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1. Endocrine function of
pancreas

2. Pancreas
Digestive functions
Secretes two important hormones:
❑Insulin
❑Glucagon
❑Secretes other hormones, such as amylin, somatostatin, and
pancreatic polypeptide

3. Physiologic Anatomy of the Pancreas
 Two major types of tissues
1) The acini,which secrete digestive juices into duodenum
2) The islets of Langerhans, which secrete insulin and glucagon into
blood.
 1 to 2 million islets of Langerhans, organized around small capillaries
into which its cells secrete their hormones.

4.  The islets contain three major types of cells alpha, beta, delta cell
 The beta cells 60 % of all the cells of the islets, lie mainly in the middle of
each islet and secrete insulin and amylin,
 The alpha cells, 25 % of the total, secrete glucagon
 The delta cells, about 10 %, secrete somatostatin.
 One other type of cell, the PP cell, is present in small numbers in the islets
and secretes pancreatic polypeptide.

6. Hormones
 Both insulin and glucagon are synthesized as large preprohormones.
In Endoplasmic reticulum, the prohormones are formed. Most of this is
further cleaved in the Golgi apparatus to form hormone and peptide
fragments before being packaged in the secretory granules.
 Insulin is a polypeptide containing two amino acid chains (21 and 30
amino acids, respectively) connected by disulfide bridges.
 Glucagon is a straight-chain polypeptide of 29 amino acid residues.
 Approximately 50% of the insulin and glucagon in blood is
metabolized in the liver; most of the remaining hormone is
metabolized by the kidneys.

7. Insulin

8. Insulin and Its Metabolic Effects
❖Insulin was first isolated from the pancreas in 1922 by Banting and Best
❖Associated with “blood sugar,”
❖Insulin has effects on carbohydrate metabolism.
❖Insulin affects fat and protein metabolism

9. 1. Insulin
❖Insulin is a peptide hormone
❖produced by beta cells of the pancreas (also called
the islets of Langerhans)
❖Regulating carbohydrate and fat metabolism in the
body. Insulin causes cells in the liver, skeletal muscles,
and fat tissue to absorb glucose from the blood.
❖In the liver and skeletal muscles, glucose is stored as
glycogen, and in fat cells (adipocytes) it is stored as
triglycerides.

10. ❖When control of insulin levels fails, diabetes mellitus can result.
As a consequence, insulin is used medically to treat some forms of
diabetes mellitus.
❖Type 1 diabetes is an auto-immune condition in which the
immune system is activated to destroy the cells in the pancreas
which produce insulin
❖Type 2 diabetes is a progressive condition in which the body
becomes resistant to the normal effects of insulin and/or gradually
loses the capacity to produce enough insulin in the pancreas

11. Insulin Structure
❖Human insulin consists of
51aa (amino acid) in two
chains (A and B)
❖A chain (21 amino acids)
❖B chain (30 amino acids)
❖Two this are connected by 2
disulfide bridges
❖If two chains brake apart
functional activity lost.

12. BIOSYNTHESIS OF INSULIN:
❖Synthesis occurs in the β cells
❖Synthesis primarily beigins with the formation of
preproinsulin
❖Preproinsulin is then cleaved by protease activity into
proinsulin (in Endoplasmic reticulum ER)
❖Proinsulin is then packaged into vesicles in the Golgi
apparatus
❖Proinsulin is then converted by enzymes (endopeptidases
known as prohormone convertases (PC1 and PC2), as well as
the exoprotease carboxypeptidase E) into insulin and
connecting peptide (C-peptide)
❖Granules are then transported to the surface of the β cells
where insulin and C-peptide are released

14. Secretion of Insulin
❖Insulin secretion by the β cells of the islets of Langerhans of the pancreas is
closely coordinated with the release of glucagon by pancreatic α cells.
❖The relative amounts of insulin and glucagon released by the pancreas are
regulated so that the rate of hepatic glucose production is kept equal to the use
of glucose by peripheral tissues.
❖In particular, insulin secretion is increased by:
❖Glucose
❖Amino acids
❖Gastrointestinal hormones

16. Glucose: The β cells are the most important glucose-sensing cells in the body.
Like the liver, β cells contain GLUT-2 transporters and have glucokinase activity,
and thus can phosphorylate glucose in amounts proportional to its actual
concentration in the blood.
Ingestion of glucose or a carbohydrate-rich meal leads to a rise in blood glucose,
which is a signal for increased insulin secretion

19. Amino acids: Ingestion of protein causes a transient rise in plasma
amino acid levels, which, in turn, induces the immediate secretion of
insulin. Elevated plasma arginine, for example, stimulates insulin
secretion.
Gastrointestinal hormones: Most gastrointestinal hormones favor
insulin release. The intestinal peptides cholecystokinin and gastric-
inhibitory polypeptide (glucose-dependent insulinotropic peptide)
increase insulin secretion in response to oral glucose, and so are
referred to as “incretins.”

20. Mechanisms of Action of Insulin
❖The insulin receptor is synthesized as a single polypeptide that is
glycosylated and cleaved into α and β subunits, which are then
assembled into a tetramer linked by disulfide bonds
❖A hydrophobic domain in each β subunit spans the plasma
membrane. The extracellular α subunit contains the insulin-binding
site.
❖The cytosolic domain of the β subunit is a tyrosine kinase, which is
activated by insulin.

22. Signal transduction:
❖The binding of insulin to the α subunits of the insulin receptor induces conformational changes that are
transduced
❖to the β subunits.
❖This promotes a rapid auto phosphorylation of specific tyrosine residues on each β subunit
❖Autophosphorylation initiates a cascade of cellsignaling responses, including phosphorylation of a family of
proteins called insulin receptor substrates (IRS).
❖ At least four IRS have been identified that show similar structures but different tissue distributions.
❖Phosphorylated IRS proteins interact with other signaling molecules through specific domains, activating a
number of pathways that affect gene expression, cell metabolism and growth.

25. Membrane effects of insulin: Glucose transport in some tissues, such as skeletal
muscle and adipocytes, increases in the presence of insulin.
Insulin promotes the recruitment of insulin-sensitive glucose transporters
(GLUT-4) from a pool located in intracellular vesicles.

28. Insulin Is a Hormone Associated with Energy
Abundance
❖When there is great abundance of energy-giving foods in the diet, especially
excess amounts of carbohydrates, insulin is secreted in great quantity.
❖Insulin plays an important role in storing the excess energy.
❖In the case of excess carbohydrates, it causes them to be stored as glycogen
mainly in the liver and muscles.
❖Excess carbohydrates is also converted under the stimulus of insulin into fats
and stored in the adipose tissue.
❖Insulin has a direct effect in promoting amino acid uptake by cells and
conversion of these amino acids into protein.
❖In addition, it inhibits the breakdown of the proteins that are already in the
cells.

29. Effect on Carbohydrate Metabolism
❖Immediately after a high-carbohydrate meal, glucose that
is absorbed into the blood causes rapid secretion of insulin
❖Insulin causes rapid uptake, storage, and use of glucose by
almost all tissues of the body, but especially by the muscles,
adipose tissue, and liver.

30. In Muscle, Insulin Promotes the Uptake and
Metabolism of Glucose
 Under two conditions the muscles do use large amounts of glucose.
1. During moderate or heavy exercise. because exercising muscle fibers
become more permeable to glucose even in the absence of insulin
because
2. During few hours after a meal: At this time the blood glucose
concentration is high and the pancreas is secreting large quantities of
insulin. The extra insulin causes rapid transport of glucose into the
muscle cells.
 Abundant glucose transported into the muscle cells is stored in the form
of muscle glycogen

31. In the Liver, Insulin Promotes Glucose Uptake and
Storage, and Use
 Insulin causes most of the glucose absorbed after a meal to be stored
almost immediately in the liver in the form of glycogen.
 The mechanism of glucose uptake and storage in the liver :
1. Insulin inactivates liver phosphorylase, which normally causes liver
glycogen to split into glucose.
2. Insulin causes enhanced uptake of glucose from blood by liver by
increasing the activity of the enzyme glucokinase, causes the initial
phosphorylation of glucose after it diffuses into liver
3. Insulin also increases the activities of the enzymes that promote
glycogen synthesis, glycogen synthase

32. Effect of Insulin on Fat Metabolism
Insulin Promotes Fat Synthesis and Storage
❖Insulin has several effects that lead to fat storage in adipose tissue.
❖Insulin promotes fatty acid synthesis, in liver cells
❖Fatty acids are then transported from the liver by way of the blood
lipoproteins to the adipose cells to be stored

33. Role of Insulin in Storage of Fat in the Adipose Cells
Insulin has two other essential effects that are required for fat storage in
adipose cells:
1. Insulin inhibits the action of hormone-sensitive lipase. This is the
enzyme that causes hydrolysis of the triglycerides already stored in the
fat cells.
2. Insulin promotes glucose transport through the cell membrane into the
fat cells. Some of this glucose is then used to synthesize minute
amounts of fatty acids, but forms large quantities of glycerol phosphate.
This substance supplies the glycerol that combines with fatty acids to
form the triglycerides that are the storage form of fat

34. Effect of Insulin on Protein Metabolism and on Growth
Insulin Promotes Protein Synthesis and Storage
During the few hours after a meal proteins are also stored in the tissues by
insulin
1. Insulin stimulates transport of many of amino acids into the cells, eg
valine, leucine, isoleucine, tyrosine, and phenylalanine.
2. Insulin increases the translation of mRNA, thus forming new proteins
3. Over a longer period of time, insulin also increases the rate of
transcription of selected DNA, forming increased quantities of RNA and
still more protein synthesis

35. 4. Insulin inhibits the catabolism of proteins
5. In the liver, insulin depresses the rate of gluconeogenesis, this
suppression of gluconeogenesis conserves the amino acids in the
protein stores of the body.

36. GLUCAGON
❖Glucagon is a polypeptide hormone secreted by the α cells of the pancreatic
islets of Langerhans.
❖Glucagon, along with epinephrine, cortisol, and growth hormone , opposes
many of the actions of insulin .
❖Most importantly, glucagon acts to maintain blood glucose levels by activation
of hepatic glycogenolysis and gluconeogenesis.
❖Glucagon is composed of 29 amino acids arranged in a single polypeptide
chain. Glucagon is synthesized as a large precursor molecule (preproglucagon)
that is converted to glucagon through a series of selective proteolytic cleavages,
similar to those described for insulin biosynthesis.

38. Stimulation of glucagon secretion
The α cell is responsive to a variety of stimuli that signal actual or potential
hypoglycemia. Specifically, glucagon secretion is increased by:
1. Low blood glucose: A decrease in plasma glucose concentration is the primary
stimulus for glucagon release. During an overnight or prolonged fast, elevated
glucagon levels prevent hypoglycemia
2. Amino acids: Amino acids derived from a meal containing protein stimulate
the release of both glucagon and insulin. The glucagon effectively prevents
hypoglycemia that would otherwise occur as a result of increased insulin
secretion that occurs after a protein meal.

39. Epinephrine: Elevated levels of circulating epinephrine produced by the adrenal
medulla, or norepinephrine produced by sympathetic innervation of the
pancreas, or both, stimulate the release of glucagon.
Thus, during periods of stress, trauma, or severe exercise, the elevated
epinephrine levels can override the effect on the α cell of circulating substrates.
In these situations—regardless of the concentration of blood glucose—glucagon
levels are elevated in anticipation of increased glucose use. In contrast, insulin
levels are depressed.

40. Inhibition of glucagon secretion
Glucagon secretion is significantly decreased by elevated blood glucose and by
insulin. Both substances are increased following ingestion of glucose or a
carbohydrate-rich meal

41. Metabolic effects of glucagon
1. Effects on carbohydrate metabolism: The intravenous administration of glucagon leads to an
immediate rise in blood glucose. This results from an increase in the breakdown of liver (not
muscle) glycogen and an increase in gluconeogenesis.
2. Effects on lipid metabolism: Glucagon activates lipolysis in adipose. The free fatty acids
released are taken up by liver and oxidized to acetyl coenzyme A, which is used in ketone body
synthesis.
3. Effects on protein metabolism: Glucagon increases uptake of amino acids by the liver,
resulting in increased availability of carbon skeletons for gluconeogenesis. As a consequence,
plasma levels of amino acids are decreased.

42. Mechanism of action of glucagon
❖Glucagon binds to high-affinity G protein-coupled receptors on the cell
membrane of hepatocytes. The receptors for glucagon are distinct from those
that bind insulin or epinephrine.
❖Glucagon binding results in activation of adenylyl cyclase in the plasma
membrane
❖This causes a rise in cAMP (the “second messenger”), which, in turn, activates
cAMP-dependent protein kinase and increases the phosphorylation of specific
enzymes or other proteins.
❖This cascade of increasing enzymic activities results in the phosphor ylation-
mediated activation or inhibition of key regulatory enzymes involved in
carbohydrate and lipid metabolism

44. Diabetes Mellitus
Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein
metabolism caused by either lack of insulin secretion or decreased sensitivity of
the tissues to insulin
Two forms of diabetes mellitus
❖Type I diabetes mellitus, also called insulin-dependent diabetes mellitus
(IDDM), is caused by impaired secretion of insulin.
❖Type II diabetes mellitus, also called non–insulin-dependent diabetes mellitus
(NIDDM), is caused by resistance to the metabolic effects of insulin in target
tissues.

45. Type I Diabetes
❖Caused by Impaired Secretion of Insulin by the Beta Cells of the Pancreas
❖Often, type I diabetes is a result of autoimmune destruction of beta cells, but
it can also arise from the loss of beta cells resulting from viral infections.
❖Because the usual onset of type I diabetes occurs during childhood, it is
referred to as juvenile diabetes.
Pathophysiological features:
❖Hyperglycemia as a result of impaired glucose uptake into tissues and
increased glucose production by the liver (increased gluconeogenesis)

46. Depletion of proteins resulting from decreased synthesis and
increased catabolism Depletion of fat stores and increased ketosis
As a result :
• Glucosuria, osmotic diuresis, hypovolemia
• Hyperosmolality of the blood, dehydration, polydipsia
• Hyperphagia but weight loss; lack of energy
• Acidosis progressing to diabetic coma; rapid and deep breathing
• Hypercholesterolemia and atherosclerotic vascular disease

47. Type II Diabetes Mellitus
❖Insulin Resistance Is the Type II Diabetes Mellitus
❖Type II diabetes is far more common than type I diabetes (accounting
for approximately 90% of all cases of diabetes)
❖Usually associated with obesity.
❖This form of diabetes is characterized by impaired ability of target
tissues to respond to the metabolic effects of insulin, which is referred
to as insulin resistance.
❖In contrast to type I diabetes, pancreatic beta cell morphology is
normal throughout much of the disease, and there is an elevated rate
of insulin secretion.

48. Metabolic syndrome
Metabolic syndrome include:
(1) obesity, especially accumulation of abdominal fat;
(2) Insulin resistance
(3) fasting hyperglycemia
(4) lipid abnormalities such as increased blood triglycerides
(5) hypertension.

49. Physiology of Diagnosis of Diabetes Mellitus
Urinary Glucose
Fasting Blood Glucose and Insulin Levels.
FBG levels in the early morning is normally 80-90 mg/100 ml.
FBG above 110 mg/100 ml often indicates diabetes
In type I diabetes, plasma insulin levels are very low or undetectable during fasting
and even after a meal.
Acetone Breath
Increased Acetoacetic acid in the blood is converted to acetone. This is volatile and
vaporized into the expired air.
Consequently, one can frequently make a diagnosis of type I diabetes mellitus
simply by smelling acetone on the breath of a patient.

50. Glucose Tolerance Test
•when a normal, fasting person
ingests 1 gram of glucose per kg
of body weight, the blood
glucose level rises from about
90 mg/100 ml to 120 to 140
mg/100 ml and falls back to
below normal in about 2 hours.
•In a person with diabetes, this
test is always abnormal

52. Other hormones
❖Pancreatic polypeptide (PP) is a polypeptide secreted by PP cells in the
endocrine pancreas predominantly in the head of the pancreas.
❖ It consists of 36 amino acids and has molecular weight about 4200 Da.
❖The function of PP is to self-regulate pancreatic secretion activities (endocrine
and exocrine); it also has effects on hepatic glycogen levels and gastrointestinal
secretions.
❖Its secretion in humans is increased after a protein meal, fasting, exercise, and
acute hypoglycemia and is decreased by somatostatin and intravenous glucose.

53. Amylin
❖Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide
hormone.It is cosecreted with insulin from the pancreatic β-cells in the ratio of
approximately 100:1.
❖Amylin plays a role in glycemic regulation by slowing gastric emptying and
promoting satiety.

54. Somatostatin
Somatostatin, also known as growth hormone–inhibiting hormone
(GHIH), is a peptide hormone that regulates the endocrine system
and affects neurotransmission and cell proliferation via interaction
with G protein-coupled somatostatin receptors and inhibition of the
release of numerous secondary hormones. Somatostatin inhibits
insulin and glucagon secretion