Diabetes Mellitus Pharmacology

1. Diabetes Mellitus-1
By
Dr. Tehreem Zulfiqar
Assistant Professor Pharmacology
Nishtar Medical University

2. Learning Outcomes
By the end of this session you will be able to:
•Describe pathophysiology of diabetes along
with its important types
•Enumerate different types of insulin
•Classify oral hypoglycemic agents.

3. Diabetes Mellitus
• “Diabetes is a group of metabolic diseases
characterized by hyperglycemia resulting from
defects in insulin secretion, insulin action, or both.”
• The chronic hyperglycemia of diabetes is associated
with long-term damage, dysfunction, and failure of
different organs, especially the eyes, kidneys,
nerves, heart, and blood vessels.

4. Criteria for Diagnosing Diabetes
According to WHO diabetes is if :
•Fasting Glucose =>7mmol or 126mg/dl
•Random Glucose =>11.1mmol or 200mg/dl

5. Clinical Classification of Diabetes
There are four clinical classifications of diabetes:
•◦Type 1 diabetes (insulin dependent diabetes
mellitus)
•◦Type 2 diabetes (non-insulin dependent diabetes
mellitus)
•◦Gestational diabetes
•◦Diabetes due to other causes (genetic defects or
medications, etc)

6. Type 1 Diabetes Mellitus
•Also known as Juvenile Onset Diabetes
•Complete or near-total insulin deficiency
•Occurs <30 years of age
•Underweight patient

7. Etiology
•T cell mediated autoimmune destruction of beta
cells /glutamic acid decarboxylase antibodies
(GAD Abs)
•Genetic predisposition (HLA- DR3 DR4 genes)
•30-50% concordance in identical twins
•May be triggered by an invasion of viruses or the
action of chemical toxins
•Due to β-cell destruction pancreas fails to
respond to glucose

8. Type 1 Diabetes Mellitus

9. Type 1 Diabetes Mellitus
•Shows classic symptoms of insulin deficiency
(polydipsia, polyphagia, polyuria, and weight loss)
•Require exogenous (injected) insulin to control
hyperglycemia and maintain blood glucose
concentrations as close to normal as possible

10. Type 2 Diabetes Mellitus
•Most common
•• >40 years of age
•• Normal or overweight
•• Genetic factor
•– Strongly positive

11. Type 2 Diabetes Mellitus
Etiology
Insulin resistance
•Initially normal or increased insulin secretion or but
later decreases.
•β-cells are usually normal but disturbance is
•*less active insulin production
•*less cellular response to insulin due to deficiency
of GLUT 4 transporter in insulin sensitive cells
•*presence of antibodies against insulin

13. Type 2 Diabetes Mellitus
•The goal in treating T2DM is to maintain blood glucose
concentrations within normal limits and to prevent
the development of long-term complications of the
disease
•◦Weight reduction, exercise, and dietary modification
decrease insulin resistance and correct the
hyperglycemia of type 2 diabetes in some patients

14. Type 2 Diabetes Mellitus
•Most patients are dependent on pharmacologic
intervention with oral glucose-lowering agents
•As the disease progresses, β-cell function declines
and insulin therapy is often required

16. Comparison of Type 1 and Type 2
Diabetes

17. Gestational Diabetes Mellitus
•Gestational diabetes is defined as carbohydrate
intolerance due to Insulin resistance with onset or
first recognition during late pregnancy
•It is important to maintain adequate glycemic
control during pregnancy
•Uncontrolled gestational diabetes can lead to fetal
macrosomia(abnormally large body), shoulder
dystocia(difficult delivery), and neonatal
hypoglycemia

18. Gestational Diabetes Mellitus
•Diet, exercise, and or insulin administration are
effective in this condition
•Glibenclamide (glyburide)and metformin may be
safe alternatives to insulin therapy for gestational
diabetes

19. Clinical Features of Diabetes
Mellitus
•Hyperglycemia
•Glycosuria
•Polyuria
•Polydipsia
•Polyphagia
•Dehydration
•Loss of weight
•Poor resistance to infections due to protein
depletion

21. Dietary modifications in diabetes
Low fat and/or high fiber foods, which are generally encouraged for people with
diabetes

23. Role of Exercise in Diabetes

24. Insulin
Insulin is a storage hormone:
•It promotes anabolism
•Inhibits catabolism of carbohydrates, fatty acids and
protein
In the absence of insulin:
•Most tissues cannot use glucose
•Fats/proteins are broken down to provide energy

25. Insulin
•Insulin is a polypeptide hormone consisting of two
peptide chains connected by disulfide bonds
•Synthesized as a precursor (proinsulin) that
undergoes proteolytic cleavage to form insulin and
C-peptide, both of which are secreted by the β cells
of the pancreas

26. 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

27. Secretion of Insulin

28. Actions of Insulin

29. Actions of Insulin

30. Sources of Insulin
•Human insulin is produced by recombinant DNA
technology using E. coli or yeast altered genetically
to contain the human insulin gene
•Modifications of the amino acid sequence of human
insulin have produced insulins with different PK
properties

31. Types of Insulin
Rapid acting and short acting insulin
•Regular insulin (Humulin-R®, Actrapid®)
•Insulin lispro(Humalog®)
•Insulin aspart (Novorapid®)
•Insulin glulisine
Intermediate acting insulin
•Neutral protamine Hagedorn(NPH) insulin
suspension of crystalline zinc insulin combined at
neutral pH with the positively charged polypeptide
protamine
•Insulin NPH is also called insulin isophane
(HumulinN NPH®)

32. Types of Insulin
Long acting insulin
•Insulin glargine(Lantus®)
•Insulin detemir
Insulin combinations
•70% NPH insulin plus 30% regular insulin
(Humulin70/30®)
•◦50% NPH insulin plus 50% regular insulin
•◦75% NPL insulin plus 25% insulin lispro
(HumalogMix®)

33. Oral hypoglycemic Agents

34. Introduction
• These drugs lower blood glucose levels and
are effective orally.
• The chief drawback of insulin is—it must be
given by injection.

35. Classification
• Enhance Insulin secretion
• 1.Sulfonylureas
• First generation: Tolbutamide
• Second generation: Glibenclamide, Glipizide,
• 2.Meglitinide analogues
• Repaglinide, Nateglinide
• 3. Glucagon-like peptide-1 (GLP-1) receptor agonists
(Injectable drugs)
• Exenatide, Liraglutide
• 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Sitagliptin, Vildagliptin.

36. Classification
• Overcome Insulin resistance
• 1. Biguanide
• Metformin
• 2. Thiazolidinediones (PPAR activator)
• Pioglitazone
• Rosiglitazone

37. Miscellaneous antidiabetic drugs
• α-Glucosidase inhibitors
• Acarbose, Miglitol, Voglibose
• Sodium-glucose cotransport-2 (SGLT-2)
Inhibitor: Dapagliflozin

39. Summary

42. Diabetes Mellitus-2
By
Dr. Tehreem Zulfiqar
Assistant Professor Pharmacology
Nishtar Medical University

43. Learning Outcomes
By the end of this session you will be able to:
•Describe different types of insulin in detail
•Discuss important adverse effects associated with
the use of insulin

44. Insulin Preparations
•Rapidly acting insulin
•Short acting insulin
•Intermediate acting insulin
•Long acting insulin
•Insulin combinations

46.  These include following preparations:
• Insulin lispro (Humalog®)
• Insulin aspart
• Insulin Glulisine
(Novorapid®)
Rapidly Acting Insulin
Preparations

47. Rapidly Acting Insulin Preparations
• Lispro, aspart and glulisine forms are classified as
rapid-acting insulins because of their rapid onset
and short duration of action
•Rapid acting insulins offer more flexible treatment
regimens and may lower the risk of hypoglycemia

48. Rapidly Acting Insulin Preparations
• Insulin aspart and insulin glulisine have
pharmacokinetic and pharmacodynamic properties
similar to those of insulin lispro
• Administered to mimic the prandial (mealtime)
release of insulin
•Usually not used alone but with a longer-acting
insulin to ensure proper glucose control
•Administered SC

49. • Insulin lispro is usually administered 15 minutes prior to
a meal or immediately following a meal
• Insulin glulisine can be taken either 15 minutes before a
meal or within 20 minutes after starting a meal
• Insulin aspart should be administered just prior to the
meal or up to 15 minutes following the meal
Rapidly Acting Insulin
Preparations

50. Short Acting Insulin- Regular
Insulin
•A short-acting, soluble, crystalline zinc insulin; now
made by recombinant DNA techniques.
•Given subcutaneously
•Given IV in emergencies
•Rapidly lowers blood glucose levels

51. Short Acting Insulin- Regular
Insulin
•In high concentrations, eg, in the vial, regular insulin
molecules self-aggregate in antiparallel fashion to
form dimers that stabilize around zinc ions to create
insulin hexamers.
• The hexameric nature of regular insulin causes a
delayed onset and prolongs the time to peak action.

52. • All of the rapid-acting formulations are suitable for IV
administration, although regular insulin is most
commonly used when the IV route is needed
• Insulin lispro, insulin aspart, and insulin glulisine may
also be used in external insulin pumps
Rapidly Acting and Short Acting
Insulin Preparations

53. • Neutral protamine Hagedorn (NPH) insulin suspension
• Its duration of action is intermediate because of the
delayed absorption from its conjugation with
protamine forming a less-soluble complex
• NPH insulin should only be given subcutaneously
(never IV)
Intermediately Acting Insulin

54. • Useful in treating all forms of diabetes except diabetic
ketoacidosis and emergency hyperglycemia
• Used for basal control and is usually given along with
rapid- or short-acting insulin for mealtime control
Intermediately Acting Insulin

55.  Insulin Glargine (Lantus®)
•Insulin glargine is a soluble, “peakless” long-acting
insulin analog.
•The attachment of two arginine molecules to the B-
chain carboxyl terminal and substitution of a glycine
for asparagine at the A21 position created an analog
•Given SC
Long Acting Insulin Preparations

56. Long Acting Insulin Preparations
•Insulin detemir
•Most recently developed long-acting insulin analog.
•Terminal threonine is dropped from the B30
position and myristic acid (a C-14 fatty acid chain) is
attached to the terminal B29 lysine.
•Insulin detemir and insulin glargine should not be
mixed in the same syringe with other insulins

57. • Various premixed combinations of human insulins are
available
• 70% NPH insulin plus
30% (70/30®)
regular insulin (Humulin
• 50% NPH insulin plus 50% regular insulin
• 75% NPL insulin plus 25% insulin lispro (Humalog
Mix®)

59. • Standard treatment involves injection of insulin twice
daily
• Intensive treatment seeks to normalize blood glucose
through more frequent injections of insulin (three or
more times daily in response to monitoring blood
glucose levels)
Standard Treatment Versus Invasive
Treatment

60. • The frequency of hypoglycemic episodes, coma,
and seizures is higher with intensive treatment
• Patients on intensive therapy show a significant
reduction in long-term complications of diabetes
as retinopathy, nephropathy, and neuropathy
• Intensive therapy is not recommended for patients
with longstanding diabetes, significant microvascular
complications, advanced age, and hypoglycemic
unawareness
Standard Treatment Versus Invasive
Treatment

62. • Insulin is degraded in the GIT if taken orally
• Insulin is administered by subcutaneous injection
• In a hyperglycemic emergency, regular insulin is
injected IV
• Continuous subcutaneous insulin infusion (insulin
pump) does not require multiple daily injections
Insulin Administration

63. • Dose, site of injection, blood supply, temperature, and
physical activity can affect the duration of action of
the various preparations
• Insulin is inactivated by insulin-degrading enzyme
(insulin protease) which is found mainly in the liver and
kidney
Insulin Administration

64. Insulin
injection
sites

65. • Symptoms of hypoglycemia in excessive dose
• Lipodystrophy
• Allergic reactions
• Local injection site reactions
• Diabetics with renal insufficiency may
require adjustment of the insulin dose
Adverse Effects of Insulin

67. Management of Hypoglycemia
1. Give simple sugar orally if pt. is conscious and can
swallow – orange juice, candy, glucose tablets, lump
of sugar
2. Give Glucagon (SC or IM) if pt. is unconscious or
cannot take sugar by mouth
3. As soon as pt. regains consciousness, he should be
given carbohydrate by mouth
4. If pt. does not respond to the above measures, he is
given 50 ml of 50% glucose I.V. or 1000 ml of 5%-10%
glucose in water I.V.

68. Preventing Hypoglycemic
Reactions Due to Insulin
Instruct the pt. as follows:
1. Hypoglycemia may be prevented by maintaining
regular exercise, diet and insulin
2. Early symptoms of hypoglycemia should by
recognized and treated
3. Carry at all times some form of simple
carbohydrate (orange juice, sugar, candy)
4. Extra food should be taken before unusual
physical activity or prolonged periods of
exercise
5. Between-meal and bedtime snacks may be
necessary to maintain a normal glucose level.

69. Exercise
•A 13-year-old boy with type 1 diabetes is brought to
the hospital complaining of dizziness. Laboratory
findings include severe hyperglycemia, ketoacidosis,
and a blood pH of 7.15. A rapidly acting insulin
preparation is being used for the management.
•Which of the following is the most likely
complication of insulin therapy in this patient?
•(A) Dilutional hyponatremia
•(B) Hypoglycemia
•(C) Increased bleeding tendency
•(D) Pancreatitis
•(E) Severe hypertension

70. Key
•Answer is B

71. Summary

72. INSULIN ROUTE
Ultra rapid acting
Insulin analog/ Short-
Acting
(Humalog)
IV/SC PRANDIAL/
SUPPLEMENTAL
Rapid acting:
Regular (Semilente)
IV/SC PRANDIAL/
SUPPLEMENTAL
Intermediate:
NPH (Lente)
SC BASAL
Long acting:
Protamine Zinc
(Ultralente)
SC BASAL

75. Diabetes Mellitus-3
By
Dr. Tehreem Zulfiqar
Assistant Professor Pharmacology
Nishtar Medical University

76. Learning Outcomes
By the end of this session you will be able to:
•Describe oral hypoglycemic agents in detail
•Discuss newer parenteral agents used for type 2
diabetes

77. • Useful in the treatment of patients who have type 2
diabetes and cannot be managed by diet alone
• Patients who have developed diabetes after age 40 and
have had diabetes less than 5 years are most likely to
respond well to oral glucose-lowering agents
• Oral glucose-lowering agents should not be given to
patients with type 1 diabetes
Oral Hypoglycemic agents

78. Agents that Increase
Insulin Secretion

79. Sulfonylureas
• First generation :
Acetohexamide, Chlorpropamide,
Tolbutamide, Tolazamide
• Second generation :
Glipizide, Glyburide
• more potent, more efficacious and fewer
adverse effects.
• Third generation : Glimiperide

80. • Promote insulin release from the β cells of the pancreas
Mechanism of action:
• Stimulation of insulin release from the β cells of the
pancreas by blocking the ATP-sensitive K+ channels,
resulting in depolarization and Ca2+ influx
• Reduction in hepatic glucose production
• Increase in peripheral insulin sensitivity
Sulfonylureas

83. Adverse effects:
• Weight gain
• Hyperinsulinemia
• Hypoglycemia
• Should be used with caution in patients with hepatic
or renal insufficiency, because drug accumulation may
cause hypoglycemia
• Glibenclamide has minimal transfer across the placenta
and may be a safe alternative to insulin therapy in
pregnancy
Sulfonylureas

84. • Repaglinide
• Nateglinide
Mechanism of action:
• Like the sulfonylureas, their action is dependent on
functioning pancreatic β cells
• Same mechanism of action as sulfonylureas
• Categorized as postprandial glucose regulators; they are
particularly effective in early release of insulin after a meal
Glinides

85. • The glinides have a rapid onset and a short duration of
action
• Combined therapy of these agents with metformin or
the glitazones is better than monotherapy in
improving glycemic control
• Glinides should not be used in combination with
sulfonylureas (overlapping MOA)
• Well absorbed orally
• Excreted in bile
Glinides

86. • Hypoglycemia (lower incidence than sulfonylureas)
• Weight gain (less than with sulfonylureas)
• Must be used with caution in patients with hepatic
impairment
Glinides- Adverse effects

87. • Amylin is a hormone produced by beta cells of pancrease
that works by delaying gastric emptying, decreasing
postprandial glucagon secretion, and improving satiety
• Administered SC and should be injected immediately
prior to meals
• Pramlintide may not be mixed in the same syringe with
any insulin preparation
• Used as an adjunct to mealtime insulin therapy in
patients with type 1 and type 2 diabetes
Synthetic Amylin Analog:
Pramlintide

88. Incretin Modulators
These include:
1. Glucagon-like peptide-1 (GLP-1) analogs:
Exanatide
2. DPP-4 inhibitor: Sitagliptin

89. • Glucagon-like peptide-1 (GLP-1) is a member of the
incretin family of peptide hormones, which are
released from endocrine cells in the epithelium of the
bowel in response to food.
• The incretins augment glucose-stimulated insulin
release from pancreatic B cells, retard gastric
emptying, inhibit glucagon secretion, and produce a
feeling of satiety.
Glucagon-like peptide-1 (GLP-1)
analogs: Exanatide

91. • These agents may be used as adjunct therapy in
patients who have failed to achieve adequate glycemic
control on a sulfonylurea, metformin, a glitazone, or a
combination of them
• Administered subcutaneously
• Exenatide should be injected twice daily within 60
minutes prior to morning and evening meals
• Exenatide should be avoided in patients with severe
renal impairment
Glucagon-like peptide-1 (GLP-1)
analogs: Exanatide

92. •Sitagliptin (Januvia®)
• Vildagliptin (Galvus®)
• Orally active DPP-4 inhibitors used for the
treatment of patients with type 2 diabetes
• Combinations with metformin are available
Dipeptidyl peptidase-IV (DPP-4)
Inhibitors

93. Mechanism of action
• Inhibit the enzyme DPP-4, which is responsible
for the inactivation of incretin hormones such
as GLP-1
• Prolonging the activity of incretin hormones
results in increased insulin release in response
to meals and reduction in glucagon secretion
Dipeptidyl peptidase-IV (DPP-4)
Inhibitors

94. • Majority of DPP-4 inhibitors are excreted in
urine therefore dosage adjustment is required
in renal impairment
• Adverse effects
• Nasopharyngitis
• Headache
• Pancreatitis has occurred with sitagliptin
Dipeptidyl peptidase-IV (DPP-4)
Inhibitors

96. • Insulin sensitizers improve insulin action
• Lower blood sugar by improving target-cell response
to insulin without increasing pancreatic insulin
secretion. These include:
• Biguanides
• Thiazolidinediones
Insulin Sensitizers

97. • Metformin (Glucophage®)
• Increases glucose uptake and use by target tissues,
decreasing insulin resistance
• Does not promote insulin secretion (hyperinsulinemia is
not a problem)
• The risk of hypoglycemia is less than with
sulfonylureas
Biguanides- Metformin

98. Mechanism of action:
• Reduces hepatic glucose output by inhibiting
hepatic gluconeogenesis
• Slows intestinal absorption of sugars and improves
peripheral glucose uptake and utilization
• The patient commonly loses weight because of loss
of appetite
Biguanides- Metformin

99. • The ADA recommends metformin as the drug of
choice for newly diagnosed type 2 diabetics
• Well absorbed orally
• Metformin may be used alone or in combination
with one of the other agents as well as with insulin
• Hpoglycemia may occur when metformin is taken in
combination with insulin
• Excreted in urine
Biguanides- Metformin

100. • GI adverse effects
• Metformin is contraindicated in diabetic patients with
renal and/or hepatic disease and in those with diabetic
ketoacidosis
• Rarely fatal lactic acidosis has occurred
• Long-term use may interfere with vitamin B12
absorption
Metformin Adverse effects

101. • Metformin is effective in the treatment of
polycystic ovary disease
• Its ability to lower insulin resistance in these women can
result in ovulation and possibly pregnancy
• It may also be used prophylactically to decrease the risk of
developing type 2 diabetes in high risk patients
Other Uses of Metformin

102. • Pioglitazone (Actos®)
• Rosiglitazone (Avandia®)
• Insulin sensitizers
• Insulin is required for their action
• Do not promote insulin release
Thiazolidinediones (glitazones)

103. • Mechanism of action
• The exact mechanism by which the TZDs lower insulin
resistance is unknown
• TZDs target the PPARγ receptors
• Ligands for PPARγ regulate adipocyte production and
secretion of fatty acids and glucose metabolism,
resulting in increased insulin sensitivity in adipose
tissue, liver, and skeletal muscle
Thiazolidinediones (glitazones)

104. • Pioglitazone and rosiglitazone can be used as
monotherapy or in combination with other glucose-
lowering agents or insulin
• The dose of insulin required for adequate glucose
control in these circumstances may have to be
lowered
• Extensively bound to serum albumin
• Undergo extensive metabolism by CYP450 system
Thiazolidinediones (glitazones)

105. • Very few cases of liver toxicity
• Weight increase can occur
• Osteopenia and increased fracture risk
• Increased risk of myocardial infarction and death from
cardiovascular causes with rosiglitazone
• Headache
• Anemia
Thiazolidinediones- Adverse
effects

106. Agents that will alter absorption
of glucose from intestine and
kidney
These include:
1. Alpha glucosidase inhibitors
2. Sodium glucose cotransporter 2 inhibitors

107. • Acarbose (Acrose®, Prandase®)
• Miglitol
• Oral drugs for the treatment of patients with type 2
diabetes
α-Glucosidase Inhibitors

108. Mechanism of action
• Taken at the beginning of meals
• Act by delaying the digestion of carbohydrates
lowering postprandial glucose levels
• Reversible inhibitors of membrane-bound α-glucosidase
in the intestine
• This enzyme is responsible for hydrolysis of
oligosaccharides to glucose and other sugars
α-Glucosidase Inhibitors

109. • Flatulence, diarrhea, and abdominal cramping
• Patients with IBD, colonic ulceration, or intestinal
obstruction should not use these drugs
• No hypoglycemia if used alone
α-Glucosidase Inhibitors-
Adverse Effects

110. • Dapagliflozin (Forxiga®)
• Canagliflozin
Mechanism of action:
• SGLT2 is responsible for reabsorbing filtered glucose in
the tubular lumen of the kidney
• By inhibiting SGLT2, these agents decrease
reabsorption of glucose, increase urinary glucose
excretion, and lower blood glucose
Sodium-Glucose Cotransporter 2
inhibitors

112. Adverse effects:
• Female genital mycotic infections urinary tract
infections, and urinary frequency
• Hypotension
Sodium-Glucose Cotransporter 2
inhibitors

114. Approach to a new Diabetic
Patient

116. Summary