The Endocrine Pancreas
Homeostatic Control: insulin and glucagon
Homeostatic Control: raising blood glucose levels
Ketogenesis: process by which
ketone bodies are produced as
a result of fatty acid
breakdown.
Gluconeogenesis: generation of
glucose from noncarbohydrate carbon
substrates such as lactate,
glycerol, and glucogenic amino
acids. Occurs in hepatocytes.
Homeostatic Control: Glucose, glucagon, and insulin levels over a 24-hour period
Regulation of Blood Glucose Levels
• Blood glucose levels maintained primarily by actions of insulin and glucagon
• Normal blood glucose = 70~120 mg/dL
• Hyperglycemia = when fasting blood glucose > ~130 mg/dL (~7 mM) (Normal fasting < 100mg/dL)
• Hypoglycemia =blood glucose < 60 mg/dL
Page 1
Becky Stepan
Rose-Hellekant – Endocrine Pancreas
What happens to glucose once it is taken up by cells: Energy Storage
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Glycogen stores in liver and muscle =
500 grams total body stores which
can last ~ 12 h.
Triglyceride stores in adipose tissue
is unlimited
Insulin regulates uptake of CHO,
lipids, amino acids
Virtually no energy stores in BRAIN.
When glucose intake and stores are low:
• Amino acids can be made into glucose via gluconeogenesis but only in the liver.
• Glycerol from triglycerides can be used to make glucose
• **GLUCOSE is the primary energy source for brain. Ketone bodies also can be used.
Fasted-State Metabolism with decreasing blood glucose
Page 2
Becky Stepan
Rose-Hellekant – Endocrine Pancreas
Islets of Langerhans
20% alpha cells – secrete glucagon, tend to be found on the outside of the islets
5% delta cells – secrete somatostatin – found scattered throughout the islet
70% beta cells – secrete insulin, amylin – found in the middle or central region of the islet
Innervation of Islets of Langerhans:
Sympathetic nerves inhibit insulin and amylin secretion during fight or Flight.
Parasympathethic nerves via Vagus N. involved in cephalic phase of insulin secretion
Proinsulin – 86AA
A. Chemistry of Insulin
1. 51 amino-acid acid mature polypeptide with approximate mol. wt. of 6000
2. Composed of two chains
a. alpha chain (acidic chain) containing 21 amino-acid acids
b. beta chain (basic chain) containing 30 amino-acid acids
c. Two disulfide bridges connect the two chains; an additional disulfide bridge is found within
alpha chain
d. The sequence 22-26 in beta chain is essential for biologic activity
3. C-chain can be measured as an indicator of endogenous insulin production in diabetic patients
** Insulin is a poly-peptide and is secreted in a pro-insulin form. There is a connecting peptide in the C chain form that has
some diagnostic funciton. You have a diabetic who makes insulin and also need to be supplemented with exogenous insulin. If
you measure C-peptide, you can have an idea of how much insulin is being produced.
Insulin Distribution & Metabolism
• Circulates free in plasma
• t1/2 < 10 minutes
• Metabolized by the liver & kidney
 50% in first pass
 Proteolytic enzymes (soluble)
 Glutathione-insulin transhydrogenase (liver/kidney microsomes)
Amylin is insulin’s co-conspirator
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37 amino acid peptide
Co-packaged and co-secreted with insulin in b-cell so that ratio is 1:1.
 Inhibits Glucagon secretin.
Reduces food intake, delays gastric emptying, inhibits secretion of digestive enzymes, stomach acid, bile ejection.
Induces satiety
(Binding occurs to C-3 receptors composed of calcitonin receptor plus RAMP (Receptor activity-modifying proteinstransmembrane proteins that transport the calcitonin receptor-like receptor to the cell surface) - presumably coupled
to Gs and Gq. Specific Amylin receptors have been proposed.) Therefore has also bone function which is less defined.
• Half life: minutes
** Amylin is co-secreted in a one-one ratio with insulin. Inhibits glucagon so it is supporter of insulin. Amylin’s
effects are as short as insulin’s effects.
Glucagon
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29 AA polypeptide
Produce in a-cell of pancreas
Synthesized as proglucagon
Increases with hypoglycemia, decreases with hyperglycemia
Decreased by GLP-1 (glucagon like peptide 1) and amylin
Increases with amino acids (to protect from hypoglycemia of an all protein meal).
Increases with Sympathetic and Vagal stimulation.
Proglucagon gene is spliced into glucagon in pancreatic beta cells and into GLP-1 and GLP-2 in intestinal cells.
Glucagon is an important physiological regulator. The stimulatory factors which promote the cleavage or the
production has to do with food substrates
Page 3
Becky Stepan
Rose-Hellekant – Endocrine Pancreas
The “Incretins” GIP and GLP-1  GI hormones that ENHANCE INSULIN secretion
Mediators of Intestinal Phase of Insulin Secretion
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GIP: gastric inhibitory peptide; AKA glucose dependent insulinotropic peptide
• 42 amino acid peptide produced by K cells of duodenum and jejunum
• in Type 2 diabetic, secretion is normal but response to endogenous peptide is impaired
• Rapidly metabolism: half-life minutes
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GLP-1: glucagon like peptide 1
• 30/31 amino acid peptide produced by lower small intestine and colon
• Product of alternative splicing of the proglucagon gene (vs. in pancreas which splices so that
glucagon is secreted).
• Stimulates insulin and inhibits glucagon secretion
• delays gastric emptying
• induces satiety
• in Type 2 diabetic secretion is impaired but response to endogenous peptide is normal
• Half-life minutes
• rapid degradation by the enzyme dipeptidyl peptidase-4.
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Phases of Insulin Secretion
Cephalic Phase
• Parasympathetic information from sight & smell
Oral Phase
• Parasympathetic information
• Carbohydrate sugar stimulation of sweet receptors
G.I. Phase
• GIP (Gastric inhibitory polypeptide also known as the glucose-dependent insulinotropic peptide is
a member of the secretin family of hormones.) Produced in response to hyperosmolarity due to
glucose in in gut. The amount of insulin secreted is greater when glucose is administered orally
than intravenously.
• Glucagon like peptide 1 (GLP-1) derived from proglucagon gene stimulates insulin and inhibits
glucagon secretion
Blood Glucose Phase
• Increase in blood glucose triggers b cell release of insulin
• Decrease in blood glucose triggers a cell release of glucagon
The Incretin Effect
A larger response from oral vs. i.v. glucose is due to oral, cephalic and intestinal phases of insulin secretion.
Note the differences between the rise in insulin from oral glucose compared to IV glucose.
Page 4
Becky Stepan
Rose-Hellekant – Endocrine Pancreas
The Pancreatic b Cell
Insulin secretion is calcium
dependent
 Cholinergic stimulation
increases and adrenergic
stimulation decreases
secretion
 Increases in intracellular
ATP CLOSES K+ channel
resulting in
depolarization of the cell
and an increase in Ca++
movement into cell via
voltage dependent Ca++
channel. This causes
release of insulin
 Glucagon, glucagon like
peptide 1stimulate
release of intracellular
Ca++.
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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 ATPdependent K-channel, which depolarizes the cell. Extracellular calcium enters via a voltage-dependent Cachannel 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.
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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)
GLUT2 on the pancreatic beta cell. Those transporters facilitate diffusion. This is a hormone producing cell
so it has a lot of RER and it is going to be stored in granules or vesicles. There will be small pulses of the
insulin being secreted at the right signals. Glucagon is another signal for secreting insulin. Fight or flight
catecholamines as well as somatostatin are inhibitory. All of the external stimuli and stimulating the
internal calcium stores to be increased or released. You can trigger it via and this will open the calcium
channel so we will have an influx of calcium and end up with an insulin like secretion.
Page 5
Becky Stepan
Rose-Hellekant – Endocrine Pancreas
Homeostatic Control: Glucose Transporters GLUT 1-5,7 sit in cell membranes and facilitate glucose diffusion
• GLUT 1 transports glucose into most cells used to maintain basal cellular levels
• GLUT 2 transports glucose into pancreatic b cells, hepatocytes, and found on basolateral epithelia of
kidneys and intestine.
• GLUT 3 transports glucose into neurons.
• Only GLUT 4 is controlled by insulin in resting skeletal muscle, cardiac muscle and adipocytes.
• GLUT 5 transports fructose across apical membrane of intestine
• GLUT 7 transports glucose in endoplasmic reticulum
 GLUT 1 is the most basic glucose transporter that you can have. It is the sensor for circulating
glucose. Glucose transporter 3 is transporting glucose into neurons.
 Glut 4 – these are sequestered in the cell until insulin is present, but they are readily available in the
heart muscle with or without regulation of insulin.
Homeostatic Control
Becky Stepan
Homeostatic Control of Skeletal Muscle & Adipose:
when insulin is present. Note: exercising muscle
induces exocytosis of GLUT4 transporters. The more
activity you have the more insulin you need.
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Rose-Hellekant – Endocrine Pancreas
Glucose Regulation by Insulin
Glucose Regulation by Glucagon
(a) If you have high plasma glucose level, this is a stimulatory thing for insulin release. You want to decrease
gluconeogenesis.
Glucagon, stimulates insulin secretion, thereby fine tuning the steady-state levels of blood glucose,
preventing wide fluctuations.
However, Insulin inhibits Glucagon secretion when blood sugar is elevated. (In the absence of insulin glucagon
persists.) Therefore hyperglycemia is exacerbated due to low insulin AND high glucagon levels).
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Insulin is working in a negative way – more narrowly secreted. Insulin has wide variations. Insulin is
inhibiting the negative glucagon secretion.
In the case of hyperglycemia, low insulin production – glucagon persist so you can have high glucagon
levels in face of low insulin levels.
GLP-1: glucagon like
peptide 1: made by distal
small bowel and colon in
response to glucose
presence. Receptors in
beta pancreatic cells and in
brain. Receptor presence
in alpha cells is
controversial. GLP-1 affects
on glucagon may be
mediated via nervous
system.
Amylin: cosecreted with
insulin in beta cells;
controls nutrient intake as
well as nutrient influx to
the blood by an inhibition
of food intake, gastric
emptying, and glucagon
secretion.
Page 7
Becky Stepan
Rose-Hellekant – Endocrine Pancreas
Normal and Abnormal Results of Glucose Tolerance Tests
Homeostatic Control:
Acute pathophysiology of type 1
diabetes mellitus
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Disease characterized by severe
hyperglycemia, hyperosmolarity, severe
dehydration, lack of urine or serum
ketones, lack of or mild to moderate
metabolic acidosis, and CNS depression.
Diabetes type 1 is an immune mediated
event where you destroy you islet cells.
This destroys the islets so that you do
not have an insulin response. Note the
different areas of metabolism. There
are free fatty acids, increased plasma
glucose and increases plasma amino
acids.
Homeostatic Control: Acute pathophysiology of type 1 diabetes mellitus
We know that the GLUT 4 receptors are not going to be present on the membranes so we are going to have this elevated
glucose level. We will have decreased glucose uptake and utilization. The cells think we have low circulating glucose and
the brain interprets this as starvation and this signals polyphagia or eating more. Then you start dumping glucose into the
urine so you start having polyuria and then you become dehydrated and have polydipsia and this is why people present in
clinic. In the face of high glucose, you have – in protein metbolism – there is an increase of tissue loss and this leads to
weight loss.
Pathophysiology
• Insulin deficiency causes reduced utilization of glucose and excessive glucose production. The resultant high, extracellular
blood glucose causes a hyperosmolar state with a reduction in extracellular fluid volume. Intracellular dehydration,
azotemia, and uremia develop and the intracellular dehydration becomes more pronounced as the glomerular filtration
rate decreases and tissue hypoxia ensues. Azotemia, hyperglycemia, and hyperosmolarity worsen as a result of glucose
retention and glucose-induced osmotic diuresis.
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Although ketonemia and ketonuria usually are not features of this syndrome, anorexia (especially when prolonged) may
cause mild ketoacidosis in some patients. However, high lactic acid is a major contributor to the metabolic acidosis that
may develop in these patients.
Systems Affected
• Renal/urologic--prerenal and primary renal azotemia because of reduced extracellular fluid volume, reduced tissue
perfusion, or diabetic glomerulonephropathy
• Urine specific gravity is low because of osmotic diuresis, diabetic glomerulonephropathy, or concurrent renal insufficiency
• Cardiovascular--hypotension because of low extracellular fluid volume, vascular collapse, and depressed myocardial
contractility
• Nervous--depression, disorientation or mental confusion, seizures, and coma are caused by intracellular dehydration and
hyperosmolarity. CNS dysfunction worsens as serum osmolarity rises.
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Prevention of Hypoglycemia
• Glucagon most important
• FYI: Other, nonpancreatic hormones are involved in maintaining euglycemia by regulating the balance of
glucagon/insulin and inducing metabolism in extrapancreatic tissues in a way that will ensure that
hypoglycemia does not occur.
Page 8
Becky Stepan
Rose-Hellekant – Endocrine Pancreas