Download Insulin

Treatment of diabetes
mellitus (1)
Pancreas:
 Has exocrine function → digestive enzyme.
 Has endocrine function → peptide hormones from islets of langerhans as: β cells:- produce insulin C-peptide, proinsulin, islets amyloid polypeptide (IAPP or
amylin) whose function is undefined.
 α2 or A cells:- produce glucagon → hyperglycemia by mobilization of glycogen
stores.
 α1 or D cells:- produce somatostatin → hyperglycemia by inhibition of secretory
cells.
 These hormones play an important role in regulating the metabolic activities of the
body, particularly the homeostasis of blood glucose
Insulin:
 A simple protein consisting of 51 A.A. arranged in 2 polypeptide chains, A and B,
1
connected by disulfide bonds.
1
Connecting peptide
A. Chain
cys
H2N
s
7
s
s
11
cys
22 21
cys
s
s
1
cys
7
Human
proinsulin
COOH
s
30
cys
19
B. Chain
(The connecting peptide is split off to release insulin consisting of 2 chains A
and B joined by 2 disulfide bridges).
 Pro-insulin has some hypoglycemic effect.
 C-peptide facilitates the correct of folding of A and B chains.
 Maintains the alignment of disulfide bond before cleavage and measured as
indicator of endogenous insulin production.
Insulin biosynthesis:
,
Preproinsulin
Larger precursor.
Cleaved in rough
EPRT of β cells.
In Golgi apparatus a
secretory granules, cleaved
by proteolytic enzyme.
Proinsulin
C-peptide
-
Insulin
Stored in secretory
granules
1
Stored in β cells
Insulin secretion:
 Specific stimulus is hyperglycemia.
 ↑ Glucose level stimulate glycoreceptors on β cells membrane. And by glucose
transporter, glucose will enter β cells of pancreas, then it phosphorylated by
glucokinase → ATP → blocks K+ channels → depolarization → influx of Ca +
ions → trigger pulsatile insulin exocytosis from storage granules of myocin
filaments.
K+ channel
Sulfonlyureas and Megtitinide
Glucose
transporter
Close
Depolarization
ATP
Open
↑ Glucose
glucokinase
Ca+2
Metabolism
Ca+2
Ca+2 channel
Ca+2
Ca+2
(Glucose-sensor)
Insulin granules
Myocin filament
Insulin
α
α
S
S
S
β
S
β
Cell membrane
Tyrosine kinase activity ↑
Insulin deficiency
Actions (some)
Long-term
complications
Hyperglycemia
Lipolysis ↑
Free fatty acids ↑
Glucosuria
Cataract
Retinopathy
Glucose uptake ↑
Amino acid uptake ↑
↑ Acetyl CoA
Polyuria
↑ Glycerol
Neuropathy
Nephropathy
MEMBRANE EFFECTS
Thirst&polydipsia
Ketonanemia
ketonuria
Premature
atheroma (from
increased blood
fatty acids)
Acidosis
INTRACELLULAR
EFFECTS
RNA and DNA synthesis ↑
Protein synthesis ↑
Glycogenesis ↑
Lipogenesis ↑
Acetoacetic acid
Coma and death
Lipolysis ↓
Promotes cell growth
Other factors → release of insulin:
 Other carbohydrates e.g. mannose, ribose.
 A.A.
 Hormones e.g. gastrin, cholecystokinin, (G.H.), incretin, pancreozymin ……...glucagon
 Somatostatin → inhibit β cells product.
 Cholinergic stimulation → ↑ insulin.
 Adrenergic stimulation → ↓ insulin secretion.
 Insulin T1/2 ≈ 3-5 min.
 The release characterized by a rapid initial secretion of insulin (lacked in D.M.), and
followed by secondary more slowly decaying release (biphasic release).
 Hyperinsulinemia (due, for example, to an insulinoma) can cause severe hypoglycemia.
 A rela-tive or absolute lack of insulin, such as in diabetes mellitus, can cause
serious hyperglycemia. If this condition is left untreated, retinopathy, nephropathy,
neuropathy, and cardiovascular complications may result.
 After release, insulin bind special receptors on the membrane of
most tissues (mainly in liver, muscles, adipose tissue) to
produce biological effects.
 Then, degradation occurs in the liver by Tyrosine kinase.
Insulinase (60%) and further degradation in kidney by
proteolytic enzyme.
 In conditions associated with ↑ insulin level e.g. obesity and
insulinoma → down regulation of insulin receptors → state of
insulin resistance.
 Insulin resistance also associated with the development of
autoantibodies to insulin receptor, and to the presence of some
hormonal/metabolic states e.g. Cushing syndrome.
Acromegaly, gestational diabetes.
 Physiological or psychological stress → insulin resistance.
Action of insulin:
 To maintain fuel homeostasis:1. Action of insulin on glucose transporters which facilitate glucose movement across
cell membrane, e.g. GluT4 which play a role in ↓ blood glucose, is inserted into
membrane of M and adipose tissue by insulin.
Defect in GluT2 →inhibits the transport of glucose → β cells → D.M.
2. Action of insulin on liver:
↑ Storage of glucose as glycogen by stimulation of glycogen synthesis, ↓
glycogenolysis, inhibition of gluconeogenesis, inhibition of ketogenesis.
3. Effect of insulin on muscles:
Promotes protein synthesis from A.A., stimulate glycogen synthesis, ↑ glucose
transport → M cells, inducing glycogen synthase and inhibits phosphorylase.
4. Effect of insulin on adipose tissue:
Inhibit lipolysis in adipose tissue by inhibiting lipase enzyme → ↓ F.F.A., and
glycerol, in insulin deficiency → ↑ FFA → liver → ketonbodies → ketoacidosis.
Diabetes mellitus (D.M.):
A heterogeneous group of disorders characterized by abnormalities in carbohydrate,
protein and lipid metabolism, clinically manifested by hyperglycemia, glucosuria,
hyperlipidemia, -ve nitrogen balance, ketonemia, ↑ thirst, polyphagia and
polydypsia. The incidence of diabetes is growing rapidly
Types of D.M.:
1. Type-I, juvenile-onset D.M., insulin dependent D.M. (IDDM):
 Affects individuals around puberty and childhood.
 Absolute deficiency of insulin due to massive β cells necrosis due to autoimmunemediated process triggered by viruses (mumps and coxackievirus B11. toxic
chemicals.
 Glucagon level ↑, non obese, ketosis. and the type 1 diabetic shows classic
symptoms of insulin deficiency (polydipsia, polyphagia, polyuria, and weight loss).
 Aim of Rx: exogenous insulin to avoid catabolic state ,hyperglycemia and
ketoacidosis.
• In a normal postabsorptive period, low basal levels of circulating insulin are
maintained through constant β-cell secretion. This suppresses lipolysis,
proteolysis, and glycogenolysis.
•
A burst of insulin secretion occurs within 2 minutes after ingesting a meal,
in response to transient increases in the levels of circulating glucose and
amino acids. This lasts for up to 15 minutes and is followed by the
postprandial secretion of insulin.
However, those with type 1 diabetes can neither maintain a basal secretion
level of insulin nor respond to variations in circulating fuels .
The development and progression of neuropathy, nephropathy, and
retinopathy are directly related to the extent of glycemic control (measured as
blood levels of glucose and/or hemoglobin A1c[HbA1c]) .
The rate of formation of HbA1c is proportional to the average blood glucose
concentration over the previous 3 months. Therefore, HbA1c provides a
measure of how well treatment has normalized blood glucose in diabetic
patients.
2. Type-II, non insulin dependent D.M. (NIDDM):
 Frequently occurs in patients over 35 years.
 The disease is influenced b genetic factors, aging, obesity, peripheral insulin
resistance. No ketosis. the long-term clinical consequences can be just as
devastating (for example, vascular complications and subsequent infection
can lead to amputation of the lower limbs).
 The pancreas retains some β cell function, variable insulin secretion
insufficient to maintain glucose homeostasis. Type 2 diabetes is frequently
accompanied by the lack of sensitivity of target organs to either
endogenous or exogenous insulin. This resistance to insulin is considered to
be a major cause of this type of diabetes.
 Rx:The goal in treating type 2 diabetes is to maintain blood glucose
concentrations within normal limits and to prevent the development of
long-term complications of the disease , by oral hypoglycemic agent
and/or insulin, diet, exercise & wt. reduction
• 3. a-Type-III D.M., MODY (Maturity Onset Diabetes
of the Young):
 Autosomal dominant, non ketotic. Occur before 25
years, non obese patients, insulin resistance is absent.
 b-drug induced
• 4. Type-IV D.M., gestational D.M:
 Glucose intolerance during pregnancy, lead to fetal
macrosomia (abnormally large body) and shoulder
dystocia (difficult delivery), as well as neonatal
hypoglycemia.
 Rx: insulin, diet, exercise. Glyburide and metformin
may be reasonably safe alternatives to insulin therapy
Sources of insulin:
a. Animal insulin (bovine, porcine).
b. Human insulin: produced by recombinant DNA technology using special strains of
E-coli or yeast (genetically altered to contain genes for human insulin).
 Modification of human insulin (insulin analogues) e.g. Lispro, aspart and
glulisine have faster onset and shorter duration of action than regular insulin
because they form no aggregates on complex.
 Absorbed rapid than animal insulin with shorter duration of action
 Glargine, detimir → longer duration that level after injection.
 Less immunogenic than bovine but not porcine.
*commercial insulin preparations differ in: purity, concentration, solubility, onset,
duration and action.
Insulin preparation:
Conjugation of insulin + zinc or protamine or both,
will convert the normally rapidly absorbed insulin to
more prolong duration of action.
A.Rapid-onset and ultra short-acting insulin
preparation:
1.Regular insulin:
Short acting, soluble, crystalline zinc insulin, rapidly
lowers blood glucose.
Given subcutaneously, I.V. in emergencies.
Safe in pregnancy,
2. Insulin Lispro.
3. Insulin aspart.
4. Insulin glulisine.
Ultra short-acting due to their rapid onset and short
duration of action, and offer more flexible Rx and
lower the risk of hypoglycemia.
 Insulin lispro differs from regular insulin in that lysine and
proline at positions 28 and 29 in the B chain are reversed.
This results in more rapid absorption after subcutaneous
injection than is seen with regular insulin, given 15 minutes
before meal or immediately following a meal .
 Has shorter duration of action.
 Peak level of Lispro 30-90 min. after injection compared
with 50-120 min. for regular insulin.
 Aspart and glulisine similar to Lispro.
Usually not used alone but with longer acting
insulin to assure proper glucose control.
Given S.C., I.V.
Insulin lispro, insulin aspart, and insulin glulisine
may also be used in external insulin pumps .
 Lispro preferred for external insulin pumps over
regular because it doesn’t form hexamers.
{Precipitation of Lispro in infusion catheter →
fluctuation in glucose control.}
-Regular insulin, insulin lispro, and insulin aspart
are pregnancy category B, and insulin glulisine is
pregnancy category C.
B. Intermediate-acting insulin preparation:
Isophane , NPH insulin suspension:
Neutral protamine Hagedorn(NPH) insulin is a suspension
of crystalline zinc insulin combined at neutral pH with the
positively charged poly-peptide protamine. (form less
soluble complex → intermediate duration of action).
Given S.C. and never I.V.
Useful in Rx of all types of D.M. except ketoacidosis or
emergency hyperglycemia.
It is used for basal control and is usually given along with
rapid- or short-acting insulin for mealtime control.
A similar compound called neutral protamine
lispro(NPL)insulin
has been prepared that is used only in combination with insulin
lispro.
C. Prolonged-acting insulin preparation:
1. Ultralente insulin:
 Poorly soluble insulin zinc crystals suspension.
 Large particles → slowly dissolved → slow onset, long lasting hypoglycemia up to
35 hours.
2. Insulin glargine:
 The isoelectric point of glargine is lower than that of human insulin →
*precipitation at injection site → extend its action.
 Slower than NPH in onset.
 Has flat prolong hypoglycemic effect.
 Must be given S.C.
3. Insulin detimir:
 Has fatty acid side chain.
Associates with tissue-bound albumin at injection site, Slow dissociation from
albumin results in long-acting properties similar to those of insulin glargine.
 Neither insulin detemir nor insulin glargine should be mixed in the same syringe with
other insulins, because doing so may alter the pharmacodynamic and pharmacokinetic
properties.
Onset and duration of action of human insulin and insulin analogs. NPH = Neutral Protamine Hagedorn
E. Aerosol preparation, oral spray
 Others: Portable pen injectors → well accepted.
 Continue S.C. insulin infusion devices {(CSII), insulin pumps} → manually
programmable pump to deliver insulin replacement according to blood-glucose selfmonitoring results.
Adverse reactions to insulin:
 Hypoglycemia. Long-term diabetic patients commonly do not produce adequate
amounts of the counter-regulatory hormones (glucagon ,cortisol , and growth hormone),
which normally provide an effective defense against hypoglycemia.
 lipodystrophy (less common with human insulin).
 Allergic reaction. and local injection site reactions.
 Wt .gain
 Adjust the dose according to renal conditions.
Uses:
1. IDDM.
2. NIDDM uncontrolled by diet and hypoglycemic agent-oral type.
3. Gestational diabetes.
4. Infection, trauma and surgery and any complication of diabetes.
5. Rx of Hyperkalemia.
• D. Insulin combination:
• Various premixed
insulins, such as:
combinations
of
human
• 70-percent NPH insulin plus 30-percent regular
insulin
• 50 percent of each of these, and
• 75-percent NPL insulin plus 25-percent insulin
lispro, are also available
Standard treatment versus intensive treatment
• For patients with diabetes mellitus who require insulin therapy, stan-dard
treatment involves injection of insulin twice daily.
• In contrast, intensive treatment seeks to normalize blood glucose through
more frequent injections of insulin(three or more times daily in response to
monitoring blood glucose levels).
• The ADA recommends a target mean blood glucose level of 154 mg/dL or less
(corresponding to a HbA1c of 7 percent or less) for patients with diabetes, and this
is more likely to be achieved with intensive treatment.
•
The frequency of hypoglycemic episodes, coma, and seizures due to excessive
insulin is higher with intensive treatment regimens.
Nonetheless, patients on intensive therapy show a significant reduction in such
long-term complications of diabetes as retinopathy, nephropathy, and
neuropathy compared to patients receiving standard care
Intensive therapy should generally not be recommended for patients with
longstanding diabetes, significant microvascular complications, advanced age, and
those with hypoglycemic unawareness.
Intensive therapy has not been shown to significantly reduce the macrovascular
complications of diabetes.
• SYNTHETIC AMYLIN ANALOG
• Pramlintide is indicated as an adjunct to mealtime insulin therapy
in patients with type 1 and type 2 diabetes.
• Mechanism of action :-delays gastric emptying, decreases
postprandial glucagon secretion, and improves satiety.
• Pramlintide is administered by subcutaneous injection
,immediately prior to meals.
• When pramlintide is initiated, the dose of rapid- or short-acting
insulin should be decreased by 50 percent prior to meals to avoid
a risk of severe hypoglycemia.
• Pramlintide may not be mixed in the same syringe with any insulin
preparation.
• Adverse effects are mainly gastro-intestinal as nausea, anorexia,
and vomiting
• Pramlintide should not be given to patients with diabetic
gastroparesis (delayed stomach emptying), cresol
hypersensitivity, or a history of hypoglycemic unawareness.-
INCRETIN MIMETICS
• Oral glucose results in a higher secretion of insulin than occurs
when an equal load of glucose is given IV. This effect is
referred to as the “incretin effect” and is markedly reduced in
type 2 diabetes.
• The incretin effect occurs because the gut releases incretin
hormones, notably glucagon-like peptide-1 GLP-1 and glucosedependent insulinotropic polypeptide, in response to a meal.
• Incretin hormones are responsible for 60 to 70 percent of
postprandial insulin secretion.
• Exenatide and liraglutide are injectable incretin mimetics used
for the treatment of patients with type 2 diabetes.
• These agents may be used as adjunct therapy in patients who have
failed to achieve adequate glycemic control on a sulfonylurea,
metformin, a glitazone, or a combination thereof.
Mechanism of action
• acting as GLP-1 receptor agonists.
• improve glucose dependent insulin secretion
• also slow gastric emptying time,
• decrease food intake, decrease postprandial
glucagon secretion, and
• promote β-cell proliferation.
• Consequently, weight gain and postprandial
hyperglycemia are reduced, and HbA1c levels
decline.
Pharmacokinetics and fate
• Being polypeptides, exenatide and liraglutide must be administered
subcutaneously.
• Liraglutide is highly protein bound and has a long half-life, allowing for
once-daily dosing without regard to meals
• Exenatideis eliminated mainly via glomerular filtration therefor, should be
avoided in patients with severe renal impairment
• has a much shorter half-life. Because of its short duration of action, it
hould be injected twice daily within 60 minutes prior to morning and
evening meals.
Adverse effects
• consist of nausea, vomiting, diarrhea, and constipation.
• Because of the peptide nature of incretin mimetics, patients may form
antibodies to these agents.,but do not result in reduced efficacy of the drug
or increased adverse effects.
• Exenatide and liraglutide have been associated with pancreatitis. Patients
should be advised to discontinue these agents and contact their healthcare
provider immediately if they experience severe abdominal pain.
• Liraglutide causes thyroid C-cell tumors in rodents. However, it is unknown
if it causes these tumors or thyroid carcinoma in humans.