diabetis mellitus

1. PCL 402: Endocrine Pharmacology
Insulin and Antidiabetic Agents

2. Certain cells in the body concert ingested food into energy /blood
glucose that cells can use.
Every time a person eats, the blood glucose rises, raised blood
glucose triggers the ß cells to release the necessary amount of
insulin.
Insulin allows the blood glucose to be transported from the blood
into the cells by activating a set of transport molecules so that
glucose and proteins can enter the cell. The cells can then use the
glucose as energy to carry out its functions. Once transported into
the cell, the blood glucose level is returned to normal within hours.

3. W/o insulin, blood glucose builds up in the & cells are starved of
their energy source. Symptoms that may occur include fatigue,
constant infections, blurred vision, numbness, tingling in the hands
or legs, increased thirst, and slowed healing of bruises/cuts.
The cells will begin to use fat, the energy source stored for
emergencies. The body then begin to produce ketones (chemicals
produced by the liver).
Ketones can poison and kill cells if they build up in the body over
an extended period of time. This can lead to serious illness and
coma.

4. The pancreas is both an endocrine gland that produces the peptide
hormones insulin, glucagon, and somatostatin and an exocrine gland
that produces digestive enzymes. The peptide hormones are
secreted from cells located in the islets of Langerhans (β cells
produce insulin, α cells produce glucagon, and δ cells produce
somatostatin). These hormones play an important role in regulating
the metabolic activities of the body, particularly the homeostasis of
blood glucose.

7. Synthesis and Release of Insulin is modulated by:
1. Glucose (most important) and ketone bodies stimulate release.
2. Glucagon and somatostatin inhibit release.
3. α-Adrenergic stimulation inhibits release (most important).
4. β-Adrenergic stimulation promotes release.
5. Elevated intracellular Ca2+ promotes release.

8. Insulin
Insulin is a 51 AA peptide arranged as two polypeptide chains,
α-chain and β-chain, connected by disulfide bonds; which are
necessary to maintain tertiary structure and biological activity
• Orally inactive.
• Insulin is inactivated by insulinase found mainly in liver
and kidney.
• Dose is reduced in renal insufficiency
• Sources of Insulin :
– Beef pancreas / Pork pancreas
– Human insulin: recombinant DNA origin

9. Insulin Human Insulin
• Do not contain measurable amounts of proinsulin or
contaminants.
• Diminished antibody
• Less allergic reactions
• Less lipodystrophy
• Preferred in gestational diabetes

10. Mechanism of action
o Insulin binds to insulin receptors on the plasma membrane and
activates tyrosine kinase primarily in adipose tissue, liver and
skeletal muscle.
o The initial rapid rise in insulin following a rise in glucose is
termed the 1st phase of insulin release and is thought to
reflect the release of the presynthesized insulin in the storage
granules; a more delayed and prolonged rise in insulin
secretion follows.
o This 2nd phase of insulin secretion is due to an upregulation
of insulin expression and production. The 1st phase of insulin
secretion is often blunted in diabetes.

11. PHARMACOKINETICS
* Elimination t ½ of IV insulin- 5 to 10 minutes
* Metabolized by kidneys, liver and placenter
* Insulin tightly bound to tissue receptors- so even though rapid
clearance, pharmacologic effects remain till 30-60 minutes.
* Insulin secreted into portal venous system at rate of 1 unit/hour
* Daily secretion of insulin is 40 units.
* Insulin response to glucose is greater for oral ingestion than for iv
infusion.

13. Diabetes mellitus
DM is a heterogeneous group of syndromes (metabolic disorder)
characterized by the elevation of glucose levels due to a relative or
absolute deficiency of insulin.
It is characterized by:
√ High level of glucose in urine and blood (fasting); ≥ 126mg/dL (≥
200mg/dL non fasting)
√ Polyuria
√ Polydypsia
√ Fatigue
√ Constant hunger
√ Weight loss.

14. Type I: Insulin dependent
 Juvenile-onset (childhood, severe type) diabetes: when the body does not
produce any insulin.
 Sudden onset, before age 20. 10%-20% of diabetic popln.
 Lack of functional pancreatic β-cells (T cell-mediated autoimmune response
destroys β cells); islet antibodies are often present
 Lack of functional β-cells prevents mitigation of elevated glucose levels &
associated insulin responses.
 Associated with ketoacidosis (DKA; Body breaks down fats rapidly= liver fats >>
ketone bodies [fuels] = blood acidic); Ketonemia & Ketonuria are present
 Depend on exogenous insulin to prevent hyperglycemia and avoid ketoacidosis.
 The goal of therapy is to mimic both the basal and reactive secretion of insulin in
response to glucose levels avoiding both hyper- and hypo-glycemic episodes.

15. Type II: Non=insulin dependent
 “Adult” diabetes (after age 40, obese individuals). 80%-90% of diabetic
popln
 Body produces insulin, but is either not enough or the cells do not
respond normally to insulin (a decrease in number of insulin receptors
or the cells cannot take it up[insulin resistance]).
• This usually occurs in obese or middle aged and older people (The
disease is influenced by genetic factors, aging, obesity, and peripheral insulin
resistance rather than by autoimmune processes or viruses).
 Controlled by dietary changes and regular exercise (wt reduction); this
↓ insulin resistance.
 The goal of treatment is to maintain glucose concentrations within
normal limits to prevent long term complications.
• Hypoglycemic agents are often required, often insulin therapy is also
required.

17. Regular Insulin
o Fast acting (rapid acting)
o Only type which can be given IV as well as SC
o For abrupt onset hyperglycaemia or
ketoacidosis
o Single iv injection 1-5Units/ continuous
infusion of 0.5-2 units/hour
Very Rapid Acting Insulin
o Ultrashort acting more rapid than regular
insulin & shorter duration
o Less associated hypoglycemia but recurrent
hyperglycemia before next meal due to shorter
duration of action.
o Given just 15 minutes prior to meals
o Provides a postprandial plasma insulin
concentration like normal insulin.

18. INTERMEDIATE ACTING-
LENTE (NPH)
Absorption delayed due to
conjugation with
protamine(0.005mg/unit)
NPH (isophane) and Lente (insulin zinc)
LONG ACTING- ULTRALENTE,
GLARGINE
Given as single bedtime
injection
Basal level
Lesser nocturnal
hypoglycaemia

20. ADVERSE EFFECTS OF INSULIN
Hypoglycaemia
Allergic reactions
Lipodystrophy
Insulin resistance
Hypokalaemia
Weight gain
Others includes
– Seizures
– Coma

21. Treatment
Type I is a disease caused by the lack of insulin. Insulin must be used
in Type I, which is given by injection.
Type II is as a result 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
GI tract.

22. Oral hypoglycemics
Agents that are given
orally to reduce the
blood glucose levels
in diabetic patients
Four main groups
oral antidiabetic
drugs:

23.  Amylin analogue: Pramlintide
 Dopamine D2 receptor agonist: Bromocriptine
 Sodium Glucose Co-Transport 2 (SGLT 2) inhibitor: Dapagliflozine
Miscellaneous

24. Biguanides :metformin
Sulfonylureas: glimepiride, glyburide, tolbutamide, glibenclamide,
glipizide
Meglitinides : nateglinide, repaglinide
Thiazolidinediones : pioglitazone, rosiglitazone
Alpha -glucosidase inhibitors: acarbose, miglitol

26. 1) Insulin secretagogues
 Useful in the treatment of patients w/ Type 2 diabetes but who
can’t be managed by diet alone.
 Patients with long-standing disease may require a combination of
hypoglycemic drugs with or without insulin to control their
hyperglycaemia.
 Oral hypoglycemics should NOT be given to patients with Type 1
diabetes.

27. Sulfonylureas :
• First generation : Acetohexamide, Chlorpropamide, Tolbutamide,
Tolazamide, glibenclamide.
• Second generation : Glipizide, Glyburide – more potent, more
efficacious and fewer adverse effects.
• Third generation : Glimepiride

28. • Are derivatives of the antibacterial sulfonamides but however possess no
antibacterial activity.
• Sulfonylureas are the most widely prescribed drugs in the treatment of
type II DM.
MoA:
 They require functioning β-cells.
 Direct stimulation of insulin release from the pancreatic β –cells by
blocking ATP-sensitive K+ channels (↓influx) resulting in depolarization of
the cell resulting in Ca2+ influx as well as release of Ca2+ from intracellular
stores which promotes insulin secretion by exocytosis.
 They also reduce glucagon secretion and increase the binding of insulin to
target tissues.
 Reduced hepatic degradation of insulin

29. 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

30. Adverse Effects
* Mild G.I. disturbance, which can be minimized by taking the drug after
meals or by antacids.
* Skin rash, blood dyscrasias, hypothyroidism, weight gain, hyperinsulinemia
and hypoglycemia.
* Hepatic or renal insufficiency causes accumulation of these agents
promoting the risk of hypoglycaemia.
* Tolbutamide is highly associated with cardiovascular mortality.
SU + alcohol:
Flushing, disulfiram-like reaction
 Should not be used in pregnancy and lactating mothers
Glyburide has minimal transfer across the placenta and may be a reasonably safe
alternative to insulin therapy for diabetes in pregnancy.

31. MEGLITINIDES [Phenylalanine
analogues]
 Repaglinide and Nateglinide act as
Secretogogues (K+ ATP channel blockers)
They bind to a distinct site on the
sulfonylurea receptor of ATP-sensitive
K+ channels, thereby initiating a series
of reactions culminating in the release
of insulin.

32.  In contrast to Sus, prompt peak effect (1 hour) and shorter duration
of action (about 4 hours)
 Taken 15-30 mins before meals
o Normalises meal time glucose levels
 Decreases risk of prolonged hypoglycemia due to short duration of
action.
 When used in combination with other oral agents they produce
better control than monotherapy.

33. S/E:
Mild headache, dyspepsia, arthralgia, weight gain
Chance of formation of tumor of thyroid gland & liver
Indications:
Type 2 DM with pronounced postprandial hyperglycaemia
o Along with Metformin/long acting insulin
 Avoid in liver disease
Pharmacokinetics
Well absorbed from the GIT
Peak concentration after 1 hr. from ingestion
Cleared by the liver
Plasma t1/2 = 1hr.

34.  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.
 Meglitinides should not be used in combination with sulfonylureas due
to overlapping mechanisms of action.

35.  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.
2. Insulin Sensitizers

36. Biguanides
Θ Increase peripheral glucose uptake and utilization by tissues (Increase
binding to insulin receptors)
Θ Inhibits hepatic gluconeogenesis.
Θ Decrease intestinal glucose absorption
Θ Does not promote insulin secretion.
Θ It increase the sensitivity of liver and muscle to insulin.
Θ It does not cause hypoglycemia
Θ It causes modest weight loss (decreases appetite).
Θ It produces a significant ↓ TG and LDL, and ↑HDL.
Θ Prevents long term complications
Θ Metformin, phenformin

37. Pharmacokinetics
± Readily absorbed from G.I.T.
± Not metabolized and excreted unchanged by the kidney
Therapeutics uses
In NIDDM together with SU, when SU failed alone
It is the only oral hypoglycemic shown to reduce cardiovascular mortality.
Adverse Effects
Metallic taste and G.I.T. upsets.
There is a serious concern about lactic acidosis especially in patients with
kidney disease.
Long term use may lead to vitamin B12 malabsorption and folate deficiency

38. Contraindications
 Hypotensive states
 Heart failure
 Severe respiratory, hepatic and renal disease
 Alcoholics
 Severe infection
 Diabetic ketoacidosis

39. Thiazolidinediones [Glitazones]
Multiple actions:
o Reverses insulin resistance
o Suppresses hepatic gluconeogenesis
 They do not promote insulin secretion from β-cells but insulin is necessary
for them to be effective.
 Act principally at adipose tissue and skeletal muscles to decrease insulin
resistance by increasing GLUT 4 glucose transporters.
 Clinical effect takes 4-12 weeks to be evident
* Lowers serum triglyceride, raises HDL
* Well tolerated
 PIOGLITAZONE, TROGLITAZONE and ROSIGLITAZONE

40. Pharmacokinetics
Well absorbed from the GIT
Metabolized through the hepatic cytochrome P450
S/E:
Plasma volume expansion, edema, weight gain, headache, myalgia,
mild anaemia, increased risk of fracture esp. in elderly women
Liver failure (Troglitazone)
Hypoglycaemia (if used together with insulin or SU)
 Contraindicated in liver disease and in CHF

41.  Orally active antidiabetic drugs used for T2 DM 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.
 Acarbose and miglitol
3) α-glucosidase inhibitors

42. MoA
 These drugs are taken at the beginning of meals. They act by
delaying the digestion of carbohydrates, thereby resulting in lower
postprandial glucose levels.
 They 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.

43. Pharmacokinetics
• Acarbose is poorly absorbed. It is metabolized primarily by
intestinal bacteria, and some of the metabolites are absorbed and
excreted into the urine.
• Miglitol is very well absorbed but has no systemic effects. It is
excreted unchanged by the kidney.
 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 SUs or with insulin, hypoglycemia may develop.
 Metformin bioavailability is severely decreased when used
concomitantly

44. Adverse effects
The major side effects are flatulence, diarrhoea, and abdominal
cramps.
Patients with inflammatory bowel disease, colonic ulceration, or
intestinal obstruction should not use these drugs.

45. 4) Dipeptidyl peptidase-4 inhibitor
o DPP-4 Is/ gliptins, are a class of oral hypoglycemics that block DPP-4.
o They can be used to treat T2 DM.
o Sitagliptin – was approved by the FDA in 2006.
o Exenatide
o 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.

46. MoA
Sitagliptin inhibits the enzyme DPPIV, 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.

47. Pharmacokinetics:
 Sitagliptin is well absorbed after oral administration. Food does not
affect the extent of absorption.
 The majority of sitagliptin is excreted unchanged in urine.
 Dosage adjustments are recommended for patients with renal
dysfunction.

48. 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.

49. Others
 Amylin analogue: Pramlintide
 A synthetic analogue of Amylin. Delays gastric emptying, suppress glucagon
secretion & appetite.
 Approved for both type I & II DM
 Given pre-prandial parenterally
 Can cause Hypoglycaemia, hence its recommended that short and intermediate
acting insulin doses be reduced by 50% when this drug is started.
 Dopamine D2 receptor agonist: Bromocriptine
• Produce modest reductions in HbA1c.
• Although indicated for the treatment of type II DM, the modest efficacy, AEs, and
pill burden limit the use in clinical practice.

50.  Sodium Glucose Co-Transport 2 (SGLT 2) inhibitor
Canagliflozin & Dapagliflozine
o The sodium–glucose cotransporter 2 (SGLT2) is responsible for
reabsorbing filtered glucose in the tubular lumen of the kidney.
o By inhibiting SGLT2, these agents decrease reabsorption of glucose,
increase urinary glucose excretion, and lower blood glucose. Inhibition of
SGLT2 also decreases reabsorption of sodium and causes osmotic
diuresis. Therefore, SGLT2 inhibitors may reduce systolic blood pressure.
However, they are not indicated for the treatment of hypertension.
* Avoid in patients with renal dysfunction.

56. Type 3 Diabetes Mellitus
The type 3 designation refers to multiple other specific causes of an
elevated blood glucose: non-pancreatic diseases, drug therapy, etc.

57. Gestational Diabetes (GDM) is defined as any abnormality in glucose
levels noted for the first time during pregnancy. During pregnancy, the
placenta and placental hormones create an insulin resistance that is
most pronounced in the last trimester. Risk assessment for diabetes is
suggested starting at the first prenatal visit. High risk individuals should be
screened immediately. Screening may be deferred in lower risk women
until the 24th to 28th week of gestation.
Type IV Diabetes