2. Diabetes Mellitus
Diabetes mellitus (DM) is a metabolic disorder resulting from a
defect in insulin secretion or insulin action, or both
Classification of DM
Type 1
• Immune Mediated
• Idiopathic
Type 2 (Maturity onset)
Other specific types
Gestational Diabetes mellitus
3. Prevalence of DM
India is the “Diabetes Capital” of the World
In 2010 - >200 million people worldwide had DM and
300 million will subsequently have the disease by 2025
India had 32 million diabetic subjects in the year 2000
and this number would increase to 80 million by the year
2030
There is increased incidence of DM in urban population
than rural
4. Classification
Type 1
Immune Mediated
Idiopathic
Type 2 (Maturity onset)
Other specific types
Gestational Diabetes mellitus
5. Development and Progression of Type 2 Diabetes*
Progression of Disease
Impaired Glucose Tolerance
Insulin level
Insulin resistance
Hepatic glucose
production
Diabetes Diagnosis
Postprandial
glucose
Fasting glucose
β-cell function
Frank Diabetes
4–7 years
0
50
100
Relative%
11. What is the role of an ideal oral hypoglycaemic agent?
Conserve islet cell function - delay the subsequent
use of insulin.
Improve patient compliance- single daily dosing.
Reduce the incidence of hypoglycaemic events
13. Role of Exercise in Type 2 DM
• Exercise - probably the best treatment for
type 2 diabetes
• Lowers blood sugar
• Decrease insulin resistance
• Raise metabolism
• Improve blood flow through capillaries
• Improve stroke volume & blood lipids
• Control & prevent moderate hypertension
• Decrease body mass
14. Pancreas – the site of action
Stimulate insulin secretion
• Sulfonylurea
• Meglitinide
Pancrease
15. Classification of Oral Antidiabetics
Oral Hypoglycaemic Agents
1. Sulphonylureas
First Generation: Tolbutamide, Chlorpropamide
Second Generation: Glibenclamide (glyburide), Glipizide,
Gliclazide, Glimepiride
2. Meglitinide Analogues:
Repaglinide, Nateglinide
16. Oral Hypoglycaemic Agents
Sulphonylureas
First Generation
Tolbutamide
• O.O.A. is within one hour & lasts for 6-12 Hrs
• It is weaker, short acting, less likely to cause hypoglycemia
Chlorpropamide
• O.O.A. is within one hour & lasts for 24-60 Hrs
• It is more potent, long lasting, risk of prolonged hypoglycemia
• Potentiates ADH action
17. Sulphonylureas (contd)
Second Generation
Glibenclamide (glyburide)
• O.O.A. is within 1-4 hours & lasts for 10-24 Hrs
• It is more potent than tolbutamide, risk of severe hypo.
Glipizide
• O.O.A. is within 1-3 hours & lasts for 10-24 Hrs
• Less potent than glibenclamide but more potent than tolbutamide
• Risk of prolonged hypoglycemia
Gliclazide
• O.O.A. & D.O.A, same as glipizide
• More potent than tolbutamide
• Has an antioxdent and antiplatelet action
• Less weight gain
Glimepiride:
• Same as glipizide
18. Sulphonylureas
M.O.A
• Stimulates Insulin release from β- cells
• Inhibits SUR-1 receptors present on ATP sensitive K+ channels → depolarization
followed by Ca+ entry → insulin release
• Glucagon levels are suppressed
Pharmacokinetics
• well absorbed
• PPB is high
• Metabolized in liver or kidney and excreted in urine
Adverse effects
• Hypoglycemia
• Weight gain
• Cross placental barrier – fetal hypoglycemia (avoid in gestational DM)
Contra indications
• Ketocanazole, chloramphenicol and anticoagulants- inhibit their metabolism
• Sulfonamides, salicylates etc- protein binding displacement
• Propranolol masks the symptoms of sulfonylureas
19. Meglitinide Analogues
Repaglinide
• Its O.O.A is within one hour & lasts for 4-5 hrs
• Dose 0.25-4mg before each meal
Nateglinide
• Its O.O.A & D.O.A, same as repaglinide
• Dose 60-120mg before each meal
• Hypoglycemic risk is low
M.A.O
• Stimulate insulin release, same as sulfonylurea
• Administered before meal to control PP blood glucose
20. Advantages of Nateglinide/Repaglinide
Flexibility in mealtime dosing - „Ramzan Drug‟
No significant increase in bodyweight
Can be utillised in mild to moderate renal failure
Nateglinide: approved in hepatic failure
Dosage:
Repaglinide: 0.5mg/1mg/2mg/4mg per dose per meal
Nateglinide: 60mg/120mg per dose per meal
Lower incidence of hypoglycemia
21. Useful Situations
– Elderly patients in whom hypoglycaemia is a concern
– Patients with kidney failure or mild hepatic impairment
– patients taking low-dose sulphonylureas who encounter
problems with hypoglycaemia
– Patients with irregular meal patterns
Int J Clin Pract. 2003 Jul-Aug;57(6):535-41.
22. Summary of insulin release and MOA of Antidiabetics
ATP Dependent K+ Channel
24. Sites of action of Antihyperglycemic Agents
Liver Muscle Adipose
tissue
• Bigunides - Metformin
• Thiazolidonediones – Rosiglitazone etc.
U
P
T
A
K
E
UTILIZATION Of GLUCOSE
25. Antihyperglycemic Agents
Biguanides
Metformin
The primary drug of choice for diabetes by ADA guidelines.
• Does not stimulate insulin release
• Not dependent on functional β- cells for its action
• Does not lower blood glucose in normal subjects
• Causes anorexia, no weight gain
• As monotherapy, rarely causes hypoglycemia
Dose:
500mg twice a day after meals
26. Biguanides Contd
Advantages:
Perpetuates weight loss
Can be combined with insulin to reduce
insulin requirements
Decreases risk of macro & microvascular
disease
Disadvantages:
Nausea, Vomiting and diarhorrea (5%),
Vitamin B12 Deficiency (0.5%)
27. Adverse effect:
Nausea, metallic taste, anorexia,
flatulence & diarrhoea
Non diabetic use of Metformin:
Hirsutism with PCOD to enhance
fertility in women
Phenformin
• Its use has been discontinued because of
lacticacidosis
Biguanides Contd
28. Biguanides Contd
M.O.A
• Increased uptake and utilization of glucose by muscles →
reduce insulin resistance
• Inhibition of hepatic and renal gluconeogenesis → reduce
hepatic glucose output
• Slowing of glucose absorption from GIT
• Promotion of insulin binding to its receptor
PK
• No PPB, Plasma t1/2 2-3 hours
• Excreted unchanged by kidneys
29. Thiazolidinediones (Glitazones)
New class of drugs – acts as agonist to nuclear
receptor PPAR-Ƴ in adipose tissue, sk. Muscle
and liver.
Pioglitazone
• D.O.A. more than 24hrs
• 10-45 mg OD
Rosiglitazone (withdrawn from the market in Oct. 2010 b/o risk of
Heart failure and MI)
• D.O.A. same as pioglitazone
• Dose 4-8mg OD
30. Glitazones Contd
MOA
• Stimulates (nuclear receptor) i.e. Peroxisome Proliferator Activated
Receptor-gamma (PPAR-Ƴ) → promotes transcription of insulin
responsive genes which control glucose & lipid metabolism → ↑
insulin sensitivity & ↓ insulin resistance
• Promotes uptake and utilization of glucose by increasing the GLUT-4
transpotors
• Decrease glucose output by inhibiting gluconeogenesis
AE
• Weight gain. hepatotoxicity is rare, yet LFT are advisable
CI
• Hepatic failure, pregnancy, lactating mother, children and heart failure
31. GIT As a Site of Target
Alpha glucosidase enzyme
facilitates digestion of complex
starches, oligosaccharides and
disaccharides into
monosaccharides so that these
are absorbed from the small
intestine. The digestion is also
facilitated by pancreatic alpha
amylase.
32. α-Glycosidase Inhibitors
Acarbose, Miglitol, Voglibose
Work on the brush border of the intestine
cause carbohydrate malabsorption
• Reduce post meal hyperglycemia
• Regular use tend to lower HbA1c,
triglycerides and body weight
• Do not directly affect insulin secretion
• No hypoglycemia
• Dose: 50-100mg TDS
33. α-Glycosidase Inhibitors contd.
M.O.A
• Reduce PP digestion and absorption of
carbohydrates by inhibiting α – glucosidase
enzyme
PK
• Absorption of acarbose is minimal, but miglitol
is absorbed well
• A Part of acarbose is excreted unchanged
while a part is metabolized by intestinal
bacterial flora
34. α-Glycosidase Inhibitors Contd.
Advantages:
• Selective for postprandial hyperglycaemia
• No hypoglycaemic symptoms
Disadvantages:
• Abdominal distension and flatus
• Only effective in mild hyperglycaemia
Dose:
Acarbose - 25 mg to 50mg TID
Miglitol - 25mg to 100mg TID
Voglibose - 0.2 to 0.3 mg TID
35. What are Incretins?
I s a group of hormones (GLP & GIP) – released
after meals and augment glucose-dependent
insulin secretion
GLP-1 (glucagon-like peptide 1) (*More Imp)
• is a prominent insulinotrophic incretin.
• half life- 1-2 min.
• metabolized quickly by DPPIV enzyme.
GIP: Glucose-dependent insulinotrophic
polypeptide
Small effect in Type 2 diabetes.
36. Incretin concept
Insulin secretion dynamics is dependent on the
method of administration of glucose
Intravenous glucose gives a marked first and
second phase response
Oral glucose gives less marked first and second
phase insulin response, but a prolonged and
higher insulin concentration
38. Insulinconcentration
0 10 20 30 40 50 60 70 80 90
Minutes
Glucose given orally
Glucose given intravenously to
achieve the same profile
Incretin effect
Iso - glycemic profiles
40. GLP-1 localisation
Cleaved from proglucagon in
intestinal L-cells (and neurons in
hindbrain/hypothalamus)
Secreted in response to meal
ingestion
Cleared via the kidneys
41. Incretin-Mimetics
Incretin–mimetics
• Glucagon Like Peptide – 1 (GLP-1) → released after meals from the upper &
lower bowel → augment glucose dependent insulin secretion, during the phase
of nutrition absorption from GIT
• t ½ GLP-1 – 1 to 2 min
• Metabolized quickly by DPP-IV enzyme
Exenatide [incretin (GLP-1) agonist]
• Obtained from salivary gland venom of Gila monster
• Resistant to DPP-IV degradation
• Potent agonist of GLP-1 receptor, Orally inactive
• Given SC (5-10μg) twice daily, 30-60 min before meals
• It reduces only post meal glucose rise
MOA
• Stimulates insulin secretion from β- cells
• Decreases glucagon release
AE
• Diarrhea, nausea, anorexia
42. GLP-1 is secreted
from the L-cells
in the intestine
This in turn…
• Stimulates glucose-dependent
insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
Long term effects
demonstrated in animals…
• Increases beta-cell mass and
maintains beta-cell efficiency
• Reduces food intake
Upon ingestion of food…
GLP-1 Modes of Action in Humans
43. His Ala Glu Gly Thr Phe Thr Ser Asp
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Ile Ala Trp Leu Val Lys Gly Arg Gly
Val
Ser
Glu
Phe
GLP-1
7
37
NH2
Native GLP-1 has short duration of action
(t½=2.6 minutes) when given intravenously
DPP IV
45. His Ala Glu Gly Thr Phe Thr Ser Asp
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Ile Ala Trp Leu Val Lys Gly Arg Gly
Val
Ser
Glu
Phe
DPP-IV (DPP4)
inhibitors7
37
NH2
DPP IV
46. DPP-IV Inhibitors
DPP-IV Inhibitors
Sitagliptin, Vildagliptin, Saxagliptin, Septagliptin, Allogliptin
• Orally active
• Selective inhibitors of DPP-IV enzyme that deactivates GLP-1
MOA
• Increase insulin secretion
• Decrease glucagon release
• Delay gastric emptying
• Suppress appetite
AE
• Nasopharyngitis because substance P is also a substrate for DPP-IV, whose
levels get elevated, GIT distress and diarrhea
47. Incretin hormones GLP-1 and GIP are released by the intestine
throughout the day, and their levels increase in response to a meal.
Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and
prolonging the actions of these hormones.
Release of
active incretins
GLP-1 and GIP Blood glucose
in fasting and
postprandial
states
Ingestion
of food
Glucagon
(GLP-1)
Hepatic
glucose
production
GI tract
DPP-4
enzyme
Inactive
GLP-1
XSitagliptin
(DPP-4
inhibitor)
Insulin
(GLP-1 and
GIP)
Glucose-
dependent
Glucose
dependent
Pancreas
Inactive
GIP
β cells
α cells
Glucose
uptake by
peripheral
tissues
30
Mechanism of Action of Sitagliptin
51. SGLT-2 Inhibitors
SGLT-2 Inhibitors
• Newer antidiabetic drugs
• Kidney continuously filters glucose through glomerulous which is reabsorbed
back from PT by Na2+ glucose co-transporter -2 (SGLT-2)
• Inhibition of SGLT – 2 decreases glucose re-absorption
Dapaglifozin, Serglifozin, Remoglifozin
Advantages
• Weight loss
• No hypoglycemia
Disadvantages
• Because of polyuria there will be more polydipsia
• Increased risk of urinary infection in presence of glycosuria
• Risk of Na2+loss