2. Insulin
• Proinsulin is converted to insulin and C
peptide.
• Insulin is referred as the storage hormone
as it promotes anabolism and inhibits
catabolism of carbohydrates, fatty acids
and protein.
• In the absence of insulin, most tissues
cannot use glucose and fats/proteins are
broken down to provide energy.
3. Insulin
Mechanism of action :
• Insulin binds to insulin receptors on the
plasma membrane and activates
tyrosine kinase – primarily in adipose
tissue, liver and skeletal muscle.
• The Nerves, RBC’s, Kidney, and Lens of
the eye do not require insulin for
glucose transport.
4. Insulin
Liver :
• Insulin increase the storage of glucose as
glycogen in the liver.
• It inserts the GLUT-2 glucose transport
molecule in the cell membrane.
• It inhibits gluconeogenesis – thus
significantly ↓ glucose output by the liver.
• It decrease the protein catabolism.
5.
6. Insulin
Muscle :
• Insulin stimulates the glycogen
synthesis and protein synthesis.
• Glucose transport into the cells is
facilitated by GLUT-4 into the cell
membrane.
• It inhibits the protein catabolism.
7. Insulin
Adipose tissue :
• Insulin facilitates the storage of
triglyceride by activating plasma
lipoprotein lipase and inhibiting
intracellular lipolysis.
• It increase the glucose uptake by
GLUT-4 insertion into the cell
membrane.
9. 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 :
– Beef pancreas / Pork pancreas
– Human insulin: recombinant DNA origin
10. Insulin
Human Insulin :
• Do not contain measurable amounts of
proinsulin or contaminants.
• Diminished antibody
• Less allergic reactions
• Less lipodystrophy
• Preferred in gestational diabetes
11. • Anti-diabetic medications treat diabetes
mellitus by lowering glucose levels in the blood.
With the exceptions of insulin, exenatide,
and pramlintide, all are administered orally
and are thus also called oral hypoglycemic
agents or oral antihyperglycemic agents.
There are different classes of anti-diabetic
drugs, and their selection depends on:
• Nature of the diabetes
• Age and situation of the person
• Other factors.
12. Diabetes Mellitus Type I
• Type 1 diabetes most commonly afflicts individuals in
puberty or early adulthood, but some latent forms can
occur later in life. The disease is characterized by an
absolute deficiency of insulin caused by massive β-cell
necrosis. Loss of β-cell function is usually ascribed to
autoimmune-mediated processes directed against the β-
cell, and it may be triggered by an invasion of viruses or
the action of chemical toxins. As a result of the destruction
of these cells, the pancreas fails to respond to glucose,
and the Type 1 diabetic shows classic symptoms of insulin
deficiency (polydipsia, polyphagia, polyuria, and weight
loss). Type 1 diabetics require exogenous insulin to avoid
the catabolic state that results from and is characterized
by hyperglycemia and life-threatening ketoacidosis.
13. Diabetes Mellitus Type II
• Most diabetics are Type 2. The disease is
influenced by genetic factors, aging, obesity,
and peripheral insulin resistance rather than by
autoimmune processes or viruses. The
metabolic alterations observed are milder than
those described for Type 1 (for example, Type
2 patients typically are not ketotic), but the
long-term clinical consequences can be just as
devastating (for example, vascular
complications and subsequent infection can
lead to amputation of the lower limbs).
14. Types of DM
• Diabetes mellitus type 1 is a disease caused by
the lack of insulin. Insulin must be used in
Type I, which must be injected.
• Diabetes mellitus type 2 is a disease of insulin
resistance by cells. Treatments include:
– agents that increase the amount of insulin
secreted by the pancreas
– agents that increase the sensitivity of target
organs to insulin
– agents that decrease the rate at which glucose is
absorbed from the gastrointestinal tract.
15. Types of DM
Type 1 Type 2
Age of onset Usually during childhood
or puberty
Frequently over age 35
Nutritional status at
time of onset
Frequently
undernourished
Obesity usually present
Prevalence 5 to 10 % of diagnosed
diabetics
90 to 95 % of diagnosed
diabetics
Genetic
predisposition
Moderate Very strong
Defect or deficiency B cells are destroyed,
eliminating the
production of insulin
Inability of B cells to
produce appropriate
quantities of insulin;
insulin resistance; other
defects
19. Adverse effects of OHAs
Meglitinide
Sulfonylureas
Hypoglycemia
Biguanides
α-Glucosidase inhibitors
GI disturbance
Biguanides
Nausea
Thiazolidinediones
Risk of hepatotoxicity
Sulfonylureas
Meglitinides
Thiazolidinediones
Weight gain
20. 1) Insulin secretagogues
• Useful in the treatment of patients who have
Type 2 diabetes but who cannot be
managed by diet alone.
• Best response to OHA is seen in one who
develops diabetes after age 40 and has had
diabetes less than 5 years.
• Patients with long-standing disease may
require a combination of hypoglycemic drugs
with or without insulin to control their
hyperglycemia.
• Oral hypoglycemic agents should NOT be
given to patients with Type 1 diabetes.
21. A. Sulfonylureas
• These agents are classified as insulin
secretagogues, because they promote
insulin release from the β cells of the
pancreas. The primary drugs used
today are tolbutamide and the
second-generation derivatives,
glyburide, glipizide, and
glimepiride.
22. Sulfonylureas :
• First generation : Acetohexamide,
Chlorpropamide, Tolbutamide,
Tolazamide
• Second generation : Glipizide, Glyburide
– more potent, more efficacious and fewer
adverse effects.
• Third generation : Glimiperide
23. A. Sulfonylureas
• Mechanism of action:
1)stimulation of insulin release from the β
cells of the pancreas by blocking the
ATP-dependent K+
channels, resulting
in depolarization and Ca2+
influx
2)reduction in hepatic glucose production
3)increase in peripheral insulin sensitivity.
24.
25. A. Sulfonylureas
• Pharmacokinetics:
• Given orally, these drugs bind to serum
proteins
• Metabolized by the liver
• Excreted by the liver or kidney
• Tolbutamide has the shortest
duration of action (6-12 hours), whereas
the second-generation agents last
about 24 hours
26. A. Sulfonylureas
• Adverse Effects:
• Weight gain
• Hyperinsulinemia
• Hypoglycemia
• These drugs should be used with caution in patients
with hepatic or renal insufficiency, because delayed
excretion of the drug-resulting in its accumulation-may
cause hypoglycemia.
• Renal impairment is a particular problem in the case of
those agents that are metabolized to active
compounds, such as glyburide.
• Glyburide has minimal transfer across the placenta
and may be a reasonably safe alternative to insulin
therapy for diabetes in pregnancy.
27. 2) Insulin sensitizers
• Two classes of oral agents-the
biguanides and thiazolidinediones
improve insulin action. These agents
lower blood sugar by improving target-
cell response to insulin without
increasing pancreatic insulin secretion.
• They address the core problem in Type
II diabetes—insulin resistance.
28. A. Biguanides
• Metformin (glucophage), the only
currently available biguanide
• it increases glucose uptake and utilization
by target tissues, thereby decreasing
insulin resistance.
• Requires insulin for its action, but it does
not promote insulin secretion.
• Hyperinsulinemia is not a problem. Thus,
the risk of hypoglycemia is far less than
that with sulfonylureas
29. A. Biguanides
• Mechanism of action:
• reduction of hepatic glucose output, largely by
inhibiting hepatic gluconeogenesis.
• Slowing intestinal absorption of sugars
• Improves peripheral glucose uptake and
utilization.
• Metformin may be used alone or in combination
with one of the other agents, as well as with
insulin.
• Hypoglycemia has occurred when metformin
was taken in combination.
30. A. Biguanides
• Pharmacokinetics:
• Metformin is well absorbed orally, is not
bound to serum proteins
• It is not metabolized
• Excretion is via the urine.
31. A. Biguanides
• Adverse effects:
• These are largely gastrointestinal.
• Contraindicated in diabetics with renal and/or
hepatic disease, acute myocardial infarction,
severe infection, or diabetic ketoacidosis.
• It should be used with caution in patients
greater than 80 years of age or in those with a
history of congestive heart failure or alcohol
abuse.
• Long-term use may interfere with vitamin B12
absorption.
32. B. Thiazolidinediones
• Another group of agents that are insulin
sensitizers are the thiazolidinediones (TZDs)
or, more familiarly the glitazones.
• Although insulin is required for their action,
these drugs do not promote its release from the
pancreatic β cells; thus, hyperinsulinemia does
not result.
• Troglitazone was the first of these to be
approved for the treatment of Type 2 diabetic,
but was withdrawn after a number of deaths
due to hepatotoxicity were reported. Presently,
two members of this class are available,
pioglitazone and rosiglitazone.
33. B. Thiazolidinediones
• Mechanism of action:
• Exact mechanism by which the TZDs
lower insulin resistance remains to be
elucidated
• They are known to target the peroxisome
proliferator-activated receptor-γ (PPARγ)-α
nuclear hormone receptor. Ligands for
PPARγ regulate adipocyte production and
secretion of fatty acids as well as glucose
metabolism, resulting in increased insulin
sensitivity in adipose tissue, liver, and
skeletal muscle.
34. B. Thiazolidinediones
• Pharmacokinetics:
• Both pioglitazone and rosiglitazone are
absorbed very well after oral administration and are
extensively bound to serum albumin.
• Both undergo extensive metabolism by different
cytochrome P450 isozymes.
• Pioglitazone:
• Renal elimination is negligible, with the majority of
the active drug and metabolites excreted in the bile
and eliminated in the feces.
• Rosiglitazone:
• The metabolites are primarily excreted in the urine.
35. Oral Anti-diabetic drugs
Mechanisms to reduce blood sugar :
• Stimulation of pancreatic insulin release –
Sulfonylureas, Meglitinide
• Reduce the bio-synthesis of glucose in
liver – Biguanides (Metformin)
• Increase the sensitivity of target cells to
insulin -- Thiazolidinediones
• Retard the absorption of sugars from the
GI tract – Acarbose, Miglitol
36. B. Thiazolidinediones
• Adverse Effects:
• Very few cases of liver toxicity have been
reported with rosiglitazone or pioglitazone.
• Weight increase can occur, possibly through
the ability of TZDs to increase subcutaneous
fat or due to fluid retention.
• Glitazones have been associated with
osteopenia and increased fracture risk.
• Other adverse effects include headache and
anemia.
37. 3) α-glucosidase inhibitors
• Alpha-glucosidase inhibitors are oral anti-
diabetic drugs used for diabetes mellitus
type 2 that work by preventing the
digestion of carbohydrates (such as
starch and table sugar). Carbohydrates
are normally converted into simple sugars
(monosaccharides), which can be
absorbed through the intestine. Hence,
alpha-glucosidase inhibitors reduce the
impact of carbohydrates on blood sugar.
39. α-glucosidase inhibitors
• Mechanism of action:
• These drugs are taken at the beginning of meals. They act
by delaying the digestion of carbohydrates, thereby
resulting in lower postprandial glucose levels. Both drugs
exert their effects by reversibly inhibiting membrane-
bound α-glucosidase in the intestinal brush border. This
enzyme is responsible for the hydrolysis of
oligosaccharides to glucose and other sugars.
Consequently, the postprandial rise of blood glucose is
blunted. Unlike the other oral hypoglycemic agents, these
drugs do not stimulate insulin release, nor do they
increase insulin action in target tissues. Thus, as
monotherapy, they do not cause hypoglycemia. However,
when used in combination with the sulfonylureas or with
insulin, hypoglycemia may develop.
40. α-glucosidase inhibitors
• Pharmacokinetics:
• Acarbose is poorly absorbed. It is
metabolized primarily by intestinal
bacteria, and some of the metabolites
are absorbed and excreted into the
urine. On the other hand, miglitol is very
well absorbed but has no systemic
effects. It is excreted unchanged by the
kidney.
41. α-glucosidase inhibitors
• Adverse effects:
• The major side effects are flatulence,
diarrhea, and abdominal cramping.
Patients with inflammatory bowel
disease, colonic ulceration, or intestinal
obstruction should not use these drugs.
42.
43. 4) Dipeptidyl peptidase-4 inhibitor
• DPP-4 inhibitors or gliptins, are a class of oral
hypoglycemics that block DPP-4. They can be used to
treat diabetes mellitus type 2.
• The first agent of the class - sitagliptin - was approved by
the FDA in 2006.
• Glucagon increases blood glucose levels, and DPP-4
inhibitors reduce glucagon and blood glucose levels. The
mechanism of DPP-4 inhibitors is to increase incretin
levels (GLP-1 and GIP), which inhibit glucagon release,
which in turn increases insulin secretion, decreases
gastric emptying, and decreases blood glucose levels.
44. Dipeptidyl peptidase-4 inhibitor
• Sitagliptin is an orally active dipeptidyl
peptidase-IV (DPP-IV) inhibitor used for
the treatment of patients with Type 2
diabetes. Other agents in this category
are currently in development.
45. Sitagliptin
• Mechanism of action:
• Sitagliptin inhibits the enzyme DPP-IV,
which is responsible for the inactivation of
incretin hormones, such as glucagon-like
peptide-1 (GLP-1). Prolonging the activity
of incretin hormones results in increased
insulin release in response to meals and a
reduction in inappropriate secretion of
glucagon. Sitagliptin may be used as
monotherapy or in combination with a
sulfonylurea, metformin or a glitazone.
46. Sitagliptin
• Pharmacokinetics:
• Sitagliptin is well absorbed after oral
administration. Food does not affect the
extent of absorption. The majority of
sitagliptin is excreted unchanged in the
urine. Dosage adjustments are
recommended for patients with renal
dysfunction.
47. Sitagliptin
• Adverse Effects:
• In general, sitagliptin is well tolerated,
with the most common adverse effects
being nasopharyngitis and headache.
Rates of hypoglycemia are comparable
to those with placebo when sitagliptin is
used as monotherapy or in combination
with metformin or pioglitazone.
48. Anti-diabetic drugs
Glucagon like Peptide : GLP-1 analog :
Xenatide : (Byetta) :
• GLP is an incretin released from the small
intestine which increase the glucose
dependent insulin secretion.
• Xenatide suppress glucagon release and
reduce appetite
• It is administered by SC injection.
50. Endocrine pancreas
Glucagon :
• It has positive inotropic action and
chronotropic action on the heart.
• It acts by stimulation of glucagon
receptors and not through beta 1
receptors.
• This is the basis for using glucagon in
beta blocker overdose.
Hinweis der Redaktion
Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Thus lowers potassium levels in blood.
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) on the cell membrane which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
Inhalable insulin was available from September 2006 to October 2007 in the United States as a new method of delivering insulin, a drug used in the treatment of diabetes, to the body. After the withdrawal of the only inhalable formulation, all currently available insulin formulations are administered by subcutaneous or intravenous injection.[1]
The first such product to be marketed was Exubera, a powdered form of recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed.[2][3][4] Once it has been absorbed, it begins working within the body over the next few hours. Diabetics still need to take a longer acting basal insulin by injection.[5]
A systematic review concluded that inhaled insulin "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective."[6] In October 2007, Pfizer announced that it would be discontinuing the production and sale of Exubera due to poor sales.[7] Several other companies are developing inhaled forms of the drug to reduce the need for daily injections among diabetics.
Tolbutamide can be used in renal failure. Glipizide dose should be reduced in liver dysfunction whereas glyburide dose should be reduced in kidney function.
The incretin hormones GLP-1 (glucagon-like peptide-1) and GIP are produced by the endocrine cells of the intestine following ingestion of food. Exenatide is believed to facilitate glucose control in at least four ways:
Exenatide augments pancreas response (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced;
Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
Exenatide helps slow down gastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
Exenatide has a subtle yet prolonged effect to reduce appetite and thus may prevent weight gain. Most people using Exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated that the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain.
Exenatide reduces liver fat content. Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice and more recently in man.
The main disadvantage of these GLP-1 analogs is that they must be administered by subcutaneous injection.
Pramlintide acetate (Symlin) is a relatively new adjunct treatment for diabetes. It is derived from amylin, a hormone that is released into the bloodstream, in a similar pattern as insulin, after a meal. Like insulin, amylin is deficient in individuals with diabetes. By substituting for amylin, pramlintide aids in the absorption of glucose by slowing gastric emptying, promoting satiety, and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin.
Symlin has been approved for use by the FDA by type 1 and type 2 diabetics who use insulin.
Symlin results in weight loss, allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating.
Symlin is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin's discovery in the early 1920s.
