimulates insulin during a high glucose situation (after feeding)
b. inhibits glucagon secretion during normal glucose levels or hypoglycemia
4. half life of GLP-1:
a. minutes
5. GLP-1 metabolism:
a. broken down by dipeptidyl peptidase 4
GIP: glucose dependent insulinotropic peptide
1. produced by:
a. K cells of the duodenum and jejunum
2. GIP in type II diabetics:
i. secretion of GIP is normal
ii. the repsonse to endogenous GIP is impaired
3. actions:
a. stimulates insulin during a high glucose situation (after feeding)
b. inhibits glucagon secretion during normal glucose levels or hypoglycemia
4. half life of GIP:
a. minutes
The incretin GLP-1 is cleaved from proglucagon in the intestinal cells:
Insuiln Secretion Phases
Cephalic Phase
Oral Phase
GI Phase
Blood Glucose Phase
Phases of insulin secretion:
1. cephalic phase:
a. parasympathetic information from:
i. sight
ii. smell
2. oral phase:
a. parasympathetic information
b. carbohydrate sugar stimulation of sweet receptors
3. GI phase:
a. the incretins
i. GIP:
a. is a member of the secretin family of hormones
b. produced in respnose to hyperosmolarity due to glucose in the gut
c. the amount of insulin secreted is greater when glucose is administered
orally instead of by IV
i. GLP-1:
a. derived from proglucagon gene
b. stimulates insulin release
4. blood glucose phase:
a. increase in blood glucose  triggers B-cell relase of insulin
b. decrease in blood glucose  triggers alpha-cell release of glucagon
The Incretin Effect:
1. larger insulin response to oral glucose than by IV:
a. due to oral/intestinal phases of insulin secretion
i. parasympathetic signals
ii. incretin signals
Net Hormone Regulation
Beta cells:
1. amylin and insulin
2. actions:
a. inhibits food intake and gastric emptying
i. controls nutrient intake and nutrient flux to the blood
GLP-1:
1. made by:
a. L cells of distal small bowel and colon
i. in response to glucose presence
2. receptors:
a. in beta pancreatic cells
b. brain
GIP:
1. made by:
a. intestinal K cells
i. in resposne to glucose presence
2. receptors:
a. in beta pancreatic cells
b. brain
3. actions:
a. increases insulin secretion at high concentrations of glucose
Epsilon cells:
1. ghrelin:
a. promotes glucagon stimulation
i. hunger signal coincides with low glucose
Somatostatin:
1. secreted from:
a. delta cells of pancreatic islets
b. GI cells
2. actions:
a. inhibits secretion:
i. insulin
ii. glucagon
iii. ghrelin
3. stimulated by:
a. insulin release
Prevention of Hypoglycemia:
1. glucagon:
a. is the most important hormone
2. other hormones maintain the “euglycemic state”:
a. regulate the glucagon/insulin balance
Glucose Transporters
SGCT (sodium glucose transporters)
Glucose transporters:
1. Sodium glucose co-transporters (SGLTS)
a. located in GI and kidney
i. uptake of hexoses from food and urine
b. energy for active transport is supplied by the sodium gradient
Sodium Glucose Transporters:
SGLT-1:
1. site:
a. small instestine
2. renal location:
a. late proximal straight tubule
3. affinity for glucose:
a. high (K = 0.4mM)
4. capacity for glucose:
a. low
5. percent of renal glucose reabsorption:
a. 10%
SGLT-2:
1. site:
a. kidney
2. renal location:
a. early proximal straight tubule
3. affinity for glucose:
a. low (K=2mM)
4. capacity for glucose:
a. high
5. percent of renal glucose reabsorption:
a. 90%
Renal Glucose Reabsorption:
1. SGLT2:
a. uses facilitated diffusion (secondary active transport)
i. couples movement of sodium with movement of glucose
2. inward sodium gradient:
a. maintained by Na+/K+ ATPases
3. glucose diffuses passively out of the cell:
a. down its concentration gradient by basolateral transporters
i. GLUT2
ii. GLUT1
Renal Glucose Reabsorption:
Glucose Transporters:
GLUT (glucose transporters)
Glucose Transporter (GLUT)
1. maintain the glucose homeostasis in the body
2. three different classes:
a. Class I:
i. GLUT 1,4 and 14
b. Class II:
i. odd transporters 5,7,9,11
c. Class III
i. even transporters 6,8,10,12 and Glut 13 (myoinositol transporter)
GLUT Transporters:
GLUT 1:
1. location:
a. most cells
2. action:
a. low level basal uptake of glucose
3. unique feature:
a. transport of glucose across the blood brain barrier
GLUT-2:
1. the glucose sensor for the pancreas
2. action:
a. starts the secretion of insulin
b. the glucose sensor and is bi-directional
3. locations:
a. kidneys
b. intestine
c. pancrease
GLUT 3:
1. location:
a. neurons
b. white blood cells
c. sperm
d. placenta
e. preimplantation embryo
GLUT 4:
1. is the only one controlled by insulin
2. location:
a. skeletal muscle
b. adipocytes
c. cardiac muscle
GLUT 5
1. location:
a. intestine
2. action:
a. transports fructose across the apical membrane
GLUT 7:
1. location:
a. endoplasmic reticulum
2. action:
a. transports glucose into the endoplasmic reticulum
The Pancreatic Beta cells
1. Insulin secretion:
a. is calcium dependent
2. nervous system control of insulin secretion;
a. parasympathetic (cholinergic) stimulation increases insulin
b. sympathetic (adrenergic) stimulation decreases insulin
3. steps of insulin release:
a. metabolism of nutrients  intracellular ATP will CLOSE an ATP-dependent K+
channel
i. cell will depolarize
b. increase in Ca2+ into the cell after opening of voltage gated Ca2+ channels
i. this causes release of insulin
4. Glucagon, GLP-1 and GIP:
a. stimulate release of intracellular Ca2+
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1.
Secretion of insulin is pulsatile.
2.
Glucose, amino acids, and ketoacids evoke insulin secretion. Primary
stimulus is glucose.
3.
Secretion is calcium dependent. A rise in ATP, due to the metabolism
of nutrients, closes an ATP-dependent K-channel, which depolarizes the cell.
Extracellular calcium enters via a voltage-dependent Ca-channel and stimulates
the secretion of insulin.
4.
Many systems involved in stimulating or modulating the secretion of
insulin.
a.
Autonomic nervous system
i.
Cholinergic stimulation increases insulin release.
ii.
Adrenergic stimulation inhibits insulin secretion.
b.
Hormones
i.
Glucagon stimulates release.
ii.
Amylin, GLP-1, gastrin, secretin, and choleocystokin increase release.
iii.
Catecholamines inhibit release.
iv.
Somatostatin inhibits release.
Glucagon, stimulates insulin secretion fine tuning the steady-state levels of
blood glucose, preventing wide fluctuations
Glucagon secretion decreases when blood sugar is elevated BUT this
inhibition is insulin-dependent so that absence of insulin means that glucagon
persists, and hyperglycemia (high blood sugar) is exacerbated by low insulin
AND by high glucagon levels)
GLUT 4 is Dependent On Insulin Signalling
Insulin Signalling
1. insulin binds to the tyrosine kinase receptor
2. receptor will phosphorylate insulin-receptor substrates (IRS)
3. second messenger pathways will alter protein synthesis and existing proteins
4. membrane transport is modified
5. cell metabolism is changed
Enzymatic shifts:
1. include:
a. promoting glucose as storage as glycogen or triglycerides
Insulin Induces GLUT4 movement to the cell membranes:
1. this occurs in:
a. muscle (skeletal and cardiac)
b. adipocytes
2. exercise also induces exocytosis of GLUT4 transportes
Summary:
• Insulin lowers blood glucose
Incretins promote insulin secretion
Somatostatin inhibits insulin secretion
• Glucagon raises blood glucose
Ghrelin promotes glucagon secretion
Amylin inhibits glucagon secretion
Somatostatin inhibits glucagon secretion
• There are 4 phases of Insulin Secretion
• SGCT recover glucose from gut and kidney
• GLUT2 transporters are sensors of glucose levels, are bidirectional and are NOT
insulin dependent found in pancreas, kidney, intestine
• GLUT4 transporters are insulin sensitive
• Insulin release from beta cells is initiated by increases in intracellular
Ca++ levels by:
Phospholipase C stimulation of release of intracellular Ca++ stores
Adenylate Cyclase stimulation of release of intracellular Ca++ stores
Closure of ATP-sensitive K+ channels which opens voltage dependent Ca++
channel