Glucose Physiology, Normal
Hans J. Woerle
Technical University, Munich, Germany
John E. Gerich
University of Rochester School of Medicine, Rochester, New York, United States
Glossary
gluconeogenesis Synthesis of new glucose molecules
from substrates such as lactate, pyruvate, alanine,
glutamine, and other amino acids by reversal of
glycolysis.
glycogen Large intracellular granules made up of
polymers of glucose used for storage of carbohydrate
mainly in liver and skeletal muscle.
glycogenolysis Breakdown of glycogen molecules to
glucose.
glycolysis Anaerobic metabolic breakdown of glucose
to lactate and pyruvate.
lipolysis Breakdown of triglyceride molecules, yielding
one molecule of glycerol and three free fatty acid
molecules.
triglyceride Fat droplets composed of molecules of
three free fatty acids esterified to one molecule of
glycerol.
Glucose is normally the only source of energy for the
brain, except during prolonged fasting, when alternative fuels,
such as ketone bodies, can be utilized. Since the brain cannot
store glucose, it is dependent on plasma glucose.
INTRODUCTION
Plasma glucose concentrations are maintained within
a narrow range throughout the day, usually avera-
ging between 70 and 100 mg/dl after an overnight
fast and before meals and never exceeding 160 mg/dl
after meals (Fig. 1). Teleologically, the reason for this
precise regulation can be explained by the adverse
effects of hypoglycemia on the brain and that of
hyperglycemia on the cardiovascular system.
An elaborate system has developed to avoid hypo-
glycemia and maintain euglycemia. In this system,
Encyclopedia of Endocrine Diseases, Volume 2. ß 2004 Elsevier Inc. All rights reserved.
hormones are the most important regulators of
glucose homeostasis. Insulin is the only hormone
that lowers plasma glucose. When plasma glucose
falls below 70 mg/dl, insulin secretion is suppressed
to prevent any additional decrease in plasma glucose.
If plasma glucose decreases further, glucose sensors in
the hypothalamus trigger the release of the counter-
regulatory hormones glucagon, catecholamines, cor-
tisol, and growth hormone to increase plasma glucose.
Hyperglycemia needs to be avoided due to its dele-
terious effect on the vasculature. Increases in plasma
glucose of as little as 10 mg/dl stimulate insulin
release and inhibit glucagon release to prevent a
further rise in plasma glucose. In addition to the
above-mentioned alterations, changes in sympathetic
nervous system activity, circulating substrate concen-
trations, nutritional factors (e.g., diet composition),
prolonged fasting, exercise, and physical fitness
influence glucose homeostasis.
DETERMINANTS OF PLASMA
GLUCOSE CONCENTRATIONS
The prevailing glucose concentration is a function of
the relative rates of entry and exit of glucose into the
circulation. In other words, plasma glucose will in-
crease only if the rate of glucose entry exceeds its rate
of removal and will decrease only if the rate of glucose
removal exceeds the rate of entry. If both entry and
removal increase or decrease simultaneously at
comparable rates, plasma glucose will not change.
The key factors that regulate glucose fluxes can be
divided into three groups: (1) those that act almost
immediately (within minutes), e.g., insulin, glucagon,
and catecholamines released via activation of the
sympathetic nervous system; (2) those that act within
an hour or so, e.g., free fatty acids (FFA); and (3) those
that take several hours or days to become apparent,
e.g., growth hormone, cortisol, and thyroid hormone.
263
264
Figure 1 Diurnal changes in plasma glucose, insulin, and glucagon concentrations.
FACTORS THAT REGULATE
GLUCOSE FLUXES
Insulin
Insulin plays a central role in glucose homeostasis
mainly by its action on liver, kidney, adipose tissue,
and skeletal muscle. In liver and kidney, it suppresses
glucose production by regulating the rate-limiting key
enzymes of gluconeogenesis (glucose-6-phosphatase
and fructose-1,6-bisphosphatase) and glycogenolysis
(glycogensynthase and phosphorylase). In skeletal
muscle, its main action is to promote glucose uptake
by causing the translocation of Glut-4 transporters
to the cell membrane from an intracellular pool. In
adipose tissue, insulin will also increase glucose trans-
port and the resultant increase in glycolysis provides
a-glycerophosphate to promote triglyceride formation
but its main effect is to inhibit hormone-sensitive
lipase. This will lead to a decrease in circulating FFA
levels, which will affect glucose production in liver and
kidney and glucose uptake in various tissues (Fig. 2).
Glucose Physiology, Normal
Binding of insulin to its receptor activates a com-
plex intracellular cascade of autophosphorylation by
protein kinases. Intracellular receptor substrates and
members of the phosphatidylinositol 3-kinase family
seem to be the most important participants. The latter
triggers the migration of glucose transporters from an
intracellular pool toward the plasma membrane,
thereby increasing the number of transporters located
on the cellular surface and thus promoting the effi-
ciency of glucose uptake (Fig. 3). This will also result
in decreases in intracellular cyclic AMP (cAMP)
levels, which mediate the effects of insulin on glucose
production and lipolysis. Insulin will also alter the
activity of various genes that will affect the amount
of certain enzymes. Finally, via its action on amino
acid transport, insulin suppresses protein degradation
and lipolysis, which will diminish the availability of
gluconeogenic precursors and thereby reduce glucose
production indirectly.
The main regulator of insulin release is the prevail-
ing plasma glucose concentration. An increase in the
Glucose Physiology, Normal
Figure 2 Postprandial insulin secretion; regulation of glucose production and disposal.
plasma glucose concentration stimulates insulin
secretion, whereas a decrease in plasma glucose in-
hibits insulin secretion so that throughout the day,
plasma glucose and insulin levels change in parallel
(Fig. 1). Amino acids, e.g., arginine, and to a lesser
extent FFA can also stimulate insulin secretion. The
small intestine produces factors called incretins (e.g.,
gastrointestinal peptide, glucagon-like peptide-2),
which are secreted after meal ingestion and aug-
ment postprandial insulin secretion. This explains
Figure 3 Insulin binding and intracellular cascade. Glut, glucose
transporter; IRS, intracellular receptor substrates; PI3-Kinase,
phosphatidylinositol 3-kinase.
265
why insulin concentrations increase to a greater extent
when glucose is given orally than intravenously.
Glucagon
Glucagon acts solely on the liver, having effects medi-
ated by changes in intracellular cAMP levels that are
opposite of those of insulin. Its secretion is also regu-
lated in a reciprocal manner to that of insulin. An
increase in plasma glucagon will increase hepatic glu-
cose release within minutes via an increase in glycogen
breakdown. Binding of glucagon to its receptor imme-
diately increases intracellular cAMP levels, which in-
creases glycogenolysis and inhibits glycogen synthase
by stimulation of phosphorylase and inactivation of
glycogen synthase. Prolonged elevation of plasma glu-
cagon can increase gluconeogenesis in the liver,
whereas it has no effect on renal gluconeogenesis.
Glucagon secretion is suppressed by increases in
plasma glucose and insulin and is increased by hypo-
glycemia and catecholamines. Amino acids are a
potent stimulator of glucagon release. Thus, after
protein-rich meals, glucagon release might not be
suppressed despite increases in plasma insulin and
glucose concentrations.
Catecholamines
Epinephrine and norepinephrine are released by the
adrenal glands and norepinephrine is released from
sympathetic nerves during exercise, various stresses
(e.g., trauma, infection), and hypoglycemia. They
266
have complex effects on glucose mediated by both
direct and indirect mechanisms. Such actions in-
clude stimulation of renal gluconeogenesis, hepatic
and muscle glycogenolysis, adipose tissue lipolysis,
and glucagon release, which are mediated by b-
adrenergic receptors. Catecholamines also inhibit
insulin release directly via a-adrenergic receptors.
Indirect effects include suppression of glucose uptake
in skeletal muscle due to the elevation of plasma
FFA and stimulation of gluconeogenesis in liver and
kidney via increases in plasma FFA and gluconeo-
genic precursors (mainly glycerol from lipolysis and
lactate from skeletal muscle glycogenolysis). Along
with glucagon, catecholamines are the most im-
portant counterregulatory factors protecting against
hypoglycemia.
Growth Hormone, Cortisol, and
Thyroid Hormone
Growth hormone, cortisol, and thyroid hormone
largely act to regulate the response of target tissues
to insulin, glucagon, and catecholamines on a long-
term basis, e.g., reducing responses to insulin and
increasing responses to glucagon and catecholamines.
Under conditions similar to those during which
catecholamines are released, growth hormone and
cortisol are released and within an hour or two
reduce the effectiveness of insulin and enhance the
action of glucagon and catecholamines. Prolonged
elevation of these hormones, such as is seen in acro-
megaly and Cushing’s syndrome, can cause severe
insulin resistance and diabetes mellitus.
FFA
FFA are a major fuel used by most tissues of the body
except the brain, renal medulla, and erythrocytes.
Increases in plasma FFA and consequently their
uptake into cells have numerous direct and indirect
effects that influence glucose homeostasis. These in-
clude direct effects on hormone secretion (a moderate
stimulating action on insulin secretion and a potent
inhibitory action on glucagon and growth hormone)
as well as stimulating effects on hepatic and renal
gluconeogenesis and an inhibitory effect on muscle
glucose uptake. The effects on liver, kidney, and
muscle are mediated in part by changes in hormonal
environment and competition with glucose as an oxi-
dative fuel (mediated primarily by changes in pyruvate
dehydrogenase and interference with insulin signaling
pathways, both of these being mediated by coenzyme
Glucose Physiology, Normal
A metabolites of FFA). In general, opposite effects are
observed when plasma FFA are low.
Circulating FFA levels, like those of glucose, are
the net result of changes in FFA entry and exit from
plasma. FFA entry into plasma largely depends on the
balance between the activation of hormone-sensitive
lipase by catecholamines, growth hormone, and
cortisol and the inhibition of lipase by insulin. The
exit of FFA from plasma is stimulated by insulin.
THE POSTABSORPTIVE STATE
General Considerations
In the period after an overnight fast, referred to as the
postabsorptive state, plasma glucose ranges between
70 and 110 mg/dl (average 90 mg/dl). This state is
considered to represent a steady-state condition
since the rate of appearance of glucose approximates
its rate of disappearance (10 mmol kg 1 min 1).
However, even though removal is often undetectable,
the rate of removal is slightly greater than the rate
of appearance so that with more prolonged fasting,
plasma glucose concentrations decrease. However,
even after 72 h of fasting, plasma glucose does nor-
mally not decrease below 50 mg/dl (2.9 mM).
Glucose Utilization
In the postabsorptive state, plasma insulin levels are
low and therefore glucose uptake in tissues is largely
dependent on tissue needs. The majority of glucose is
taken up by the brain (50%) and is completely oxi-
dized; glucose taken up by muscle (20%), adipocytes
(5%), erythrocytes (5%), splanchnic organs
(10%), and kidney (5%) (Fig. 4) undergoes mostly
nonoxidative glycolysis, resulting in the release
of 3-carbon precursors (lactate, pyruvate, and ala-
nine), which are used for gluconeogenesis, into the
circulation.
Glucose Production
Glucose production in the postabsorptive state is
regulated to match tissue demand, which may increase
during exercise or stresses such as infection and
trauma. Normally, approximately 50% of the glucose
released into the circulation is the result of hepa-
tic glycogenolysis; the remaining 50% is due to
gluconeogenesis (30% liver; 20% kidney).
The proportion of glucose produced due to gluco-
neogenesis increases with the duration of the fast
since glycogen stores are rapidly depleted. The liver
Glucose Physiology, Normal 267

Figure 4 Glucose production and utilization after an overnight fast.

contains a total of 75 g glucose. Assuming that the secretion is not appropriately reduced and leads to a
liver releases glucose from glycogen at a rate of further reduction of endogenous glucose production
5 mmol kg 1 min 1, glycogen stores would be de- together with increased glucose uptake and conse-
pleted within 20 h. Thus, the proportion due to quently to the development of hypoglycemia with
gluconeogenesis must increase so that after 72 h, plasma glucose levels below 50 mg/dl.
glucose production by the liver is almost exclusively
due to gluconeogenesis. The kidney, in contrast, con-
tains little glycogen stores and the cells that could
THE POSTPRANDIAL STATE
make glycogen lack glucose-6-phosphatase; conse- General Considerations
quently, all the glucose released by the kidney is due
The major function of meal ingestion is to replenish
to gluconeogenesis. (Renal gluconeogenesis increases
tissue glucose (glycogen) and lipid (triglyceride) stores
with fasting to a greater extent than hepatic gluconeo-
that have been depleted due to fasting and physical
genesis.) Insulin suppresses both hepatic and renal
activity. Thus, after meal ingestion, endogenous
glucose release; however, glucagon promptly increases
glucose and FFA release is suppressed, favoring glyco-
hepatic glucose release, whereas catecholamines
gen accumulation. Glucose replaces FFA as the
stimulate more renal glucose release.
predominant energy fuel as plasma FFA decrease,
Prolonged Fasting
Table I Glucose Release and Disposal after Prolonged
With the duration of fasting, plasma insulin levels Fasting (60 h)
decrease, whereas those of glucagon, catecholamines,
growth hormone, and cortisol increase. Therefore, the Glucose Glucose
release disposal
oxidation of glycerol, plasma FFA and FFA products, (mmol (mmol
and the ketone bodies b-hydroxybutyrate and acetoa- kg 1 min 1) kg 1 min 1)
cetate increases. Hepatic glycogen stores become de-
Overall 6.0 Overall 6.0
pleted and after 60 h virtually all of glucose released is
Gluconeogenesis 5.5 Oxidation 4.8
due to gluconeogenesis. During the first 60–72 h of
Glycogenolysis 0.5 Glycolysis 1.2
fasting, the decrease in glucose release is greater than
Tissues Tissues
the decrease in glucose uptake, so that plasma glucose
Liver 2.7 Brain 3.5
levels decrease. At approximately 60 h, with plasma
Kidney 2.8 Skeletal muscle 1.0
glucose averaging 60 mg/dl, a new pseudo-steady
Splanchnic organs 0.5
state is achieved (Table I). This stabilization is the
Kidney 0.4
basis for the 72 h fast for the diagnosis of patients
Adipose tissue 0.2
with hypoglycemia due to insulin-producing tumors
Blood cells 0.4
of the pancreas (insulinoma). In such patients, insulin
268
favoring FFA incorporation into triglyceride stores, so
that ingested carbohydrate becomes the major fuel
used by the body. Various factors, such as the size of
the meal, prior physical exercise and duration since
the last meal, and composition of the meal, can affect
postprandial glucose homeostasis. However, from a
practical point of view, the most important factors
are changes in insulin and glucagon secretion and
their effects on hepatic sequestration of meal carbo-
hydrates, suppression of endogenous glucose produc-
tion, and finally stimulation of the uptake, storage,
glycolysis, and oxidation of glucose in hepatic and
posthepatic tissues.
Postprandial Glucose Concentrations
and Fluxes
After a meal, plasma glucose concentrations increase
since the rate of appearance of glucose in plasma
exceeds the rate of disappearance. Subsequently,
plasma glucose decreases when the rate of disappear-
ance exceeds the rate of appearance. The appearance of
glucose in plasma represents the sum of glucose from
the meal reaching the circulation and the remaining
Figure 5 Postprandial changes in plasma glucose, insulin, glucagon concentrations, rates of plasma glucose appearance/
disappearance, and hepatic and renal glucose production.
Glucose Physiology, Normal
endogenous glucose production. The time courses of
these changes are shown in Fig. 5. Endogenous glu-
cose release is suppressed 60% after a meal. The
appearance of ingested glucose is detected within
15 min after a meal, reaches a maximum at 60 min,
and decreases gradually thereafter. Only 75% of the
glucose in a meal reaches the systemic circulation; the
remaining 25% is sequestrated by the splanchnic bed.
Of a theoretical meal containing 100 g of glucose,
20–30% is initially extracted in the splanchnic bed. At
least half of this is taken up by the liver and incorpor-
ated into hepatic glycogen; the remainder is probably
released as lactate due to hepatic glycolysis. Of the
glucose in the meal that reaches the systemic circula-
tion, approximately 30–40% is taken up by skeletal
muscle to be initially oxidized in favor of FFA and
later to be stored as glycogen. Little of the glucose
taken up by muscle is released as lactate or other
gluconeogenic substrates into the circulation. Of the
remaining glucose released into the systemic circula-
tion, 20% is taken up by the brain, 10% by the kidney,
and 5% by adipose tissue.
Approximately 40% of the glucose disposed of
after a meal is stored predominantly as glycogen in
Glucose Physiology, Normal
Figure 6 Contribution of storage and glycolysis to the disposal of
glucose after a meal.
liver and muscle and, to a lesser extent, as triglycerides
in adipose tissue. The remaining 60% is undergoes
glycolysis either oxidatively to CO2 and H2O (40%)
or nonoxidatively to lactate (20%) (Fig. 6). That a
substantial amount of glucose undergoes nonoxidative
glycolysis is not surprising if one considers that gly-
colysis is needed to provide 3-carbon fragments for
gluconeogenesis and precursors for the indirect
pathway of hepatic glycogen formation.
Renal glucose production initially increases after a
meal (Fig. 5). The physiological role of this increase
still needs to be elucidated. Teleologically, postpran-
dial renal glucose release may facilitate efficient
liver glycogen repletion by permitting substantial
suppression of hepatic glucose release.
It can be readily appreciated that three main factors
regulate postprandial glucose levels: suppression of
hepatic glucose release, hepatic sequestration of the
ingested glucose, and uptake of glucose from the sys-
temic circulation. Initial suppression of endogenous
glucose release and hepatic sequestration depend
largely on the reciprocal secretion of glucagon and
insulin. Insulin increases the number of glucose trans-
porters in muscle and thereby increases glucose frac-
tional extraction, an index of the efficiency of glucose
uptake; glucose fractional extraction by brain and
other insulin independent tissues actually decreases.
SUMMARY
In most circumstances, regulation of glucose
production is more important than regulation of
glucose utilization in determining plasma glucose
269
concentrations. Recall that in the fasting state, 80%
of glucose utilization is insulin independent. Insulin
levels are low and are needed only to suppress exces-
sive endogenous glucose production and lipolysis.
Another example of the importance of glucose produc-
tion is fasting hyperglycemia in type 2 diabetes. Rates
of glucose utilization are generally normal, whereas
rates of glucose production are increased. Of interest
is the finding that renal glucose release initially in-
creases after a meal, whereas hepatic glucose release
decreases; these reciprocal changes permit efficient
repletion of glycogen stores. This finding and other
observations have provided convincing evidence for
the concept of hepatorenal reciprocity. According to
this concept, when the release of glucose by either
liver or kidney is reduced, the other organ will increase
its glucose release to maintain euglycemia. Similar
reciprocal changes are found during recovery from
insulin-induced hypoglycemia in patients with type 2
diabetes. The strongest support for the concept of
hepatorenal reciprocity has been provided by the ob-
servation that during the anhepatic stage of liver trans-
plantation (when liver glucose release is absent), the
kidney increases its release of glucose threefold so that
hypoglycemia does not occur.
See Also the Following Articles
Catecholamines . Diabetes, Type 2 . Glucagon and Gluca-
gon-like Peptides . Glucose, Impaired Tolerance . Glucose
Toxicity . Insulin Secretion, Physiology
Further Reading
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