Diabetes Mellitus Overview and

Treatments
Diana Holidah

DIANA HOLIDAH
Bagian Farmasi Klinik dan
Komunitas
Fakultas Farmasi-Unej

Management of
Diabetes Mellitus

General Objectives of Diabetes Management:

To relieve symptoms
To correct associated health problems and to reduce
morbidity, mortality and economic costs of diabetes
To prevent as much as possible acute and long-term
complications and to provide timely intervention
To improve the quality of life and productivity of the
individual with diabetes

Glycemic goal of therapy

Correlation of HbA1c with Average Glucose (AG)

HbA1c (%)
6

7
8
9
10
11
12

Mean plasma glucose

mg/dL
mmol/L
126
7.0
154
8.6
183
10.2
212
11.8
240
13.4
269
14.9
298
16.5

Management of DM
The major components of the treatment of diabetes are:

Diet and Exercise

Oral hypoglycaemic
therapy

Insulin Therapy

A. Diet
Diet is a basic part of management in every case.
Treatment cannot be effective unless adequate
attention is given to ensuring appropriate nutrition

Dietary treatment should aim at:

ensuring weight control

providing nutritional requirements
allowing good glycaemic control with blood glucose
levels as close to normal as possible
correcting any associated blood lipid abnormalities

The following principles are recommended as dietary

guidelines for people with diabetes:
Dietary fat should provide 25-35% of total intake of calories
but saturated fat intake should not exceed 10% of total
energy. Cholesterol consumption should be restricted and
limited to 300 mg or less daily.
Protein intake can range between 10-15% total energy (0.81 g/kg of desirable body weight). Protein should be derived
from both animal and vegetable sources.
Carbohydrates provide 50-60% of total caloric content of the
diet. Carbohydrates should be complex and high in fibre.
Excessive salt intake is to be avoided.

Exercise
Physical activity promotes weight reduction and improves
insulin sensitivity, thus lowering blood glucose levels.
Together with dietary treatment, a programme of regular
physical activity and exercise should be considered for
each person.
People should, however, be educated about the potential
risk of hypoglycaemia and how to avoid it.

Oral Drug Therapy for Type 2 DM

Sulfonylureas

Repaglinide
Nateglinide

Biguanides
Thiazolidinediones
Acarbose
Miglitol

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Insulin secretagogues

Insulin sensitizers
Inhibitors of CHO
absorption

Sulfonylureas :
stimulate cells to produce more insulin
1st generation

Rel. Potency

bind to protein

(1)Orinase

(tolbutamide)
(3)Tolinase (tolazamide)
(6)Diabinese (chlorpropamide)

2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)

was used in treatment of typhoid fever in 1940s hypoglycemia

may become dislodged delayed activity

2nd generation

(glipizide)
(150)Glucotrol XL (ex. rel. glipizide)
(150)Micronase, Diabeta (glyburide)
(250)Glynase (micronized glyburide)

(350)Amaryl

(75)Glucotrol

(glimepiride)

*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway
*Hydroxylated derivatives have much lower hypoglycemic activity

Sulfonylureas: Mechanism of Action

Na+

GLUT2

K+

Sulfonylureas

KIR K+

Na+
K+

K+
Ca2+

Pancreatic
cell
Ca2+
Insulin granules

Vm

Ca2+
Voltage-gated
Ca2+ channel

Mechanism of Action
Sulfonylureas interact with receptors on pancreatic
b-cells to block ATP-sensitive potassium channels
This, in turn, leads to opening of calcium channels
Which leads to the production of insulin

Second Generation Sulfonylureas

Glipizide
Oxidized to inactive metabolites

Half-life - 2 to 4 hours

HN O
S
O

Potency - High
O

(2.5 to 40 mg/d)
N
N

C NH

N
H

Extended-release preparation- glipizide GITS

Glipizide gastrointestinal therapeutic system
Does not induce weight gain

Second Generation Sulfonylureas

Glyburide
O

Oxidized to weakly
active metabolites

HN O
S
O

Half-life - 6 hours

Duration of action-

24 hours

Potency - High
(1.25 to 20 mg/d)

C NH

Cl

N
H
OCH3

Second Generation Sulfonylureas

Glimepiride
Converted by liver to inactive
metabolites
Half-life- 5 hours
Potency - Highest
(1 to 8 mg/d)

CH3
O

HN

O
S
O

C2H5
N
C2H5

Increases muscle insulin sensitivity

Approved for once-daily use

C NH

N
H

Sulfonylureas: Metabolism & Excretion

Metabolized in the liver
Hepatic dysfunction will alter pharmacokinetics
Excretion
Second generation: significant fecal excretion
Glyburide -50%
Glimeperide - 40%

Clinical Uses of Sulfonylureas

Hypoglycemic agents for treatment of Type 2
diabetes mellitus
Act by increasing endogenous insulin secretion
not indicated for Type 1
Most effective when cell function has not been
severely compromised
Increased insulin secretion favors lipogenesis
Most appropriate in non- or mildly obese
Up to 160 % of ideal body weight

Choice of Sulfonylurea
Consider:
Duration of action, potency, metabolism, side effects
In presence of renal dysfunction:
- Dual routes of elimination
Glyburide or glimepiride
- Metabolized to inactive metabolites
Glipizide
Second generation SUs bind nonionically to plasma albumin
and have fewer drug interactions than earlier SUs, which
bind albumin ionically and compete with other drugs for
binding sites

Biguanides : improves insulins ability to

move glucose into cells (esp. muscle)

Metformin
Glucophage, Fortamet,
Riomet

H
N

H
N

N
H

HCl

- mechanism improves insulin sensitivity by increasing peripheral glucose uptake

and utilization.
- Zhou et al (2001) showed that metformin stimulates the hepatic enzyme AMPactivated protein kinase
- Metformin was first described in the scientific literature in 1957 (Unger et al).
-It was first marketed in France in 1979 but did not receive FDA approval for Type
2 diabetes until 1994.

Metformin is a widely used monotherapy, and also used in combination with the
sulfonylureas in treatment of type 2 diabetes

Biguanides
First Generation- Phenformin
Phenethylbiguanide
Adverse Effects
Lactic acidosis
Risk of cardiovascular disorder

CH2H2C

NH2

NH2

C
N
H

N
H

NH2

guandino

Second Generation- Metformin

1,1-Dimethylbiguanide
Currently in use in the U.S.
Rarely produces lactic acidosis
except under predisposing
conditions

H3C
N
H3C

NH2

NH2

C
N
H

NH2

Biguanides
Mechanism of action: antihyperglycemic
Correct elevated hepatic glucose output
Inhibit gluconeogenesis
Inhibit glucose-6-phosphatase activity glycogen sparing
insulin resistance
Mediated by activation of 5AMP-activated protein kinase
(AMPK) in hepatocytes and muscle
Do not increase insulin secretion
Not hypoglycemic, even at high doses

Second Generation Biguanides

Do not produce hypoglycemia
Secondary beneficial effects on lipids
Reduced triglycerides
Reduced total cholesterol
Reduced LDL
Increased HDL
Insulin levels unchanged or reduced
Weight loss, some reduction of blood pressure
Appropriate for obese Type 2 diabetics

Metformin
Excreted unchanged in the urine
Half-life - approximately 2 hours
Does not bind to plasma proteins
Should not be used with renal or hepatic dysfunction
Also approved for prevention of Type 2 diabetes in high
risk individuals
Use also for polycystic ovary syndrome: insulin
resistance with ovarian hyperandrogenism

Thiazolidinediones (TZDs) : make

cells more sensitive to insulin (esp. fatty cells)
O

Pioglitazone
- Actos,

Avandia

O
S
NH

O
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione

binds to and activates the gamma isoform of the peroxisome proliferator-activated

receptor (PPAR).
PPAR is a member of the steroid hormone nuclear receptor superfamily, and is
found in adipose tissue, cardiac and skeletal muscle, liver and placenta

upon activation of this nuclear receptor by a ligand such as a

TZD, PPARligand complex binds to a specific region of
DNA and thereby regulates the transcription of many genes
involved in glucose and fatty acid metabolism.
- Marketed in USA in August of 1999

PPAR -

Thiazolidinediones: Rosiglitazone

Bioavailability of oral dose is 99%

Metabolites have no significant activity
Excreted in urine and feces
Half-life: plasma half-life is 3 to 4 hours Extensively (99.8%)
bound to albumin
Potency: 4 to 8 mg/day
As single dose or divided into 2 doses
No evidence of drug-induced hepatotoxicity
Should not be used in patients who experienced jaundice
while taking troglitazone

lpha glucosidase inhibitors :

Block enzymes that help digest starches slowing the
rise in B.G.L.

AGIs
- Precose (acarbose),
Glucobay
H

- Glyset (miglitol)

O
H

O
N

H
1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol

a glucosidase inhibitors
Mechanism of action:

competitive and reversible inhibitors of a glucosidase in the

small intestine
Delay carbohydrate digestion and absorption
Smaller rise in postprandial glucose

Clinical use:
For mild to moderate fasting hyperglycemia with significant postprandial
hyperglycemia
Taken with the first bite of a meal
Do not produce hypoglycemia or significant weight gain
Effective regardless of age, genetic factors, body weight, duration or
severity of disease

Acarbose
Metabolized within the digestive tract by enzymes and
intestinal bacteria
Low systemic bioavailability
< 2 % is absorbed as intact molecule
Adverse effects: Gastrointestinal disturbances
Flatulence
Nausea
Diarrhea
Use gradual dose titration
Contraindicated for inflammatory and obstructive
bowel disease, colonic ulcers

Meglitinides : Stimulate more insulin

production ; dependant upon level of glucose present

Meglitinides

O
N

OH

NH

- Prandin (repaglinide)

2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

NH
O

- Starlix (nateglinide)

O OH
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

Repaglinide and Nateglinide

Mechanism of action:
+
decrease ATP-sensitive K conductance
Additional high affinity binding site identified in
mouse -cells for repaglinide
Action is glucose dependent
High potency
Elicited insulin release is rapid and brief
Taken with meals for postprandial hyperglycemia
Reduced risk of long-lasting hypoglycaemia

Oral Hypoglycaemic Medications

Dipeptidyl-Peptidase 4 Inhibitors
Agent in Class: Sitagliptin, Saxagliptin
Mechanism of action:
slows the inactivation of incretin hormones (glucagon-like
peptide 1 and glucose-dependent insulinotropic
polypeptide)
Increases glucose-stimulated insulin secretion
Causes glucose-stimulated glucagon suppression
primarily lowers postprandial glucose levels but has also
been shown to reduce fasting plasma glucose

DPP-IV inhibitors exhibit both

short term and long term actions of
GLP-1
Augment glucose induced insulin
secretion
Inhibit glucagon secretion
Slow gastric emptying
Increase insulin biosynthesis
Promote beta cell differentiation

INSULIN
Who need insulin medicine
Type I (insulin dependent) diabetes patients whose body
produces no insulin.
Type 2 diabetes patients that do not always produce
enough insulin.

Treatment
subcutaneous injection

Insulin drug evolution

Stage 1 Insulin was extracted from the glands
of cows and pigs. (1920s)

Stage 2 Convert pig insulin into human insulin

by removing the one amino acid that
distinguishes them and replacing it with the
human version.

 Stage 3 Insert the human

insulin gene into E. coli and
culture the recombinant E.coli
to produce insulin (trade name
= Humulin). Yeast is also used
to produce insulin (trade name
=
Novolin) (1987).

Recombinant DNA technology has also made it possible to

manufacture slightly-modified forms of human insulin that
work faster (Humalog and NovoLog) or slower
(Lantus) than regular human insulin.

Insulin Preparations
from LillyDiabetes.com

lispro

Ultra fast/ultra
short-acting

regular

Short-acting

Long-acting

Plasma [Insulin]

Intermediate-acting

NPH
lente
ultralente
glargine

Ultra long-acting
0

from lantus.com

12

16

20

24

Ultrafast/ultra short-acting insulin

Insulin lispro
monomeric
not antigenic
the most rapidly acting insulin
used within 15 minutes of beginning a meal
short duration of action- must be used with
longer-acting preparation for Type 1 diabetes
unless used for continuous infusion

Short-acting insulin
Regular insulin (insulin injection)
denoted on vial by R
zinc insulin crystals in a neutral, nonbuffered,
suspending solution

can be given I.V.

Intermediate-acting insulin
NPH insulin (Neutral protamine Hagedorn,
isophane insulin suspension)
denoted on vial by N
stoichiometric mixture of regular and protamine zinc
insulin (complexed with excess of positively charged fish
sperm protamine)

LENTE insulin (insulin zinc suspension)

denoted on vial by L
30% SEMILENTE insulin (amorphous precipitate of
insulin with zinc in acetate buffer)
70% ULTRALENTE insulin

Long-acting insulin
ULTRALENTE insulin (extended insulin zinc
suspension)
denoted on vial by U
delayed onset
prolonged action
acetate buffer
excess zinc
large crystals with low solubility

Ultra long-acting insulin

Insulin glargine

Recombinant insulin analog that precipitates in the neutral

environment of subcutaneous tissue
Peakless- prolonged action
Administered as single bedtime dose

glargine

ASN
GLY

ARG
ARG

Amino Acid Substitutons

A- chain
Position

B- chain Position

Source/
Type

A21

B3

B28

B29

B30

Human

Asn

Asn

Pro

Lys

Thr

Aspart

Asn

Aspartic
acid

Lys

Thr

Lispro

Asn

Lys

Pro

Thr

Glulisin
e

Asn

Pro

Glu

Thr

Glargine

Gly

Pro

Lys

Thr

Lys

Myristic
acid

Detemir

Lys

B31
And
B32

rapid-acting

Arg

long-acting

Overview of Insulin and Action

Insulin treatment regimens

Conventional insulin treatment
1 or 2 daily subcutaneous injections
mixture of short- and intermediate or long-acting
insulins

total

regular
lente

am

12

pm

12

am

12

Insulin treatment regimens

Intensive insulin treatment
Frequent monitoring of blood glucose
3 or more daily injections of insulin
Some regular alone, some combined regular and intermediateor long-acting
Adjusted to needs of individual patient
4

12

am

regular
lente
4

am

12

pm

12

am

lispro
glargine

12

12

12

am

pm

12

am

pm

12

12

am

Insulin treatment regimens

Continuous subcutaneous insulin infusion
Insulin pump with lispro or regular insulin
Programmed basal delivery
allows control of dawn phenomenon
Patient-triggered bolus before meals

Continuous
infusion
regular or
lispro

am

12

pm

12

am

12

Other Factors Affecting Insulin Pharmacokinetics

Method of injection
Standard- subcutaneous
Intradermal- poor absorption
Intramuscular - accelerated absorption
Rate of blood flow through injection site
Site of injection
absorption from abdomen or buttock faster
than from thigh or deltoid
Ambient temperature
Exercise

Insulin Injection Site

Adverse Effects of Insulin Therapy

Hypoglycemia
Especially dangerous in Type 1 diabetics
Glucose or glucagon treatment
Allergy and resistance to insulin
Local cutaneous reactions or systemic
Switch to less antigenic form or desensitization
Lipohytertrophy
Due to lipogenic effect of insulin when small area used for
frequent injections
Absorption from such sites is unpredictable
Lipoatrophy
Due to impurities: switch to highly purified insulin
Lipogenic effect of insulin can repair lesion
Insulin edema- transient, rare

Special Considerations
Pregnancy
Both hyperglycemia and hypoglycemia adversely affect fetal
growth and differentiation
Increased insulin requirement during 2nd half

Pediatric diabetes
Approximately 75% of Type 1 diabetics are diagnosed before 18
years of age
Hypoglycemic unawareness in younger children
Higher frequency of other illness

Compromised renal function

Insulin clearance reduced, effectiveness prolonged

Self-Care
Patients should be educated to practice self-care.
This allows the patient to assume responsibility
and control of his/her own diabetes
management. Self-care should include:

Blood glucose monitoring

Body weight monitoring
Foot-care
Personal hygiene
Healthy lifestyle/diet or physical
activity
Identify targets for control
Stopping smoking

Thank you