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The Endocrine Pancreas
By pharmacist
Maha A. Hamdi
Production of Pancreatic Hormones
Alpha cells produce glucagon.
Beta cells produce insulin.
Delta cells produce somatostatin.
F cells produce Pancreatic poly peptide→regulation of HCO3
secretion to intestine
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Biosynthesis & Secretion
•
Insulin is synthesized in the rough endoplasmic reticulum of the B
cells .
•
It is then transported to the Golgi apparatus, where it is packaged
into membrane-bound granules.
•
granules move to the plasma membrane by a process involving
microtubules, and their contents are expelled by exocytosis .
•
The insulin then crosses the basal lamina of the B cell and a
neighboring capillary and the fenestrated endothelium of the
capillary to reach the bloodstream.
•
insulin is synthesized as part of a larger preprohormone.
•
Preproinsulin has a 23-amino-acid signal peptide removed as it
enters the endoplasmic reticulum.
•
The remainder of the molecule is then folded, and the disulfide
bonds are formed to make proinsulin.
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Metabolism
•
The half-life of insulin in the circulation in humans is about 5 min.
•
Insulin binds to insulin receptors, and some is internalized.
•
It is destroyed by proteases in the endosomes formed by the
endocytotic process.
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Roles of Insulin
Acts on tissues (especially liver, skeletal muscle,
adipose) to increase uptake of glucose and amino
acids.
- without insulin, most tissues do not
take in glucose and amino acids well (except brain).
Increases glycogen production (glucose storage) in the
liver and muscle.
Stimulates lipid synthesis from free fatty acids and
triglycerides in adipose tissue.
Also stimulates potassium uptake by cells (role in
potassium homeostasis
Principal Actions of Insulin.
Rapid (seconds)
Increased transport of glucose, amino acids, and K
+
into insulin-
sensitive cells
Intermediate (minutes)
Stimulation of protein synthesis
Inhibition of protein degradation
Activation of glycolytic enzymes and glycogen synthase
Inhibition of phosphorylase and gluconeogenic enzymes
Delayed (hours)
Increase in mRNAs for lipogenic and other enzymes
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Effects of Insulin on Various Tissues.
Adipose tissue
Increased glucose entry
Increased fatty acid synthesis
Increased glycerol phosphate synthesis
Increased triglyceride deposition
Activation of lipoprotein lipase
Inhibition of hormone-sensitive lipase
Increased K
+
uptake
Muscle
Increased glucose entry
Increased glycogen synthesis
Increased amino acid uptake
Increased protein synthesis in ribosomes
Decreased protein catabolism
Decreased release of gluconeogenic amino acids
Increased ketone uptake
Increased K
+
uptake
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Liver
Decreased ketogenesis
Increased protein synthesis
Increased lipid synthesis
Decreased glucose output due to decreased
gluconeogenesis, increased glycogen synthesis, and
increased glycolysis
General
Increased cell growth
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Glucose Transporters
•
Glucose enters cells by facilitated diffusion or, in the intestine and
kidneys, by secondary active transport with Na
+
.
•
In muscle, adipose, and some other tissues, insulin stimulates
glucose entry into cells by increasing the number of glucose
transporters in the cell membranes.
•
glucose transporters, named GLUT 1–7 .
•
their affinity for glucose varies.
•
GLUT 4 is the transporter in muscle and adipose tissue that is
stimulated by insulin.
•
A pool of GLUT 4 molecules is maintained within vesicles in the
cytoplasm of insulin-sensitive cells.
•
When the insulin receptors of these cells are activated, the vesicles
move rapidly to the cell membrane and fuse with it, inserting the
transporters into the cell membrane .
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•
When insulin action ceases, the transporter-containing patches of
membrane are endocytosed and the vesicles are ready for the next
exposure to insulin.
•
Activation of the insulin receptor brings about the movement of the
vesicles to the cell membrane by activating phosphatidylinositol 3-
kinase (IP3) .
•
In the tissues in which insulin increases the number of glucose
transporters in the cell membranes, the rate of phosphorylation of
the glucose, once it has entered the cells, is regulated by other
hormones.
•
Growth hormone and cortisol both inhibit phosphorylation in certain
tissues
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•
Insulin-sensitive tissues also contain a population of GLUT 4 vesicles
that move into the cell membrane in response to exercise, a process
that occurs independent of the action of insulin.
•
This is why exercise lowers blood sugar.
Relation to Potassium
•
Insulin causes K
+
to enter cells, with a resultant lowering of the
extracellular K
+
concentration.
•
insulin increases the activity of Na
+
–K
+
ATPase in cell membranes, so
that more K
+
is pumped into cells.
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The Insulin Receptor
•
The insulin receptor is composed of two subunits, and has intrinsic
tyrosine kinase activity.
•
Activation of the receptor results in a cascade of phosphorylation
events:
•
The growth-promoting protein anabolic effects of insulin are mediated
via phosphatidylinositol 3-kinase (PI- 3K)
Insulin: Summary and Control Reflex Loop
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Insulin Action on Cells:
Dominates in Fed State Metabolism
•
glucose uptake in most cells
to ↑glycogen storage (not active muscle)
•
glucose use and storage
•
protein synthesis
•
fat synthesis
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Oral Glucose Tolerance Test
Oral Glucose Tolerance Test
•
Measurement of the ability of
β
cells to secrete insulin.
•
Ability of insulin to lower blood glucose.
•
Normal person’s rise in blood [glucose] after drinking solution is
reversed to normal in 2 hrs.
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Glucose Tolerance
•
In diabetes, glucose piles up in the bloodstream, especially after
meals.
•
If a glucose load is given to a diabetic, the plasma glucose rises higher
and returns to the baseline more slowly than it does in normal
individuals.
•
The response to a standard oral test dose of glucose, the oral glucose
tolerance test, is used in the clinical diagnosis of diabetes
Glucose Tolerance
•
Impaired glucose tolerance in diabetes is due in part to reduced entry
of glucose into cells (decreased peripheral utilization).
•
In the absence of insulin, the entry of glucose into skeletal, cardiac,
and smooth muscle and other tissues is decreased .
•
Glucose uptake by the liver is also reduced, but the effect is indirect.
•
Intestinal absorption of glucose is unaffected, as is its reabsorption
from the urine by the cells of the proximal tubules of the kidneys.
•
Glucose uptake by most of the brain and the red blood cells is also
normal
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•
The second and the major cause of hyperglycemia in diabetes is
derangement of the glucostatic function of the liver .
•
The liver takes up glucose from the bloodstream and stores it
as glycogen, but because the liver contains glucose 6-
phosphatase it also discharges glucose into the bloodstream.
•
Insulin facilitates glycogen synthesis and inhibits hepatic
glucose output.
•
When the plasma glucose is high, insulin secretion is normally
increased and hepatic glucogenesis is decreased.
•
This response does not occur in type 1 diabetes (as
insulin is absent) and in type 2 diabetes (as tissues
are insulin resistant).
•
Glucagon can contribute to hyperglycemia as it
stimulates gluconeogenesis.
•
Glucose output by the liver can be stimulated by
catecholamines, cortisol, and growth hormone (ie,
during a stress response).
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Effects of Hyperglycemia
•
Hyperglycemia cause symptoms resulting from the hyperosmolality
of the blood.
•
In addition, there is glycosuria because the renal capacity for glucose
reabsorption is exceeded.
•
Excretion of the osmotically active glucose molecules entails the loss
of large amounts of water (osmotic diuresis;
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•
The resultant dehydration activates the mechanisms regulating water
intake, leading to polydipsia. There is an appreciable urinary loss of
Na
+
and K
+.
•
every gram of glucose excreted, 4.1 kcal is lost from the body.
•
Increasing the oral caloric intake to cover this loss simply raises the
plasma glucose further and increases the glycosuria, so mobilization
of endogenous protein and fat stores and weight loss are not
prevented.
•
.
•
When plasma glucose is episodically elevated over time, small
amounts of hemoglobin A are nonenzymatically glycated to form
HbA
Ic
. Careful control of the diabetes with insulin reduces the
amount formed and consequently HbA
Ic
concentration is measured
clinically as an integrated index of diabetic control for the 4- to 6-wk
period before the measurement.
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Effects of Intracellular Glucose Deficiency
•
Glucose catabolism is normally a major source of energy for cellular
processes, and in diabetes energy requirements can be met only by
drawing on protein and fat reserves. Mechanisms are activated that
greatly increase the catabolism of protein and fat, and one of the
consequences of increased fat catabolism is ketosis
•
Deficient glucose utilization and deficient hormone sensing (insulin,
leptin, CCK) in the cells of the hypothalamus that regulate satiety are
the probable causes of hyperphagia in diabetes.
•
The feeding area of the hypothalamus is not inhibited and thus
satiety is not sensed so food intake is increased.
•
Glycogen depletion is a common consequence of intracellular glucose
deficit, and the glycogen content of liver and skeletal muscle in
diabetic is usually reduced.
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Other Factors Regulating Insulin Release
•
Amino acids stimulate insulin release (increased uptake into cells,
increased protein synthesis).
•
Keto acids stimulate insulin release (increased glucose uptake to prevent
lipid and protein utilization).
•
Insulin release is inhibited by stress-induced increase in adrenal
epinephrine
- epinephrine binds to alpha adrenergic receptors on beta cells
- maintains blood glucose levels
•
Glucagon stimulates insulin secretion (glucagon has opposite actions).
Actions of Glucagon
1-Acts on the liver to cause breakdown of glycogen
(glycogenolysis), releasing glucose into the bloodstream.
2-Inhibits glycolysis
3-▲ production of glucose from amino acids (gluconeogenesis).
4- ▲lipolysis, to free fatty acids for metabolism.
Result: maintenance of blood glucose levels during fasting
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Mechanism of Action of Glucagon
•
Main target tissues: liver, muscle, and adipose tissue
•
Binds to a Gs-coupled receptor, resulting in increased cyclic AMP and
increased PKA activity.
•
Also activates IP3 pathway (increasing Ca
++
)
Glucagon Action on Cells:
Dominates in Fasting State Metabolism
•
Glucagon prevents hypoglycemia by cell production of glucose
•
Liver is primary target to maintain blood glucose levels
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Regulation of Glucagon Release
•
Increased blood glucose levels inhibit glucagon release.
•
Amino acids stimulate glucagon release (high protein, low
carbohydrate meal).
•
Stress: epinephrine acts on beta-adrenergic receptors on alpha cells,
increasing glucagon release (increases availability of glucose for
energy).
•
Insulin inhibits glucagon secretion.
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Other Factors Regulating Glucose
Homeostasis
•
Glucocorticoids (cortisol): stimulate gluconeogenesis and lipolysis,
and increase breakdown of proteins.
•
Epinephrine/norepinephrine: stimulates glycogenolysis and lipolysis.
•
Growth hormone: stimulates glycogenolysis and lipolysis.
•
Note that these factors would complement the effects of glucagon,
increasing blood glucose levels.
Hormonal Regulation of Nutrients
Right after a meal (resting):
•
- blood glucose elevated
•
- glucagon, cortisol, GH, epinephrine low
•
- insulin increases (due to increased glucose)
•
- Cells uptake glucose, amino acids.
•
- Glucose converted to glycogen, amino acids into protein,
lipids stored as triacylglycerol.
•
- Blood glucose maintained at moderate levels.
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Hormonal Regulation of Nutrients
A few hours after a meal (active):
•
- blood glucose levels decrease
•
- insulin secretion decreases
•
- increased secretion of glucagon, cortisol, GH, epinephrine
•
- glucose is released from glycogen stores (glycogenolysis)
•
- increased lipolysis (beta oxidation)
•
- glucose production from amino acids increases (oxidative
deamination; gluconeogenesis)
•
- decreased uptake of glucose by tissues
•
- blood glucose levels maintained
Regulation of Insulin and Glucagon Secretion
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Consequences of Uncorrected Deficiency in
Type I Diabetes Mellitus
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Type II Diabetes Mellitus
•
Slow to develop.
•
Genetic factors are
significant.
•
Occurs most often in people
who are overweight.
•
Decreased sensitivity to
insulin or an insulin
resistance.
•
Obesity.
•
Do not usually develop
ketoacidosis.
•
May have high blood
[insulin] or normal [insulin].
Treatment in Diabetes
•
Change in lifestyle:
•
Increase exercise:
•
Increases the amount of membrane GLUT-4 carriers in the skeletal muscle cells.
•
Weight reduction.
•
Increased fiber in diet.
•
Reduce saturated fat.
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Hypoglycemia
•
Over secretion of
insulin.
•
Reactive
hypoglycemia:
•
Caused by an
exaggerated response
to a rise in blood
glucose.
•
Occurs in people who
are genetically
predisposed to type II
diabetes.
Metabolic Regulation
•
Anabolic effects of insulin are antagonized by the hormones of the
adrenals, thyroid, and anterior pituitary.
•
Insulin, T
3
, and GH can act synergistically to stimulate protein synthesis.