Blood glucose homeostasis revised

BLOOD GLUCOSE
HOMEOSTASIS
Professor (Dr.) Namrata Chhabra
Biochemistry for medics- Lecture notes
11/07/14 Biochemistry for medics- Lecture notes
1

Homeostasis
Biochemistry for medics- Lecture notes 11/07/14
2
Homeostasis is the maintenance of a stable
internal environment within an organism, and
maintaining a stable internal environment in a
human means having to carefully regulate
many parameters including glucose levels in
the blood.

Glucose homeostasis
3
 Glucose homeostasis reflects a balance
between hepatic glucose production and
peripheral glucose uptake and utilization.
 Insulin is the most important regulator of this
metabolic equilibrium, but neural input,
metabolic signals, and other hormones (e.g.,
glucagon) result in integrated control of
glucose supply and utilization.

Homeostasis Of Blood Glucose
Levels
4
 Glucose is an obligate metabolic fuel for the
brain under physiologic conditions.
 The brain cannot synthesize glucose or store it
as glycogen
 Therefore requires a continuous supply of
glucose from the arterial circulation.

Brain and glucose
5
 As the arterial plasma glucose concentration
falls below the physiologic range, blood-to-brain
glucose transport becomes insufficient to
support brain energy metabolism and function.
 However, redundant glucose counter
regulatory mechanisms normally prevent or
rapidly correct hypoglycemia.

Plasma glucose concentrations
6
Plasma glucose concentrations are normally
maintained within a relatively narrow range,
roughly 70–110 mg/dL (3.9–6.1 mmol/L) in the
fasting state with transient higher excursions
after a meal, despite wide variations in
exogenous glucose delivery from meals and in
endogenous glucose utilization by, for
example, exercising muscle.

Plasma glucose concentrations
7
Between meals and during fasting, plasma
glucose levels are maintained by-
 Endogenous glucose production, hepatic (and
renal) gluconeogenesis,
 Hepatic glycogenolysis.

Hepatic glycogen stores
8
Although hepatic glycogen stores are usually
sufficient to maintain plasma glucose levels for
approximately 8 hour , this time period can be
shorter if glucose demand is increased by
exercise or if glycogen stores are depleted by
illness or starvation.

Gluconeogenesis
9
 Gluconeogenesis requires a coordinated
supply of precursors from muscle and adipose
tissue to the liver (and kidneys).
 Muscle provides-o
Lactate,
o Pyruvate,
o Alanine, glutamine, and other amino acids.

Gluconeogenesis
10
 Triglycerides in adipose tissue are broken
down into fatty acids and glycerol, which is a
gluconeogenic precursor.
 Fatty acids provide an alternative oxidative fuel
to tissues other than the brain (which requires
glucose).
 Fatty acids can not be used for glucose
production.

Systemic glucose balance
11
Maintenance of the normal plasma glucose
concentration—is accomplished by-
 A network of hormones,
 Neural signals, and
 Substrate effects that regulate endogenous
glucose production and glucose utilization by
tissues other than the brain

Role of Insulin
12
 Glucose is the key regulator of insulin
secretion by the pancreatic beta cells
 Glucose levels > 3.9 mmol/L (70 mg/dL)
stimulate insulin synthesis
 Glucose stimulation of insulin secretion begins
with its transport into the beta cell by the
GLUT2 glucose transporter
 Insulin promotes peripheral glucose uptake
and utilization, and inhibits gluconeogenesis
as well as glycogenolysis.

Systemic glucose balance
13

Role of insulin in the fasting
state
14
 In the fasting state, low insulin levels increase
glucose production by-
 Promoting hepatic gluconeogenesis and
glycogenolysis and
 Reducing glucose uptake in insulin-sensitive
tissues (skeletal muscle and fat), thereby
promoting mobilization of stored precursors
such as amino acids and free fatty acids
(lipolysis).
 These effects are mediated by Glucagon.

Role of Glucagon in the fasting
state
15
 Glucagon, secreted by pancreatic alpha cells
when blood glucose or insulin levels are low,
stimulates –
 Glycogenolysis
 Gluconeogenesis by the liver and renal
medulla and
 Prevents glucose uptake by the peripheral
cells

Postprandial Glucose
homeostasis
16
 Postprandially, the glucose load elicits a rise in
insulin and fall in glucagon, leading to a
reversal of these processes.
 Insulin, an anabolic hormone, promotes the
storage of carbohydrate and fat and protein
synthesis.
 The major portion of postprandial glucose is
utilized by skeletal muscle, an effect of insulin-stimulated
glucose uptake.
 Other tissues, most notably the brain, utilize
glucose in an insulin-independent fashion.

Phases of glucose homeostasis
17
Phase 1 Phase 2 Phase 3 Phase 4
Nutritional
status
Well fed
state
Post- Absorptive
state
Fasting Prolonged
fasting/
Starvation
Source of
glucose
Diet Hepatic glycogen
and
Gluconeogenesis
Hepatic and
Renal
gluconeogenesi
s
Renal and
hepatic
gluconeogenesi
s
Tissues
using
glucose
All All tissues, but in
Liver, muscle and
adipose tissue,
the rate of
utilization is
slowed.
Brain and
RBCs and cells
lacking
mitochondria;
small amount
by muscle.
Brain at a
slower rate,
RBCs normal
rate
Major fuel
of brain
Glucose Glucose Glucose and
ketone bodies
Ketone bodies
and glucose

Glucose homeostasis in well fed
state
18
In the well fed state,
glucose absorbed from
gut is supplied to all cells;
it acts as a signal for the
release of insulin from
Beta cells of pancreas; it
is oxidized completely to
provide energy; the
surplus is stored as
glycogen in liver and
muscle. Acetyl co A
obtained from pyruvate,
can be used for
lipogenesis , the
triglycerides are stored in
adipose tissue.

Glucose homeostasis in post-
Absorptive Phase
19
1) Glucose
utilization is
decreased in the
liver, muscle and
adipose tissue
2) Liver
glycogenolysis
provides the most
glucose (75%)
3) gluconeogenesis
providing the
remainder
4) The glucose-alanine
cycle
becomes active.
5) 50-60% of
glucose is
consumed by the

Glucose homeostasis in the early
fasting state
20
1) The peripheral cells
switch to alternative
fuels, such as fatty
acids and ketone
bodies.
2) Ketone bodies are
synthesized by the
liver but utilized in the
peripheral cells.
3) Glycerol and amino
acids released form
the adipose tissue
and muscle
respectively are used
for glucose
production.
4) Glucose is the main
fuel for brain.

Glucose homeostasis in the state
of Starvation
21
1) Glucose alanine
cycle is active.
2) Alanine and
glutamine released
from muscle are
used in liver and
kidney respectively
for glucose
production
3) Ketones play a
central role in
prolonged starvation,
replacing glucose as
the primary fuel for
the brain and
signaling a reduction
in protein catabolism
and alanine output
from muscle.

Role of hormones in glucose homeostasis
22
Insulin Glucagon Catechol
amines
Glucocort
icoids
Growth
hormone
Thyroid
hormone
Glucose
absorption
No
effect
No effect No effect No effect No effect
Peripheral
uptake
Glycolysis
Gluconeogen
esis
Glycogenesis
Glycogenolysi
s
Lipolysis
Protein
catabolism
Net effect Hypogly
cemia
Hyperglyc
emia
Hypergly
cemia
Hyperglyc
emia
Hypergly
cemia
Hyperglycemia

Variations in blood glucose
levels
23
A) Hypoglycemia- Decrease in blood glucose below
the normal is called hypoglycemia.
 A decrease in insulin secretion is the first defense
against hypoglycemia.
 As plasma glucose levels decline just below the
physiologic range, glucose counter regulatory
(plasma glucose–raising) hormones are released.
Among these, pancreatic α cell glucagon, which
stimulates hepatic glycogenolysis, plays a primary
role.
Glucagon is the second defense against
hypoglycemia.

A) Hypoglycemia (contd.)
24
 Adreno- medullary epinephrine, which
stimulates hepatic glycogenolysis and
gluconeogenesis (and renal gluconeogenesis),
is not normally critical, however, it becomes
critical when glucagon is deficient.
Epinephrine is the third defense against
hypoglycemia.
 When hypoglycemia is prolonged, cortisol and
growth hormone also support glucose
production and limit glucose utilization.

Hypoglycemia
25
 Hypoglycemia is a laboratory ‘diagnosis’ which
is usually considered a blood glucose level
below 60 mg/dL.
 Symptoms begin at plasma glucose levels in
the range of 60 mg/dL and
 Impairment of brain function at approximately
50 mg/dL.

Types of Hypoglycemia
26
 Spontaneous hypoglycemia in adults is of two
principal types:
1) Fasting hypoglycemia is often sub acute or
chronic and usually presents with
neuroglycopenia as its principal manifestation.
2) Postprandial hypoglycemia is relatively acute
and is often heralded by symptoms of
neurogenic autonomic discharge (sweating,
palpitations, anxiety, and tremulousness).

Common causes of
hypoglycemia
27
A) Physiological- Pronged fasting or starvation.
B) Pathological
1) Fasting hypoglycemia
o Drug induced- Insulin, oral hypoglycemic drugs,
alcohol, sulfonamides etc.
o Critical illnesses - Hepatic, renal, or cardiac
failure, and sepsis.
o Hormone deficiencies- Cortisol, growth hormone,
or both, Glucagon and epinephrine (in insulin-deficient
diabetes)

Common causes of
hypoglycemia
28
o Endogenous hyperinsulinism
o Insulinoma
o Autoimmune (autoantibodies to insulin or the
insulin receptor)
o Ectopic insulin secretion
o Congenital hyperinsulinism and
o Inherited enzyme deficiencies

Common causes of
hypoglycemia
29
2) Postprandial (reactive) hypoglycemia
a) Alimentary (Postgastrectomy)
b) Hereditary fructose intolerance,
c) Galactosemia
d) Idiopathic.

B) Hyperglycemia
30
Increase in blood glucose level above the normal
physiological limit is called as Hyperglycemia
Causes of hyperglycemia
Diabetes mellitus
Diseases of pancreas(pancreatitis,
hemochromatosis, carcinoma head of pancreas,
Cystic fibrosis)
Infections and sepsis
Anesthesia
Asphyxia

B) Hyperglycemia
31
Causes of hyperglycemia (contd.)
 Hormonal tumors-o
Acromegaly,
o Cushing's syndrome,
o Glucagonoma and
o Pheochromocytoma

B) Hyperglycemia
32
 Causes of hyperglycemia (contd.)
o Pharmacologic agents (corticosteroids,
sympatho mimetic drugs, thiazide diuretics
and niacin)
o Liver disease (cirrhosis, hemochromatosis)
o Muscle disorders (myotonic dystrophy)
o Adipose tissue disorders (Lipodystrophy and
truncal obesity)

Clinical implication of disturbed
glucose homeostasis-Glycosuria
33
 Although normal urine contains virtually no
sugar but under certain circumstances,
glucose or other sugars may be excreted in
urine.
 This condition is called ‘Melituria’. The term
Glucosuria, Fructosuria, Galactosuria,
Lactosuria and Pentosuria are applied
specifically for urinary excretion of glucose,
fructose, galactose, lactose and pentose
respectively.

Types of Glycosuria
34
Glycosuria(Glucosuria) can be classified in to
two main groups
A) Hyperglycemic glycosuria
B) Renal glycosuria

A) Hyperglycemic glycosuria
35
 Alimentary Glycosuria(Excessive ingestion of
carbohydrates)
 Emotional Glycosuria(Excessive
catecholamine release)- Stress, anxiety etc.

Hyperglycemic glycosuria
36
 Glycosuria due to endocrinal disorders
e.g.
o Diabetes Mellitus
o Hyperthyroidism
o Epinephrine hyper secretion
o Hyperactivity of anterior
pituitary(Acromegaly)
o Hyperactivity of Adrenal
cortex(Cushing’s syndrome/disease)
o Increased secretion of glucagon

B) Renal Glycosuria
37
 Renal Tubular disease
 Fanconi's Syndrome
 Toxic renal tubular disease
o Lead Toxicity
o Mercury Toxicity

Renal glycosuria
38

Diabetes mellitus
39
 Diabetes mellitus is a syndrome with disordered
metabolism and inappropriate hyperglycemia due
to either a deficiency of insulin secretion or to a
combination of insulin resistance and inadequate
insulin secretion to compensate.
 Type 1 diabetes is due to pancreatic islet B cell
destruction predominantly by an autoimmune
process, and these patients are prone to
ketoacidosis.
 Type 2 diabetes is the more prevalent form and
results from insulin resistance with a defect in
compensatory insulin secretion

Blood glucose homeostasis
(Summary)
40
 Glucose homeostasis reflects a balance between
hepatic glucose production and peripheral glucose
uptake and utilization. Insulin is the most
important regulator of this metabolic equilibrium.
 In the fasting state, low insulin levels increase
glucose production by promoting hepatic
Gluconeogenesis and glycogenolysis and reduce
glucose uptake in insulin-sensitive tissues
 Glucagon, secreted by pancreatic alpha cells
when blood glucose or insulin levels are low,
stimulates glycogenolysis and gluconeogenesis
by the liver and renal medulla.

Blood glucose homeostasis
(Summary)
41
 Postprandially, the glucose load elicits a rise in
insulin and fall in glucagon, leading to a
reversal of these processes.
 Insulin, an anabolic hormone, promotes the
storage of carbohydrate and fat and protein
synthesis.
 The major portion of postprandial glucose is
utilized by skeletal muscle, an effect of insulin-stimulated
glucose uptake.
 Other tissues, most notably the brain, utilize
glucose in an insulin-independent fashion.

Blood glucose homeostasis revised

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Blood glucose homeostasis revised