Drug treatment of diabetes mellitus

Question 1

How is blood glucose regulated?

Answer 1

 Insulin
 Lowers blood
glucose.
 Increased blood
glucose stimulates
insulin secretion.

 'Counter-regulatory'
hormones:
 Glucagon
 Adrenaline
 Glucocorticoids
 Growth hormone

Question 2

What are the pancreatic cells?

Answer 2

Alpha cell - secretes glucagon
beta cells - secretes insulin
delta cell - secretes somatostatin
Exocrine pancreas - acinar cells and duct cells
F-cell - secretes pancreatic polypeptide

Question 3

What is the structure of insulin?

Answer 3

 It consists of two peptide
chains (of 21 and 30
amino acid residues)
linked by disulfide
bonds.

There is a steady basal
release of insulin and
also a response to an
increase in blood
glucose.

Question 4

How is insulin secreted?

Answer 4

 Glucose enters B cells via a
membrane transporter called
Glut-2.
 Metabolism of glucose
increases intracellular ATP.
 ATP blocks KATP channels,
causing membrane
depolarisation and opening
of voltage-dependent calcium
channels, leading to Ca2+
influx.
 The increase in cytoplasmic
Ca2+ triggers insulin
secretion.

Question 5

What are the actions of insulin?

Answer 5

 It is an anabolic hormone.

 Acutely, it reduces blood glucose.

Question 6

What are the actions of insulin in the liver?

Answer 6

 In the liver:
 Inhibits glycogenolysis.
 Inhibits gluconeogenesis.
 Stimulates glycogen synthesis.
 Increases glucose utilisation (glycolysis).
 The overall effect is to increase hepatic
glycogen stores.
 Decreases protein catabolism and inhibits
oxidation of amino acids.
 Increases the synthesis of fatty acid and
triglyceride and inhibits lipolysis.

Question 7

What are the actions of insulin in muscle?

Answer 7

 In muscle:
 Increases the facilitated transport of glucose
via a transporter called Glut-4
 Stimulates glycogen synthesis.
 Stimulates glycolysis.
 Stimulates the uptake of amino acids into
muscle and increases protein synthesis.

Question 8

What are the functions of insulin in adipose tissue?

Answer 8

 In adipose tissue:
 Increases glucose uptake by Glut-4.
 Enhances glucose metabolism to form
glycerol, which is esterified with fatty acids to
form triglycerides.
 Inhibits lipolysis.

Question 9

What is the mechanism of action of insulin?

Answer 9

Insulin receptor:

• A large transmembrane glycoprotein
complex belonging to the tyrosine kinase linked receptor superfamily and
consisting of two α and two β subunits

• Receptor autophosphorylation-the first
step in signal transduction-is a
a consequence of dimerization, allowing
each receptor to phosphorylate the other.

• Insulin receptor substrate (IRS) proteins
undergo rapid tyrosine phosphorylation.

• Phosphorylated IRS interact with SH2 domain of phosphatidylinositol 3-kinase
and activate it. As a result recruitment of
insulin-sensitive glucose transporters
(Glut-4) from the Golgi apparatus to the
plasma membrane in muscle and fat cells
occurs.

• The longer-term actions of insulin entail
effects on DNA and RNA, mediated partly
at least by the Ras signalling complex
which regulates cell growth.

Question 10

What are incretins?

Answer 10

Glucagon-like insulinotropic peptide
(GIP)
• Secreted by enteroendocrine cells
in the duodenum and proximal
jejunum.
Glucagon-like peptide-1 (GLP-1)

• Secreted by enteroendocrine cells
more widely distributed in the
gut, including in the ileum and
colon as well as more proximally.

Question 11

What is the action of these hormones?

Answer 11

Actions of these hormones:
• An early stimulus to insulin
secretion after food ingestion
• Inhibition of pancreatic glucagon
secretion
• Slowing the rate of absorption of
digested food by reducing gastric
emptying
Dipeptidyl peptidase-4 (DPP-4)
• Terminates rapidly the actions of
GIP and GLP-1.

Question 12

What is diabetes mellitus?

Answer 12

 Reduced (or absent)
secretion of insulin

 Often coupled with insulin
resistance (reduced
sensitivity to its action)
which is closely related to
obesity

Question 13

What is the difference between type 1 and 2 diabtes?

Answer 13

 Type 1 diabetes
 Previously known as:
 Insulin-dependent diabetes mellitus-IDDM
 Juvenile-onset diabetes
 Pathogenesis: autoimmune process

 Type 2 diabetes
 Previously known as:
 Non-insulin-dependent diabetes mellitus-NIDD
 Maturity-onset diabetes
 Pathogenesis: insulin resistance (which precedes overt
disease) and impaired insulin secretion

Question 14

What are insulin preparations?

Answer 14

 Insulin for clinical use was once either porcine or bovine
but is now human (made by recombinant DNA
technology).

Question 15

What are the routes of administration of insulin preparation?

Answer 15

 Routes of administration – as insulin is destroyed in the
gastrointestinal tract, it must be given parenterally:
 Usually subcutaneously
 Intravenously or occasionally intramuscularly in emergencies

Question 16

What is the PK of insulin preparations?

Answer 16

 PK
 Plasma half-life of approximately 10 min.
 Inactivated enzymatically in the liver and kidney; 10% -
excreted in the urine.
 Renal impairment reduces insulin requirement.

Question 17

How are insulins classified?

Answer 17

1. Insulins and analogs
with fast onset and short
duration of action
• insulins
Insulin Actrapid
Insulin Actrapid Penfill
Humulin R
• analogs
Insulin lispro
Insulin aspart

2. Insulins with intermediate duration of
action
• monopreparations
Humulin N
Insulatard
• insulin mixtures
Insulin + Isophane insulin:
Insulin Mixtard 10 (20, 30, 40, 50) Penfill
Humulin M1 (M2, M3, M4)
• mixtures of analogs
Insulin lispro + Insulin lispro protamine:
Humalog Mix 25, Humalog Mix 50 

3. Insulin analogs with long duration of
   action
   Insulin glargine
   Insulin detemir

Question 18

What do the insulin analogs do?

Answer 18

Insulin analogs:

Insulin lispro 
Acts more
rapidly but for
a shorter time
than natural
insulin

Insulin
glargine 
Provides a
constant basal
insulin supply

Question 19

What are the clinical uses of insulin?

Answer 19

 Maintenance treatment for patients with type 1 diabetes:
 Intermediate-acting preparation (e.g. isophane insulin) or a longacting analogue (e.g. glargine) is often combined with soluble insulin
or a short-acting analogue (e.g. lispro) taken before meals.

 Insulin Actrapid (i.v.) in hyperglycemic emergencies (e.g. diabetic
ketoacidosis).

 In type 2 diabetes in combination with oral drugs

 Short-term treatment of patients with type 2 diabetes during
intercurrent events (e.g. operations, infections, myocardial infarction).

 During pregnancy, gestational diabetes is not controlled by diet alone.

 Emergency treatment of hyperkalemia: insulin is given with glucose to
lower extracellular K+ via redistribution into cells.

Question 20

What are some adverse reactions to insulin?

Answer 20

 Hypoglycemia:
 Treatment of severe
hypoglycemia - i.v glucose
and i.m. glucagon.

 Allergy to human insulin –
unusual but can occur. It
may take the form of local
or systemic reactions.

 Insulin resistance as a
consequence of antibody
formation – rare.

 Lipodystrophy at the
injection site

Question 21

What are the drugs used in type II diabetes mellitus?

Answer 21

1. Biguanides
   Metformin

2. Sulfonylureas
Glibenclamide
Gliclazide
Glipizide
Glimepiride

3. Meglitinides
   Repaglinide
   Nateglinide
4. Thiazolidinediones
   Pioglitazone
5. Alpha-glucosidase inhibitors
   Acarbose

6. Inhibitors of DPP4
Sitagliptin
Vildagliptin
Linagliptin
Saxagliptin

7. Incretin mimetics
Exenatide
Liraglutide
Dulaglutide
Lixisenatide

8. Glucuretics
   Dapagliflozin
   Empagliflozin
   Canagliflozin

Question 22

What does metformin do?

Answer 22

 Reduces hepatic glucose
production
(gluconeogenesis)

 Increases glucose uptake
and utilisation in
skeletal muscle (i.e. it
reduces insulin
resistance)

 Reduces carbohydrate
absorption

 Reduces LDL and VLDL

Question 23

What are the adverse effects of metformin?

Answer 23

Adverse effects
Gastrointestinal
disturbances (e.g. anorexia,
diarrhoea, nausea)

Lactic acidosis – a rare but
potentially fatal toxic effect.
Metformin should not be
given to patients with:
 Reduced tissue
oxygenation (repiratory
and heart failure)
 Reduced drug elimination
(renal or hepatic disease)

 It does not cause
hypolgycemia!

Question 24

What is the clinical use of metformin?

Answer 24

 Clinical use:
 Type 2 diabetes, especially
in obese patients

Question 25

What are some examples of sulfonylureas?

Answer 25

Glibenclamide
Gliclazide
Glipizide
Glimepiride

Question 26

What is the mechanism of action of sulfonylureas?

Answer 26

Mechanism of action:

 Receptors for sulfonylureas on the KATP channels
 Block by sulfonylurea drugs of KATP channel activation
 Depolarisation
 Ca2+ entry
 Insulin secretion

Question 27

What is the PK of sulfonylureas?

Answer 27

PK:

 Oral absorption
 High binding to plasma proteins
 Renal excretion of the drugs or their
active metabolites
 Cross the placental barrier

Question 28

What are the ADRs and clinical uses of sulfonylureas?

Answer 28

 Adverse drug reactions
 Hypoglycemia, especially in
patient with renal imparment
 Weight gain –stimulate appetite
 Gastrointestinal upsets
 Allergic skin rashes can occur
 Bone marrow toxicity although
rare, can be severe.

 Clinical use
 Type 2 diabetes

Question 29

What are the drug interactions of sulfonylureas?

Answer 29

 Drug interactions:

 Drugs augmenting the
hypoglycaemic effect (competition
for metabolising enzymes,
interference with plasma protein
binding or with transport
mechanisms for excretion):
 Non-steroidal anti-inflammatory drugs
 Coumarins
 Alcohol
 Some antibacterial drugs (including
sulfonamides, trimethoprim and
chloramphenicol)
 Some imidazole antifungal drugs

 Agents that decrease the action of
sulfonylureas
 Thiazide diuretics
 Corticosteroids

Question 30

What are meglitinides?

Answer 30

Repaglinide
Nateglinide

• Much less potent than most sulfonylureas
• Have rapid onset and offset kinetics
• Short duration of action
• Low risk of hypoglycemia
• Administered shortly before a meal to reduce the
postprandial rise in blood glucose in type 2
diabetic patients
• Less weight gain than sulfonylureas.

Question 31

What are the effects of thiazolidinediones?

Answer 31

 Effects:
Reduce hepatic glucose output.
Increase glucose uptake into muscle, by
enhancing the effectiveness of endogenous
insulin.
Decrease triglycerides.

Question 32

What is the mechanism of action of thiazolidinediones?

Answer 32

 Mechanism of action:

Thiazolidinediones bind to a nuclear
receptor called the peroxisome
proliferator-activated receptor-γ (PPARγ),
which is mainly in adipose tissue, but also
in muscle and liver. It is complexed with
retinoid X receptor (RXR).

Thiazolidinediones cause the PPARγ-RXR
complex to bind to DNA, promoting
transcription of several genes with
products that are important in insulin
signalling. These include Glut-4.

PPARγ causes differentiation of
adipocytes, increases lipogenesis and
enhances uptake of fatty acids and
glucose.

Question 33

What is the PK, ADRs, and clinical uses of thiazolidionediones?

Answer 33

PK:
Rapidly and nearly
completely absorbed
Metabolized in the liver

Adverse reactions:
Weight gain and fluid
retention:
 Contraindicated in heart
failure
Increased risk of fractures
with chronic use.

Clinical use:
In combination with
metformin or with a
sulfonylurea in patients
whose blood glucose is
inadequately controlled on
one of these drugs

Question 34

What are α-Glucosidase inhibitors

Answer 34

Acarbose
 It delays carbohydrate absorption, reducing the
postprandial increase in blood glucose.
 Adverse effects:
 Flatulence, loose stools or diarrhoea, and abdominal
pain and bloating
 Clinical use:
 Like metformin, it may be particularly helpful in obese
type 2 patients, and it can be co-administered with
metformin.

Question 35

What is an example of Incretin mimetics and related drugs?

Answer 35

Exenatide

Other incretin mimetics:
Liraglutide
Dulaglutide
Lixisenatide

Question 36

What are the effects, ADRs, and clinical use of Exenatide?

Answer 36

 A synthetic version of exendin-4, a peptide found in the saliva
of the Gila monster (a lizard disabling its prey by rendering
them hypoglycemic).

 Effects – mimics the effects of GLP-1, but is longer acting:
 Increases insulin secretion
 Suppresses glucagon secretion
 Slows gastric emptying
 Reduces food intake (by an effect on satiety) and is associated
with modest weight loss.
 Subcutaneous administration twice daily before the first and
last meal of the day.

 Adverse effects:
 Hypoglycemia
 Gastrointestinal effects
 Pancreatitis (rare but sometimes severe)

 Clinical use:
 Type 2 diabetes in combination with oral drugs

Question 37

What are examples of gliptins?

Answer 37

Sitagliptin
Vildagliptin
Linagliptin
Saxagliptin

Question 38

What do gliptins do?

Answer 38

 Synthetic drugs that
competitively inhibit
dipeptidylpeptidase-4 (DPP-4),
thereby potentiating endogenous
incretins (GLP-1 and GIP).

 Do not cause weight loss or
weight gain.

 Well absorbed from the gut.

 Used for type 2 diabetes, usually
in addition to other oral
hypoglycemic drugs

Question 39

What are examples of glucuretics?

Answer 39

Dapagliflozin
Empagliflozin
Canagliflozin

 A novel class of glucose-lowering agents known as
sodium-glucose co-transporter-2 (SGLT2) inhibitors

Question 40

What is the mechanism of action of glucuretics?

Answer 40

 Mechanism of action:
 Inhibition the transporter protein SGLT2 in the kidneys
 Reduction of renal glucose reabsorption
 Urinary glucose excretion
 Reduction if blood glucose levels

 The efficacy of glucuretics is independent of insulin
secretion and action.
 Used in the treatment of patients with type 2 diabetes.
 An important addition to the therapeutic options for the
management of type 2 diabetes, particularly when used as
add-on therapy
 Associated with reductions in body weight

Question 41

What are the ADRs of glucuretics?

Answer 41

 ADR:
 Genital infections and urinary tract infections affecting
about 8–9% of patients.
 In clinical trials patients taking dapagliflozin had
higher rates of breast cancer (nine cases versus none in
comparator arms) and bladder cancer (nine cases
versus one in placebo arm)