ANTIDIABETIC DRUGS

RAYMUND N. TAPAOAN, RPH

Glucose Metabolism

Glucose levels in the blood rise after a

meal. This increase stimulates the β-cell
s in the islets of Langerhans to secrete i
nsulin. Insulin has effects on several tiss
ues: liver, adipose tissue, muscle tissue
and other body cells. In general insulin s
timulates glucose uptake. In the liver an
d in muscle tissue insulin also induces g
lycogen synthesis. These events result i
n a decrease of the blood glucose levels
to normal values. In adipose tissue the s
ynthesis of triglyceride is stimulated.
Regulation of Glucos
e Uptake
The physiological regulation of glucose uptake is de
picted below. After food intake (1) the complex sugar
s are broken down in the small intestine into glucose
molecules. L-cells in the distal intestinal wall secrete
the incretin GLP-1 upon stimulation by food/glucose
(2).
This glucagon-like peptide-1 is released proportional
to the amount of food post-prandial in the distal intes
tine. GLP-1 is key player in many processes after a m
eal. It stimulates the release of insulin by the β-cells i
n the pancreas (3)
Similarly, GLP-1 inhibits the release of glucagon by t
he α-cells (4).
The rise in insulin will stimulate the glucose uptake f
rom the blood into the cells (8).
Further, GLP-1 inhibits gastric emptying (5) and indu
ces the feeling of satiety (6) in order to reduce furthe
r carbohydrate intake.
GLP-1 is metabolised by the enzyme dipeptidyl pepti
dase 4 (DDP-IV) which is present in the cell wall (7).
Diabetes Mellitus
Diabetes mellitus (DM) It is a meta
bolic disorder characterized by hy
perglycaemia, glycosuria and keto
naemia.
Pathophysiology of DM
A widespread pathological change is t
hickening of capillary basement mem
brane, increase in vessel wall matrix
and cellular proliferation resulting in v
ascular complications like
• lumen narrowing,
• early atherosclerosis,
• sclerosis of glomerular capillaries,
• retinopathy,
• neuropathy
• peripheral vascular insufficiency.
Pathophysiology of DM
Enhanced glycosylation of tissue pro
teins due to persistent exposure to hi
gh glucose concentrations and the a
ccumulation of larger quantities of so
rbitol (a reduced product of glucose)
in tissues are believed to be causativ
e in the pathological changes of diab
etes.
Risk Factors of DM
Blood Sugar Level Chart
DM Type 1 (IDDM-Insulin-dependent diabetes mellitus
In diabetes mellitus type I, there is an absol
ute shortage of insulin resulting from autoi
mmune destruction of pancreatic β-cells.
Due to this insulin deficiency, the mechanis
ms that decrease glucose levels in the bloo
d do not work.
As a result, dangerously high blood glucos
e levels occur, whereas glucose levels in c
ells are low.
Because DM type I patients cannot even pr
oduce modest amounts of insulin, dangero
us ketone bodies are formed by fat breakd
own and ketoacidosis can occur.
Symptoms of diabetic patients are polyuria,
dehydration, fatigue, muscle weakness and
coma.
 Insulin
Insulin, used for the treatment of diabetes is produ
ced by recombinant DNA techniques. Insulin affect
s glucose-, fat-, and protein metabolism.
It binds to a tyrosine kinase receptor at the cell sur
face. Activation of the receptor is the beginning of
a cascade of phosphorylations of enzymes in the
cytoplasm, eventually resulting in changes in cellul
ar processes.
Insulin stimulates the transport of vesicles containi
ng glucose transporters towards the cell membran
e. At the level of carbohydrate metabolism, insulin
stimulates uptake of glucose in muscle and adipos
e tissue.
In the liver, insulin inhibits glucose production by i
nhibiting glycolysis and gluconeogenesis and by st
imulating glycogen synthesis. In adipose tissue, in
sulin stimulates triglyceride formation and inhibits r
elease of fatty acids. Protein synthesis is induced
by insulin.
Insulin
Insulins with different durations of action are us
ed to treat diabetes:
short-acting insulin (4-6 hours, in blue): normal i
nsulin Actrapid®
short-acting insulin analogues (4-6 hours, in blu
e): aspart (Novorapid®) and lispro (Humalog®)
long-acting insulin (14-28 hours, in purple): glar
gin (Lantus®) and detemir (Levemir®)
Normal insulin and glucose levels and administ
ered insulin levels are compared in the graphs
below.
Patients must control their own sharp setting of
insulin administration.
Short-acting insulin needs to be injected 2-3 tim
es a day just prior to a meal. In addition, 1-2 inj
ections a day with long-acting insulin are neces
sary.
The arrows represent the injections
with short-acting insulin (blue) during
the day and the injection with long-a
cting insulin (purple) in the evening.ti
ons a day with long-acting insulin are
necessary.
DM Type 2 (NIDDM Noninsulin-dependent diabetes
mellitus)
Type II diabetes mellitus is caused by a mi
sbalance between β-cell function and insul
in resistance (1).
Insulin levels can be normal or elevated. T
ype II patients develop hyperglycemia, be
cause insulin secretion does not fully com
pensate for insulin resistance (2).
They do not show ketoacidosis, because t
hey secrete enough insulin to prevent the
conversion of fatty acids to ketoacids. Tre
atment consists of weight loss and caloric
restriction.
Usually this does not help appropriately a
nd drugs have to be used to decrease glu
cose uptake, increase insulin secretion an
d to decrease insulin resistance.
Pathophysiology of Glucose Uptake
In DM type II patients, the physiology by the
GLP-1 regulation is clearly disturbed, as sho
wn in the graphic below. These patients mos
tly have a larger food intake (1).
The postprandial incretin GLP-1 response is
diminished (2).
The insufficient GLP-1 concentration in the
blood has several unwanted effects: the β-c
ells in the pancreas release less insulin (3),
the glucagon release by the α-cells is less in
hibited (4),
the gastric emptying is not delayed (5), the
appetite remains (6)
and the dipeptidyl peptidase 4 (DPP-IV) enz
yme is overactivated (7). All these events re
sults in postprandial hyperglycemia (8).
Sulphonylureas
Sulphonylurea derivatives enhance the secr
etion of insulin from pancreatic tissue (β-cel
ls).
These drugs can block ATP-dependent pot
assium channels in the cell membrane of β-
cells. The block of the potassium efflux cau
ses a depolarization of the membrane pote
ntial, resulting in an influx of calcium ions.
The increase of calcium in the cytoplasm e
nhances the secretion of insulin.
The short-acting tolbutamide, gliclazide, an
d glimepiride are the most prominent sulph
onylureas.
The long-acting glibenclamide is not used
very often, because it increases the risk of
hypoglycemia.
Biguanides
The exact mechanism of action of big
uanides is not known. It is thought tha
t biguanides inhibit the production an
d release of glucose by the liver and t
hat they increase the sensitivity for in
sulin in peripheral tissues.
Metformin is the main representant of
this group of drugs.
The recommended dose for metformi
n is 500 mg 3 times a day.
Thiazolidinediones
Thiazolidinediones are a new group of drug
s that improve insulin sensitivity. The precis
e mechanism of action is not known.
Thiazolidinediones bind to peroxisome proli
ferator-activated receptors in the nucleus
(PPARs), specifically PPARγ.
In that way, thiazolidinediones alter transcri
ption of certain genes. They are most effect
ive in adipose tissue, muscle tissue and the
liver.
Rosiglitazon and pioglitazon belong to this
group of drugs.
When metformin or sulphonylderivatives ar
e not effective, addition of thiazolidinedione
s to these drugs might obtain better effectiv
ity.
Insulinoma induced hypoglyc
emia
Hypoglycemia can occur as a result of i
nappropriate insulin use by diabetics.
In addition, insulinoma creates a pathol
ogical condition of inappropriately high
insulin levels and decreased glucose le
vels.
Hypoglycemia causes nervousness, ta
chycardia, tremor, sweating, paleness
and ultimately coma.
The ultimate treatment of insulinoma is
surgical resection.
For acute treatment of insulin-induced
hypoglycemia, glucagon can be used.
Glucagon
Glucagon increases plasma glucose le
vels by stimulation of glycogenolysis in
the liver. After binding to a G-protein co
upled receptor, the second messenger
cAMP stimulates enzymes of glycogen
olysis. The glucose is released by the li
ver and glucose blood levels rise.
Glucagon is indicated in cases of sever
e hypoglycemia after the use of blood
glucose lowering drugs. One (1) mg of
glucagon should be injected intramusc
ularly or intravenously.
When the patient is conscious again, h
e/she should take carbohydrate rich fo
od.
 THANK YOU
RNTER TEXT

MEDICAL EXPERTS TO LECTURE