2. Diabetes mellitus
DM is characterized by elevated blood sugar
levels due to absolute or relative lack of
insulin.
Type 1 diabetes - β-cell failure at outset
◦ Insulin dependent
Type 2 diabetes - Gradual β-cell deterioration
◦ Early stages: Diet and Oral agents
◦ Late-stage: Insulin therapy
5. Glycosylated hemoglobin Hb-A1c
Itis used to monitor the plasma glucose
concentration over prolonged periods of time (4-6
weeks).
Insulin secretion is promoted by:
◦ ↑ blood glucose levels
◦ ↑ amino acids
◦ GI hormones
◦ β-2 agonist: stimulates
glycogenolysis
release of glucagon
9. Insulin
Insulin is a storage hormone:
i. it promotes anabolism
ii. inhibits catabolism of carbohydrates, fatty
acids and protein.
In the absence of insulin:
i. most tissues cannot use glucose
ii. fats/proteins are broken down to provide
energy.
10. Mechanism of action:
Insulin binds to insulin receptors on the
plasma membrane and activates tyrosine
kinase – primarily in adipose tissue, liver and
skeletal muscle.
11. Liver:
1. Insulin increase the storage of glucose as
glycogen in the liver.
◦ It inserts the GLUT-2 glucose transport molecule in
the cell membrane.
1. It inhibits gluconeogenesis – thus significantly
↓ glucose output by the liver.
2. It decrease the protein catabolism.
13. Muscle :
1. Insulin stimulates the glycogen synthesis
and protein synthesis.
◦ Glucose transport into the cells is facilitated by
GLUT-4 into the cell membrane.
1. It inhibits the protein catabolism.
14. Signs and symptoms
The classic symptoms of untreated diabetes are
loss of weight, polyuria (frequent urination),
polydipsia (increased thirst) and polyphagia
(increased hunger).[11] Symptoms may develop
rapidly (weeks or months) in type 1 diabetes,
while they usually develop much more slowly and
may be subtle or absent in type 2 diabetes.
Prolonged high blood glucose can cause glucose
absorption in the lens of the eye, which leads to
changes in its shape, resulting in vision changes.
Blurred vision is a common complaint leading to
a diabetes diagnosis. A number of skin rashes
that can occur in diabetes are collectively known
as diabetic dermadromes.
15. Diabetic emergencies
People (usually with type 1 diabetes) may
also present with diabetic ketoacidosis, a
state of metabolic dysregulation
characterized by the smell of acetone, a
rapid, deep breathing known as
Kussmaul breathing, nausea, vomiting
and abdominal pain, and altered states of
consciousness.
16. Complications
typically develop after many years (10–
20).
damage to blood vessels.
Diabetes doubles the risk of
cardiovascular disease,
”macrovascular" diseases, (related to
atherosclerosis of larger arteries) include
ischemic heart disease (angina and
myocardial infarction), stroke and
peripheral vascular disease.
17. Diabetes also damages the capillaries
(causes microangiopathy).
Diabetic retinopathy, which affects blood
vessel formation in the retina of the eye,
can lead to visual symptoms, reduced
vision, and potentially blindness.
Diabetic nephropathy, the impact of
diabetes on the kidneys, can lead to
scarring changes in the kidney tissue, loss
of small or progressively larger amounts of
protein in the urine, and eventually chronic
kidney disease requiring dialysis.
18. Diabetic neuropathy is the impact of
diabetes on the nervous system, most
commonly causing numbness, tingling and
pain in the feet and also increasing the risk
of skin damage due to altered sensation.
Together with vascular disease in the legs,
neuropathy contributes to the risk of
diabetes-related foot problems (such as
diabetic foot ulcers) that can be difficult to
treat and occasionally require amputation.
19. Insulin
Adipose tissue :
1. Insulin facilitates the storage of
triglyceride by:
i. activating plasma lipoprotein lipase
ii. inhibiting intracellular lipolysis.
2. It increase the glucose uptake by GLUT-4
insertion into the cell membrane.
21. Insulin is a 51 AA peptide
Not active orally.
Insulin is inactivated by insulinase (insulin
transhydrogenase ) found mainly in liver and
kidney.
Dose reduced in renal insufficiency
Sources of Insulin :
◦ Beef pancreas / Pork pancreas
◦ Human insulin: recombinant DNA origin
22. Human Insulin:
Do not contain measurable amounts of
proinsulin or contaminants.
Diminished antibody
Less allergic reactions
Less lipodystrophy
Preferred in gestational diabetes
23. Insulin preparations:
A.Rapid acting insulin: Lispro,
Aspart and Glulisine
B.Short acting insulin:
Regular (crystalline)
C. Intermediate acting insulin:
NPH (isophane) and Lente (insulin zinc)
D. Long acting insulin:
Protamine—zinc , Ultralente, Detimir and Glargine
24. Insulin Duration Route Features
Lispro 3 – 5 hrs I.V or S.C Onset within 15
minutes
Rapid acting
Regular 7 – 10 hrs I.V or S.C common
(crystalline)
Short acting
NPH 16 – 20 hrs S.C NPH can mix
(Neutral protamine with regular
hagedorn)
Intermediate acting
Ultralente 24 – 30 hrs S.C Basal level
Long acting
27. Adverse effects of Insulin
Hypoglycemia
Allergicreactions
Lipodystrophy
Others includes
◦ Seizures
◦ Coma
29. Examples of four regimens that provide both prandial and basal insulin
replacement. B = breakfast;L = lunch; S = supper. NPH = neutral protamine
Hagedorn.
34. Oral Anti-diabetic drugs
Mechanisms to reduce blood sugar
1.Stimulation of pancreatic insulin release –
Sulfonylureas, Meglitinide
2.Reduce the bio-synthesis of glucose in liver –
Biguanides (Metformin)
3.Increase the sensitivity of target cells to insulin
-- Thiazolidinediones
4.Retard the absorption of sugars from the GI
tract – Acarbose, Miglitol
36. Major actions of the principal oral antidiabetic drugs used to treat type 2 diabetes
37. A. Alpha-Glucosidase Inhibitors:
Acarbose (Glucobay) , Miglitol (Glyset)
1. They inhibit α-glucosidase which converts
dietary starch and complex carbohydrates
into simple sugars
2. It reduces absorption of glucose after
meals.
The main side effects includes flatulence
and diarrhea.
38. B. Insulin secretagogues
1. Sulfonylureas :
First generation :
◦ Acetohexamide
◦ Chlorpropamide
◦ Tolbutamide
◦ Tolazamide
Second generation : Glipizide, Glyburide
more potent
more efficacious
fewer adverse effects.
Third generation : Glimiperide
39. Mechanism of Action:
1)Stimulation of insulin release from the β
cells of the pancreas by blocking the ATP-
sensitive K+ channels, resulting in
depolarization and Ca2+ influx
2)reduction in hepatic glucose production
3)increase in peripheral insulin sensitivity.
43. Sulfonylureas: Adverse effects :
Hypoglycemia
Cholestatic jaundice
Weight gain
Cross placenta – fetal hypoglycemia.
Chlorpropamide :
◦ It can cause water retention by ↑ release of ADH
(SIADH)
◦ Disulfiram-like reaction with alcohol.
44. 2. Glinides: Repaglinide, Nateglinide
More rapidly acting insulin enhancers
and shorter duration than sulfonylurea.
These are insulin secretagogues that act by
blocking ATP-dependent K+ channels.
This leads to increased insulin secretion by
pancreatic β-cells.
Hypoglycemia is the common adverse effect.
Less weight gain
45. Repaglinide, Nateglinide
The drug has minimal renal excretion thus
useful in patients with DM and impaired renal
function.
It is designed to be taken with each meal to
stimulate insulin release with meal. If a meal is
skipped, so is the repaglinide.
46. C. Insulin sensitizers
1. Biguanides
2. Thiazolidinediones
1. Biguanides (Metformin):
◦ Inhibits glucose output (gluconeogenesis).
◦ It increase the sensitivity of liver and muscle to insulin.
(increase uptake of glucose)
◦ Does not promote insulin secretion.
◦ It causes modest weight loss.
47. Biguanides: Metformin (Glucophage)
◦ It does not cause hypoglycemia.
◦ It produces a significant ↓ TG and LDL, and ↑HDL.
There is a serious concern about lactic acidosis
especially in patients with kidney disease.
48. 2. Thiazolidinediones (glitazones)
Enhance glucose and lipid metabolism through
action on Peroxisome Proliferator Activated
Receptor (PPAR–γ)
Enhance sensitivity to insulin in muscle and fat
by increasing the GLUT 4 glucose transporters.
E.g. :
Pioglitazone Actos,
Rosiglitazone Avandia: EMA recommended in Sep
2010 to be suspended from the EU market due to elevated
cardiovascular risks
49. Thiazolidinediones:
Beneficial effects on serum lipid; ↓TG and
↑HDL.
Troglitazone(Rezulin), was withdrawn in 1990s
from the market due to an increased incidence of
drug-induced hepatitis.
The main side effect of all thiazolidinediones is
water retention, leading to edema .
51. Agent Mechanism Site of action Main advantages Main side effects
Stimulating insulin
production by •Effective •Hypoglycemia
Sulfonylureas inhibiting the KATP
Pancreatic beta cells
•Inexpensive •Weight gain
channel
•GI symptoms,
•May result in mild including
Decreases insulin weight loss diarrhea, nausea,
Metformin resistance
Liver
•Does not cause abdominal pain
hypoglycemia •Lactic acidosis
•Metallic taste
•GI symptoms,
including
Reduces intestinal diarrhea,
Acarbose glucose absorption
GI tract •Low risk
abdominal
cramping,
flatulence
Reduce insulin
Thiazolidinedion
resistance by Fat, muscle Hepatoxicity
es activating PPAR-γ
56. • Function of incretins:
1. augment glucose-dependent insulin secretion
after a meal.
2. They also slow the rate of absorption of nutrients
into the blood stream by:
1. reducing gastric emptying
2. may directly reduce food intake
3. They inhibit glucagon release from the alpha cells
of the Islets of Langerhans.
57. Both GLP-1 and GIP are rapidly
inactivated by the enzyme dipeptidyl
peptidase 4 (DPP-4).
DPP-4
GIP Inactive products
GLP-1
59. A. Incretin Mimetics:
• Exenatide (Byetta)
• Liraglutide (Victosa): long duration of action approved in 2010
• GLP-1 analogs.
• improves glucose-dependent insulin secretion
• slows gastric emptying time
• decreases food intake
• decreases postprandial glucagon secretion
• promotes β-cell proliferation.
• Consequently, weight gain and postprandial
hyperglycemia are reduced, and HbA1c levels decline.
• Exenatide is administered subcutaneously.
60. Exenatide : Short duration of action.
Use:
as an adjunct to therapy in patients with
Type 2 diabetes who have failed to achieve
adequate glycemic control on a sulfonylurea,
metformin, glitazone, or combination thereof.
Adverse effects:
Nausea, vomiting, and diarrhea.
61. Sitagliptin(Januvia) FDA approved Oct 2006
Vildagliptin (Galvus) EU Approved 2008
Saxagliptin (Onglyza) FDA Approved July 2009
Linagliptin (Tradjenta) FDA Approved May 2, 2011
B. Dipeptidyl Peptidase-IV Inhibitors
62. Sitagliptin (Januvia)
Mechanism of action
• Sitagliptin inhibits the enzyme DPP-IV, which is
responsible for the inactivation of incretin
hormones.
• Prolonging the activity of incretin hormones
results in increased insulin release in response to
meals and a reduction in inappropriate secretion
of glucagon.
• Use:
– as monotherapy or in combination with a
sulfonylurea, metformin or a glitazone.
63. Pharmacokinetics and fate
• Well absorbed after oral administration.
• Food does not affect the extent of absorption.
• The majority excreted unchanged in the urine.
• Dosage adjustments are recommended for
patients with renal dysfunction.
Adverse effects
• Nasopharyngitis and headache.
64. Synthetic Amylin Analog:
Pramlintide (SYMLIN):
Amylin:
37-aa peptide produced by beta cells
and co-secreted with insulin.
Effects:
1. Inhibits glucagon secretion
2. delay gastric emptying
3. suppress appetite
65. Pramlintide (SYMLIN):
•indicated as an adjunct to mealtime insulin
therapy in patients with Type 1 or Type 2
diabetes.
•Effects:
- delays gastric emptying
- decreases postprandial glucagon secretion
- improves satiety
66. •Administration of Pramlintide:
•subcutaneous injection
•injected immediately prior to meals.
•When pramlintide is initiated, the dose of rapid-
or short-acting insulin should be decreased by
50% prior to meals to avoid a risk of severe
hypoglycemia.
•Adverse effects are mainly gastrointestinal and
consist of nausea, anorexia, and vomiting.
67. Agents that increase blood glucose
(hyperglycemics)
Glucagon: Uses
A.firstaid in cases of severe hypoglycemia when the
victim is unconscious or for other reasons cannot
take glucose orally.
B.treatment of overdose with beta blockers
◦ It has positive inotropic action and chronotropic
action on the heart.
◦ It acts by stimulation of glucagon receptors and not
through beta 1 receptors.
68. Diazoxide
Diazoxide is a nondiuretic thiazide that promptly
increases blood glucose levels by direct inhibition of
insulin secretion.
Diazoxide is useful in cases of insulinoma or leucine-
sensitive hypoglycemia.
Diazoxide may cause sodium retention, gastrointestinal
irritation, and changes in circulating white blood cells.