Diabetes mellitus (D.M)
Diabetes mellitus is a clinical syndrome characterized by hyperglycaemia
due to absolute (type 1) or relative (type 2) deficiency of insulin . It has
multiple etiologies and segregates into two major forms. Type 1 diabetes
is an autoimmune disease in which the patient’s own immune system
reacts against islet antigens and destroys the beta cell. Type 2 diabetes is
a polygenic syndrome with multiple etiologies
Insulin
Physiological action:
Insulin secreted from β-cells directly in an
unbound form, having
half life 6 minutes so cleared from the blood
rapidly.
Effects of insulin on the metabolism of carbohydrate, fats, and
proteins:
On carbohydrate, it promotes glucose uptake and utilization, increase
hepatic glycogen formation and inhibits hepatic gluconeogenesis.
It inhibits lipolysis and increase protein synthesis.
Differentiation by species
Animal Insulin
Until 1980 insulin was obtained by extraction and purification from
pancreata of cows and pigs (bovine and porcine insulin).
Human Insulin is produced in two ways:
• By enzymatic modification of porcine insulin by introduction of
human insulin genes into E.coli and yeasts.
• Recently, protein engineering techniques that alter the amine acids of
insulin have been used to produce analogue of insulin which are more
rapidly absorbed from the side of injection (insulin Lispro and aspart).
• Insulin preparation
• Fast-acting insulin: insulin lispro and aspart: effects begin within
5 to 15 min. and persist for 6-8hrs. Make them an ideal mealtime
insulin and even after eating in contrast regular insulin is generally
administered 30- 60min. before meal.., and persist for 6-8hrs.
• short-acting insulin (soluble, regular or neutral insulin)
considered a meal time insulin.
• onset within 0.5- 1 houre,peak effect 2-4 hours,duration 4-8 hours.
And therefore has significant activity after food is absorbed.. is
dispensed as a clear solution and is the only form that can be
administered intravenously .
• -Intermediate-acting: Lente and NPH :
Lente insulin is produced by comlexing regular insulin with zinc.
NPH ( Neutral Protamin Hagedorn) is prepared by by conjugating
regular insulin with protamine, the presence of protamine and zinc
decrease the solubility of NPH and lente insulin respectively ,and
thereby retard absorption., as a result onset is delayed and duration is
extended (onset within 2.5 hours, duration up to 24 hours).
• .The humnan lente insullin have a longer pharmacokinetic patern
than NPH insulin (isophane) and some clinicians prefer Lente
insulin to NPH
• Pre-mixed: contain both a fast- and an intermediate-acting NPH
insulin ( mostly used 30% short-acting and 70% NPH
• onset within 30-45 min,
• peak effect 4–12 hours,
• duration up to 24 hours .
long acting insulin ; ultralente insulin , onset within 2-4hr. And
dutation up to 24hrs.
Starting insulin therapy:
there is no standard calculation which will establish the correct starting
dose of insulin ,the usual daily dose is around 0.5 i.u /kg. Body weight,
larger doses are needed for overweight people, those with concurrent
illness, very high glucose concentration, ketosis.
-Smaller doses are needed for slim people, those who exercise regulary,
and those who have residual insulin (those in whom oral hypoglycemic
drugs are only just inadequate.
-Doses above 1 i.u/kg. suggest insulin resistance. The total daily dosage is
divided by the rule of thirds: two-thirds before breakfast and one third
before the evening meal; at each time of administration two-thirds
intermediate or long acting insulin and one third of short acting.
Oral hypoglycemic agents
Various classes of oral hypoglycaemic are available for treatment of
NIDDM that target the different pathophyisological factors contributing
to diabetes.
Sulphonylureas
• Sulfonylureas
that
are
gliclazide,glimepiride,glyburide
currently
and
available
glibenclamide
are
:
(daonil).
These agents are generally comparable in their effectiveness in
reducing hyperglycaemia, difference in pharmacokinetics and
pharmacodynamics may influence the choice in an individual
patient.
Drug
Tablet
Contents
in mg
Chlorpropamide
250
Dosage Duration Peak
per day of action time
(h)
o.m.*
long
3-4
Glibenclamide
5
o.m.-tds
medium
3-4
6-12
Gliclazide
80
o.m.-tds
medium
3-4
6-12
Glipizide
5
p.m.-tds
short
1
3
1-6 mg
o.m..
long
2
5-9 hrs
Glimeperide
1,2 or 4
o.m.: in the morning
** tds: three times a day
Mechanism of action:
Bind to sulphonylureas receptors on the surface of pancreatic cells
resulting in increase influx of calcium that cause microtubules to contract
and exocytosis of insulin from vesicles leading to release of insulin in
response to glucose.
Some evidence suggests that sulphonylureas reduce hyperglycemia by
methods other than augmentation of insulin secretion by:
• Increasing insulin receptor binding.
• Increase numbers of insulin recepters on cell membrane
• Improve insulin sensitivity in peripheral tissues.
• Reduction in hepatic glucose output.
Therfore they are of no value in treating patients who are severely
insulin deficient.
Half
life (h)
26-72
Efficacy and clinical uses:
Drugs in this class have similar efficacies and particulary used for
the non-obese patients.
Side effects and limitations:
SUs are not always effective, ~25% (primary failure), 5-10%
yearly (secondary failure)
• 60% failure in 6 years of SU monotherapy
• SUs mainly improve mean blood glucose not post prandial
glycaemia
• Inducing continous hyperinsulinemia - risk of hypoglycaemia and
weight gain.
Others : GIT disturbances, skin rashes, a plastic anaemia.
Non- Sulphonylureas – Meglitinides
This relatively new class of insulin secretagues repressented by
nateglinide and repaglanide introduced in used un 1998.
Mechanism of action:
The mechanism of action is similar to that of sulphonylureas; how ever
,they bind to sulphonylureas receptor at different site and with different
kinetics,those the onset of action is faster which result in prief stimulation
of insulin secretion and for a short period, i.e. insulin secretion is
stimulated only at the time when needed – mealtime
• Repaglanide:NovoNorm® (Prandin®),
• Nateglinide: Starlix®
Efficacy and clinical uses
The efficacy of repaglinide appears to be similar to that of
sulphonylureas) and the efficacy of nateglinide appears to be somewhat
less .These medications can be used either as monotherapy or in
combination
with
other
oral
hypoglycemic
agents
(but
not
sulphonylureas), they are preferred for elderly patients and patients with
impaired renal functions because is metabolized in the liver and excreted
mainly via bile .Because of its rapid onest and short duration of actions,
they are indicated for use in controlling postprandial glucose excursions.
Repaglanide should be taken before each main meal ( 15 min.
before a meal).
• If no meal is taken, no tablet is taken
• Dosing:
- Start with 0.5mg before each meal
- Patients transferred from SU with 1.0mg each meal
Dose is increased weekly until target FBG
Side Effects :As with sulphonylureas, the main side effect of this class is
hypoglycemia, the risk of hypoglycemia is lower than that with
sulphonylureas .
• The amount of weight gain appears to be less than that seen with
sulphonylureas, perhaps because of the limited duration of elevated
insulin secretion.
Biguanides :Metformin(glucophage),
Mechanism of action:
-Decrease
liver
glucose
production,
by
inhibiting
gluconeogenesis.
-Increase glucose uptake by the muscles and supress appetite.
-Inhibite intestinal glucose absorption.
Efficacy and Clinical Use
hepatic
The efficacy of metformin monotherapy is equivalent to that of
sulfonylurea monotherapy. It is associated with weight loss, or at least
with no weight gain.
Metformin is approved for use in diabetes either as monotherapy or
incombination with other oral hypoglycemic agents, as well as with
insulin. It is recommended as first line therapy for overweight patients
with type 2 diabetes.
Metformin should never be used in patients with renal impairment
because of the risk of lactic acidosis.
Side effects:
• Gastrointestinal complaints (frequent and transient)
• Lactic acidosis (rare and serious)
• Since insulin secretion is not altered, hypoglycemia is not aside effect.
• Weight gain is not a side effect and some patients experience weight
loss.
Contraindications:
• Renal and hepatic dysfunction
• Hypoxic conditions
• Elderly ?
• Alpha- glucosidase inhibitors(Acarbose and Miglitol)
This class of oral hypoglycemic agents inhibits enzymes in small
intestinal brush border that are responsible for the breakdown of
oligosacchrides and disaccrides into monosaccharides suitable for
absorption .It works mainly in α- glucosidase which is found in the
proximal half of small intestine, therefore the absorption of carbohydrate
is delayed and shifted to more distal parts of the intestine and colon, this
retards glucose entry into the systemic circulation and lower post prandial
glucose levels .
Efficacy and Clinical Uses:
The blood glucose lowering effect of alpha- glucosidase inhibitors is less
than that of most of other classes of oral hypoglycemic agents , thus they
are rarely used alone, and most useful in combination with other
hypoglycemic agents.
Side effects: G.I.T disturbances (bloating, abdominal discomfort,
diarrhea and flatulence occure in about 20% of patients.
Intestinal lipase inhibitor (orlistat).
In the 2003 ,orlistat was added to the list other oral hypoglycemic agents .
it is antiobesity agent that act as inhibitor of of gastric and pancreatic
lipases and thereby inhibits the hydrolysis of dietary fat into absorbable
free fatty acids and monoglycerides which result in decreased energy
intake and weight loss.
Orlistats role in the treatment of diabetes is limited to obese patients and
since its blood glucose lowering effect is relatively small, it should use in
combination with other hypoglycemic agents.
Side effects:
G.I.T side effect occure in the first 3months of treatment, this include
flatulence with discharge, oily spotting, fecal urgency and steatorhea .