Pharmacology – III
PHL-418
Pancreatic Hormones
& Antidiabetic Drugs
Dr. Hassan Madkhali
Assistant Professor
Department of Pharmacology
E mail: h.madkhali@psau.edu.sa
Content Layout with List
• OVERVIEW: PANCREASE and PANCREATIC
HORMONES
• INSULIN AND GLUCAGON
• ACTIONS OF INSULIN
• DIABETES MELLITUS
• DRUGS FOR THE TREATMENT OF DIABETES MELLITUS
• INSULIN
• ORAL ANTI-DIABETIC DRUGS
Pancreas
•
•
Digestive functions
Secretes two important hormones
Insulin
Glucagon
Secretes other hormones, such as amylin, somatostatin, and pancreatic
polypeptide
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.
 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.
Hormones
 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.
 Both insulin and glucagon circulate unbound to carrier proteins
and have short half-lives of 6 minutes.
 Approximately 50% of the insulin and glucagon in blood is
metabolized in the liver; most of the remaining hormone is
metabolized by the kidneys.
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.
Actions of Insulin
• To initiate its effects on target cells, insulin first binds with and
activates a membrane receptor protein
• The insulin receptor is a tetramer made up of two α-subunits
that lie outside the cell membrane and two β-subunits that
penetrate the cell membrane and protrude into the cytoplasm
• When insulin binds with the alpha subunits on the outside of the
cell, portions of the beta subunits protruding into the cell
become autophosphorylated.
• Thus, the insulin receptor is an example of an enzyme-linked
receptor
• Autophosphorylation of the beta subunits of the receptor
activates a local tyrosine kinase, which in turn causes
phosphorylation of multiple other intracellular enzymes including
a group called insulin-receptor substrates (IRS).
• The net effect is to activate some of these enzymes while
inactivating others.
• In this way, insulin directs the intracellular metabolic machinery
to produce the desired effects on carbohydrate, fat, and protein
metabolism.
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.
In Muscle, Insulin Promotes the Uptake and Metabolism
of Glucose
 Mostly muscle tissue depends not on glucose for its energy but on fatty
acids, because normal resting muscle membrane is only slightly
permeable to glucose, except when the muscle fiber is stimulated by
insulin.
 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
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
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
Glucose Is Released from the Liver Between Meals
 When the blood glucose level begins to fall to a low level between
meals, several events cause the liver to release glucose back into the
circulating blood:
1. The decreasing blood glucose causes the pancreas to decrease its
insulin secretion.
2. The lack of insulin then reverses all the effects for glycogen storage
3. The lack of insulin activates the enzyme phosphorylase, causes the
splitting of glycogen into glucose phosphate.
4. The enzyme glucose phosphatase, now becomes activated by the
insulin lack and causes the phosphate radical to split away from the
glucose
 Thus, the liver removes glucose from the blood when it is present in
excess after a meal and returns it to the blood when the blood glucose
concentration falls between meals
Insulin Promotes Conversion of Excess Glucose into
Fatty Acids and Inhibits Gluconeogenesis in Liver.
• When the quantity of glucose entering the liver cells is
more, insulin promotes the conversion of all this excess
glucose into fatty acids.
• These packaged as triglycerides in VLDL and transported
by blood to the adipose tissue and deposited as fat.
• Insulin also inhibits gluconeogenesis.
Lack of Effect of Insulin on Glucose Uptake and
Usage by the Brain
• Insulin has little effect on uptake or use of glucose in brain
• Instead, the brain cells are permeable to glucose
• The brain cells are also quite different from most other
cells of the body in that they normally use only glucose for
energy and can use other energy substrates, such as fats,
only with difficulty.
• It is essential that the blood glucose level always be
maintained above a critical level
• When the blood glucose falls too low, symptoms of
hypoglycemic shock develop, characterized by progressive
nervous irritability that leads to fainting, seizures, and even
coma.
Effect of Insulin on Carbohydrate Metabolism in Other
Cells
• Insulin increases glucose transport into and
glucose usage by most other cells of the body
• The transport of glucose into adipose cells mainly
provides substrate for the glycerol portion of the
fat molecule.
• Therefore, in this indirect way, insulin promotes
deposition of fat in these cells.
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 increases the utilization of glucose by body
• 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
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 a-glycerol phosphate. This
substance supplies the glycerol that combines with fatty
acids to form the triglycerides that are the storage form of
fat
Insulin Deficiency Increases Use of Fat for
Energy
• All aspects of fat breakdown and use for providing energy
are greatly enhanced in the absence of insulin.
• This occurs even normally between meals when secretion
of insulin is minimal, but it becomes extreme in diabetes
mellitus .
• Insulin Deficiency Causes Lipolysis of Storage Fat and
Release of Free Fatty Acids.
• Consequently, the plasma concentration of free fatty acids
begins to rise within minutes.
• This free fatty acid then becomes the main energy
substrate used by essentially all tissues of the body
besides the brain.
Insulin Deficiency Increases Plasma Cholesterol and
Phospholipid Concentrations
• The excess of fatty acids in the plasma associated with
insulin deficiency also promotes liver conversion of some
of the fatty acids into phospholipids and cholesterol, two of
the major products of fat metabolism.
• These two substances, along with excess triglycerides
formed at the same time in the liver, are then discharged
into the blood in the lipoproteins, so the plasma
lipoproteins increase
• This high lipid concentration—especially the high
concentration of cholesterol—promotes the development
of atherosclerosis in people with serious diabetes.
Excess Usage of Fats During Insulin Lack Causes
Ketosis and Acidosis
• Insulin lack also causes excessive amounts of
acetoacetic acid to be formed in the liver cells.
• At the same time, the absence of insulin also
depresses the utilization of acetoacetic acid in the
peripheral tissues.
• Thus, so much acetoacetic acid is released from the
liver
• Some of the acetoacetic acid is also converted into bhydroxybutyric acid and acetone.
• These two substances, along with the acetoacetic acid,
are called ketone bodies, and their presence in large
quantities in the body fluids is called ketosis.
• In severe diabetes the acetoacetic acid and the bhydroxybutyric acid can cause severe acidosis and
coma, which often leads to death.
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
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.
Summary
The major effects of insulin on muscle and adipose tissue are:
• (1) Carbohydrate metabolism:
(a) it increases the rate of glucose transport across the cell membrane.
(b) it increases the rate of glycolysis by increasing hexokinase (glucokinase) and
6-phosphofructokinase activity.
(a) it stimulates the rate of glycogen synthesis and decreases the rate of glycogen breakdown.
• (2) Lipid metabolism:
(a)
(b)
(c)
(d)
it decreases the rate of lipolysis in adipose tissue and hence lowers the plasma fatty acid level.
it stimulates fatty acid and triacylglycerol synthesis in tissues.
it increases the uptake of triglycerides from the blood into adipose tissue and muscle.
it decreases the rate of fatty acid oxidation in muscle and liver.
• (3) Protein metabolism:
(a) it increases the rate of transport of some amino acids into tissues.
(b) it increases the rate of protein synthesis in muscle, adipose tissue, liver, and other
tissues.
(a) it decreases the rate of protein degradation in muscle (and perhaps other tissues).
Insulin and Growth Hormone Interact Synergistically to
Promote Growth
• Because insulin is required for the synthesis of proteins,
it is as essential for growth of an animal as growth
hormone is.
• A combination of these hormones causes dramatic
growth.
• Thus, it appears that the two hormones function
synergistically to promote growth.
Mechanisms of Insulin Secretion
Insulin vesicles
or granules
Glycolysis
Beta-cell
GLUCAGON
-Glucagon is also called the hyperglycemic hormone
-The binding of glucagon to hepatic receptors results in
activation of adenylyl cyclase and generation of the second
messenger cyclic AMP, which in turn activates protein
kinase, leading to phosphorylation that results in the
activation or deactivation of a number of enzymes.
Effects on Glucose Metabolism
• Glucagon Promotes Hyperglycemia
• Greatly enhance the availability of glucose to the organs of the
body
Glucagon stimulates glycogenolysis:
• Glucagon has immediate and pronounced effects on the liver to
increase glycogenolysis and the release of glucose into the blood.
• This effect is achieved through activation of liver phosphorylase and
simultaneous inhibition of glycogen synthase.
Glucagon stimulates gluconeogenesis:
• Glucagon increases the hepatic extraction of amino acids from the
plasma and increases the activities of key gluconeogenic enzymes.
Other Effects of Glucagon
• Occurs only when its concentration rises well above the
maximum normally found in the blood.
• Activates adipose cell lipase, making increased quantities
of fatty acids available to the energy systems of the body.
• Glucagon also inhibits the storage of triglycerides in the
liver, which prevents the liver from removing fatty acids
from the blood.
• Enhances the strength of the heart
• Increases blood flow in some tissues, especially the
kidneys
• Enhances bile secretion
• Inhibits gastric acid secretion.
Regulation of Glucagon Secretion
• Increased Blood Glucose Inhibits Glucagon
Secretion
• Increased Blood Amino Acids Stimulate
Glucagon Secretion
• Exercise Stimulates Glucagon Secretion
• Somatostatin Inhibits Glucagon and Insulin
Secretion
Somatostatin
Somatostatin is a peptide hormone secreted by δ cells of the
pancreatic islets (also produced in the hypothalamus) in response to:
- blood glucose
- plasma amino acids
- fatty acids
Somatostatin decreases gastrointestinal functions by:
- motility
- secretion
- absorption
Somatostatin
splanchnic blood flow
Somatostatin release of:
- insulin
- glucagon
Diabetes Mellitus (DM)
•
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 major forms of diabetes mellitus
• Type I diabetes mellitus, also called insulindependent 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.
Other forms include:
-Gestational DM, GDM (triggered by pregnancy)
-DM can also result rarely from diseases of the
pancreas, and medications (Drug-induced
diabetes: thiazide diuretics, beta-blockers and
statins).
DM in KSA
The yearly total number of registered cases of diabetes according to gender (G) and type (T) of diabetes from the start of registry in 2000 to 2012.
Ref: Khalid Al-Rubeaan et al. A Web-Based Interactive Diabetes Registry for Health Care Management and Planning in Saudi Arabia. J Med Internet Res
2013;15(9):e202.
DM in KSA
Source: International Diabetes Federation
Middle East & North Africa (MENA)
TREATMENT OF DM
Anti-diabetic drugs:
• Insulin
• Incretin mimetics
• Oral Anti-diabetics
Insulin
• Insulin is a 51 AA peptide
• Not active orally.
• Insulin is inactivated by insulinase found mainly in
liver and kidney.
• Dose reduced in renal insufficiency
• Sources of Insulin :
– Bovine pancreas / Porcine pancreas
– Human insulin: Recombinant DNA origin
Insulin preparations :
• Rapid acting insulin : Lispro, Aspart and Glulisine
• Short acting insulin: Regular (crystalline)
• Intermediate acting insulin: NPH (isophane) and
Lente (insulin zinc)
• Long acting insulin: Ultralente, Detimir and
Glargine
Insulin
Duration
Route
Features
Lispro
3 – 5 hrs
I.V or S.C
Onset within 15
minutes
Regular
7 – 10 hrs
I.V or S.C
common
NPH
16 – 20 hrs
S.C
NPH can mix with
regular
Ultralente
24 – 30 hrs
S.C
Basal level
(crystalline)
(Neutral
protamine hagedorn)
https://en.wikipedia.org/wiki/Insulin_(medication)
Oral Anti-diabetic drugs
A. Sulfonylureas:
1st generation
2nd generation
Acetohexamide (Dymelor)
Glyburide (Micronase)
Glipizide (Glucotrol)
Glimepiride (Amaryl)
Chlorpropamide (Diabinese)
Tolazamide (Tolinase)
Tolbutamide (Orinase)
B. Meglitinides (Glinides): Repaglinide (Prandin), Nateglinide
(Starlix)
C. Biguanines: Metformin (Glucophage)
D. Thiozolidonediones (glitazones): Pioglitazone (Actos),
rosiglitazone (Avandia)
E. α-Glucosidase inhibitors: Acarbose (Precose), Miglitol (Glycet)
F. Dipeptidyl peptidase IV inhibitors (DPP-4 inhibitors): Sitagliptin
(Januvia)
G. Sodium-glucose cotransporter 2 (SGLT2) inhibitors:
Canagliflozin (Invokana)
Note:
Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes, why?
because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or
posing a risk of hypoglycaemia.
(This is explain why it is included in the most of combination therapies)
Ref: BEATRIZ LUNA and MARK N. FEINGLOS. Oral Agents in the Management of Type 2 Diabetes Mellitus. AMERICAN FAMILY PHYSICIAN.
MAY 1, 2001 / VOLUME 63, NUMBER 9
Combinations:
•
•
•
•
•
•
•
Pioglitazone & metformin (Actoplus Met)
Glyburide & metformin (Glucovance)
Glipizide & metformin (Metaglip)
Sitagliptin & metformin (Janumet)
Saxagliptin & metformin (kombiglyze)
Repaglinide & metformin (Prandimet)
Pioglitazone & glimepiride (Duetact)
Metformin MOA
MOA
PPARs: peroxisome
proliferator-activated
receptors
Sulfonylureas & Meglitinides MOA
Sulfonylureas
Meglitinides,
inhibit the efflux
of K+
α-Glucosidase inhibitors MOA
Dipeptidyl peptidase IV inhibitors and Incretin mimetics MOA
Incretin mimitics bind to
GLP-1 receptors
GLP-1 :glucagon-like peptide-1
SGLT2 inhibitors MOA
Pharmacist roles and responsibilities in diabetes care
and management
•
Inform the diabetic patients that health education could make a significant difference
and it is needed to give the diabetic patients a certain understanding of the disease
•
Inform them about the importance of compliance with medication, diet and exercise,
weight control and the use of herbal preparations.
•
Encourage them to do self blood glucose monitoring regularly.
•
Monitor and promote patient adherence to recommended treatment regimens
•
Identify and resolving drug-related problems
•
Provide education
•
Remind them about the importance of doing regular exams
•
Inform and convince them that unhealthy diet and physical inactivity are the most
important risk factors of DM. Encourage them to participate actively in managing and
monitoring their condition.
Thank you
?