Download Glucose Metabolism

Hormonal Control of Nutrient
Metabolism and Storage
Dr. Mujeeb Ahmed Shaikh
Assistant Professor
AlMaarefa College
Learning Objectives
• Describe the effect of insulin on glucose, fat,
and protein metabolism.
• Explain what is meant by counter-regulatory
hormones, and describe the actions of
glucagon, amylin, somatostatin, gut-derived
hormones, epinephrine, growth hormone, and
the adrenal cortical hormones in the
regulation of blood glucose levels.
Nutrient Metabolism and Storage
• The body uses glucose, fatty acids, and other
substrates as fuel to satisfy its energy needs.
Glucose Metabolism and Storage
• The brain and nervous system rely almost
exclusively on glucose as a fuel source.
• Other tissue can use fatty acids & ketone
bodies
• Body tissues obtain glucose from the blood.
• In normal person the fasting blood glucose
levels are tightly regulated between 80 and 90
mg/dL (4.4 and5.0 mmol/L).
• After meal 2/3 of the glucose is removed from
the blood & stored in liver as glycogen.
• Between meals, the liver releases glucose as a
means of maintaining the blood glucose
within its normal range.
• Extra glucose - glycogen / fats.
• After muscle & liver get saturated the extra
glucose used for FA & triglyceride synthesis.
• Between meals, the liver releases glucose as a
means of maintaining the blood glucose
within its normal range.
• The liver synthesizes glucose from amino
acids, glycerol, and lactic acid in a process
called gluconeogenesis.
Glucose Regulating Hormones
• The hormonal control of blood glucose resides
largely within the endocrine pancreas.
• The pancreas is made up of two major tissue
types: the acini and the islets of Langerhans.
• Acini – digestive juices into duodenum
• islets of Langerhans - secrete hormones into
the blood.
Islet cells
•
•
•
•
Alpha cells – Glucagon
Beta cells – insulin & amylin
Delta cells - Somatostatin.
PP cells - pancreatic polypeptide
Endocrine
pancreas:
Islets of
Langerhans
Alpha
cells
Beta cells
Glucagon
Insulin
and amylin
Delta cells
PP cells
Somatostatin
Pancreatic
polypeptide
Functions of Pancreatic Hormones
• Glucagon: causes cells to release stored food into
the blood
• Insulin: allows cells to take up glucose from the
blood
• Amylin: slows glucose absorption in small intestine;
suppresses glucagon secretion
• Somatostatin: decreases GI activity; suppresses
glucagon and insulin secretion
Anabolism and Catabolism
available foodstuffs
(in blood)
glucose
amino acids
free fatty acids
liver can convert amino acids
and free fatty acids into
ketones
Anabolism
Insulin,
anabolic
steroids
Catabolism
glucagon,
epinephrine,
cortisol
stored foodstuffs
(in cells)
glycogen
proteins
triglycerides
Insulin and Glucagon Are the Main
Controls
available foodstuffs
(in blood)
glucose
Anabolism
Insulin ,
anabolic
steroids
stored foodstuffs
(in cells)
glycogen
amino acids
Catabolism
Glucagon,
proteins
free fatty acids
epinephrine,
cortisol
triglycerides
liver can convert amino acids
and free fatty acids into
ketones
Insulin
• Insulin is the only hormone known to have a direct
effect in lowering blood glucose levels.
• The actions of insulin are threefold:
1. it promotes glucose uptake by target cells and provides
for glucose storage as glycogen,
2. it prevents fat and glycogen breakdown, and
3. It inhibits gluconeogenesis and increases protein
synthesis
• Insulin acts to promote
– fat storage by increasing the transport of glucose into fat
cells
– It also facilitates triglyceride synthesis from glucose in cells
and inhibits the intracellular breakdown of stored
triglycerides.
• Insulin also inhibits protein break-down and
increases protein synthesis by increasing the
active transport of amino acids into body cells,
and it inhibits gluconeogenesis, or the building
of glucose from new sources, mainly amino
acids.
Metabolic Effects of Insulin
Glycogen
Glucose
Glucose-P
Glucose
Pyruvate
Free fatty
acids
Protein
Amino
acids
CO2
Ketoacids
Adipose
tissue
Liver
Muscle
Plasma
Stimulate
Inhibit
 Glucose
 Free fatty acids
 Ketoacids
 Amino acids
Approximate Rates of Insulin Secretion
at Different Blood Glucose Levels
Insulin Response
)
(
100%
50%
0
40
80
120
160
200
Plasma glucose (mg/dl)
240
Insulin
Proinsulin
α - chain
Active
insulin
β - chain
C - Peptide
• The C-peptide chains can be measured
clinically, and this measurement can be used
to study beta cell function (i.e., persons with
type 2diabetes with very little or no remaining
beta cell function will have very low or
nonexistent levels of C-peptide in their blood,
and thus will likely need insulin replacement
for treatment).
Insulin vs Blood Glucose
Increase blood
glucose
Increased
insulin secretion
• Secretion of insulin occurs in a pulsatile fashion.
After exposure to glucose, which is a nutrient
secretagogue, a First-phase release of stored
preformed insulin occurs, followed by a secondphase release of newly synthesized insulin.
• Serum insulin levels begin to rise within minutes
after a meal, reach a peak in approximately 3 to 5
minutes, and then return to baseline levels within
2 to 3 hours.
• Insulin has a half-life of approximately 15 minutes
once it is released into the general circulation.
Mechanism of Glucose Stimulated Insulin
Secretion
Factors Affecting Insulin Secretion
Inhibitors
Stimulators
Glucose
Mannose
Galactose
Amino acids
Arginine
Lysine
Leucine
Alanine
Fasting
Neural influences
Vagal activity
(acetylcholine)
b-adrenergic stimulation
Drugs like Sulfonylurea
Free fatty acids, Keto acids
Glucagon (direct and indirect effects)
Gastro intestinal hormones
Glucagon like peptide 1 (GLP-1)
Glucose dependant Insulinotropic
Peptide (GIP)
Secretin
Exercise
Somatostatin
Neural influences
Sympathetic activity-adrenergic stimulation
norepinephrine, epinephrine)
Processing of Proinsulin and C-Peptide
Connecting peptide
HOOC
NH2
20
1
1
S S
5
A-chain
B-chain
15
10
S
SS
5
30
S
25
10
20
15
Proinsulin
C-Peptide
S S
NH2
NH2
20
COOH
1
5
1
5
S
S
10
15
S
S
15
20
A-chain
Insulin
COOH
10
B-chain
25
30
The Insulin Receptor & Mechanisms of
Insulin Action
Insulin Receptors
• Cell membranes are impermeable to glucose,
they require a special carrier, called a glucose
transporter, to move glucose from the blood
into the cell.
• GLUT 1, GLUT 2, GLUT 3, GLUT 4.
• GLUT-4 is the insulin-dependent glucose
transporter for skeletal muscle and adipose
tissue
• GLUT-2 is the major transporter of glucose
into beta cells and liver cells. It has a low
affinity for glucose and acts as a transporter
only when plasma glucose levels are relatively
high, such as after a meal.
• GLUT-1 is present in all tissues. It does not
require the actions of insulin and is important
in transport of glucose into cells of the
nervous system.
Glucagon
• A polypeptide molecule produced by the
alpha cells of the islets of Langerhans,
maintains blood glucose between meals and
during periods of fasting.
• Glucagon produces an increase in blood
glucose.
• Initiate breakdown of glycogen between meals
• Gluconeogenesis
• Makes fatty acids available for use as energy
Factors Affecting Glucagon Secretion
Inhibition
Stimulation
Hypoglycemia
Glucose
Amino acids
Arginine
Alanine
Somatostatin
Gastrointestinal hormones
Cholecystokinin (CCK)
Gastrin
Gastrointestinal hormones
Secretin
Glucagon-like peptide-1 (GLP-1)
Fasting
Free fatty acids
Exercise
Ketoacids
Neural influences
Vagal activity-acetylcholine
Sympathetic activityb-adrenergic stimulation
(norepinephrine, epinephrine)
Neural influences
-adrenergic stimulation
Insulin (direct effect)
Approximate Rates of Insulin &
Glucagon Secretion at Different Blood Glucose Levels
100%
Glucagon Response
(
)
Insulin Response
)
(
100%
50%
50%
0
0
40
80
120
160
200
Plasma glucose (mg/dl)
240
Amylin, Somatostatin, and Gut-Derived
Hormones
• A polypeptide that is co secreted with insulin
from the beta cells.
• Plasma levels of amylin increase in response
to nutritional stimuli to produce inhibition of
gastric emptying and glucagon secretion.
• he less soluble and insoluble forms, which
may cause degeneration of the beta cells and
contribute to the pathogenesis of overt
diabetes
Somatostatin
• Its a polypeptide hormone containing only 14
amino acids that has an extremely short half-life.
• Secreted by the delta cells acts locally in the islets
of Langerhans to inhibit the release of insulin and
glucagon.
• It also decreases gastrointestinal activity after
ingestion of food.
• Almost all factors related to ingestion of food
stimulate somatostatin secretion.
Incretins
• Several gut derived hormones have been
identified as having what is termed an incretin
effect, meaning that they increase insulin release
after an oral nutrient load.
• The two hormones that account for about 90% of
the incretin effect are glucagon like peptide-1,
which is released from L cells in the distal small
bowel, and glucose-dependent insulinotropic
polypeptide, which is released by K cells in the
upper gut (mainly the jejunum).
Counter regulatory Hormones
• They counteract the storage functions of
insulin in regulating blood glucose levels
during periods of fasting, exercise, and other
situations that either limit glucose intake or
deplete glucose stores.
1. The catecholamines,
2. Growth hormone, and
3. Glucocorticoids.
Epinephrine
• helps to maintain blood glucose levels during
periods of stress.
• Glycogenolysis in the liver
• Inhibits insulin release
• Increasing the breakdown of muscle glycogen
stores.
• A direct lipolytic effect on adipose cells,
Growth Hormone
• Increases protein synthesis
• Mobilizes fatty acids from adipose tissue, and
antagonizes the effects of insulin.
• Chronic hypersecretion of growth hormone, as
occurs in acromegaly, can lead to glucose
intolerance and the development of diabetes
mellitus.
Glucocorticoid Hormones
• Gluconeogenesis by the liver
• Hypoglycemia is a potent stimulus for cortisol
secretion.
• In predisposed persons, the prolonged
elevation of glucocorticoid hormones can lead
to hyperglycemia and the development of
diabetes mellitus.
Hormonal Interactions in the Maintenance
of Blood Glucose Concentration
Glucose
Production
(Liver Hepatic Glucose Output)
(-)
(+)
(+)
Insulin
Glucagon
Blood Glucose
(+)
Epinephrine
Glucocorticoids
Growth Hormone
(-)
Glucose
Consumption
(Skeletal Muscle and
Adipose Tissue)
Hormonal Effects on FFA Production
in Adipose Tissue
Epinephrine
Insulin
Triglycerides
Insulin
+ Hormone
_ Sensitive
Lipase
-Glycerol-P
+
_
glucose
Fatty Acids
Growth hormone
Cortisol
Epinephrine
glycerol
FFA