Chapter 5

Endocrine Regulation of Glucose Metabolism

Overview of Glucose Homeostasis

Glucose metabolism is critical to normal physiological functioning. Glucose acts both

as a source of energy and as a source of starting material for nearly all types of
biosynthetic reactions. The diagram shows the major players in the regulation and
utilization of plasma glucose.

Figure 1. The organs that control plasma glucose levels. The normal plasma glucose
concentration varies between about 70 and 120 mg/dL (3.9-6.7 mM). Note that whole
blood glucose values are about 10-15% lower than plasma values due to the removal
of cellular components during preparation of plasma.

The brain uses about 120 grams of glucose daily: 60-70% of the total body glucose
metabolism. The brain has little stored glucose, and no other energy stores. Brain
function begins to become seriously affected when glucose levels fall below ~40
mg/dL; levels of glucose significantly below this can lead to permanent damage and
death. The brain cannot use fatty acids for energy (fatty acids do not cross the blood-
brain barrier); ketone bodies can enter the brain and can be used for energy in
emergencies. The brain can only use glucose, or, under conditions of starvation,
ketone bodies (acetoacetate and hydroxybutyrate) for energy.

The diet is one source of circulating glucose, and provides carbon and energy sources
for liver gluconeogenesis.

The liver is the major metabolic regulatory organ. About 90% of all circulating
glucose not derived directly from the diet comes from the liver. The liver contains
significant amounts of stored glycogen available for rapid release into circulation,
and is capable of synthesizing large quantities of glucose from substrates such as
lactate, amino acids, and glycerol released by other tissues. In addition to
controlling plasma glucose, the liver is responsible for synthesis and release of the
lipoproteins that adipose and other tissues use as the source of cholesterol and free

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fatty acids. During prolonged starvation, the liver is the source of both glucose and
the ketone bodies required by the brain to replace glucose. The liver uses glycolysis
primarily as a source of biosynthetic intermediates, with amino acid and fatty acid
breakdown providing the majority of its fuel.

Like the liver, the kidney has the ability to release glucose into the blood. Under
normal conditions gluconeogenesis in the kidney provides only a small contribution
to the total circulating glucose; however, during prolonged starvation, the kidney
contribution may approach that of the liver. Kidney function is critical for glucose
homeostasis for another reason; plasma glucose continuously passes through the
kidney and must be efficiently reabsorbed to prevent losses.

The muscle cannot release glucose into circulation; however, its ability to
rapidly increase its glucose uptake is critical for dealing with sudden increases in
plasma glucose. Skeletal muscle has an additional role in maintaining plasma
glucose levels: it releases free amino acids into circulation to serve as substrates for
liver gluconeogenesis. The muscle can use glucose, fatty acids, and ketone bodies for
energy. The muscle normally maintains significant amounts of stored glycogen,
small amounts of fatty acids, and contains a large pool of protein that can be broken
down in emergencies. The resting muscle uses fatty acids as its primary energy
source; however, glucose (from its own glycogen stores and from circulation), is
preferred for rapid energy generation (e.g. in sudden exercise).

The adipose tissue is the major site of fatty acid storage. Fatty acids are stored in
the form of triacylglycerol, which is synthesized in the adipose tissue from glycerol-
phosphate and free fatty acids. The glycerol-phosphate used must be derived from
glycolysis in the adipose tissue; free glycerol cannot be phosphorylated because
adipocytes lack the relevant kinase. In conditions when liver gluconeogenesis is
necessary the adipose tissue supplies free fatty acids and glycerol to the circulation
to be taken up by the liver as substrate.

Finally, the pancreas is the source of insulin and glucagon, two of the most
important metabolic regulatory hormones. The synthesis, release, and actions of
these hormones is the major subject of this chapter.

Glycolysis and Gluconeogenesis

Glycolysis (Figure 2) is a major energy production pathway used at least to some

degree in all cells. In addition, glycolytic intermediates and products act as carbon
sources for nearly all biosynthetic reactions, and the reducing equivalents required
for most biosynthetic reactions are derived from the flow of glucose through the
pentose phosphate pathway. Glucose homeostasis is thus of central importance in
metabolism and is heavily regulated.

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Glucose Pentose phosphate pathway

Hexokinase

Glycogen
Glucokinase UDP-Glucose Synthase
Phospho
Pyrophosphorylase
glucomutase
Glucose Glucose-6-P Glucose-1-P UDP-Glucose Glycogen
Phospho
Glucose-6- glucoisomerase
Phosphatase Phosphorylase
Fructose-6-P
Fructose Phosphofructokinase
Bis Phosphatase
Fructose-1,6-P 2

Aldolase

Glyceraldehyde-3-P + Dihydroxyacetone-P Glycerol

Glyceraldehyde-3-phosphate Triose phosphate

dehydrogenase isomerase

1,3-Bisphosphoglycerate
Phosphoglycerate
kinase

3-Phosphoglycerate Serine
Phosphoglycerate
mutase

2-Phosphoglycerate

Enolase Phosphoenolpyruvate
carboxykinase
Phosphoenolpyruvate Oxaloacetate
Pyruvate
kinase
Pyruvate
Amino acids Pyruvate carboxylase
TCA intermediates

{ }
Lactate
TCA Cycle
Fatty acid biosynthesis
Amino acid biosynthesis
Nucleotide biosynthesis

Figure 2. The glycolytic, gluconeogenic, pentose phosphate, and glycogen synthetic

pathways. The primary regulated steps are catalyzed by the underlined enzymes.
Note the convergence of the pathways at glucose-6-phosphate. Note also that
although glucose can be phosphorylated in all tissues, the reversal enzyme glucose-6-
phosphatase is only found in liver and kidney.

Metabolism of free glucose begins with a phosphorylation reaction that yields

glucose-6-phosphate. This reaction is catalyzed by hexokinase in most tissues.

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Hexokinase has a relatively high affinity for glucose; in most tissues the rate of the
hexokinase reaction is limited by the rate of glucose import into the cell, or by
glucose-6-phosphate inhibition of the enzyme. In the liver and pancreas, another
enzyme, glucokinase, also catalyzes this reaction. Unlike hexokinase, glucokinase
has relatively low affinity for glucose and is regulated by glucose regulatory
hormones; glucokinase thus acts as a mechanism for the liver to remove excess
glucose from circulation. In liver, although not in pancreas, glucokinase protein
synthesis is regulated by insulin and glucagon.

The Km of hexokinase is <1 mM. Hexokinase is therefore saturated at physiological glucose

concentrations; its activity is controlled by either glucose uptake (in most tissues), a combination of
uptake and the amount of the enzyme present (in liver), or (in conditions of high glucose availability),
by inhibition of the enzyme by glucose-6-phosphate. In contrast, the K m of glucokinase is ~10 mM
(180 mg/dL); therefore the rate of the glucokinase reaction is essentially linearly proportional to the
plasma glucose concentration, with half-maximal activity not achieved until glucose levels reach the
hyperglycemic range; glucokinase is not regulated by glucose-6-phosphate.

The phosphorylation of glucose prevents the glucose molecule from leaving the cell.
Since, except in liver and kidney, cells lack the ability to remove the phosphate, the
hexokinase reaction is essentially a signal that the cell intends to retain the glucose
molecule. Although the phosphorylation step is often referred to as the first step in
glycolysis, glucose-6-phosphate is not necessarily committed to the glycolytic
pathway; it can also be a substrate for glycogen synthesis or be diverted to the
pentose phosphate pathway. In the liver and kidney, the enzyme glucose-6-
phosphatase removes the phosphate and allows the release of glucose to circulation.

The first committed step, and primary regulatory step in the glycolytic pathway is
catalyzed by phosphofructokinase. This enzyme is regulated by several hormones
and by the energy state of the cell. The effect of the hormones on
phosphofructokinase activity is tissue-dependent (e.g. insulin increases
phosphofructokinase activity in liver, but inhibits the activity in muscle).

Phosphofructokinase is activated by fructose-2,6-bis-phosphate, AMP, and ammonia (an amino acid

breakdown product) and is inhibited by ATP and citrate. In muscle, epinephrine increases the level
of fructose-2,6-bis-phosphate; in liver, epinephrine and glucagon decrease fructose-2,6-bis-phosphate
levels by stimulating phosphorylation of the bifunctional enzyme fructose-2,6-bis-phosphatase/
fructose-6-phosphate 2-kinase. Fructose-1,6-bis-phosphatase is regulated by same compounds as
phosphofructokinase, but in the opposite direction.
Particularly in liver and muscle, the flow of glucose to the glycolytic pathway is regulated the
combination of hormonal influences (insulin, cortisol, and epinephrine, and, in liver, glucagon) and
by the ATP:AMP ratio. When the ATP:AMP ratio is high, energy generated has met or exceeded
requirements, and glycolysis decreases. It is primarily this mechanism that controls the ratio of
glycogen synthesis to glycolysis in liver during insulin stimulation (insulin stimulates both
pathways).

Pyruvate kinase is the last regulated step of glycolysis. Liver pyruvate kinase is
phosphorylated by cAMP-dependent protein kinase, which inhibits the activity of

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the enzyme; liver pyruvate kinase is also regulated by several allosteric effectors.
Muscle uses a different isozyme of pyruvate kinase; muscle pyruvate kinase is not
inhibited by phosphorylation.

Liver pyruvate kinase gene expression has been shown to be stimulated by glucose metabolites
directly activating transcription factors. Glucose metabolites are also thought to increase GLUT2
and (in β-cells) insulin gene expression. These findings suggest that glucose can act to regulate its
own metabolism in a fashion at least partially independent of insulin, and may prove useful in
developing new therapies for diabetes.

Gluconeogenesis (Figure 2) is the reverse of glycolysis. Many of the enzymes

involved are easily reversible, and are common to both pathways. However, the
reactions catalyzed by phosphofructokinase and pyruvate kinase are not reversible.
The gluconeogenic pathway must use different enzymes to reverse these steps.
These enzymes (phosphoenolpyruvate carboxykinase and fructose-bis-phosphatase)
are the ones regulated by hormonal stimuli.

Under normal circumstances, alanine is the preferred liver gluconeogenic substrate.

However, all amino acids except leucine can be used as substrate for
gluconeogenesis. Alanine and glutamine are the major (~50% of total) amino acids
released by muscle, although they comprise only about 15% of muscle protein.
Alanine is produced in muscle from pyruvate derived from both glycolysis and
amino acid metabolism.

Gluconeogenesis is inhibited by ethanol (ethanol metabolism in the liver uses up

NAD, and therefore prevents the conversion of lactate to pyruvate). In normal
individuals, liver glycogen breakdown yields sufficient glucose to maintain plasma
levels until the ethanol has been metabolized. In conditions of malnutrition or
poorly managed diabetes mellitus, ethanol inhibition of gluconeogenesis may result
in hypoglycemia.

Pancreatic Anatomy and Function

The pancreas has two major functions: it produces and releases digestive enzymes,
and it produces and releases the two major hormones responsible for the endocrine
control of glucose metabolism: insulin and glucagon.

The exocrine pancreas comprises about 98% of the mass of the organ. The acinar
cells synthesize and secrete the digestive enzymes (trypsin, chymotrypsin, elastase,
amylase, and others) that break down food into simpler components that can be
absorbed by the intestine.

The endocrine pancreas is comprised of small groups of cells distributed throughout

the organ. These groups, the Islets of Langerhans, consist of four cell types (α, β, δ,
and F). The islet composition varies in different parts of the pancreas (posterior
primarily F-cells with some β-cells, and anterior primarily β-cells with some α and
smaller amounts of δ-cells). Each cell type secretes one major hormone: the β-cells
are the insulin producing cells, while the α-cells produce glucagon, the δ-cells

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produce somatostatin, and the F cells produce Pancreatic Polypeptide.

The function of pancreatic somatostatin appears to be limited to inhibition of insulin

and glucagon release; the function of Pancreatic Polypeptide is unknown. The
control of insulin and glucagon release is discussed in detail in the next few
sections.

Synthesis and Release of Insulin

Insulin is a peptide hormone. It is synthesized in the rough endoplasmic reticulum

as part of an 11.5 kDa precursor protein called pre-proinsulin. The endoplasmic
reticulum-targeting sequence is cleaved during peptide synthesis to release
proinsulin. Proinsulin is packaged into secretory vesicles, where it is processed into
the mature peptide hormone (Figure 3).

The half-life of circulating insulin is about 5 minutes; the major sites of degradation
are the liver and kidney. Under normal conditions, some proinsulin secretion occurs,
amounting to 3-5% of the insulin secretion; during periods of high rates of insulin
release, the processing tends to be less complete, and therefore proinsulin release
constitutes a larger proportion of the total released peptides. The released
proinsulin has a longer half-life than insulin. It cross-reacts with the insulin RIA,
and therefore plasma “insulin” levels include about 10-20% proinsulin. Proinsulin
has some activity, but only ~10% of that of insulin.

The C-peptide also has a longer half-life than insulin. Measurement of C-peptide is
useful for monitoring pancreatic β-cell activity because it does not cross-react in the
insulin RIA and is not present in therapeutic insulin preparations.

C-peptide
Specific (31 A.A.)
N processing
proteases A chain

C
B chain

Proinsulin Mature insulin (51 A.A.)

Figure 3. Cleavage of proinsulin to form insulin and C-peptide.

Mature insulin is composed of two peptide chains (the A and B-chains) linked by disulfide bonds. A
connecting sequence, termed the C-peptide, is removed to produce the mature hormone; the mature
hormone and the C-peptide are released by the β-cells in equimolar amounts along with small
amounts of unprocessed proinsulin. Cleavage of proinsulin is catalyzed by a protease that recognizes
dibasic sequences (e.g. Lys-Arg). An exopeptidase then removes the basic residues to yield the
mature insulin and C-peptide. (This system is also responsible for the processing (in other cell types)
of a variety of peptide hormone precursors, such as glucagon and ACTH.)
The mature insulin forms hexameric crystals with zinc ions in the secretory vesicles. This process is

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thought to increase the amount of insulin that can be stored in vesicles of a given size. The crystals
dissolve upon release into circulation.
The C-peptide was long thought to be inactive. Recent studies, however, have suggested that some
complications of diabetes may actually be alleviated or prevented by injection of C-peptide. The
mechanism by which C-peptide may be acting is under investigation.

Insulin is released from the β-cell in response to elevated plasma glucose, mannose,
and some amino acids, especially leucine (Figure 4). Stimulation of insulin release
by glucose can be enhanced by other hormones (especially those released by the gut,
such as gastrin inhibitory peptide and cholecystokinin; this is why insulin release
due to oral administration is greater than release due to intravenous infusion of
glucose), by arginine and some other amino acids, and by β-adrenergic agonists.
Insulin release is inhibited by somatostatin, by cortisol, and by catecholamines
acting via α-adrenergic receptors. Although specific α and β-adrenergic agonists
have opposite effects on insulin release, the net effect of physiological catecholamine
action is strongly inhibitory.

Regulators of Regulators of
Insulin release Insulin release
Rough Endoplasmic Reticulum

Leucine
(+) pre-pro-insulin proinsulin (–) Somatostatin

(+) (+) Transcription

Glucagon
Glycolysis Golgi (–) α-adrenergic

(+) Release
agonists

Arginine
(+) Glucose
GLUT2

High
Plasma
Glucose
Insulin
Release

Figure 4. Insulin release is affected by a variety of different positive and negative

stimuli.

Prolonged high levels of glucose decrease the β-cell response to the glucose
stimulation, without altering β-cell responsiveness to other stimuli. Although not
completely understood, this appears to be due at least in part to a decrease in the
amount of GLUT2 glucose transporter in the β-cell membrane. Prolonged elevation
of glucose (such as that caused by hypersecretion of glucocorticoids) may exhaust
the β-cell stores of insulin and exceed the ability of the β-cell to synthesize
additional hormone, resulting in hyperglycemia; it is possible that this down-

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regulation of GLUT2 is one mechanism for reducing risk of β-cell exhaustion.

Transcription of the insulin gene and translation of the insulin mRNA are
stimulated by glucose. Acute increases in glucose levels largely affect secretion of
pre-formed insulin from secretory vesicles and mRNA translation and stability,
while chronic increases in glucose levels increase transcription of insulin mRNA.
Increases in transcription and translation require some time to become effective.
Stimulation with glucose may therefore result in two phases of insulin release
(Figure 5); a rapid phase, due to release of pre-formed hormone from mature
vesicles, and a slower phase requiring synthesis of new protein. During onset of
Type I diabetes the rapid phase disappears first, because basal insulin secretion
rates become such a large proportion of the remaining β-cell capacity that storage of
pre-formed insulin in vesicles is no longer possible.
Rapid
Slow phase
phase

Glucose Stimulation

Time

Figure 5. The two phases of insulin secretion observed during prolonged stimulation
with glucose. The rapid phase represents release of previously synthesized hormone;
the slow phase represents the induction of new hormone synthesis (the delay is due
to the time required for transcription, protein synthesis and post-translational
processing. Time scales: rapid phase begins less than one minute after stimulation,
and ends about 10 minutes later; slow phase begins about 15-20 minutes after initial
stimulation, and ends when stimulation ends.

Mechanism of Insulin Action

Insulin action is mediated by the insulin receptor, a complex multi-subunit cell

surface glycoprotein. Binding of insulin activates the intrinsic tyrosine kinase
activity of the receptor. Tyrosine phosphorylation of the insulin receptor itself and of
some other proteins is thought to be required for insulin action. As a result of these
phosphorylation (and probably other) events, a number of other intracellular
proteins are activated, including several kinases, phosphatases, and transcription
factors. One important enzyme activated by the second messenger cascade is
phosphodiesterase, which decreases cellular cAMP levels. Insulin action is
illustrated in Figure 6.

Acute increases in insulin levels result in phosphorylation or de-phosphorylation of

existing proteins (e.g. the enzymes involved in the glycolytic and gluconeogenic
pathways), which have rapid but transient effects on their activity. High levels of

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insulin, or prolonged stimulation by insulin results in alterations in the rate of

transcription of a variety of genes, and therefore in increased or decreased capacity
for the processes mediated by those gene products.

Prolonged high levels of insulin result in desensitization (de-coupling of the

receptor from the cellular responses) and down-regulation (decreased amounts of
the receptor on the cell-surface). These phenomena protect the cell from over-
stimulation (similar effects are seen with a number of other hormones).
Desensitization and down-regulation of the insulin receptor are important in Type
II diabetes, since these phenomena occur upon prolonged high levels of insulin and
contribute to the insulin resistance that characterizes the disorder. It is therefore
preferable, although not always possible, to avoid use of exogenous insulin for Type
II diabetics, since this tends to further down-regulate the receptor and worsen the
desensitization that has already occurred.

Insulin -S-S- Insulin

Plasma
membrane

Insulin GLUT4
receptor
Translocation
Auto- (+) to
plasma membrane
phosphorylation

other GLUT4
second IRS
messengers

Gene
transcriptional
effects Reduced
Protein cAMP levels
phosphorylation
and dephosphorylation

Figure 6. Intracellular effects of insulin binding to the insulin receptor. Insulin

binding activates the insulin receptor tyrosine kinase. The phosphorylation of various
intracellular proteins results in changes in activity of the proteins, in altered gene
transcription rates for specific genes, and (in muscle and adipose tissue) in
translocation of the GLUT4 glucose transporter to the plasma membrane, and
therefore increased glucose uptake into these tissues.

Insulin receptor phosphorylates at least four insulin receptor substrate proteins (IRS-1 through
IRS-4) on tyrosine residues. The tyrosine phosphorylated forms of the IRS proteins are thought to act
as second messengers for a variety of intracellular responses. Serine phosphorylation of the IRS
proteins or of the insulin receptor, in contrast, attenuates or abolishes the effect of insulin. Thus,
insulin acting alone has “insulin action”; other hormones may decrease or prevent these actions by
increasing activity of some serine kinases.

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One important short term effect of insulin action is a translocation of the GLUT4
glucose transporter to the cell surface in muscle and adipose tissue. Stimulation of
the cell for longer periods results in altered rates of transcription of a variety of
proteins, including decreased rate of GLUT4 transcription.

At least five different glucose transport proteins are known. These proteins mediate the passive (i.e.
non-energy dependent) transport of glucose across the plasma membrane of various cell types. They
were named in order of discovery.

GLUT1 and GLUT3 are found in most tissues and are especially important in transport of glucose
into the brain. GLUT1 and GLUT3 have a high affinity for glucose, and therefore transport glucose
efficiently throughout the normal range of plasma glucose concentration.

GLUT2 is found primarily in pancreas and liver. It has a low affinity for glucose and therefore
mediates glucose transport only during high plasma glucose levels. GLUT2 is the transporter that is
responsible for allowing the β-cells to sense hyperglycemia, and for transporting high glucose levels
into the liver for storage.

GLUT4 is the primary hormonally-responsive transporter. GLUT4 is found primarily in muscle and
adipose tissue, where it is normally sequestered in intracellular vesicles; it is translocated to plasma
membrane in response to insulin, resulting in enhanced glucose uptake. In contrast, cortisol
decreases the amount of GLUT4 in the plasma membrane. Prolonged high levels of the hormones
that affect GLUT4 localization result in effects on GLUT4 gene transcription in the opposite
direction of the effects on activity; thus GLUT4 gene transcription is increased by high levels of
glucocorticoids and inhibited by high levels of insulin. However, GLUT4 expression is also reduced
by low insulin states, such as in muscle during fasting, and in insulin-resistant adipose tissue.

The remaining GLUT gene products are much less important for glucose transport. GLUT5 is found
in gut, liver and spermatozoa, and is thought to function primarily as a fructose transporter. GLUT6
is thought to be a non-functional pseudogene. GLUT7 is an intracellular liver protein responsible for
glucose-6-phosphate transport into the endoplasmic reticulum.

In contrast to the passive transport mediated by GLUT gene products, the kidney and intestine
contain active (energy dependent) glucose pumps that catalyze the transport of glucose against a
concentration gradient. These pump proteins are responsible for the absorption of glucose from the
diet and the reabsorption of glucose in the kidney.

The kidney is very efficient under normal conditions; however, at plasma glucose concentrations
above about 180 mg/dL, the kidney pump becomes saturated. Glucose from concentrations above 180
mg/dL therefore ends up in the urine.

Insulin Action in Target Tissues

The liver is the main site of action of the pancreatic hormones. Because blood flow
from the pancreas proceeds directly to the liver, and because the liver is the major
site of inactivation of most peptide hormones, the liver is exposed to higher levels of
pancreatic hormones than any other tissue.

In liver, insulin stimulates glycogen synthesis and inhibits glycogen breakdown. It

also stimulates glycolysis and inhibits gluconeogenesis. In addition to its effects on

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glucose metabolism, insulin has a variety of anabolic actions in the liver,

stimulating lipid synthesis and release and protein synthesis, and inhibiting the
breakdown of these compounds.

The liver has some ability to respond directly to high levels of plasma glucose by
increasing glucose uptake and glycogen synthesis in an insulin-independent
manner; however, the majority of liver glucose regulatory functions require insulin
action. The liver has about 300,000 insulin receptors per cell (a very large number),
but experiences maximal response to insulin when a small fraction of the receptors
are occupied; this allows the organ to respond to insulin even when the plasma
insulin concentration is less than the Kd for the receptor.

In muscle, insulin stimulates amino acid uptake and protein synthesis, and glucose
uptake and incorporation into glycogen. The muscle plays an important role in
absorbing the majority (80-95%) of sudden increases in plasma glucose levels, such
as those observed during a rich carbohydrate meal. The muscle expresses
significant amounts of the GLUT4 glucose transporter, which, upon insulin
stimulation, is translocated to the plasma membrane (see Figure 6), allowing a
massive increase in glucose uptake. During exercise the muscle becomes more
sensitive to insulin action and therefore retains the ability to import glucose from
circulation in spite of the exercise-induced reduction in insulin levels.

Insulin stimulates glucose uptake into adipose tissue, and has three major actions
which result in net fat deposition: 1) insulin increases the amount of lipoprotein
lipase, an enzyme that mediates release of free fatty acids from circulating
lipoproteins; 2) insulin stimulates synthesis of glycerol-phosphate (required for
triacylglycerol synthesis) from glucose; and 3) insulin inhibits hormone-sensitive
lipase, the enzyme responsible for the first step in triacylglycerol breakdown.

The brain does not depend on insulin for glucose uptake, and insulin probably does
not have a direct metabolic role in the CNS. However, some evidence suggests that
insulin may act as a behavioral modulator, with high levels of insulin promoting
decreased food intake, and low levels acting as a caloric deprivation signal. Since
these behaviors are extremely complex and therefore difficult to measure
accurately, and since insulin is only one of many hormones and other stimuli that
affect feeding behavior, the role of insulin in the CNS is poorly understood.

The insulin resistance resulting from glucocorticoid action is also observed in the
CNS. Individuals with low glucocorticoid levels generally have difficulty gaining
weight; this may in part be due to the increased sensitivity to insulin (and
consequent decreased feeding impulse) resulting from the low glucocorticoid action.
Diabetics (in particular Type II diabetics) often exhibit significant weight gain in
spite of restoration of insulin action; however, this is probably largely due to
normalization of metabolism and prevention of glucose loss in the urine.

Glucagon

The other major regulatory hormone of the pancreas is glucagon, a 29 amino acid
peptide synthesized as part of a 160 amino acid precursor. This precursor also
contains several other peptide hormones: glucagon-like peptide-1 (GLP-1), glucagon-

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like peptide-2 (GLP-2), and glicentin-related peptide. In the intestine, glucagon is

not separated from glicentin-related peptide, resulting in a peptide called glicentin.
GLP-1 may be further processed to a shorter form GLP-1[7-37], which (unlike GLP-
1 itself) is a powerful stimulator of insulin release.

In serum samples, the glucagon RIA actually measures a mixture of proglucagon,

glicentin, GLP-1, and GLP-2 as well as glucagon; glucagon normally comprises only
30-40% of the immunoreactive material measured.

Release of glucagon from the α-cells is stimulated by low plasma glucose and by
catecholamines and glucocorticoids. Release of glucagon is inhibited by insulin and
somatostatin. Release of glucagon is also inhibited by glucose; it is not known
whether this is a direct effect of glucose on the α-cell, or an indirect consequence of
elevated insulin levels.

Glucagon has actions opposite to those of insulin, and therefore functions to

maintain plasma glucose levels between meals. However, unlike insulin, glucagon
action is probably limited to the liver, with limited effects in other tissues. Glucagon
stimulates liver amino acid uptake, gluconeogenesis, and glucose release, and
inhibits glycolysis and fatty acid synthesis.

The glucagon receptor is coupled to adenylyl cyclase, and glucagon actions are
mediated by elevation in cAMP levels. In general, actions of glucagon are mediated
by increased phosphorylation of existing enzymes. Prolonged stimulation by
glucagon may have some effects on gene transcription, usually in the opposite
direction from that of insulin. If the insulin:glucagon ratio is low for a prolonged
period (i.e. several days), an alteration in liver enzyme levels occurs, which causes
increased production of ketone bodies.

Somatostatin

Somatostatin is released from the δ-cells under control of the same stimuli that
result in insulin release. Somatostatin is thought to act primarily as a paracrine
regulator of insulin release, preventing insulin levels from rising too rapidly. It may
also have an endocrine role as an inhibitor of nutrient absorption in the gut,
although this is not completely established. The somatostatin in circulation is
thought to be derived from the pancreas, and not from the hypothalamus (which
produces this peptide in order to inhibit growth hormone release from the pituitary).

Somatostatin is produced as part of a larger precursor. Pre-prosomatostatin (116

amino acids) is cleaved to release the 28 amino acid prosomatostatin upon transport
into the endoplasmic reticulum. The 14 amino acid mature somatostatin is released
from prosomatostatin by the dibasic processing protease system.

The Islet of Langerhans

One important regulator of pancreatic hormone release is the paracrine signaling

that occurs within the islets. Insulin inhibits its own release, and also inhibits the
release of glucagon. Glucagon inhibits its own release, and stimulates insulin
release. Somatostatin inhibits the release of both insulin and glucagon. The local

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changes in hormone levels act as a primary negative feedback mechanism to

prevent excessive changes in pancreatic hormone levels. This is illustrated by the
effects of untreated Type I diabetes mellitus, in which the loss of insulin inhibition
of glucagon secretion results in overproduction of glucagon; the high levels of
glucagon in the absence of insulin action throughout the body result in the severe
metabolic changes of diabetic ketoacidosis (see Chapter 6).

Counter-regulatory Hormones

Glucagon (discussed above), the catecholamines epinephrine and norepinephrine,

glucocorticoids, and growth hormone all act to raise plasma glucose levels. Their
actions generally oppose those of insulin, and as a group, they are called counter-
regulatory hormones. Due to the dependence of the brain on plasma glucose for
energy, hypoglycemia can rapidly result in unconsciousness, brain damage, and
death; the counter-regulatory hormones act to prevent hypoglycemia. It is thought
that the variety of systems that oppose insulin action are in part a safety
mechanism to prevent hypoglycemia; the influence of a variety of systems on
glucose homeostasis also reflects the central importance of glucose in metabolism.

Epinephrine is released by the adrenal medulla in response to hypoglycemia (as

well as other stress stimuli), and as part of the preparation for exercise.
Norepinephrine is released from sympathetic neurons. Both catecholamines have
significant roles in maintaining glucose levels in exercise (especially in supporting
the massive increase in glucose use by the muscle), and in stress-related conditions.
Catecholamines stimulate glucagon release and inhibit insulin release, causing a
decrease in insulin:glucagon ratio and therefore having indirect effects on liver
glucose metabolism. Epinephrine also has direct effects in stimulating liver
gluconeogenesis, muscle glycolysis, and glycogen breakdown in both tissues. (Note
that glycolysis regulation by epinephrine is different in liver (inhibited) and muscle
(stimulated); this is due in part to the presence of different isozymes of pyruvate
kinase in the two tissues.) Catecholamine action is covered in more detail in
Chapter 4.

Glucocorticoids (primarily cortisol in humans) are released from the adrenal cortex
in response to stress; one such stress is a decrease in plasma glucose.
Glucocorticoids stimulate gluconeogenesis and glycogen synthesis in the liver, and
reduce muscle and adipose tissue glucose uptake. They also acutely inhibit insulin
release, and over longer term, insulin action; prolonged cortisol hypersecretion can
result in diabetes. Glucocorticoid synthesis, release, and action are covered in more
detail in Chapters 2 and 3.

Growth hormone is released in response to falling plasma glucose levels. The

actions of growth hormone related to increases in plasma glucose are poorly
understood. The only established actions of growth hormone in this regard are a
stimulation of lipolysis and an inhibition of insulin action. In acromegaly, the
overproduction of growth hormone can lead to diabetes.

The effect of the metabolic regulatory hormones is summarized in Table I.

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Chapter 5. Glucose Homeostasis Endocrine -- Dr. Brandt

Table I.
Hormonal Regulation of Metabolism

Insulin Glucagon Epinephrine Cortisol Growth

Hormone

Liver
Glycogen breakdown ↓ ↑ ↑
Glycogen synthesis ↑ ↓ ↓ ↑

Gluconeogenesis ↓ ↑ ↑ ↑
Glycolysis ↑ ↓ ↓

Glucose release ↓ ↑ ↑ ↑
Glucose uptake ↑ ↓ ↓

Glucagon receptor ↑

Skeletal Muscle
Glycogen breakdown ↓ ↑
Glycogen synthesis ↑ ↓

Glycolysis ↑† ↓

Glucose uptake ↑ † ↓

Protein catabolism ↓ ↑

Amino acid uptake ↑ ↓ ↑

Amino acid release ↓ ↑

Adipose Tissue
Lipolysis ↓ ↑ ↑ ↑

Glucose uptake ↑ ↓

Pancreas
Insulin release ↓ ↑ ↓ ↓

Glucagon release ↓ ↓ ↑

Systemic Effects
Insulin action ↑* ↓ ↓

*Note: Insulin obviously has “insulin actions”, hence the ↑; however, prolonged high levels of insulin
decrease the insulin response in target tissues.
†Note: epinephrine effects on muscle glycolysis are relatively small except during exercise. Glucose
uptake in muscle is stimulated by exercise, but is probably not directly affected by epinephrine.

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Chapter 5. Glucose Homeostasis Endocrine -- Dr. Brandt

Effect of Food Ingestion on Pancreatic Hormone Release

The pancreas alters its release of insulin and glucagon in response to changes in
plasma glucose and other circulating nutrients. One major cause of these changes is
eating. The response to a meal varies significantly depending on the composition of
the food.

Intravenous infusion of glucose elicits a smaller rise in insulin release than does
oral administration of an equivalent amount of glucose. The greater increase in
insulin levels caused by actually eating is thought to be due to gastrointestinal
peptide hormones. These peptides are released in response to food absorption and
potentiate the glucose effect on insulin release.

When eating a meal rich in carbohydrate, insulin levels rise and glucagon levels fall.
The decrease of glucagon is due to inhibition of its release by insulin, and to the
elevation in plasma glucose.

When eating a meal rich in protein, insulin levels rise, because insulin secretion is
stimulated by amino acids. Glucagon levels also rise; glucagon release is also
stimulated by amino acids. In this case, unopposed insulin action would result in
hypoglycemia, since little glucose is being absorbed; glucagon must increase to
maintain plasma glucose.

When eating a mixed meal, insulin levels rise, and glucagon levels rise, fall, or
remain unchanged as appropriate to maintain plasma glucose. The pancreas uses
its ability to monitor the influx of nutrients, supplemented by signals in the form of
intestinal peptide hormones, to regulate the disposal of the nutrients without
allowing an undue change in plasma glucose (glucose levels usually rise to the
upper limit of the normal range, ~120 mg/dL, but little further). Mimicking this
tailored change in pancreatic hormone release is difficult to achieve by injections of
insulin, and explains part of the problem faced by individuals with Type I diabetes.

References

Bliss (1982) The Discovery of Insulin. University of Chicago Press, Chicago.

Phillipe (1991) “Structure and pancreatic expression of the insulin and glucagon genes.” Endocr. Rev.
12: 252-271.

Schwartz et al. (1992) “Insulin in the brain: a hormonal regulator of energy balance.” Endocr. Rev.
13: 387-414.

Stryer (1995) “Chapter 30: Integration of Metabolism.” Biochemistry, 4th ed. W.H. Freeman &
Company, New York.

Cheatham & Kahn (1995) “Insulin action and the insulin signaling network.” Endocr. Rev. 16: 117-
142.

Stephens & Pilch (1995) “The metabolic regulation and vesicular transport of GLUT4, the major
insulin-responsive glucose transporter.” Endocr. Rev. 16: 529-546.

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