Physiology for Medical Students

Endocrine 7
Glucose Homeostasis

Fatima Daoud. MD. PhD.

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Insulin, Glucagon, and
Diabetes Mellitus

CHAPTER 78

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 The Pancreas

o 1) The acini, which secrete

digestive juices into the
duodenum
o 2) The islets of
Langerhans, which secrete
insulin and glucagon
directly into the blood.

Scattered among the exocrine acini are 1–2 million tiny clusters of endocrine tissue
called pancreatic islet or islets of Langerhans. Abundant capillaries serve both the
exocrine and endocrine portions of the pancreas.
The islets make up about 1% to 2% of the total pancreatic mass.

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 the Pancreas
o Each pancreatic islet
includes:
o The beta cells (60%):
secrete insulin and amylin
o The alpha cells (25%):
secrete glucagon.
o The delta cells (10%)
secrete somatostatin.
o The gamma, or F, cells
secrete pancreatic
polypeptide.

o pancreatic polypeptide. a hormone that plays a possible role in reducing appetite

and food intake.

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 Insulin Is a Hormone Associated with Energy
Abundance
o Insulin plays an important role in storing the excess energy.
o Excess carbohydrates → be stored as glycogen mainly in the
liver and muscles.
o Excess carbohydrates → converted under the stimulus of
insulin into fats and stored in the adipose tissue.
o Promotes amino acid uptake by cells and conversion of these
amino acids into protein.
o Inhibits the breakdown of the proteins that are already in the
cells.

• Insulin has important effects on carbohydrate, fat, and protein metabolism. It

lowers the blood levels of glucose, fatty acids, and amino acids and promotes their
storage.
• As these nutrient molecules enter the blood during the absorptive state, insulin
promotes their cellular uptake and conversion into glycogen, triglycerides, and
protein, respectively.
• Insulin exerts its many effects by altering either transport of specific blood-borne
nutrients into cells or activity of the enzymes involved in specific metabolic
pathways.
• To accomplish its effects, in some instances insulin increases the activity of an
enzyme, for example glycogen synthase, the enzyme that synthesizes glycogen
from glucose molecules. In other cases, however, insulin decreases the activity of
an enzyme, for example by inhibiting hormone-sensitive lipase, the enzyme that
catalyzes the breakdown of stored triglycerides back to free fatty acids and
glycerol.

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 Metabolic effect of Insulin

It lowers the bloodlevels of glucose, fatty acids, and amino acids and promotes
their storage.
oAs these nutrient molecules enter the blood during the absorptive state, insulin
promotes their cellular uptake and conversion into glycogen, triglycerides, and
protein, respectively.
• Insulin exerts its many effects by altering either transport of specific blood-borne
nutrients into cells or activity of the enzymes involved in specific metabolic
pathways.

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 Effect of Insulin on Carbohydrate Metabolism

o Insulin promotes glucose uptake

and metabolism.
o Increases glycogen storage in
skeletal muscle and liver.
o Insulin inhibits glycogenolysis and
gluconeogenesis.

*The transporter responsible for glucose uptake by most body cells is GLUT-4, which
operates only at the binding of insulin. Glucose molecules cannot readily penetrate
most cell membranes in the absence of insulin, making most tissues highly
dependent on insulin for uptake of glucose from the blood and for its subsequent
use.
* GLUT-4 is especially abundant in the tissues that account for the bulk of glucose
uptake from the blood during the absorptive state, namely, resting skeletal muscle
and adipose tissue cells.
*GLUT-4 is the only type of transporter that responds to insulin. Unlike the other
types of GLUT molecules, which are always present in the plasma membranes at the
sites where they perform their functions, GLUT-4 is not present in the plasma
membrane in the absence of insulin. Insulin promotes glucose uptake by transporter
recruitment.

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 Effect of Insulin on Carbohydrate (Liver)

• Insulin exerts its many effects by altering either transport of specific blood-borne
nutrients into cells or activity of the enzymes involved in specific metabolic
pathways.

1. Insulin causes enhanced uptake of glucose from the blood by the liver cells. It
does this by increasing the activity of the enzyme glucokinase, which is one of the
enzymes that causes the initial phosphorylation of glucose after it diffuses into
the liver cells. Once phosphorylated, the glucose is temporarily trapped inside the
liver cells because phosphorylated glucose cannot diffuse back through the cell
membrane.
4. Insulin also increases the activities of the enzymes that promote glycogen
synthesis, including especially glycogen synthase, which is responsible for
polymerization of the monosaccharide units to form the glycogen molecules.
3. Insulin inactivates liver phosphorylase, the principal enzyme that causes liver
glycogen to split into glucose. This prevents breakdown of the glycogen that has been
stored in the liver cells.

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 Effect of Insulin on Fat Metabolism

Actions on Fat Insulin exerts multiple effects to lower blood fatty acids and promote
triglyceride storage:
1. It enhances entry of fatty acids from the blood into adipose tissue cells.
2. It increases transport of glucose into adipose tissue cells by means of GLUT-4
recruitment. Glucose serves as a precursor for formation of fatty acids and
glycerol, which are the raw materials for triglyceride synthesis.
3. It inhibits lipolysis

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 Effect of Insulin on Protein Metabolism and on
Growth
o insulin promotes protein synthesis and storage.
o 1. insulin stimulates transport of many of the amino acids into
the cells.
o 2. insulin increases the translation of messenger RNA, thus
forming new proteins.
o 3. insulin also increases the rate of transcription of selected
DNA genetic sequences.
o 4. insulin inhibits the catabolism of proteins.
o 5. in the liver, insulin depresses the rate of gluconeogenesis

Insulin lowers blood amino acid levels and enhances protein synthesis.
The collective result of these actions is a protein anabolic effect. For this reason,
insulin is essential for normal growth.

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Insulin and Growth Hormone Interact
Synergistically to Promote Growth

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 Metabolic effect of Insulin

In short, insulin primarily exerts its effects by acting on the liver, adipose tissue, and
nonworking skeletal muscle. It stimulates biosynthetic pathways that lead to
increased glucose use, increased carbohydrate and fat storage, and increased protein
synthesis. In so doing, this hormone lowers the blood glucose, fatty acid, and amino
acid levels. This metabolic pattern is characteristic of the absorptive state. Indeed,
insulin secretion rises during this state and shifts metabolic pathways to net
anabolism

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 Control of
Insulin
Secretion

** The primary control of insulin secretion is a direct negative feedback system

between the pancreatic b cells and the concentration of glucose in the blood
** An elevated blood amino acid level, such as after a high protein meal, directly
stimulates the b cells to increase insulin secretion. In negative-feedback fashion
.

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 Glucagon

CHAPTER 78

Glucagon affects many of the same metabolic processes that insulin influences, but in
most cases glucagon’s actions are opposite to those of insulin. The major site of
action of glucagon is the liver, where it exerts a variety of effects on carbohydrate, fat,
and protein metabolism.

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Glucagon Effects on carbohydrates Metabolism

(1) Enhances glycogenolysis (within minutes).

(2) Increased gluconeogenesis in the liver.
o Increase the rate of amino acid uptake by the liver.
o Activating multiple enzymes that are required for amino acid
transport and gluconeogenesis (converting pyruvate to
phosphoenolpyruvate, a rate-limiting step in
gluconeogenesis).
→enhance the availability of glucose to the other organs of
the body.

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Glucagon Effects on Fat Metabolism

o Glucagon also antagonizes the actions of insulin with

regard to fat metabolism by:
o promoting lipolysis and inhibiting triglyceride synthesis,
thus increasing blood levels of fatty acids

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Glucagon Effects on Protein Metabolism
• Glucagon inhibits hepatic protein synthesis and promotes degradation of
hepatic protein.
• Stimulation of gluconeogenesis further contributes to glucagon’s
catabolic effect on hepatic protein metabolism.
• Glucagon promotes protein catabolism in the liver, but it does not have
any significant effect on blood amino acid levels because it does not
affect muscle protein, the major protein store in the body.

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The opposite effects exerted by blood concentrations of glucose and fatty acids on
the pancreatic a and b cells are appropriate for regulating the circulating levels of
these nutrient molecules because the actions of insulin and glucagon on
carbohydrate and fat metabolism oppose one another.
** The effect of blood amino acid concentration on the secretion of these two
hormones is a different story. A rise in blood amino acid concentration stimulates
both insulin and glucagon secretion. Why this seeming paradox because glucagon
does not exert any effect on blood amino acid concentration? The identical effect of
high blood amino acid levels on both insulin and glucagon secretion makes sense if
you consider the concomitant effects these two hormones have on blood glucose
levels. If, during absorption of a protein-rich meal, the rise in blood amino acids
stimulated only insulin secretion, hypoglycemia might result. Because little
carbohydrate is available for absorption following consumption of a high-protein
meal, the amino acid–induced increase in insulin secretion would drive too much
glucose into the cells, causing a sudden, inappropriate drop in blood glucose.
However, the simultaneous increase in glucagon secretion elicited by elevated blood
amino acid levels increases hepatic glucose production. Because the hyperglycemic
effects of glucagon counteract the hypoglycemic actions of insulin, the net result is
maintenance of normal blood glucose levels.

V2: page 4, this sentence has been added

o pancreatic polypeptide. a hormone that plays a possible role in reducing appetite
and food intake.

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