Slide 1

Endocrine Pancreas: Physiology

Dr. Bruce Wright

Contribution by Dr. Michael Yakubovskyy, Pathology

 865-338-5741
 brucewright@RossU.edu
Office hours:
- email to set a time! I’ll also have at least one
virtual office hour per teaching week so that both St.
Kitts and Knoxville can reach me electronically.
Note: For all Endocrine Physiology lectures, practice questions are posted
in the Practice Questions folder for your course, FM02 or FM2X
immediately below the Week 14 folder in Canvas.
1

“Housekeeping” information:

Here are my contact details. I welcome questions and feedback on my teaching so please
feel free to let me know how you think it might be improved.

• The best way to contact me is by email.

• Office hours: open door – you can see me at any time during the normal working
day. If my door is open, then just knock and come in. I’ll let you know if I’m busy
then.
• If you want to see me however, the BEST thing is to first email me - giving me
and idea of what you want to talk about and give me some days & times when
you are available. I shall get back to you with a mutually convenient time.
• I shall always try to get back to you within 24 h of receiving your message,
though I can’t promise availability on weekends.

• May 18 Term: My “office” is Cubicle P-1 in Building 2 in Knoxville, TN.

Slide 2

• Hormones of the Endocrine Pancreas: Physiology

• After this lecture, students should be able to demonstrate the following abilities:

• 19. To describe the physiological functions of insulin, glucagon, somatostatin, and the
incretins.

• 20. To describe the biosynthesis, control, transport, and effects of insulin. Includes
cellular mechanism of signal transduction and whole-body effects on metabolism.

• 21. To describe the biosynthesis, control, transport, and effects of glucagon. Includes
cellular mechanism of signal transduction and whole-body effects on metabolism.

• 22. To summarize the physiological interrelationships required to maintain glucose

homeostasis.

• 23. To explain physiological changes associated with fasting and starvation.

• 24. Pathology: To compare and contrast hypoglycemia and hyperglycemia. To define

diabetes mellitus (DM) and its types, to describe pathologic changes of islets of
Langerhans, and to list major complications of DM. 2

Note: There is a section in this presentation on Diabetes Mellitus prepared by Dr.

Michael Yakubovskyy, Professor and Chair of Pathology. I thank him for this material
and hope you do as well.

As with every lecture in Endocrine Physiology, unless it is specifically excluded (e.g.

SUPPLEMENTAL material), all material from the slides and the notes is examinable
content.

Note: The physiology-specific learning objectives in Hypothalamus-Pituitary Histology &

Physiology, and in Adrenal Histology & Physiology are the “missing” objectives
between those in Introduction to Endocrinology and Endocrine Pancreas Physiology.
Slide 3

• Purpose: Regulate blood

glucose (sugar) in the
INSULIN
normal range

• Action: Stimulates many

cells of the body to
absorb and use glucose
thereby decreasing blood
sugar levels

• Secreted in response
to: High blood glucose

• Secretion inhibited by:

Low blood glucose A C-peptide (connecting peptide)
from the original proinsulin molecule
is co-secreted with insulin.
3

Objectives 19, 20.

There are many other factors that stimulate and inhibit insulin secretion, but plasma
glucose is the most important.
Slide 4

Insulin Production
and Secretion

• Insulin is a peptide hormone

• It requires hnRNA transcription,

• mRNA processing,
• translation,
• and post-translational processing.

• Its secretion is via exocytosis,

like every other peptide hormone.

Objective 20.
Slide 5

Insulin Secretion
Arterial blood

• Insulin is secreted by
beta (b) cells

• Arterial and venous

blood are on opposite
sides of the beta cells

• Receptors concentrated Venous blood

on arterial-facing
membrane Venous blood – to portal circulation
(directly or indirectly)
• Insulin is secreted into
the venous blood,
enroute to the liver
5

Objective 20.

Technically, each cell operates relatively independently, but they combine for a powerful
collective effect on secretion.

Note: Arterial-facing membranes are better for determining the state of glucose levels
and hormone levels in the general circulation than are venous-facing membranes.
Slide 6

Homeostasis of Plasma Insulin and Plasma Nutrients

An example of product-mediated negative feedback
(Different than, say, levels of GH in blood)

(But mostly glucose)

6
6

Objectives 20, 22.

Recall from Introduction to Endocrinology that secretion of insulin is not a pulsatile

secretion, it is an episodic secretion. When blood glucose levels rise, then by the
mechanism shown on slide 6 above, insulin is secreted until blood glucose levels fall
again to a normal range.
Slide 7

Main Pathway Mechanism of Insulin Secretion. 1

• Main path:
• 1. Glucose entry
• via GLUT-2
• Other nutrients too

• 2, 3. Metabolize
glucose
• or other nutrients

• 4,5. ATP, NADH

levels up

• 6. K+ channel closes,
& Ca++ channels open

• 7. Ca++ then binds to

motor (exocytosis)
proteins.

• 8. Exocytosis

Objective 20.

Figure revised from Figure 38-14 Berne & Levy

Main Pathway for Insulin Secretion

The concentration of glucose is THE primary factor regulating insulin secretion. The
transition point seems to be about 8-10 mmol/L ((>145 mEq/L). Above this point the
levels of ATP produced within the cell cause it to become an intracrine messenger.
ATP acts inside the cell as a messenger via closing potassium channels which then
produce the membrane potential changes and subsequent exocytosis of insulin.

Other energy sources such as fatty acids or amino acids such as leucine or arginine
also increase ATP levels in the cell, turning on the intracellular signal.

When the (ATP) ligand-gated potassium channels close, the membrane depolarizes and
voltage-gated calcium channels open. This calcium along with other calcium from
intracellular stores bind to motor proteins that “drag” vesicles containing insulin to the
basolateral membrane resulting in exocytosis of insulin molecules.
Thus, it is that the extracellular concentration of glucose alters the concentration of ATP
and that proportionally increases intracellular calcium. If ECF glucose is up, then ATP is
up, calcium is up, and insulin secretion is up.

This Main Pathway will be modified by agents that affect adenylyl cyclase (AC) and
phospholipase C (PLC) activity in the cell. See next slide.
Slide 8

Modulation Pathways Mechanism of Insulin Secretion. 2

• 1. YOU MUST have
the main path active
FIRST !

• 2. AC Pathway:
• Stimulators: Incretins
via Gs (e.g. GLP-1)
• Inhibitors:
Sympathetics via Gi
• PKA potentiates motor
protein action

• 3. PLC Pathway:
• Stimulators:
Parasympathetics via
muscarinic receptors
and FFAs via GPR40
• Both act through Gq
• IP3 increases
intracellular Ca++
• More motor protein
8 binding
• More Exocytosis 8

Objective 20.

Figure revised from Figure 38-14 Berne & Levy

Modulation Pathways for Insulin Secretion

The main pathway is an absolute requirement for insulin secretion from beta cells. That
said, with the right modulation a given increase in blood glucose could result in as much
as three times more insulin being secreted than with no modulation at all. The
intracellular ATP, the “green light” signal, must be increased before modulation even
matters.

This modulation affects the last few stages of the main pathway. The glucose will still
be oxidized, the potassium channels close, and the calcium channels for extracellular
calcium entry will still open, but these are not modified and therefore are grayed out of
the picture. What is modified is either the amount of additional calcium in the cytoplasm
whose source are intracellular calcium depots (e.g. endoplasmic reticulum), or the
responsiveness and/or activity of the motor proteins involved in the actual exocytosis.
To increase the response of the motor proteins such that a given level of intracellular
calcium results in more exocytosis, the adenylyl cyclase second messenger pathway is
used. You are expected to know the G proteins, etc. of this pathway. With respect to the
beta cell, the stimulators of this are incretins (described in the following slides) binding
to GLP-1 receptors. Inhibitors are sympathetic neurotransmitters/hormones acting on
alpha 2 adrenergic receptors.

To increase the quantity of intracellular calcium beyond what is entering from the ECF,
the PLC pathway is used. The two most common stimulators are parasympathetic
neurotransmitters (ACh) acting through muscarinic receptors, and free fatty acids
(FFAs) acting through a GPR40 receptor. You are expected to know how the PLC
pathway works.

When BOTH are active, you have both greatly increased intracellular calcium AND
increased responsiveness/activity to that calcium. That’s when you can get the 3X
main-path-only insulin secretion rate.

Clinical correlation: It is possible to provide parenteral nutrition, but oral food intake is
always preferred because the incretins associated with oral nutrition yield a better
insulin secretion and better blood glucose control.
Slide 9

Modulators of Insulin Secretion

Factors Stimulating Insulin Secretion Factors Inhibiting Insulin Secretion

• Increased blood glucose • Decreased blood glucose

• Increased blood free fatty acids • Fasting
• Increased blood amino acids • Somatostatin
• Gastrointestinal hormones (gastrin, • Alpha-adrenergic activity
cholecystokinin, secretin, glucose- • Leptin
dependent insulinotropic peptide)
• Growth hormone, cortisol
• Parasympathetic stimulation:
acetylcholine
• Beta-adrenergic stimulation
• Insulin resistance; obesity
• Certain drugs
9

Objectives 20, 22.

Table lightly modified from Guyton & Hall Table 79.1, p. 990. Quote below:

[In addition to glucose] “other nutrients, such as certain amino acids, can also be
metabolized by the beta cells to increase intracellular ATP levels and stimulate insulin
secretion. Some hormones, such as … glucose-dependent insulinotropic peptide
(gastric inhibitory peptide) and acetylcholine, increase intracellular calcium levels
through other signaling pathways and enhance the effect on glucose, although they do
not have major effects on insulin secretion in the absence of glucose. Other hormones,
including somatostatin and norepinephrine (by activating alpha-adrenergic receptors)
inhibit exocytosis of insulin.”

Note that the somatostatin used to modulate beta cells in the pancreatic islet is almost
always paracrine, from delta cells in the same islet. Here it is not an endocrine
hormone as it would be, say, when secreted from the hypothalamus and affecting the
anterior pituitary somatotrophs. And yet even Guyton calls it a hormone in the quote
above.
Slide 10

The Incretins
• The rise in insulin after parenteral administration of a given dose
of glucose is 2 to 3 times lower than that for the same quantity of
glucose from the oral route.

• The difference is attributed to Incretins

• Primarily Glucose-dependent Insulinotropic Polypeptide
a.k.a. Gastric Inhibitory Peptide [GIP] and
• Glucagon-like peptide 1 [GLP-1]),
• A class of gastrointestinal-secreted hormones, among whose targets are
beta cells.

10

Objectives 19, 20, and 22.

The implications that GI-secreted hormones can boost insulin secretion support a feed-
forward effect in which presence of glucose in the tract causes the hormones to prime
the beta cells for glucose arrival following absorption.

Incretins modulate the sensitivity of insulin secretion. Remember that they are typically
secreted just prior to the first glucose absorption by the gut. So, on a functional
standpoint, their job is to make sure that when that first glucose does pass the liver and
make its way back into the systemic arteries and finally pass the beta cell sensors, that
the insulin secretion that follows will be more robust and adequate to perform the job of
stimulating anabolism and glucose uptake throughout the body. They do this by going
through the blood like any other hormones then binding to receptors on the pancreatic
beta cell, increasing cAMP within that cell. The more cyclic AMP there is the more
secretory proteins are in a ready state, so that when the calcium does arrive from
somewhere else (e.g. extracellular fluid secondary to high plasma glucose), the motor
proteins that the calcium bind to are as “charged up” as possible.

This is different from the effects of, say, acetylcholine from PNS postganglionic neurons
or (possibly) CCK, which operate through PLC, increasing IP3 which promotes more
Ca++ in the cytoplasm from ER stores, and DAG which works in concert with cAMP to
maximize the reaction of proteins involved with insulin production and secretion.
Only the GIP and GLP-1 are usually called incretins, but all of these assist the primary
route of promoting insulin secretion from the main pathway for insulin secretion, the
glucose metabolism-ATP rise-ion channels closing and opening-calcium levels rise
pathway.
Slide 11

Biphasic Secretion of Insulin

• When glucose rises, at

first insulin secretion
goes up dramatically then
it drops then it rises
slowly to the level at
which it first was
secreted.

• This is generally
attributed to an initial
release of stored insulin
in secretory vesicles,
followed by production of
new insulin after a few
minutes. 11

Objective 20.

RRP = Readily Releasable Pool for insulin secretion within the beta cell

As discussed in Introduction to Endocrinology, when insulin’s EFFECTS have

successfully reduced blood glucose, the glucose signal for further insulin secretion ends
and the metabolism and clearance of already-secreted insulin rapidly follows. During
this “down time”, the beta cells store a new set of insulin proteins and store them in
vesicles, functionally replacing the readily releasable pool of insulin that had been
depleted by the end of the first phase.
Slide 12

Why Regulate Plasma Glucose?

• Primary Target Tissues for Insulin:
• Liver hepatocytes,
• Skeletal muscle cells, (+ cardiac)
• Adipocytes

• Most neurons are not target

tissues, nor are erythrocytes.
• Though they use glucose, their
glucose transporters (GLUT-1 or
GLUT-3), are insulin-independent.

• Regulation of plasma glucose levels

are therefore necessary to prevent
neurons from becoming overactive,
and potentially “burning out” (e.g.,
in severe diabetic coma) It is the only major hormone to lower blood glucose
12

Objective 20, 22.

The opposite is also true of course, and more acutely. A severe hypoglycemia will
cause neurons to run out of ATP, since their ability to produce ATP anaerobically is
minimal. This will also produce neuronal damage and could lead to death.
Slide 13

Actions of Insulin
1. Insulin acts on many cell types to
lower the blood level of glucose,
fatty acids and amino acids and
promote their storage.

2. As these molecules enter the blood

during the absorptive state, insulin
directs their cellular uptake and
conversion into glycogen,
triglycerides (fat) and protein.

• Insulin acts on cells by

• stimulating the uptake of glucose,
amino acids and fatty acids
• stimulating enzymes involved in
specific metabolic pathways
often associated with growth 13

Objective 20.

The gathering of energy sources and raw materials for protein synthesis into target
tissues with initiation of transcription of mRNA for those proteins is what makes the
production of so many proteins in target tissues possible. And the net increase in
proteins and other useful molecules in those tissues promotes growth of those tissues.
As such, though another hormone has the official name, insulin can be thought of as a
“growth-promoting hormone” in its own right.
Slide 14

Insulin Receptor
• The insulin receptor is composed of
two alpha subunits and two beta
subunits linked by disulfide bonds.
• The alpha chains are entirely
extracellular and bind to insulin
• beta chains penetrate through
the plasma membrane and
transduce the signal.

• The insulin receptor is a tyrosine

kinase receptor.

14

Objective 20.

Picture source for this and certain others from this section:
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html
Slide 15

Characteristics Glucose Transporters

SGLT-1
Class I

I.D.
Class II

15

Objective 20.

Glucose transporters in this context are cell membrane bound proteins that facilitate
passage of glucose across those cell membranes.

GLUT-1, 2,3, and 4 are the Class I glucose transporters. (Note: These four are also
discussed in Biochemistry in this module)

The ONLY glucose transporter that is insulin-dependent is GLUT-4. It is found in the

tissues that make up much of the gross mass of the body (skeletal muscle + fat) and
cardiac muscle, too. It isn’t found in hepatocytes.

GLUT-2 is also particularly important in metabolism, and it is on the beta cell itself.
Unlike the others, GLUT-2 is co-directional, allowing release of or absorption of glucose
into cells such as hepatocytes.

GLUT-1 and GLUT-3 are dependent on the concentration of glucose and are mainly
expressed in brain and erythrocytes, with some GLUT-3 in other tissues.
GLUT-5 is a Class II FRUCTOSE transporter, which is important both in digestion and
absorption of carbohydrates, but also in maintenance of sperm motility, in locations
where fructose will not otherwise be used as a food source (spermatozoa, in the uterus
and uterine tubes).

The Sodium-Glucose Transporter (SGLUT-1) is particularly important in absorption of

glucose in the small intestine and of reabsorption of glucose in the proximal convoluted
tubule, but it is not intended to support metabolism directly. It doesn’t seem to fall
directly into either class I or II because of its cotransporter function.

There are a variety of other Class II and Class III glucose transporters, but they won’t
be discussed further as the purpose of most of them are not well understood. You are
not responsible for them in Endocrine Physiology.

You are responsible for knowing all the classes in the slide, their expression
sites, and their characteristics.
Slide 16

General Mechanism of
Action of Insulin*
• Tyrosine Kinase receptor activity;
activates several classes of
intracellular messengers

• GLUT-4 transporters to cell

membrane of select tissues*,
increase glucose uptake

• Increased activity of enzymes that

store and/or process glucose

• Induction of transcription, increase

in protein synthesis**

• Increased glucose utilization occurs

even in target cells with no GLUT-4s
16

Objective 20.

•* The mobilization of GLUT-4 transporters for a direct increase in glucose uptake is

ONLY applicable to those tissues– including cardiac muscle, skeletal muscle and
adipose tissue, but NOT hepatocytes-- which express GLUT-4 transporters. But
increased glucose utilization will occur in all target tissues, so some increase in
glucose uptake (from concentration gradient changes) can be induced in all target
cells.

The target tissues containing GLUT4 are primarily heart, skeletal muscle, and adipose
tissue. The former two are tissue classes with highly variable energy needs and the
latter is an energy sink and gland for other hormones’ secretion. In either case, excess
glucose can only be readily moved into the cells of these tissues with placement of
numerous movable GLUT4 molecules to supplement the low number of glucose
transporters of other types (e.g. GLUT10, a Class III molecule).

In other tissues and organs that DO have insulin receptors but DO NOT have GLUT-4
transporters (e.g., hepatocytes), insulin’s promotion of enzymatic effects that increase
anabolism and otherwise utilize glucose indirectly increase the concentration gradient
for glucose. With this change in gradient will come increased glucose uptake by
facilitated diffusion through whatever glucose transporters these cells do have (e.g.,
GLUT-2 transporters in hepatocytes). Immediate phosphorylation of any entering
glucose by hexokinase etc. should ensure that this concentration gradient does not
appreciably change until the glucose levels in the ECF fall.
Slide 17

Opposing Effects of Insulin and Glucagon

in Hepatic Glucose Metabolism

More
glucose
to blood

More
ATP
in cell

Activity: Short term activation or inactivation of already-present enzymes

Gene Expression: Production or lack of production of new enzymes, to change number in cell 17

Objectives 20, 21, and 22.

The take-home point of this slide is that insulin drives metabolism by driving changes in
enzyme activity towards higher activity in those enzymes involved with storing and
processing incoming energy, and glucagon works in the oppose direction.

The physiology of glucose metabolism is more directed towards general processes

being increased and decreased rather than specific enzymes activated, so in this case
one can see that insulin promotes glycolysis to pyruvate and further oxidation past
pyruvate and decreases gluconeogenesis. In contrast, glucagon inhibits glycolysis and
promotes gluconeogenesis and eventual glucose export into the plasma. This “arrow-
driven” approach is used on the USMLE, so you should get used to it.

For all the hormones that affect energy metabolism it is helpful to focus on these larger
processes, such that one can compare and contrast related processes performed by the
different major hormones (e.g. GH, insulin, glucagon, cortisol, epinephrine) for
carbohydrate, fat, and protein processing.

Note: The production of more enzymes so that eventually there will be greater changes
in the response of the cell to a given hormone is an example of a permissive effect. So
is stoppage of production so that as existing proteins wear out eventually there will be
smaller changes in cellular responsiveness to that hormone. Permissive effects are
discussed in more detail in Adrenal Physiology.
Slide 18

Actions of Insulin on Carbohydrates

1. Insulin promotes glucose transport into most cells in the body.
• Insulin stimulates an increase in the number of glucose carrier proteins (GLUT-4)
within the cell membranes of those target cells that use GLUT-4 (adipose tissue,
skeletal muscle, and cardiac muscle).
• Glucose enters cells by facilitated diffusion (it needs a carrier protein in the cell
membrane).
• If the number of glucose carriers in the cell membrane of a cell increases, then the
cell can takes up more glucose.

• 2. Insulin stimulates glycogenesis, the production of the storage polysaccharide,

glycogen from glucose in skeletal muscle and the liver.
• Thus even in tissues lacking GLUT-4’s the increased concentration gradient from increased glucose use
within the cell drives more glucose uptake into those cells whose metabolism changes.

• 3. Insulin inhibits glycogenolysis, the break down of glycogen into glucose. This
decreases glucose output by the liver and promotes storage of glucose as glycogen.
• See above, concentration gradients for uptake

• 4. Insulin inhibits gluconeogenesis which is the conversion of amino acids or fatty acids
into glucose by the liver.

• Overall effect: Glucose is stored, not produced. Combined with increased glucose
uptake and cellular respiration, this has the net effect of reducing plasma glucose. 18

Objective 20.

This slide is very wordy, but that is because there isn’t room even on a wide-format slide
to discuss what insulin does and put in a comprehensive picture.
Slide 19

Actions of Insulin on Fats (Lipids)

1. Insulin increases the transport and
conversion of glucose into fat.

2. Insulin promotes the transport of

fatty acids from the blood into
adipose tissue.

3. Insulin inhibits lipolysis which is the

break down of adipose tissue into
fatty acids. Instead, it promotes
triglyceride formation in the
adipocytes.

4. At adipocytes, this decreases fatty

acid (and thus glucose) output and
promotes storage of both ingested
and de novo triglycerides.
19

Objective 20.

The ability of insulin to stimulate the conversion of glucose molecules into component
parts of triglycerides (glycerol and, from acetyl-CoA’s, fatty acids) is one reason why
someone on a high carbohydrate, nearly-no-fat diet with excess caloric intake can
become obese. The biochemical conversion processes are beyond the scope of this
lecture as are the transport processes using lipoproteins. Remember the overall result–
insulin promotes the deposition of energy reserves as triglyceride molecules within
adipose tissue.

Source: Voet et al. Fundamentals of Biochemistry: Life at the Molecular Level, 4th Ed.
(2013), pp. 692-693.
Slide 20

Actions of Insulin on Proteins

• 1. Insulin promotes the transport and

incorporation of amino acids from the
blood into muscles and other tissues.

• This decreases blood amino acids

levels and promotes protein
synthesis in target cells.

• 2. Insulin inhibits protein degradation.

• 3. Net anabolic effect in the body.

20

Objective 20.

One of the most productive ways to store excess energy from the blood is to promote
growth, production of new proteins, some of which will be functional and others
structural. As such, though insulin changes the activity of many enzymes, its net effect
on body metabolism favors anabolism over catabolism.

Note: This particular insulin effect is the overall opposite effect from, say, cortisol which
by stimulating release of muscle-based amino acids and their hepatic conversion into
other fuel sources, promotes catabolism more than anabolism. It is the balance of
many different hormones of metabolism (e.g. glucagon, growth hormone), each with its
own particular pattern of anabolic and catabolic enzyme activations for protein-altering
enzymes, that determine the overall metabolic balance of the body. This will be further
discussed later in this lecture.
Slide 21

Insulin Effects on Whole-Body Uptake and Use of Nutrients

• Associated with
the absorptive
state
• Overall
decrease in
glucose and
ketoacids
(fuels)
• Decrease in
plasma fats
• Nutrients used
to promote
overall energy
storage and
anabolism
21
21

Objectives 19, 20, and 22.

There are many hormones that can increase blood glucose in the presence of
hypoglycemia. For the postabsorptive state the most important is glucagon, but others
(e.g. cortisol, epinephrine, growth hormone, and thyroid hormone) also play major roles.

In contrast, ONLY INSULIN is usually available to directly deal with a hyperglycemic

state and bring it back towards a normal blood glucose level. The most typical
hyperglycemic state is the transient period known as the absorptive state, the condition
in which the digestive tract is absorbing nutrients and these nutrients are being directed
to appropriate tissues and processed.

The clinical implication of this is, insulin has no backup hormone in case it fails.
Slide 22

GLUCAGON
• Glucagon is a peptide hormone
secreted by the alpha cells in the
islets of Langerhans in the
pancreas into the hepatic portal
circulation.

• Glucagon affects many of the

same metabolic processes as
insulin, but most of glucagon's
actions are opposite those of
insulin.

• The major site of action for

glucagon is the liver, with a lesser
role at other tissues (e.g., adipose
tissue).
22

Objective 21.
Slide 23

Control of Glucagon Release

+
• Glucagon release from the alpha cells in the -
pancreas is regulated by negative feedback
in response to the level of blood sugar.

• Elevated blood glucose level inhibits

glucagon secretion -

• A fall in blood glucose below normal,

increases glucagon secretion. +

• Amino acids (substrates for

gluconeogenesis) increase glucagon
secretion
+

23

Objective 21, 22.

Back on slide 7, many students noted that glucagon can increase insulin secretion just
like other incretins do (slide 10). That this seemingly paradoxical effect occurs is
undisputed, but the reason for this is less clear. In the new edition of Guyton and Hall
Textbook of Medical Physiology (13th Ed. 2016), on page 993 it says the following:

“High concentrations of amino acids, such as those that occur in the blood after a meal
containing protein (especially the amino acids alanine and arginine) stimulate the
secretion of glucagon. This is the same effect that amino acids have in stimulating
insulin secretion. Thus, in this instance, the glucagon and insulin responses are not
opposites. The importance of the amino acid stimulation of glucagon secretion is that
the glucagon then promotes rapid conversion of the amino acids to glucose, thus
making even more glucose available to the tissues”.

In theory then, in a diet low in carbohydrates but high in proteins, glucagon’s ability to
act like an incretin (slides 7, 10) to help a little more insulin be secreted will help get
more newly-produced glucose molecules into tissues and thus retain both a normal
blood glucose level and adequate energy supplies to skeletal muscle, etc.

Supplemental clinical note: Glucagon release is often increased in patients with

hyperthyroidism or hypercortisolemia.
Slide 24

Mechanism of Glucagon Secretion

• Increased glucose converted to
ATP, just as in beta cells–
• but in alpha cells, this
INACTIVATES cell membrane
calcium channels and increases
calcium sequestration into
endoplasmic reticulum
• No cytosolic calcium, no Reduced
glucagon secretion Plasma
Glucose

• Decreased glucose decreases

the ATP/ADP ratio, resulting in
calcium channel opening---
increasing in intracellular Basically, insulin’s control process in reverse—
calcium and causing exocytosis High glucose, high ATP, so shut down the secretion
of glucagon
24

Objective 21.

This slide is supplemental, as it is derived from a review article, not a physiology

textbook. Nevertheless, it is included in your handout to compare and contrast control
mechanisms between alpha and beta cells.

Note: The color patterns for alpha cells are the same as those used in beta cells’
insulin secretion (slide 6) for analogous structures/processes.

Picture Source: Diabetes. 2009 Feb 58(2): 299-301.

Slide 25

Modulators of Glucagon Secretion

Factors Stimulating Glucagon Secretion Factors Inhibiting Glucagon Secretion

• Decreased blood glucose • Increased blood glucose

• Increased amino acid • Somatostatin (SST, from delta cells)
• Exercise
• Circulating catecholamines (b2)

For examination purposes you are only responsible for the six factors listed above.

25

Objectives 21, 22.

Increased amino acids can stimulate glucagon secretion. Remember that certain amino
acids are substrates for gluconeogenesis so an individual on a low-carbohydrate, high
protein diet might require glucagon to process the abundant but wrong-form energy into
a fuel (glucose) that the brain’s neurons require. This effect is most noticeable when
carbohydrate consumption is minimal because increased blood glucose is a more
powerful inhibitor than increased amino acid is a stimulator of glucagon secretion.

Other possible inhibitors (e.g. zinc, insulin, GABA) exist but you are not responsible for
them.
Slide 26

Actions of Glucagon on Carbohydrates

1. Glucagon causes an increase in glucose

production by the liver and thus raises the
blood glucose level.
2. Glucagon decreases glycogen synthesis.
3. Glucagon stimulates glycogenolysis (the
break down of glycogen into glucose).
4. Glucagon stimulates gluconeogenesis
(the conversion of amino acids into
glucose). This mostly occurs in the liver.

Glycerol from triglyceride breakdown can also

enter into gluconeogenesis

26

Objective 21.

It is worth mentioning that for many metabolic functions performed by the liver, that cells
in the kidney have some reserve capacity to perform the same functions, and vice
versa. This typically only manifests in a significant way only in extreme circumstances
(e.g. some degree of renal gluconeogenesis during extended fasting), or in certain
pathologies. We acknowledge this without going into any particular details in
physiology.

Note: Details of which enzymes are stimulated into activity by glucagon, cortisol, etc.
are covered in Dr. Pedersen’s metabolism lectures. For physiology, focus on the
general processes.
Slide 27

Actions of Glucagon on Fats (Lipids)

1. Glucagon stimulates lipolysis (the

breakdown of triglycerides into fatty
acids and monoglycerides)

2. Glucagon inhibits triglyceride synthesis

(the storage of fat in adipose tissue).
3. Glucagon promotes conversion of TG
glycerol component into glucose (see
previous slide)
4. Glucagon promotes conversion of free
fatty acids into ketoacids as an alternate
fuel source for muscle, particularly when
glucose is more chronically low.

Generally opposite of insulin effects. 27

Objective 21.
Slide 28

Actions of Glucagon on Proteins

• Glucagon inhibits protein
synthesis in the liver.

• Glucagon stimulates protein

breakdown in the liver*.

• Glucagon does not normally

affect protein in skeletal
muscle

• Glucagon stimulates pathways

that raise blood levels of
glucose and fatty acids, a
characteristic of the post-
absorptive state.
Generally opposite of Insulin Effects
• Increased glucagon release
during times of fasting (the
post-absorptive state). 28

Objectives 21, 22.

Note that cortisol, which helps facilitate protein breakdown in skeletal muscle,
INCREASES protein synthesis in the liver. So does growth hormone. All three promote
gluconeogenesis, however.

* Glucagon does not normally affect skeletal muscle where most protein is stored and
thus glucagon usually has little effect on the blood level of amino acids. This is because
most glucagon does not make it past the liver, so though theoretically there are
receptors there, the effect is normally minimal. However, another function of the stress
hormone cortisol is in skeletal muscle to permissively increase glucagon’s ability to
affect metabolism there, as discussed in Adrenal Physiology, so there might be some
effect under certain stressful conditions.

Also note that glucagon’s increase in gluconeogenesis is largely from amino acid
sources, which makes use of both external a.a. sources (remember plasma a.a.’s
stimulate glucagon release), and newly-degraded hepatic proteins. Glycerol from
triglyceride breakdown can serve as a source as well.
Lipids mobilized from adipose tissue are not usually used in glucagon-driven
gluconeogenesis, but instead are directed towards production of an alternate fuel
source for the body, the ketone bodies (ketoacids). This is particularly important when
glucagon and cortisol are interacting to preserve plasma energy reserves in an
extended fasting state.
Slide 29

Effect of Glucagon on Fuel Flow in the Body

Glycerol
Associated with
postabsoptive state

Results in increased
glucose and ketoacid
release. Note use of
released fatty acids in
ketoacid production.

Both glucose and ketoacids

are fuels. The latter is
especially important in
prolonged fast
(starvation)
29 29

Objectives 21, 22.

There are many hormones that can increase blood glucose in the presence of
hypoglycemia. For the postabsorptive state the most important is glucagon, but others
(e.g. cortisol, epinephrine, growth hormone, and thyroid hormone) also play major roles.
The precise control of which other hormones supplement glucagon’s control give the
potential for finely tuned nutrient control in a state in which nutrients are not entering the
body from the intestinal tract. To further complicate issues, in skeletal muscle increased
intracellular glucose won’t directly turn into increased plasma glucose, because it
doesn’t release glucose. It does decrease demand for plasma glucose to enter skeletal
muscle cells, though, so indirectly these intracellular processes result in more glucose in
the plasma.

In contrast, ONLY INSULIN is usually available to directly deal with a hyperglycemic

state and bring it back towards a normal blood glucose level. The most typical
hyperglycemic state is the transient period known as the absorptive state, the condition
in which the digestive tract is absorbing nutrients and these nutrients are being directed
to appropriate tissues and processed.

The clinical implication of this is, insulin has no backup hormone in case insulin fails.
Slide 30

SOMATOSTATIN (SS, SST, SRIF, GHIH)

• Somatostatin
• Peptide hormone secreted by
pancreatic delta cells and the GI tract,
and the hypothalamus

• Stimulus for pancreatic delta cell

release is increased blood glucose

• Delta cell’s SST inhibits both insulin

secretion and glucagon secretion

• It can alter PLC/PKC, reduce cAMP, and Structure of somatostatin.

alter Ca2+ flux to counter other hormones’ Source: Wikipedia
stimulatory effects on target tissue.
30

Objective 19.

Somatostatin has many abbreviations denoting it, to the point where it is almost the
personal preference of an author which one to use. Here I choose to use SST.

In the pancreatic islets, somatostatin is a paracrine agent, secreted from cells in the
endocrine pancreas’ delta cells to prevent oversecretion of both glucagon and insulin.

It therefore prevents “burnout” of either alpha cells or beta cells in the pancreatic islet.

Somatostatin’s secretion from delta cells is stimulated by increased plasma glucose at

levels lower than that needed to stimulate insulin secretion. (Supplemental: There is
some recent evidence that ghrelin might also stimulate somatostatin release from islet
delta cells)

Supplemental: To read further on somatostatin, see Diabetes. 2009 Feb 58(2): 299-
301. Regulating Glucagon secretion: Somatostatin in the Spotlight.
Slide 31

Insulin and Glucagon:

Many biochemical processes,
one stable blood glucose

• Insulin’s metabolic effects

result in decreased blood
glucose
• Glucagon’s metabolic
effects result in increased
blood glucose
• These hormones are
normally kept in balance
such that blood glucose
stays within the normal
range by negative feedback
on both hormones’
production

31

Objective 22.

You are responsible for knowing this figure: The hormones, the stimuli for secretion of
each, the specific effects of each, and how each ultimately balances the other with
respect to maintaining a normal blood glucose.
Slide 32

Absorptive and Post-Absorptive States

• Absorptive (Fed) State:
• The body’s endocrine/metabolic status at the time when
• Energy levels in the gut and blood are very high, Absorption occurring
• This typically lasts for 2-4 hours after a meal (post-prandial period).
• Insulin promotes anabolism of target tissues
• Fuels are absorbed into cells and used and/or stored there.

• Post-Absorptive State:
• The body’s endocrine/metabolic status at the time when
• Absorption is long over but energy reserves are still high
• Typically begins by about 4 hours after a meal
• Glucagon is the primary hormone of the post-absorptive state.
• It may promote catabolism
• Fuel is mobilized from storage sites for body-wide usage.
• Eventually transitions into a starvation state over several days
32

Objectives 22, 23.

At the transition state from the absorptive to the post-absorptive states, the hormone
effects at the tissues which had been mostly due to insulin, end with the decrease in
insulin levels. At the same time, those enzymes which do things like process
gluconeogenesis, which had been inhibited during the absorptive (fed) state, are
activated once more as inhibitory first messenger insulin becomes less influential and
excitatory second messenger glucagon becomes more important as its concentration
rises.

The same thing is true in the other transition, as the post-absorptive state transitions
into an absorptive state upon feeding, insulin effects gradually overtake glucagon effects
at the target tissues.
Slide 33

Fasting and Starving

• Big difference– or no difference– depending on your point of view.

• Fasting is voluntary abstention from eating, while hunger cues last (24-48
hours since the person’s last meal).

• Starving is involuntary lack of food consumption despite hunger cues.

• The body’s response, to maintain energy availability to brain and other fuel-
sensitive tissues, will be the same, though more means may be employed than
during a normal post-absorptive state.

• In this context, the fasting state (chronic starvation) is a “survival mode” variant of a typical
(early) post-absorptive state.

• Cortisol is not a typical hormone of the early post-absorptive state but is of the fasting state.

• Epinephrine and growth hormone also support glucagon’s continued maintenance of blood
glucose.
33

Objective 23.

The point at which a normal post-absorptive state transitions into a full-fledged fasting
state is a gray area. But by a few days after one’s last meal, this fasting state for
metabolic purposes should be fully established.
Slide 34

Adjustments to
Chronic Fasting
• No cortisol component at first

• As body transitions into chronic

starvation, ketone body
production increases
• Cortisol secretion promotes
skeletal muscle protein wasting as
a source of emergency energy

• Muscle begins to use fatty acids

and ketone bodies as major fuel
sources, & stops using glucose.

• After 3 days, glucose is

reserved mostly for brain and
erythrocytes 34

Objective 23.

This is a summary slide, see the five slides below for more details.

Prolonged chronic starvation results in muscle breakdown, autophagy and eventual

organ failure.
Slide 35

Adjustment to Fasting/Starvation, part 1

• First 3-4 hours after fed state ends:

• Glucagon is the main hormone active

• Cortisol not yet involved at all

• Hepatic glycogenolysis is THE source for blood glucose

• No role yet for gluconeogenesis

• Skeletal muscle “feeds itself” glucose through muscle glycogenolysis

• All tissues use glucose for energy.

• Neither muscle nor adipose tissue release energy precursors

35

Objective 23.

When the skeletal muscle “feeds itself”, it takes less plasma glucose to keep skeletal
muscle functioning, thus INDIRECTLY supporting plasma levels at a normal level.
Slide 36

Adjustment to Fasting/Starvation, part 2

• 4-24 hours into fasting state

• Hepatic glycogen breakdown continues

• Hepatic gluconeogenesis begins

• Glycerol, alanine, glutamine, lactate all possible precursors

• Muscle begins to provide alanine for hepatic gluconeogenesis

• Cortisol begins to be involved, stimulating muscle breakdown
(proteolysis), see Adrenal Physiology and Biochemistry

• Adipose tissue begins to break down triglycerides

• Free fatty acids from blood and VLDL gradually replaces plasma
glucose as fuel source for most tissues including skeletal muscle
36

Objective 23.
Slide 37

Adjustment to Fasting/Starvation, part 3

• 1-3 days

• Hepatic glycogen depleted, therefore almost all glycogenolysis ends

• Cortisol increases glycogen synthesis so there is always a trace quantity available for
glucagon, epinephrine etc. to mobilize, but it is very little.

• Hepatic gluconeogenesis becomes source for blood glucose

• Glycerol, alanine (ala), glutamine, lactate all possible precursors
• Brain and red blood cells continue to use glucose as a fuel

• Ketone body formation from fat begins, and accelerates from days 1 to 3
• Includes acetone, acetoacetate, 3-hydroxybutyrate
• Tissues other than blood (erythrocytes) begin to use ketone bodies for fuel

• Muscle proteolysis continues to provide ala for hepatic gluconeogenesis

• Adipose tissue continues to break down triglycerides

• Free fatty acids from blood delivery used as fuel and as a source for ketogenesis
37

Objective 23.
Slide 38

Adjustment to Starvation, part 4– Long term “fast”

• 3 days and beyond, adjustments are complete

• Hepatic-produced ketone bodies are the primary fuel source of the

body, including brain cells but not blood cells

• Some hepatic gluconeogenesis continues, from amino acid sources

(cortisol).
• Brain and blood cells still use glucose. Erythrocytes can only use glucose

• Muscle proteolysis continues to provide ala for hepatic

gluconeogenesis

• Adipose tissue continues to break down triglycerides

• Primary source of fatty acids used in ketogenesis
38

Objective 23.
Slide 39

Depletion of Energy Stores, 0-8 weeks from normal body mass

• By 0.5 weeks at the latest, the

last traces of stored
carbohydrates are gone

• Fat remains the main source of

fuel for the next 5-7 weeks
• Protein levels only gradually drop
for the first five weeks

• Eventually as lipid reserves are

used up, protein levels drop too
• When protein levels drop too low,
the person can die of starvation 39

Objective 23.
Slide 40

Pathophysiology of the Endocrine Pancreas

Hypoglycemia, Hyperglycemia, and Diabetes Mellitus

40
Slide 41

Hypoglycemia

• Euglycemia (normal glucose

70-110 mg/dL) is always
preferred
• Hypoglycemia: Blood glucose
< 60 mg/dL
• Hypoglycemia when extreme
is fatal quickly

41

Objective 24.

Image: http://www.ada.gov/images/hypogly.gif
Slide 42

Hyperglycemia
• Fasting blood glucose levels
above 125 mg/dL

• This is normal after a large meal,

insulin is secreted. But when
hyperglycemia persists there can
be problems as seen to the right.

• Leads to a large number of

possible symptoms, both acute
and chronic– if chronic and
sustained, diagnosed as diabetes
mellitus (see below slides)

• If extreme can lead to

ketoacidosis, coma and death
42

Objective 24.
Slide 43

Diabetes Mellitus: LO
•Define diabetes mellitus and its types, describe
pathologic changes of islets of Langerhans, and list
major complications

43

Slides 37-44 were created by Dr. Yakubovskyy, Professor and Chair of Pathology,
specifically for students in Endocrine Systems 1.
Slide 44

Diabetes Mellitus (DM)

•Classic clinical presentation: polyuria, polydipsia, and
polyphagia
•Biochemistry
– Fasting blood sugar (FBS) >126 mg/dL
– Random blood sugar (RBS) >200 mg/dL
– HbA1c >6.5%

If symptomatic: 1 abnormal value

If asymptomatic: 2 abnormal values
44

Objective 24.

By definition, a symptom is something reported by a patient while a sign must be

observed or measured by a physician, nurse, or other medical professional. It is
possible for a patient to have the signs of DM but not have noticed them. This would be
asymptomatic DM.
Slide 45

DM: Type 1 vs Type 2

• DM type 1 • DM type 2
– Prevalence: 5 - 10% – Prevalence: 90 - 95%
– Mechanism: injury
and/or inflammation – Mechanism
(insulinitis) of islets • Peripheral insulin
of Langerhans resistance
– Morphology • Impaired insulin
• Lymphocyte
infiltration secretion
• β-cell destruction – Morphology
• Amyloid accumulation
• β-cell atrophy 45

Objective 24.
Slide 46

DM: Insulinitis vs Amyloidosis

Control DM type 1: insulinitis DM type 2: amyloidosis

46

Objective 24.
Slide 47

DM: Complications
• Macrovascular: early and more severe atherosclerosis
→ ischemic heart disease and myocardial infarction
• Microvascular: accumulation of advanced glycation
end-products (AGEs) in the capillary basement
membrane
– Kidneys: nephropathy → kidney failure
– Eyes: retinopathy → blindness
– Peripheral nerves: neuropathy → diabetic foot
47

Objective 24.
Slide 48

DM: Retinopathy, Capillary Basement

Membrane

Control DM: basement membrane

thickening 48

Objective 24.
Slide 49

Diabetic Foot

49

Objective 24.
Slide 50

DM: Metabolic Complications

• DM type 1: ketoacidosis
– Hyperglycemia >250 mg/dl
– Ketosis
– Metabolic acidosis pH <7.3
• DM type 2: hyperglycemic hyperosmolar non-ketotic
state (formerly known as hyperosmolar coma)
– Plasma glucose level >600 mg/dL
– Serum osmolality >320 mOsm/kg
– RR: 285-295 mOsm/kg
50

Objective 24.