Diabetes Mellitus

Chronic systemic disease

characterized by metabolic and
vascular abnormalities
Disorder of carbohydrate metabolism
Results from inadequate production
or underutilization of insulin
Diabetes Mellitus
Type 1 Diabetes Type 2 Diabetes
- cells that produce insulin are - blood glucose levels rise
destroyed due to
- results in insulin dependence 1) Lack of insulin
- commonly detected before 30 production
2) Insufficient insulin
action (resistant
cells)
- commonly detected after
40
- effects > 90%
- eventually leads to β-cell
failure
(resulting in insulin dependence)

Gestational Diabetes
3-5% of pregnant women in the US
develop gestational diabetes
 Diabetes Mellitus
Symptoms: hyperglycemia, glucosuria,
polyuria, polydipsia, polyphagia, and
possibly itching.
Fasting blood glucose is higher than 126
Manifested by: weight loss, weakness,
increased frequency of infections, poly’s
Complications: retinopathies, glaucoma,
neuropathies, cardiovascular disease.
 Pathophysiology
Insulin secreted by beta cells
Insulin binds with and activates 80% of cells
Liver, muscle, and fat cells are primary tissues
for insulin action
With insulin receptor binding, cell
membranes permeable to glucose into the cells
Increased cell permeability also allows for
amino acids, fatty acids and electrolytes to
enter cells
Changes cause anabolism and inhibit
catabolism
 Carbohydrate metabolism
Insulin increases glucose transport into liver, skeletal muscle,
adipose tissue, the heart, and even uterus.
Must be present for muscle and fat tissues to use glucose for
energy
Insulin regulates glucose metabolism to produce energy for
cellular functions
If excess glucose is present after need is met, it is converted
to glycogen and stored or converted to fat and stored.
The excess glucose transported to liver cells is converted to
fat only after glycogen stores are saturated. Liver is
especially important in restoring blood sugar levels by
breaking down glycogen or by forming new glucose.
 Fat Metabolism
Insulin promotes glucose into fat cells where it is
broken down
One of breakdown products is A-
glycerophosphate, combines with fatty acids
which ultimately forms triglycerides
This is the mechanism by which insulin promotes
fat storage
 Fat Metabolism
When insulin is lacking, fat is released into the
bloodstream as free fatty acids.
Blood concentrations of triglycerides,
cholesterol and phospholipids are also increased
Thus the high lipid concentration probably
contributes to the accelerated atherogenesis
seen in diabetics. Some of the free fatty acids
may be converted to ketones, resulting in
ketosis.
 Protein Metabolism
Insulin increases the total amount of body protein
by increasing transport of amino acids into cells and
synthesizing protein within the cells
Insulin potentiates the effects of growth hormone
Lack of insulin causes protein breakdown into amino
acids
These amino acids are not replaced by synthesis of
new proteins; thus, protein wasting occurs resulting
in weakness, weight loss and abnormal functioning
of many body organs
 Endogenous Insulin
Glucose is the major stimulus of insulin
secretion
Oral glucose is more effective than
intravenous glucose because glucose in
digestive tract increases the release of
gastrin, secretin, chlecystokinin, and gastric
inhibitory peptide
 Endogenous Insulin
Other hormones that raise blood glucose
levels include:
Cortisol
Glucagon
Growth hormone
Epinephrine
Estrogen
Progesterone
 Endogenous Insulin
Factors that inhibit insulin secretion include:
Hypoxia
Hypothermia
Stimulation of alpha adrenergic 2 receptors
Antidiabetic drugs
 Hypoglycemic Drugs
Insulin lower glucose levels by increasing
glucose uptake by cells
Available insulins are pork and human
 Insulin
Human insulin is chemically identical to
endogenous insulin but it is not derived
from the human pancreas
Cannot be given orally
Insulins differ in onset and duration of
action. Ultra-short, short, intermediate and
long acting.
 Rapid acting insulin
Insulin lispro (Humalog) or insulin aspart
(Novolog) are very shorting acting insulins
More effective in decreasing post-prandial
hyperglycemia
Less likely to cause hypoglycemia before
the next meal
Onset is 15’, peaks in 1-3 hours, duration is
3-5 hours
 Intermediate-acting Insulins
Isophane insulin suspension (NPH, NPH
Iletin II, Humulin N, Novolin N)
Onset is 1-1.5 hours, peaks in 8-12 hours
and duration is 18-24
 Long-acting Insulin
Extended insulin zinc suspension
Onset is 4-8 hours, peaks in 10-30 hours
and duration is 36+ hours
 Insulins
Insulin Mixtures
NPH 70/30 (Humulin or Novolin 70/30)
Durations of actions same as individual
components
 Insulins
Insulin Analogs
Lispro and aspart as previously
described
Insulin glargine (Lantus)-once daily at
bedtime. Onset is 1.1 hours, peak is
none, duration is 24 hours
Must not be diluted or mixed with
any other insulin or solutions
Adverse Effects

Hypoglycemia
Allergic reaction
Insulin resistance
Hypokalemia
Lipoatrophy
 Adverse Effects
1. Allergic reaction: foreign protein enter into
human body
Insulin has antigenicity, the slight reaction
includes local swelling, itch, ache. It rarely
occurs urticaria, angioedema and anaphylactic
shock.
It often uses antihistamine drug and adrenal
cortex hormone to treat with severe allergic
reaction ， and these patients should change to
use high purity insulin or human insulin.
 Adverse Effects
2. Hypoglycemia
（ the most common and serious adverse ）
It is the result of an imbalance between
glucose intake (e.g. missing a meal), glucose
utilisation (e.g. unusual exercise) and insulin
dose.
The result is sympathetic activation and
neuroglycopenia.
 Adverse Effects
Patients and their families should be
trained to spot the warning signs and how
to treat hypoglycaemia, including possibly
administration of glucagon if the patient
loses consciousness.
Treatment is by administration of
carbohydrate orally to a conscious patient,
or i.v. glucose or i.m. glucagon.
 Adverse Effects
4.Hypokalemia: may occur in the acidosis
patients who use a lot of insulin and
glucose, it can lead to the patient death
with abnormal heart beat.
5.Lipoatrophy:
5. is the atrophy or
hypertrophy of fat at the site of injection.
Diabetes – Oral Medications
Sulfonylureas

Biguanides

Alpha-glycosidase inhibitors

Thiazolidinediones

Meglitinides
Oral Antidiabetic Drugs
Sulfonylureas
Tolbutamide
Chlorpropamide
Glibouclamide
Glipizide
Glimepiride
Glibenclamide
 The Mechanism of Action
Efek hipoglikemik obat ini tergantung pada fungsi sel β.
Sulfonilurea, seperti glukosa, depolarisasi sel β dan
melepaskan insulin. Hal ini dilakukan dengan mengikat
reseptor sulfonilurea (SUR) dan memblokir ATP-
dependent saluran kalium (KATP); mengaktivasi
depolarisasi yang dihasilkan dengan tegangan-sensitif
kanal Ca2+, pada gilirannya menyebabkan masuknya ion
Ca2+ dan terjadi sekresi insulin
The Clinical Application of Sulfonylureas
Diabetes Mellitus ： A sulfonylurea drug is
often used to treat type II DM that cannot
be controlled with dietary restrictions.
Diabetes Insipidus ： coadministrating with
Hydrochlorothiazide can improve the effect
Farmakokinetik sulfonilurea
 Adverse Effects of Sulfonylureas
Hypoglycaemia
Gastrointestinal upsets
Hypersensitivity: rashes etc.
Weight gain: stimulation of appetite can

be a problem in obese patients.

Oral Antidiabetic Drugs

Biguanides
Phenformin
Metformin
α-glucosidase inhibiors
Acarbose
Biguanides

[Physiological Disposition]
Metformin is administered orally from
two to four times a day and is eliminated
by renal excretion of the parent
compound. Its duration of action is about
18 hours.
 Biguanides
Does not cause hypoglycemia
May be used alone or in combination
Must check renal function before beginning this
medication
 Mekanisme Biguanid
Meningkatkan sensitivitas insulin pada liver dan jaringan
perifer. Hal ini menyebabkan terjadinya peningkatan
masukan glukosa pada jaringan perifer.
Tidak mempunyai efek langsung pada sel β pankreas,
meskipun kadar insulin menurun. Selain itu diketahui
bahwa efek utama adalah dengan menurunkan produksi
glukosa hepatik melalui aktivasi enzim AMP-activated
protein kinase dan meningkatkan stimulasi ambilan
glukosa oleh otot skelet dan jaringan lemak.
 Adverse Effects of Biguanides

The most common adverse effects of

metformin are gastrointestinal disturbances.
Patients with renal or hepatic disease,
alcoholism, or a predisposition to metabolic
acidosis should not be treated with
metformin, because they are at increased
risk of lactic acidosis.
 Glitazones
Pioglitazone (Actos) and rosiglitazone
(Avandia) are also called
thiazolidinediones or TZDs
Are insulin sensitizers
Decrease insulin resistance. Stimulate
receptors on muscle, fat, and liver cells.
Results in increased uptake of glucose in
periphery and decreased production by the
liver.
Mekanisme Glitazone
Obat bekerja dengan berikatan pada peroxisomen
proliferator activated reseptor gamma (PPAR gamma)
suatu respeptor inti di sel otot dan sel lemak.
 Obat ini mempunyai efek menurunkan resistensi insulin
dengan meningkatkan jumlah pentranspor glukosa,
sehingga meningkatkan ambilan glukosa di perifer.
TZD mempengaruhi adipokin (misal angiotensinogen,
TNF alfa, interleukin-6, PAI-1), yang mempengaruhi
sensitivitas insulin. Adinopektin yang menurun pada
kondisi obese dan diabetes ditingkatkan oleh TZD,
memperbaiki fungsi endotel, sensitivitas insulin dan
memiliki efek antiinflamasi yang poten.
 Glitazones
Contraindicated in patients with liver
disease or who have ALT levels > 2.5 of
normal
May be used as monotherapy or in
combination with insulin, metformin
(Glucophage) or a sulfonylurea
Caution in patients with heart failure
Mekanisme Aksi
 Acarbose menghambat baik alpha amilase dan alpha-glukosidase lainnya,
sehingga mencegah penyerapan pati dan karbohidrat lain dari perbatasan
intestine.
 Kelas ini mengandung senyawa yang menunda penyerapan karbohidrat
di usus, mengurangi glikemia postprandial, dan membantu mengelola
diabetes. Acarbose juga memiliki efek hemat insulin, menyebabkan
peningkatan hormon incretin, glukagon seperti peptide- 1 dan
menghambat pelepasan postprandial dari gastric inhibitory polypeptide
(GIP), dan membantu mengurangi berat tubuh.
 Acarbose tidak diserap dari usus, dan memiliki bioavailabilitas yang
rendah.
 Didistribusikan di ruang ekstraselular, dengan afinitas jaringan rendah
dan variabel protein yang mengikat. Acarbose diekskresikan melalui jalur
fekal
The Indications of Acarbose

Acarbose is used in the treatment of

type II DM.
It is administered with each meal and
is particularly effective when given
with meals containing large amounts of
starch.
 Adverse effects of Acarbose
The most common side effect of
acarbose are increased flatulence and
abdominal bloating.
Acarbose may increase the oral
bioavailability of metformin and cause a
decrease in iron absorption.
Contraindicated in cirrhosis,
malabsorption, severe renal impairment
Mekanisme DPP-IV inhibitor
Incretin peptida seperti gastric inhibitory polypeptide (GIP) dan
glucagon like peptide (GLP-1) bertanggung jawab untuk modulasi
glukosa darah postprandial dengan mempromosikan sekresi
insulin dari sel β pankreas dan melalui efek glukagonostatik.
GLP-1 dan GIP cepat tidak aktif oleh DPP-IV, yang mengarah ke
waktu paruh pendek.
DPP-IV juga menunjukkan peningkatan sensitivitas insulin,
mengurangi hipertrofi islet pankreas, dan perlindungan terhadap
streptozotocin yang menginduksi hilangnya sel β dan
hiperglikemia.
Penghambatan DPP-IV juga meningkatkan kontrol glikemik
postprandial, menunjukkan mekanisme tambahan untuk DPP-IV
pada efek antihiperglikemik
Diabetes – Insulin
(synthesis, storage, secretion)
 Produced within the pancreas
by β cells  islets of
Langerhans
 insulin mRNA is translated as
a single chain precursor
called preproinsulin Zn
 removal of signal peptide
during insertion into the
endoplasmic reticulum
generates proinsulin
 Within the endoplasmic
reticulum, proinsulin is
exposed to several specific
endopeptidases which excise
the C peptide, thereby
generating the mature form
of insulin
 Stored as β granules
Sulfonylureas
[physiological disposition]
The sulfonyureas are administered orally
and undergo varying degrees of hepatic
metabolism and renal elimination of the
parent compound and metabolites. Most
of the sulfonylureas are metabolized to
inactive or less active compounds in the
liver.
 Meglitinides
Nateglinide and repaglinide are
nonsulfonylureas that lower blood sugar by
stimulating pancreatic secretion of insulin
Monotherapy or in combination with
metformin
Should be taken before or up to 30 minutes
before a meal. Dosage and frequency is
flexible depending on food intake.