DIABETES MELLITUS

Categories:
1)Type I : Insulin dependent diabetes
2) Type II: Non insulin-dependent dependent
diabetes
3) Types III: Other (non pancreatic disease
drug therapy etc
4) Type IV: Gestational diabetes mellitus.

INSULIN:
- A small protein with Mw in human of 5808
- It contains 51 a.a. arranged in two chains
(A+B) linked by disulphide bridges; there
are species differences in the a. as of both
chains.

INSULIN SECRETION
Insulin is released from pancreatic Cells
at a low based rate and a much higher
stimulated rate in response to a variety of
stimuli esp. glucose. other stimulants eg
other sugars (eg mannose), certain a. as
(eg leucine arginine), hormones eg
glucagon-like polypeptide-I and vagal
activity are recognized.

Hyperglycaemia results in increased intracellular

ATP levels, which close the ATP- dependent
potassium channels. Decreased out ward
potassium efflux results in depolarization of the
cells and opening of voltage-gated calcium
channels. The resulting intracellular calcium
triggers secretion of the hormone. The insulin
secretagogues (sulphonylurea, meglitinides+ Dphenylalanine) exploits parts of this
mechanism.

Insulin degradation
The liver and the kidney are the two main
organs that remove insulin from the
circulation. The liver normally clears the
blood of approx.60% of the insulin
released from the pancreas by virtue of its
location as the terminal site of portal vein
blood flow; with kidney removing 35-40%
of the endogenous hormone.

In patient receiving subcutaneous insulin

injections, This ratio is reversed, with as
much as 60% of exogenous insulin being
cleared by the kidney and the liver
removing no more than 30-40%
The t1/2 of circulating insulin is 3-5 minutes

Circulating insulin
Basal insulin values of 5-15 u/me (30-90 pmoI/L)
are found in normal humans with a peak rise to
60-90 m U/ml (360-540 pmolL) during meals.
The insulin receptor:
After insulin has entered the circulation,it diffuses
into tissues , where it is bound by specialized
receptors that are found on the membranes of
most tissues. The receptors bind insulin with
high

Specificity and affinity in the picomolar range. The full

insulin receptor consists of two covalently linked
heterodimers, each containing an - subunit, which is
entirely extracellular and constitutes the recognition site
and a -subunit that spans the membrane. The subunit contains a tyrosine kinase. The binding of an
insulin molecule to the -subunits at the outside surface
of the cell activates the receptor and through a
conformational change brings the catalytic loops of the
opposing cytoplasmic -subunits and tyrosine kinase
activity directed at proteins. This network of
phosphorylations within the cell represents insulins
second messenger and results in multiple effects, on
protein synthesis,

lipolysis, and lipogenesis, and activation of

transcription factors that enhance DNA
synthesis and cell growth and division,
Various hormonal agents (eg
glucocorlicoids) lower the affinity of insulin
receptors for insulin; growth hormone in
excess increases this affinity slightly

Effects of Insulin on its targets

Effect on liver
-Reversal of catabolic features of insulin
deficiency
Inhibits glycogenolysis
Inibitis conversion of fatty acids and a.a.s
to lectoacids
Inbibits conversion of a.a.s to glucose.

-Anabolic action
Promotes glucose storage as glycogen
(induces glucokinase and glycoglu,
inhibits phorphorylase)
Increases triglyceride synthesis and low
density lipoprotein formation.

Effect on Muscle
-Increased protein synthesis
Increases a.a.s transport
Increases ribosomal protein synthesis
-Increased glycogen synthesis
Increases glucose transport
Induces glycogen syntheses and inhibits
phosphorylase.

Effect on adipose tissue

-Increased triglyceride storage
Lipoprotein lipase is induced and activated
by insulin to hydrolyze triglycerides from
lipoprotteins
Glucose transport into cell provides
glycerol phosphate to permit etherification
of fatty acids supplied by lipoprotein
transport

 Intracellular lipase is inhibited by insulin

Characteristics of available insulin
preparations
4.Principal types of injected insulins are
available
a) rapid acting, with rapid onset of
action

b. Short acting with rapid onset of action

c. Intermediate acting
d. long-acting, with slow onset of action.
An inhaled form of rapid acting insulin is also marketed.
Injected rapid-acting and short-acting insulins are
dispensed as clear solutions at neutral pH and contains
small amounts of zinc to improve their solubility and
shelf-life. (whaled rapid-acting human insulin is available
as a powder for alveolar absorption. Injected
intermediate-acting NPH insulins have been modified to
provide prolonged action and are dispensed as a turbid
suspension at neutral pH with protamine in phosphate
buffer

Insulin glargine and insulin determir are the

soluble Long-acting insulins.
1.Rapid acting insulin
Three injected rapid-acting insulin
analogues:
- insulin lispro
-insulin aspart
-insulin glulisine

-one inhaled form of rapid acting insulin-are commercially

available.
The rapid acting insulins permit more physiologic
prandial insulin replacement because their rapid onset
and early peak action more closely mimic normal
endogenous prandial insulin secretion than does regular
insulin and they have the additional benefit of allowing
insulin to be taken immediately before the meal without
sacrificing glucose control. Their duration of action is
rarely more than 3-sh. ( with the exception of inhaled
insulin which may lest 6-7h

Which decreases the risk of late portmeal

hypoglycaemia.
The injected rapid-acting insulins have the
lowest variability of absorption (approx.
5%) of all availeke commercial insulins
(compared to 25% for regular insulin and
25-50% for intermediate and long-acting
formulations).

2. Short acting insulin

Regular insulin is a short-acting soluble
crystalline zinc insulin made by
recombinant DNA techniques to produce a
molecule identical to human insulin.
Its effect appears within 30min. and peaks
between 2 and 3h. After S/C injection and
generally lasts 5-8h.

When regular insulin is administered at mealtime

the blood glucose rises faster than the insulin
with resultant early post prandial
hyperglycaemia and an increased risk of late
post prandial hypoglycaemia. Regular insulin
should be injected 30-45 min before the meal to
minimize the mismatching. As with the older
formulations , the duration of action as well as
the time of onset and the intensity of peak
action increases with the size of the dose.

Short-acting soluble insulin is the only type

that should be administered I.V. because
the dilution causes the hexameric insulin
to immediately dissociate into monomers.
It is particularly useful for i.v. therapy in the
management of diabetic Keto acidosis and
when insulin requirement is changing
rapidly eg. After surgery or during acute
infection.

3. Intermediate-acting and long-acting insulins

a) NPH (neutral protamine Hagedorn or isophane) insulin,
is an intermediate acting insulin wherein absorption and
the onset of action are delayde by combining appropriate
amounts of insulin and protemine so that neither is
present in an uncomplexed form (isophane) Protamine
is a mixture of six major and some minor compounds of
similar structure isolated from sperm of rainbow trout.
They appear to be basic, arginine-rich peptides with an
average MW of approx. 4400.To form an isophane
complex (one in which neither component retains and
free binding site)

Approx.a 1:10 ratio by weight of protamine to

insulin is required ,representing approx.six
molecules of insulin per molecule of
protamine.After s/c injection, proteolytic tissue
enzymes degrade the protamine to permit
absorption of insulin.
NPH insulin has an onset of approx. 2-sh. And
duration of action of 4-12h.
b) Insulin glargin
is a soluble peak less (ie having a broad
plasma concentration plateau), ultra-long-acting
insulin analogue.

Has a slow onset of action (1-1.5h) and

achieves a maximum effect after 4-6h.
This maximum effect is maintained for 1124h. or longer.
To maintain solubility the formulation is
unusually acidic (Ph4), should not be
mixed with other insulins.

c) Insulin detemir
has the most reproducible effect of the
intermediate and long-acting insulins, and
its use is associated with less
hypoglycaemia than NPH insulin.
-it has a dose dependent onset of action of
1-2h. and duration of action of more than
24h.

-it is given twice daily to obtain a smooth

back ground insulin level.
ORAL ANTIDIABETIC AGENTS
Four categories of oral antidiabetics are now
available:
a) Insulin secretagogues-sulphonylureas,
meglitinides, D-phenylalanine derivatives)

b) Biguanides
c) Thiazolidine diones
d)-glucosidase inhibitors.
INSULIN SECRETAGOGUES:
Sulphonylureas:
MA:- increase insulin release from the pancreas.
- closure of potassium channels in extra
pancreatic tissues.

a) Insulin release from pancreatic B cells.

Sulphonylureas bind to a 140-IC Da highaffinity sulphonylurea receptor that is
associated with a -cell in ward rectifier ATPsensitive potassium channel. Binding of a
sulphonylurea inhibits the efflux of potassium
ions through the channel and results in
depolarization. Depolarization opens a voltagegated calcium channel and results in calcium
influx and the release of preformed insulin.

b) Reduction of serum glucagon concentrations

The mechanism for this suppressive effect is
unclear but appears to involve indirect inhibition
due to enhanced release of both insulin and
somatostatin, which inhibit A-cell secretion.
c) Potassium channel closure in extra pancreatic
tissues,
The clinical significame of extra pancreatic
binding is not known.

First generation sulphonylureas

Tolbutamide
is well absorbed but rapidly
metabolized in the liver. Its duration of
effect is relatively short with an elimination
t1/2 of 4-sh. and best administered in
divided doses. Because of its short-half
life it is the safest sulphonylurea for elderly
patients (dialeted )

Chlorpropamide
t1/2 = 32h. and is slowly metabolized in
the liver to products that retain some
biologic activity; approx,20-30% is
excreted unchanged in the urine. It
interacts with dicoumarol, phenylbutazone
+ some sulphonamides) which inhibit
hepatic metabolism and contraindicated in
pts with hepatic or renal insuffiency.

Prolonged hypoglycaemic reactions are more

common in elderly pts.C/1 in this group.
Tolazamide
is comparable to chlorpropamide in potency but
has a shorter duration of action. It is more slowly
absorbed that the other sulphonylazeas and its
effect on blood glucose does not appear for
several hours.t1/2= 7h. Is metabolized to
several compounds that retain hypoghycaemic
effects.

2.Second-Generation Sulphonylureas
- have fewer adverse effects and drug
interactions Include: glyburide, glipizide
and glimepiride
Glyburide
Metabolized in the liver to products with
very low hypoghycaemic activity.
-has few adverse effects other than its
potential for consing hypoghycaemia

C/1 in the presence of hepatic impairment and

pts with renal insufficiency.
Glipizide
has the shortest t1/2 (2-4hr).For maximum effect
in reducing part prandial hyperglycaemia, this
agent should be ingested 30min. before
breakfast, because absorption is deluged when
the drug is taken with food.90% metabolized in
the liver to inactive products and 10% is
excreted unchanged in Urine.

Glimepiride
adrieves blood glucose lowering with the lowest
dose of any sulphonylurea compound.
A single daily dose of 1mg has been shown to
be effective It has a long duration of effect with a
t1/2 of 5h.allowing once daily dosing. It is
completely metabolized by the liver to inactive
products,

Insulin secretegogues
Meglitinides: Repaglinide
These drugs modulate -cell insulin release
by regulating potassium efflux through the
potassium channels. There is an overlap with
the sulphonylureas in their molecular sites of
action because the meglitimides have two
binding sites in common with sulphonglurea and
one unique binding site.

Repaglinide has a very fast onset of

action, with a peak conc. And peak effect
within approx Ih after ingestion but the
duration of action is 5-8h. It hepatically
cleared by CYP 3A4 with a plasma t1/2 of
Ih.
Indicated for use in controlling port
prandial glucose rise at doses of 0.25-4
mg just before meal (mmax.16mg/day)

Insulin secretagosues:
D-Phenylalanine derivative; Nateglinide.
-stimulates very rapid and transient release of insulin from
-cells through closure of the ATP-sensitive K+ channels .
It also partially restores initial insulin release in response
to an I.V. glucose to lerance test. This may be of
significant advantage of the drug because type 2 diabetes
is associated with loss of this initial insulin response. The
restoration of more normal insulin secretion may
suppress glucagon release early in the meal and result in
less endogenous or hepatic glucose production. Taken
before to peak conc. of len than Ih. Metabolized by CYP
2C9 and CYP3A4.t1/2=1.5h.

BIGUANIDES:
Metformin:
MA: not well Known.
Proposed mechanism of action include;
(1) reduced hepatic and renal
gluconeogesis
(2) Slaving of glucose absorption from
git with increased glucoze to lactate
conversion by enterocytes

3) Direct stimulation of glycolysis in tissues,

with increased glucoze removal from
blood.
4) Reduction of plasma glucagon levels.
Metabolism and excretion
Metformin has a t1/2 of 1.5-3h; is not
bound to plasma proteins, is not
metabolized and is excreted by the
kidneys as the active compound.

As a consequence of metformins blockade

of gluconeogenesis, the drug may impair
the hepatic metabolism of lactic acid.
Clinical Uses
Has been most often prescribed for
patients whose hyper glycaemia is due to
ineffective insulin secretagogues or
thiazolidine diones in type 2 diabetes in
whom oral monotherapy is inadequate.

Adverse effects
G17 (anorexia, nausea, vomiting, abdominal
discomfort, diarrhoea) and occur in up to 20%
of patients. They are dose-related. Vit 12
appear to be reduced during long-term
melformin therapy
C/I in patients with renal diseas,alcoholism,
hepatic disease or condition of an biguanides in
the presence of these diseases.

THIAZOLIDINEDIONES (Tzds)
These act to decrease insulin resistance.
Their primary action is the regulation of
genes involved in glucose and lipid
metabolism and adipocyte
differentiation.Tzds are ligands of
perixisome proliferator-activated receptorgamma (PPAR-) part of the steroid and
thyroid super family of nuclear receptors.

These PPAR receptors are found in

muscle, fat and liver. PPAR-& receptors
are complex and modulate the expression
of the glues involved in lipid and glucose
metabolism, insulin signal transduction.
Tzds have significant effects, on vascular
endothelium, the immune system , the
ovaries and tumour cells.

A major site of Tzd action is adipoze tissue,

where the drug promotes glucose uptake and
utilization and modulates synthesis of lipid
hormones or cytokines and other proteins of lipid
hormones r cytokiness and other proteins
involved in energy regulation .Also regulate
adipocyte apoptosis and differentiation.
Two Tzds are available: Pioglitazone and
Rosiglitazone

Pioglitazone
has PPAR- as well as ppar-& activity. It is
absorbed with in 2h within 2h of ingestion,
although food may delay uptake, total bio
availability is not affected.
It metabolized by CYP 2C 8 and CYP 3A4 to
active metabolites.
Taken once daily ,usual starting dose is 15-30mg
Approved as a monotherapy and in combination
with metformin,sulphonylurea and insulin for the
treatment of types of type 2 diabetes,

Rosiglitazone:
is rapidly absorbed and highly proteinbound It is metabolites, predominantly by
CYP2C8 and to a lasses extent by CYP 2
9.
Administered once or twice daily, 4-8mg is
the usual total dose,

Approved for use in type 2 diabetes as

monotherapy or in combination with
biguawide,and sulphonylurea and insulin.
Adverse effect common to both Tzds is
fluid retention which present as a mild
anaemia and peripheral oedema, esp ,
when used in combination with insulin or
insulin secretagogues.

-Dose-elated weight gain

-Anovulatory women may resume ovulation (increased risk
of pregnancy).
ALPHA-GLUCOSIDASE INHIBITORS
Acarbose and miglitol;
-competitive inhibitors of the intestinal -glucosidases and
reduce the post prandial digestion and absorption of
starch and dissacharides. Miglitol differs structurally from
acarbose is six times more potent in inhibiting
sucrase.Alhough the binding affinity of the two
compounds differs, acarboses; sucrase, maltase,
glycoamylase and dextranase.

Miglitol alone has effects on isomaltase and on

-glucosidases, which split -linked sugars eg
lactose. Acorbose alone has a small effect on anylase
The consequence of enzyme inhibition is to
minimize upper intestinal digestion and defer
digestion (and thus absorption) of the ingested
starch and disaccharides to the distal small
intestine, thereby lowering portmeal glycaemic
excursions as insulin- sparing effect.

Approved for type 2 diabetes as

monotherapy and in combination with
sulphonylurea in which the glycaemic
effect is additive.
Both acarbose and miglitol are taken in
doses of 25-100mg fast before ingestion
of the first portion of each meal.
Adverse effects; Flatulence, diarrhoea,
abdominal pain

PRAMLINTIDE
A synthetic analogue of amylin, is an
injectable antihyper glycaemic that
modulates portprandial glucose level and
is approved for preprandial use in
individuals with types I and type II
diabetes. It suppresses glucagon release
via undetermined mechanisms, delays
gastric emptying and has CNS mediated
anoretic effects.

It is rapidly absorbed after s/c

administration, levels peak within 20min
and the duration of action is not more than
150 min.
It is renally metabolized and excreted
Adverse effects, hypoglycaemia
GIT- nausea, vomiting and anorexia.

 EXENATIDE;
A synthetic analogue of glucagon like polypeptides I
(GLP-1)
Approved as adjunctive therapy in individuals with type 2
diabetes treated with metformin or sulphonylurea who
still have suboptimal glycaemic control.
Has multiple actions eg potentiation of glucose-mediated
insulin secretion, suppression of post prandial insulin
secretion, suppression of post prandial glucagon release
through as get unlcuown mechanisms, slowed gestric
emptying, and a central loss of appetite.

The increased insulin secretion is speculated to

be due in part to an increase in -cell man
Exenatide is absorbed equally from arm,
abdomen or thigh injection site, reaching peak
conc. In approx 2h with a duration of up to 10h.
It undergoes glomerular filtration and dosage
adjustment is reguired only when the creatimine
clearance is less than 30ml/min.
Adverse effect nausea (44% of uses), vomiting,
diarrhoea

SITAGLIPTIN
Is an inhibitor of dipeptidyl peptidase-4 (
DPP-4) the enzyme that degrades incretin
and other GLP-I-like molecules.
Approved for use in type 2 diabetes.
Control of hyperglycaemia and reduction
in HbA1c were documented at doses of
100mg orally once daily.

Can be combined with metformin, Tzds or

sulphonglureas.
GLUCAGON:
is synthesized in the A cells of the
pancreatic islets of Langerhans.
is a peptide, identical in all mammalsconsisting of a single chain of 29 a.a.s
with a MW of 3485.

Its t1/2 in plasma is 3-6 min.

Pharmacologic effects of glucagon
a) Metabolic effects
The first six a.a.s at the amino terminal of the
glucagon molecule bind to specific receptors on liver
cells.
This leads to a Gs protein-compled increase in
adenylyl cyclase activity and the production of Camp,
which facilitates catabolism of stord glycogin and
increases gluconeogenesis result of glucagon influsion
is to raise blood glucose at the expense of stored
hepatic glycogen.

b) Cardiac effects:
Glucagon has a potent inotropic and
chronotropic effect on the heart, mediated
by the Camp mechanism described above.
c) Effect on Smooth muscle
Large doses of glucagon produce profound
relaxation of the intestine which may be
due to mechanisms other than adenylyl
cyclase activation.

Clinical Uses
a) Severe hypoglycaemia
b) Endocrine diagnosis (endocrine
disorders)
c) -blocker poisoning
d) Radiology of the bowel
Adverse effects;
Transient nausea and occasional vomiting