Faculty of Medicine

Medical Education-
Damietta University

Level 2
Semester 3
Module 1A
 Drug therapy
for
diabetes mellitus
Mohamad-Hesham Daba
 Mohamad-Hesham Daba
Prof. of clinical pharmacology
• Contact: clinical pharmacology Department.
• Official email: mhdaba@du.edu.eg
• Mobile (optional): 01119950988
• Academic hours:
Sunday day: 11:00-12:00 AM
Wednesday day: 11:00-12:00 AM
Learning Outcomes
By the end of the 3 lecture, the students will be able to:
1. List different insulin preparations
2. Describe the mechanism of action of insulin
3. Select appropriate dosage forms in clinical situations
4. Recognize side effects of insulin
5. Describe the mechanism of action and side effects of sulphonylureas,
metformin, acarbose, glitazones
6. Recognize side effects of sulphonylureas, metformin, acarbose,
glitazones
7. Describe newer antidiabetic drugs.
Case scenario, Clinical Correlate, Practice points
A 16-year-old boy working at Pizza shop presents with a history of
polyuria, polydipsia, and weight loss of 6 kg over 2 months.
His biochemical evaluation shows fasting plasma glucose –280 mg/dl,
postprandial plasma glucose – 380 mg/dl and HbA1c 8.5 %.
How would you manage?
Diabetes mellitus
• Definition of DM: It is a clinical syndrome
• Manifestations: Polyuria, polydipsia, polyphagia.
• Complications: neuropathy, retinopathy, nephropathy, DKA……….
• Laboratory investigations:
1. Urine analysis:
2. Blood glucose: fasting and 2-hrs postprandial.
3. Glycated hemoglobin (HbA1C): Indicates average blood sugar level
for the past 2-3 months
 Normal Prediabetes DM

Fasting BG < 100 mg/dl 100-125 > 126 mg/dl

IFG
2 hr after oral < 140 mg/dl 140-200 > 200 mg/dl
75 g glucose IGT

HbA1C < 6% 6-6.5%  6.5%

(uncontrolled
DM over the
last 2-3 m).
 20

# patients,
in millions
15

Common types of DM: 10

0
total type 1 type 2

• Type 1 diabetes:
can develop at any age, but occurs most frequently in children and
adolescents.
• Type 2 diabetes:
is more common in adults and accounts for around 90% of all diabetes
cases.
• Gestational diabetes (GDM):
is a type of diabetes that consists of high blood glucose during
pregnancy and is associated with complications to both mother
and child.
Lines of treatment:
1. Diet control.

2. Diet + insulin (type 1).

3. Diet + oral antidiabetic drugs ± insulin (type 2).

Insulin
Secretion Chemistry Actions
 Insulin release: normal levels
Meal
120

Insulin, U/ml
100
Glucose, mg/dl

80 80

60

40

20
Basal

Minutes 0 30 60 90 120
Sources of insulin:
Traditional (animal) insulin:
Human insulin:
- Identical to human insulin
- Prepared by recombinant DNA technology.
- Less antigenic & rare development of insulin resistance.
Insulin analogs:
- Few a.a. of the human insulin are switched or replaced
- The different molecule have different pharmacokinetic properties.
Insulin preparations:
 Generic
Category Features Onset Peak Duration
names

(1)
Rapid acting
insulin analogs (1) insulin lispro
Given just before 0-15
(2) insulin aspart 1-2 h. 3-5 h.
meal min
 Generic
Category Features Onset Peak Duration
names

(2) Regular, Identical to

Short acting soluble, human insulin
insulin neutral 30
min 2-4 h. 6-8 h.
(Only one to be given
I.V.)
Category Generic name Features Onset Peak Duration

(3) Made by
Intermediate Isophane insulin adding
acting (N.P.H.) protamine to
Insulin: insulin to 1-2 h. 4-6 h. 12-16 h.
increase the
duration of
action
Category Generic name Features Onset Peak Duration

(4) insulin “peakless”

Long
glargine Given once 1-2 h. 18-24 h.
acting
& detemir daily
insulin:
Category Generic name Features Onset Duration

(5)
Premixed Humalin 70/30 Rapid onset
Insulin (NPH/Reg.) (mixtard) <30 12-16 h.
(Biphasic) Long duration min
Mechanism of action of insulin:
Indications of insulin:
Type 1 DM.
Type 2 DM in some conditions:
After failure of oral drugs.
“stress conditions” e.g. infections, surgery,
or pregnancy.
Diabetic ketoacidosis (DKA):
 regular insulin is the only type used i.v.
Insulin administration:
• All insulins are given by s.c.
injection.
• Regular insulin is the only type
that can be given i.v. in diabetic
emergencies.
• The standard insulin
concentration is 100 units/mL.
• It should be injected with a
standard U-100 syringe.
Insulin requirement
• A total daily dose of 0.4
units/kg/d is given initially
to a newly diagnosed
patient.

• The dose is then adjusted

according to the blood
glucose level.
• Basal-Bolus regimen:
- Give long acting insulin at bed time; plus three daily injection of
short acting insulin before each meal.
- The long-acting insulin provides basal level of insulin that controls
blood glucose during night and in-between meals (50% of total).
- The short acting insulin controls postprandial hyperglycemia (10-
20% for each).
Twice-daily biphasic insulin regimen
- Use biphasic insulin.
Give the 2/3 of the TDD in the morning
and the 1/3 at evening.
Methods of administration:
S.c. injection (using insulin syringes).
Portable pen injector.
Pump.

Follow up of insulin therapy:

From capillary blood glucose level
using portable glucometers
Self-Monitoring of Blood Glucose (SMBG)
Side effects of insulin:
Hypoglycemia: the most common and dangerous side effect.
• Causes: Large dose of insulin or Missed meal while taking insulin.
• Treatment:
If the patient is conscious or semiconscious
→ give him sugar solution.
If the patient is in deep coma:
(1) i.v. glucose
(2) Glucagon i.m.
 Hypersensitivity reactions:
urticaria, angioedema or anaphylactic shock.
 Lipodystrophy:
(atrophy or hypertrophy)of
S.C. tissue after repeated injections.
prevented by changing the injection site.
Insulin resistance (IR)
Definition: failure of the body cells to respond to either endogenous
or exogenous insulin. As a result, larger doses of insulin are required
to give the desired response.
Causes:
- The metabolic syndrome - Obesity.
- Pregnancy - Severe infection or stress.
- Drugs: e.g. corticosteroids.
Treatment:
Life-style modification: - Weight reduction – Physical exercise.
Correction of any precipitating factor: e.g. infection or stress.
Case Discussion/reflection
This young man has type 1 diabetes mellitus and thus requires replacement insulin
therapy in the form of basal bolus regimen using short-acting human insulin or
insulin analogs as bolus insulin for prandial coverage and long-acting insulin analogs
or neutral protamine Hagedorn (NPH) for basal coverage.
Based on the economic status of this patient, he can be advised regular insulin with
each meal and bedtime NPH.
He can be started on 0.5 U/kg/day of total insulin dose which can be split into 40%
dose as NPH bedtime and 60% regular insulin for prandial coverage (20% before
breakfast, lunch, and dinner).
He must be educated on dietary plan, physical activity, SMBG, and hypoglycemic
symptoms.
The insulin has to be titrated based on SMBG reading every 2–3 days.
Q1
Insulin causes reduction in blood sugar level by the
following mechanisms, EXCEPT:
a) Increased glucose uptake in the peripheral tissue
b) Reduction of breakdown of glycogen
c) Diminished gluconeogenesis
d) Decreased glucose absorption from the gut
Q2
Insulin can not be administered by:
a) Oral route
b) Intravenous route
c) Subcutaneous route
d) Intramuscular route.
Q3
Correct statements about crystalline (regular)
insulin include all of the following, EXCEPT:
a) It can serve as replacement therapy for juvenile-
onset diabetes
b) It can be administered intravenously
c) It is a short-acting insulin
d) It can be administered orally
Q4
Diabetic coma is treated by the administration of:
a) Lente insulin
b) Glucose
c) Crystalline insulin
d) Oral anti-diabetic drugs.
Q5
The following is peakless insulin preparation:
A. Regular insulin.
B. NPH insulin.
C. Zinc insulin.
D. Insulin galrgine.
E. Lispro insulin
Q6
Which of the following is an important effect of insulin?
A. Increased conversion of amino acids into glucose
B. Increased gluconeogenesis
C. Increased glucose transport into cells
D. Inhibition of lipoprotein lipase
E. Stimulation of glycogenolysis
Q7
Which of the following agents should be administered to achieve
rapid control of the severe ketoacidosis in a diabetic boy?
A. Regular insulin
B. Glyburide
C. Insulin glargine
D. NPH insulin
E. Tolbutamide
Q8
Which of the following is the most likely complication of insulin
therapy?
A. Hypoglycemia
B. Increased bleeding tendency
C. Pancreatitis
D. Severe hypertension
Q9
The following regimens is Most appropriate for tight
control of diabetes mellitus:
A. Morning injections of mixed insulin lispro and insulin
aspart.
B. Evening injections of mixed regular insulin glargine.
C. Morning and evening injections of regular insulin,
supplemented by small amounts of NPH insulin at
mealtimes.
D. Evening injections of insulin glargine, supplemented by
small amounts of insulin lispro at meal times.
Q10
• The following is a long acting insulin preparation:
A. Regular insulin.
B. NPH insulin.
C. Insulin detemir
D. Lispro insulin
Case scenario, Clinical Correlate, Practice points
• During routine medical checkup a 45-year male office
executive with sedentary lifestyle was diagnosed
to have developed type 2 diabetes mellitus.
• His fasting and post-meal blood glucose was 130 mg/di and 190 mg/di
respectively, HbA1 c was 7.8%, BP was 130/82 mm Hg and body mass
index was 27 kg/ m2•
• He was advised suitable diet, exercise and other lifestyle modifications.
• Should he be prescribed an antidiabetic medication as well?
If so, which drug/ combination of drugs should be selected, and why?
Oral ant diabetic drugs
Sulfonylureas
• Classification:
First-generation compounds: chlorpropamide, tolbutamide
Second-generation compounds:
glibenclamide, gliclazide
Third-generation compounds:
glimepiride
Pharmacokinetics:
• They are effectively absorbed from GIT.
• Food can reduce the absorption.
• Plasma protein binding is high (90 %).
• All sulfonylurea are metabolized by liver and excreted in urine.
• Sulfonylurea should be administered with caution to patients with
either renal or hepatic insufficiency.
Mechanism of action:
• ↑ insulin secretion

by pancreatic β cells. They block K+

channels in β- cells, leading to
depolarization, increased Ca2+ entry
via voltage-dependent calcium
channels, and increased insulin
secretion.
Therapeutic uses:
• Type 2 DM

• Given 30 minutes before food.

Adverse effects:
1- Hypoglycemia:
especially with long acting drugs or in elderly patients with
hepatic or renal dysfunction.

2 - Hepatotoxicity.
3 - Teratogenicity.

4 - Hypersensitivity reactions.
Glinides: repaglinide & nateglinide
• They increase insulin secretion
by the same mechanism like sulfonylureas .

• Fast onset and short duration

so; they are taken orally just before meals
to control postprandial hyperglycemia.

• They don't contain sulfur,

so they can be used in patients allergic to sulfonylureas.
Biguanides: metformin
Pharmacokinetics:

• Metformin is well absorbed from small intestine.

• Does not bind to plasma proteins
• Half life is short.
• Excreted unchanged in urine.
Therapeutic uses:
Type 2 DM
either alone (in mild cases) or
in combination with other drugs.
Obese patients:
to enhance weight loss in
Adverse effects:
GIT upset (the most common):
anorexia, vomiting, and diarrhea.
Lactic acidosis (the most important):
due to increased anaerobic glycolysis
especially in patients with severe renal
or hepatic diseases
or cardiopulmonary dis.
Vitamin B12 deficiency
Thiazolidinediones (TZD): Pioglitazone
 They act on nuclear
genes called PPAR- γ
present in muscles,
adipose tissue, and liver
cells leading to:
 ↑ number of glucose
transporters →↑
glucose uptake.
 ↑ insulin receptor
sensitivity (by about
60%).
Pioglitazone
• Therapeutic uses:
in type 2 DM To improve insulin resistance.

• Adverse effects:
Hepatotoxicity
Salt and water retention leading to:
peripheral edema & weight gain.
(avoid in patients with CHF).
α-Glucosidase inhibitors: Acarbose
• They act by competitive
inhibition of intestinal α-
glucosidase enzyme → ↓
digestion & absorption of
carbohydrates. (starch blockers)
• GIT side effects are common:
Flatulence, diarrhea, abdominal
pain.
Case Discussion/reflection
• According to the current recommendation of professional guidelines, the patient
should be prescribed metformin therapy concurrently with dietary and lifestyle
measures. This is based on the finding that metformin can delay progression of
diabetes and prevent microvascular as well as macrovascular (heart attack,
stroke) complications. Metformin does not increase circulating insulin, reduces
insulin resistance, is unlikely to induce hypoglycaemia and may have a positive
influence on pancreatic p cell health. Lack of serious toxicity over several decades
of use of metformin is well established. No other antidiabetic drug has all these
favourable features, and therefore, it is considered the first-choice drug.
Metformin is particularly suitable for this patient who is overweight, because it
can help weight reduction. A combination of antidiabetic drugs is not indicated at
this stage. Another drug needs to be added only when the target blood glucose
and HbA1 , levels are not attained by metformin alone.
Q1

Treatment of DK include the following except:

A. Regular insulin.
B. Normal sodium.
C. KCL.
D. Sulphonylurea.
Q2
Sulphonylureas act by:
a) Reducing the absorption of carbohydrate from the gut
b) Increasing the uptake of glucose in peripheral tissues
c) Reducing the hepatic gluconeogenesis
d) Stimulating the beta islet cells of pancreas to produce insulin
True or False: Sulphonylureas are effective in totally insulin deficient
patients. This consideration is:
• a) True
• b) False
Q3
Thiazolidinediones act by:
a) Diminishing insulin resistance by increasing glucose
uptake and metabolism in muscle and adipose tissues
b) Reducing the absorption of carbohydrate from the gut
c) Stimulating the beta islet cells of pancreas to produce
insulin
d) Stimulating the hepatic gluconeogenesis
Q4.
Alpha-glucosidase inhibitors act by:
a) Diminishing insulin resistance by increasing glucose uptake and
metabolism in muscle and adipose tissues
b) Competitive inhibiting of intestinal alpha-ghucosidases and
modulating the postprandial digestion and absorption of starch
and disaccharides
c) Reducing the absorption of carbohydrate from the gut
d) Stimulating the beta islet cells of pancreas to produce insulin
Q5
• Which of the following drugs is most likely to cause hypoglycemia
when used in the treatment of type 2 diabetes?
A. Acarbose
B. Glibenclamide
C. Metformine
D. Rosiglitazone
Q6.
Which one of the following drugs promotes the release of
endogenous insulin?
A. Acarbose
B. Pioglitazone
C. Glimpride
D. Metformin
Q7.
The combination of metformin and ethanol increases the risk of
which of the following?
A. Serious hepatotoxicity
B. Excessive weight gain
C. Hypoglycemia
D. Lactic acidosis
Q8.
Which of the following drugs is taken during the first part of a meal
for the purpose of delaying the absorption of dietary carbohydrates?
A. Acarbose
B. Repaglinide
C. Glipizide
D. Pioglitazone
Q9.
The PPAR-γ receptor that is activated by thiazolidinediones
increases tissue sensitivity to insulin by which of the
following mechanisms?
A. Activating adenylyl cyclase and increasing the intracellular
concentration of cAMP
B. Inactivating a cellular inhibitor of the GLUT2 glucose
transporter
C. Inhibiting acid glucosidase, a key enzyme in glycogen
breakdown pathways
D. Regulating transcription of genes involved in glucose
utilization
Q10
A 55 years old obese lady discovered to have random blood glucose
260 mg/dl during screening at 100 million health and her fasting
blood glucose later was 160 mg/dl. She was told that she has type 2
DM. What is the next step?
A. Just follow up
B. Metformin should be started
C. She can be given a small dose sulphonyl urea
D. Pioglitazone is given to improve insulin resistance
E. Long acting insulin at bed time
Q11
• The release of insulin from pancreatic beta cells would most likely
be stimulated by which of the following?
(A) Clonidine
(B) Norepinephrine
(C) Diazoxide
(D) Glipizide
Q12
• To supplement other oral type 2 diabetes medication, a patient is
prescribed a drug to inhibit the intestinal absorption of
carbohydrates. What would be an appropriate drug?
(A) Metformin
(B) Acarbose
(C) Repaglinide
(D) Pioglitazone
Newer antidiabetic drugs
Glucagon-like peptide-1 (GLP-1)
is released from the gut in response to oral glucose.
Exenatide :
is a synthetic GLP-1 analog
Mechanism of action:
1. They ↑ insulin secretion and ↓ glucagon secretion.
2. They slow gastric emptying and ↓ appetite.
Therapeutic uses:
Type 2 DM: given by injection (s.c.)
used either alone or in combination.
Major adverse effects:
nausea, vomiting
Acute pancreatitis is a risk.
Liraglutide:
• longer-acting GLP- 1 agonist due to its tight binding to plasma
proteins extends t½ to > 12 hours and duration of action to > 24
hours.
• Injected s.c. once daily.
• Use of liraglutide lead to weight loss and it is approved for use in
obesity.

Dulaglutide:
• is a very long acting GLP-1 receptor agonists which need to be
injected once weekly.
Dipeptidyl peptidase 4 inhibitors (Gliptins):
Sitagliptin
Mechanism of action:
inhibits dipeptidyl peptidase 4 (DPP-4),
the enzyme responsible for the proteolysis of the incretins (GLP-1).

Therapeutic uses:
Type 2 DM: given orally
Used alone or in combination with metformin.

Side effects:
headache and nausea.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors

• Practically all the glucose filtered

at the glomerulus is reabsorbed
in the proximal tubules.
• The major transporter which
accomplishes this is SGLT-2
• Its inhibition induces glucosuria
and lowers blood glucose in type
2 OM, as well as causes weight
loss.
Dapagliflozin
• These SGLT-2 inhibitors are approved for use in type 2 DM patients.
• After once daily dosing, they produce round-the-clock glucosuria and
lower blood glucose levels.
• Used alone or in combination with other antidiabetic drugs, they
reduce HbA1c levels by 0.5-1.0%, but do not cause hypoglycaemia.
• Can predispose lo urinary tract infections and increased urinary
frequency.
• They are contraindicated in patients with renal insufficiency.
• SGLT-2 inhibitors reduce the risk of hospitalizations for heart failure
by ∼30% and often decrease the risk of cardiovascular death.
Treatment of diabetic
complications
▌Hypoglycemic coma
• Causes:
1. Large dose of insulin or sulfonylurea.
2. Missed meal while taking insulin or sulfonylureas.

• Treatment:
1. If the patient is conscious or semiconscious → give him sugar solution.
2. If the patient is in deep coma:
(1) i.v. glucose
(2) Glucagon i.m.
Treatment of diabetic ketoacidosis
• Fluids:
isotonic saline solution i.v. immediately.
• Regular insulin:
i.v infusion (0.1 unit/kg/hr). switch to s.c. insulin
when the patient is biochemically stable.
• Potassium: is given according to K+ level.
• Bicarbonate (HCO3): only in severe acidosis.
• Treatment of precipitating factors e.g. antibiotics for infection.
Q1. Sitagliptin acts by:
a) Reducing the absorption of carbohydrate from the gut
b) Increasing the uptake of glucose in peripheral tissues
c) Reducing the hepatic gluconeogenesis
d) Inhibits dipeptidyl peptidase 4 (DPP-4)
Q2. One the main advantages of Liraglutide over exenatide is that

A. It longer in duration.
B. It is a synthetic amylin analogue.
C. It increases glucagon secretion.
D. It is used instead of insulin in type 1 diabetes
Q3. Dapagliflusin acts by:
a) Reducing the absorption of carbohydrate from the gut
b) Inhibits sodium-glucose cotransporter-2 (SGLT2)
c) Reducing the hepatic gluconeogenesis
d) Inhibits dipeptidyl peptidase 4 (DPP-4)
Q4. What is the first step in the management of diabetic
ketoacidosis?
a. To provide fluids intravenously
b. To provide insulin
c. To provide bicarbonate
d. To initiate insulin and fluids simultaneously
Q5. In a patient with type 2 diabetes, which drug mimics the action of
incretins to augment glucose-dependent insulin secretion?
(A) Acarbose
(B) Glucagon
(C) Exenatide
(D) Metformin
Nice to know
Amylin analogue: Pramlintide
• Amylin is produced by pancreatic beta cells and is stored in the same
granules as insulin. As such it is secreted along with insulin. acts in the
brain to reduce glucagon secretion from alpha cells.
• Pramlintide is a synthetic amylin analogue which is used to with
insulin injection when insulin alone fails to control postprandial
glycemic peak.
• Hypo glycaemia is the most important adverse effect.
Q4. Pramlintide is
A. a synthetic amylin analogue
B. a synthetic GLP-1 analogue
C. Sodium-glucose cotransporter-2 (SGLT2) inhibitor
D. An Alpha-glucosidase inhibitor
GLUCAGON
• It is secreted by the alpha cells of the islets of Langerhans and
commercially produced now by recombinant DNA technology.
• Uses
I. Hypoglycaemia Use of glucagon to counteract insulin/ oral
hypoglycaemic drug induced hypoglycaemia is only an appropriate
measure for the emergency, and must be followed by oral
glucose/sugar given repeatedly till the blood glucose level
stabilizes.
II. Glucagon may be used to stimulate the heart in beta adrenergic
blocker treated patients.
Simplified flow chart of management approaches in
diabetes mellitus (nice to know)
References or further readings

1) Kaplan USMLE STEP1, lecture notes

Pharmacology latest edition.

2) Lippincott’s illustrated review:

Pharmacology, latest edition