Download The Endocrine Pancreas

The Endocrine Pancreas:
Introduction
• The pancreas houses two distinctly different tissues.
The bulk of its mass is exocrine tissue and associated
ducts, which produce an alkaline fluid loaded with
digestive enzymes which is delivered to the small
intestine to facilitate digestion of foodstuffs
•
Scattered throughout the exocrine tissue are several
hundred thousand clusters of endocrine cells which
produce the hormones Insulin and Glucagon, plus a
few other hormones.
• Insulin and Glucagon are critical participants in
glucose homeostasis and serve as acute regulators
of blood glucose concentration.
•
From a medical perspective, insulin in particular is
enormously important - a deficiency in insulin or deficits
in insulin responsiveness lead to the disease diabetes
mellitus.
• The endocrine portion of the pancreas takes the form of
many small clusters of cells called islets of
Langerhans.
•
• Pancreatic islets house three major cell types, each of
which produces a different endocrine product:
• Alpha cells (A cells) secrete the hormone glucagon.
• Beta cells (B cells) produce insulin and are the most
abundant of the islet cells.
• Delta cells (D cells) secrete the hormone somatostatin
which is also produced by a number of other endocrine
cells in the body.
Structure of Insulin
• Insulin is protein, composed of two chains
held together by disulfide bonds
• Proinsulin consists of three domains: an
amino-terminal B chain, a carboxyterminal A chain and a connecting peptide
in the middle known as the C peptide
• Within the endoplasmic reticulum, proinsulin is
exposed to several specific endopeptidases which
excise the C peptide, thereby generating the
mature form of insulin.
• Insulin and free C peptide are packaged in the Golgi
into secretory granules which accumulate in the
cytoplasm.
• When the B cell is appropriately stimulated, insulin is
secreted from the cell by exocytosis and diffuses into
islet capillary blood.
• C peptide is also secreted into blood, but has no
known biological activity
Biochemistry of insulin
b
51 amino acids
after cleavage,
(86 before)
S
S
S
Chains
S
S
S
a
C-peptide
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C-peptide = Connector Peptide
Control of Insulin Secretion
• Insulin is secreted in primarily in response to
elevated blood concentrations of glucose.
• Elevated concentrations of glucose within the B
cell ultimately leads to membrane depolarization
and an influx of extracellular calcium.
• The resulting increase in intracellular calcium is
thought to be one of the primary triggers for
exocytosis of insulin-containing secretory
granules
INSULIN RELEASE
• The normal fasting blood glucose concentration
in humans is 80 to 90 mg per 100 ml,
associated with very low levels of insulin
secretion.
• Almost immediately after meals, plasma insulin
levels increase dramatically.
• Elevated glucose not only simulates insulin
secretion, but also synthesis i.e. transcription of
the insulin gene and translation of its mRNA
Insulin Release Over Time
Insulin
Conc.
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6 min.
Time
90 min.
The Insulin Receptor and Mechanism of Action
• The insulin receptor is a tyrosine kinase.
• Binding of insulin to the receptor phosphorylate
themselves (autophosphorylation), thus
activating the catalytic activity of the receptor.
• The activated receptor then phosphorylates a
number of intracellular proteins, which is insulin
receptor substrate 1 or IRS-1, which in turn
generate a biological response that ultimately
mediate insulin's effects.
Peripheral Uptake of Glucose
• Glucose cannot diffuse across cell
membranes
• Tissue uptake is by facilitated transport
• *In some tissues insulin regulates the number
of membrane transporters
Glucose Transport
• GLUT 1 and GLUT 3 mediate basal glucose uptake
in most tissues including brain, nerves, and red
blood cells. Their high affinities for glucose ensure
glucose entry even during periods of relative
hypoglycemia.
• GLUT 2, a low-affinity transporter, is in hepatocytes
and beta-islet cells. After a meal, portal blood from
the intestine is rich in glucose. GLUT 2 captures the
excess glucose primarily for storage. When the
glucose concentration drops below the Km for the
transporter, much of the remainder leaves the liver
and enters the peripheral circulation.
• GLUT 4 is in adipose tissue and muscle and
responds to the glucose concentration in peripheral
blood. The rate of glucose transport in these two
tissues is increased by insulin.
Insulin Actions 1
• Liver Cells
– Store Glucose as Glycogen, reduce blood
Glucose concentrations
• Glycogen synthesis from glucose
• Increase glucose transport into cells
– Increase Protein Synthesis
• Increase amino acid transport into cells
• Positive Nitrogen Balance
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Insulin Actions 2
• Muscle Cell Actions
– Increase glucose uptake
– Increase amino acid uptake
– Increase protein synthesis (enzymes &
structural)
– Decrease protein degradation
– Increase fatty acid uptake as needed
– Increase muscle glycogen synthesis
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Insulin Actions 3
• Adipose Cell Actions
– Increase protein synthesis ( for lipogenesis)
– Increase glucose uptake into cells
– Increase lipid formation (lipogenesis)
– Decrease lipid degradation (lipolysis)
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Effects of insulin on carbohydrate metabolism
• Insulin increases the uptake of glucose and its
metabolism in muscle and fat.
• Insulin increases glycogen synthesis in liver and muscle
• Effects of insulin on protein metabolism
• Insulin increases amino acid uptake by muscle cells
• Insulin increases protein synthesis, and decreases protein
breakdown
METABOLIC ACTIONS OF INSULIN
• Effects of Insulin on Fat Metabolism
•
Increase lipid formation (lipogenesis)
– Decrease lipid degradation (lipolysis)
– Increase lipoprotein lipase activity
– Decrease hormone sensitive lipase activity
• Insulin Effects on Potassium
• Insulin pumps K+ into cells
• This K+-lowering action of insulin is used to
treat acute, life-threatening hyperkalemia
Tissues that require insulin for glucose uptake
are:
• Adipose tissue
• Resting skeletal muscle
• In exercise: glucose can enter exercising
muscle without the aid of insulin
Tissues in which glucose uptake is not
affected by insulin are:
• Nervous tissue
• Kidney tubules
• Intestinal mucosa
• Red blood cells and b-cells of pancreas
• Insulin accelerates, but is not required, for glucose
uptake by the liver
Diabetes mellitus
• Insufficient production of insulin (either absolutely or relative to
the body's needs), or the inability of cells to use insulin leads to
hyperglycemia and diabetes mellitus.
• This latter condition affects mostly the cells of muscle and fat
tissues, and results in a condition known as "insulin
resistance.“
• This is the primary problem in type 2 diabetes.
• The absolute lack of insulin, usually secondary to a destructive
process in the pancreas, is the particular disorder in type 1
diabetes.
• Only approximately 10% of the patients with diabetes mellitus
have type 1 diabetes and the remaining 90% have type 2
diabetes mellitus
• Normal fasting plasma glucose levels are less than 110
milligrams per deciliter (mg/dl).
• Fasting plasma glucose levels of more than 126 mg/dl
on two or more tests on different days indicate diabetes.
• A random blood glucose test can also be used to
diagnose diabetes.
• A random blood glucose level of 200 mg/dl or higher
indicates diabetes, but it must be reconfirmed on another
day with a fasting plasma glucose or an oral glucose
tolerance test.
Glucagon Physiology 1
• Produced in a cells of pancreas
• 29 amino acid linear molecule
• Stimuli
– 1 stimulus is a fall ( ) in plasma glucose
– 2 stimulus is rise in gut glucose
– 3 stimulus is rise ( ) in plasma amino acids
• Circulation via portal blood to Liver
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ACTIONS OF GLUCAGON
• The primary target for glucagon action is the
liver
• Note: Skeletal muscle is not a target tissue for
glucagon
Specific Actions of Glucagon on the Liver
• Increases liver glycogenolysis
• Increase liver gluconeogenesis
• Increases lipolysis in the liver
Effects of Glucagon on Intermediary
Metabolism
• Carbohydrate Metabolism
•
•
•
•
Stimulation of glycogenolysis
Inhibition of glycogen synthesis
Stimulation of gluconeogenesis
Inhibition of glycolysis
• Lipid Metabolism
• Stimulation of lipolysis - Adipose
• Stimulation of ketogenesis - Liver
• Inhibition of triglyceride synthesis
• Protein metabolism
• Stimulation of proteolysis