Diabetes mellitus overview and treatments

1. Diabetes Mellitus
Overview and
Treatments

2. Diabetes - a growing threat
 There are currently more than 230 million people with
diabetes worldwide. If nothing is done to slow the epidemic,
the number will exceed 350 million by 2025.
 In 2003, the five countries with the largest numbers of
persons with diabetes were
 India (35.5 million)
 China (23.8 million)
 the United States (16 million)
 Russia (9.7 million)
 Japan (6.7 million).
 By 2025, the number of people with diabetes is expected
to more than double in Africa, the Eastern Mediterranean, the
Middle East, and South-East Asia.

3. Diabetes Mellitus :
a group of diseases characterized by high levels of blood glucose
resulting from defects in insulin production, insulin action, or both
 Criteria of diagnosis of DM:
- Polyuria, polydipsia and unexplained weight loss
- Random plasma glucose level of greater than 200 mg/dl (11.1
mmol/L)
- Fasting plasma glucose level of more than 126 mg/dl (7 mmol/L)
- Plasma glucose level of more than 200 mg/dl 2 hours after
ingestion of an oral glucose load.
 Complications :
- Stroke
- Heart attack
- Kidney disease
- Eye Disease
- Nerve Damage
Consists of 3 types:
1. Type 1 diabetes
2. Type 2 diabetes
3. Gestational diabetes

4. Diabetes Mellitus
 Type 1 Diabetes
- cells that produce insulin are
destroyed
- results in insulin dependence
- commonly detected before 30
 Type 2 Diabetes
- blood glucose levels rise due to
1) Lack of insulin production
2) Insufficient insulin action
(resistant cells)
- commonly detected after 40
although it is being increasingly
being detected in younger people
- effects > 90%
- eventually leads to β-cell failure
(resulting in insulin dependence)
Gestational Diabetes
Gestational diabetes (GDM) is
defined as any abnormality in
glucose levels noted for the first
time during pregnancy.

5. Testing :
Fasting Plasma Glucose Test
(FPG) - (cheap, fast)
*fasting B.G.L. 100-125 mg/dl
signals pre-diabetes
*>126 mg/dl signals diabetes
Oral Glucose Tolerance Test
(OGTT)
*tested for 2 hrs after
glucose- rich drink
*140-199 mg/dl signals pre-
diabetes
*>200 mg/dl signals diabetes
 80 to 90 mg per 100 ml, is the normal fasting blood glucose
concentration in humans and most mammals which is
associated with very low levels of insulin secretion.
A.K.A.: Glycated Hemoglobin tests
A1C

6. Pancreas
Kidneys
Stomach
Pancreas

7. The bulk of the pancreas is an exocrine gland
secreting pancreatic fluid into the duodenum
after a meal.
Inside the pancreas are millions of clusters of
cells called islets of Langerhans. The islets
are endocrine tissue containing four types of
cells. In order of abundance, they are:
beta cells, which secrete insulin and amylin;
alpha cells, which secrete glucagon;
delta cells, which secrete somatostatin
gamma cells, which secrete a polypeptide.

8. Diabetes - Insulin
 Discovered in 1921 by Banting and Best
 Consist of A & B chains linked by 2
disulfide bonds
(plus additional disulfide in A)
~~~~
A = 21amino acids B = 30 amino acids

9. 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(110 aa)
 removal of signal peptide during
insertion into the endoplasmic
reticulum generates proinsulin(86 aa)
 Within the endoplasmic reticulum,
proinsulin is exposed to several specific
endopeptidases which excise the C
peptide, thereby generating the mature
form of insulin(51 aa)
 Stored as β granules
This light micrograph of a section of
the human pancreas shows one of the
islets of Langerhans, center, a group of
modified glandular cells. These cells
secrete insulin, a hormone that helps
the body metabolize sugars, fats, and
starches. The blue and white lines in
the islets of Langerhans are blood
vessels that carry the insulin to the
rest of the body.
Zn

10. B chain
Beta cells have channels in their
plasma membrane that serve as
glucose detectors. Beta cells
secrete insulin in response to a
rising level of circulating
glucose.
Insulin is a small protein consisting of an A chain of 21 amino
acids linked by two disulfide (S—S) bridges to a B chain of 30
amino acids.
A chain

11. Insulin secration is a tightly regulated process. The regulation is
achieved by coordinated interplay of various factors.
•Food stuffs stimulate insulin secretion
Glucose: Orally ingested glucose has a greater capacity to stimulate insulin
secretion than intravenous glucose administration.
amino acids (Arg, Lys)
fatty acids and ketones
•Several GI hormone promote secretion of insulin: The most potent of
these GIP, GLP-1. Beside these sectetin, gastrin, cholecystokinine, VIP, gastrin-releasing
peptide, enteroglucagon.
Other Hormones: Insulin release is under reciprocal control by glucagon (α
cells). Glucagon stimulates insulin secretion: Insulin inhibits the release of
glucagon.
•Autonomic Mechanisms:
Autonomic regulation of insulin release is regulated by the
ventrolateral (vagal) and the ventromedial (sympathetic)
hypothalamus. Stimulation of a2 adrenergic receptors inhibit insulin
release, where as 2 and vagal nerve stimulation enhance release.
Secretion of Insulin

12. •The majority of insulin in the blood circulates unbound. The
volume of distribution approximates the volume of extracellular fluid.
•Pancreas secretes about 40 mg of insulin/hour in portal vein
resulting 0.5 ng/ml in peripheral circulation.
• The half-life of insulin in plasma about 5-6 minute for both
normal and diabetics.
•Degradation of insulin occurs primarily in liver, kidney and
muscle. 50% of insulin reaching the liver is destroyed by thiol
metalloproteinase in a single pass. Insulin is filtered by the glomerulus
and reabsorbed by the tubular epithelial cells which degrade it.
•Degradation of insulin in the liver and other target tissues occurs
primarily through insulin-receptor internalization which results in
proteolytic degradation of insulin and return of the receptor to the
cell surface.
Distribution and Degradation of Insulin

13.  It stimulates skeletal muscle
fibers.
 It stimulates liver cells.
 It acts on fat cells
 It inhibits production of
certain enzyme.
In each case, insulin triggers
these effects by binding to
the
insulin receptor.
glucose
uptake
glycogen
synthesis
protein
synthesis
amino acids
uptake
enzyme
production
glycogen
breaking
fat
synthesis
Insulin affects many organs

14. Diabetes – Insulin
(Biochemical Role)
-Tyrosine Kinase
receptors are the locks
in which the insulin
key fits
- Involved in signal
transduction
(insulin hormone being 1st messenger)

15. Diabetes – Insulin
(Biochemical Role)

16. In the case of type 1 diabetes, insulin
levels are grossly deficient. Thus type 1
diabetes is invariably treated with insulin
Type 2 diabetes is frequently associated
with obesity. Serum insulin levels are
normal or elevated, so this is a disease of
insulin resistance.
Insulin and diabetes
This leads to an increase in the amount of
glucose in the blood. This high concentration
of glucose or ’high blood sugar’ is termed
hyperglycaemia.

17.  Chronic elevation of blood glucose eventually
leads to tissue damage.
 The kidneys, eyes, peripheral nerves and
vascular tree manifest the most significant
diabetic complications.
 The mechanism for this is complex and not yet
fully understood. It involves:
• The direct toxic effects of high glucose
levels
• The impact of elevated blood pressure
• Abnormal lipid levels
• Functional and structural abnormalities of
small blood vessels
Tissue damage

18.  Out-of-control diabetes, when severe, leads to
the body using stored fat for energy and a
subsequent build-up of acids (ketone bodies) in
the blood. This is known as ketoacidosis and is
associated with very high glucose levels. It
requires emergency treatment and can lead to
coma and even death.
 Recurrent or persistent infections (including
tuberculosis).
 Both hyperglycaemia and hypoglycaemia
(abnormally low blood glucose resulting from
treatment) may cause coma and, if untreated,
may be fatal.
The short term effects of
diabetes

19. The long term effects of diabetes can be divided into
– macrovascular complications
– microvascular complications.
 Macrovascular complications affect the larger
blood vessels, such as those supplying blood to the
heart, brain and legs. The most common
macrovascular fatal complication is coronary
artery disease. Strokes are also a common cause of
disability and death in people with diabetes.
 Microvascular complications affect the small blood
vessels, such as those supplying blood to the eyes
and kidneys. The microvascular complications of
diabetes are retinopathy, nephropathy and
neuropathy.
The long term effects of diabetes

20. Visual impairment:
diabetic retinopathy,
cataract and glaucoma
Kidney disease
(diabetic nephropathy)
Sexual dysfunction
Sensory impairment
(peripheral neuropathy)
Ulceration
Stroke
(cerebrovascular disease)
Heart disease
(cardiovascular disease)
Severe hardening of
the arteries (atherosclerosis) Autonomic neuropathy
(including slow emptying
of the stomach and diarrhea)
Necrobiosis lipidoica
Gangrene
Poor blood supply to lower limbs
(peripheral vascular disease)
The major diabetic complications
Bacterial and fungal
infections of the skin

21.  The close association of type 2 diabetes with
cardiovascular disease has led to the hypothesis that
they both share a common antecedent. This concept
has been labeled ‘The Metabolic Syndrome’ by the
World Health Organization and others.
The metabolic syndrome reflects the clustering of central obesity with several
other major cardiovascular disease risk factors commonly found in those with
type 2 diabetes.
Central obesity Dyslipidaemia
Hypertension
Impaired glucose regulation or diabetes
Insulin resistance
The metabolic syndrome
Increased levels of procoagulant factors

22. Insulin resistance: A state in which a given
level of insulin produces a less than expected
biological effect.

23. Diabetic Emergencies

24. Diabetic ketoacidosis is a serious complication of
diabetes.
Diabetic ketoacidosis develops when there is too little
insulin in body. Without enough insulin, sugar (glucose)
can't enter cells. Blood sugar level rises, and body begins
to break down fat for energy. This produces toxic acids
known as ketones. Left untreated, diabetic ketoacidosis
may cause one to lose consciousness. Eventually,
untreated diabetic ketoacidosis can be fatal.
Diabetic ketoacidosis is most common in people who
have type 1 diabetes, but people who have type 2
diabetes may develop diabetic ketoacidosis, too. In fact,
in a few cases diabetic ketoacidosis is the first sign that a
person has diabetes.
Diabetic Ketoacidosis

25. Diabetic Ketoacidosis: Symptom
Diabetic ketoacidosis symptoms often develop quickly, sometimes
within 24 hours. Symptoms includes:
 Excessive thirst
 Frequent urination
 Nausea and vomiting
 Abdominal pain
 Loss of appetite
 Weakness or fatigue
 Shortness of breath
 Fruity-scented breath
 Confusion
More specific signs of diabetic ketoacidosis — which can be
detected through home blood and urine testing kits — include:
 High blood sugar level
 High ketone level in your urine

26. Treatment is usually a three-prong approach:
• Fluid replacement. either orally or through a vein
(intravenously) — until rehydrated. The fluids will replace fluid
lost through excessive urination, as well as help dilute the excess
sugar in blood.
• Electrolyte replacement. Electrolytes are minerals in blood
that carry an electric charge, such as sodium, potassium and
chloride. The absence of insulin can lower the level of several
electrolytes in our blood. Electrolytes should be administered
through veins to help keep heart, muscles and nerve cells
functioning normally.
• Insulin therapy. Insulin reverses the processes that cause
diabetic ketoacidosis. Along with fluids and electrolytes, IV
insulin therapy should be started. When blood sugar level falls
below 250 mg/dL (14 mmol/L) and blood is no longer acidic,
intravenous insulin therapy may be stop and conventional
therapy should be started.
Diabetic Ketoacidosis: Treatment

27. Hyperglycemic Hyperosmolar State
This second most common form of hyperglycemic
coma is characterized by severe hyperglycemia in the
absence of significant ketosis, with hyperosmolality
and dehydration. It occurs in patients with mild or
occult diabetes, and most patients are at least middle-
aged to elderly. Lethargy and confusion develop as
serum osmolality exceeds 310 mosm/kg, and coma
can occur if osmolality exceeds 320-330 mosm/kg.

28.  Weeks of symptoms
 Polyuria
 Weight loss
 Decreased PO intake
 Elderly patient
 Confusion
 Altered mental status
 Lethargy
 Profound dehydration
 Hypotension
 Tachycardia
Hyperglycemic Hyperosmolar State:
Clinical Features

29. Hyperglycemic Hyperosmolar State:
Treatment
 Significant fluid and electrolyte replacement
Insulin treatment started via IV but not aggressive

30. Hypoglycemia Defined
Fall in blood glucose concentrations that elicits
symptoms of glucose deprivation in the central
nervous system.
• Sudden (Adrenergic sx)
• Diaphoresis, pallor
• Tremulousness
• Tachycardia, palpitations
• Visual distubances
• Mental confusion, weakness,
• Gradual
• Fatigue
• Confusion
• Headach
• Memory loss
• Seizures, coma
Hypoglycemia

31. Hypoglycemia
Alterations in consciousness;
Seizures; Headache;
Unusual Behavior
Brain lacks adequate glucose
Pale; Cool skin;
Sweating; Tachycardia;
Increased BP; Nausea
Adrenal Glands release Epinephrine
Blood Sugar Falls
Pale, cool skin; sweating; nausea; tachycardia
Is that why hypoglycemia sometimes is called
“Insulin Shock?”

32.  Prehospital Management of Diabetic Emergencies
1. ABC’s/O2
2. Determine BGL (Normal range 60-120 mg/Dl)
3. Oral Glucose if BGL <60 and patient conscious.
4. If unable to take orally, est. IV and administer
25 g D50/W Child 0.5 g/kg
5. If unable to eat. IV or orals, Glucagon 1 mg
SC/IM
6. Repeat glucoscan after glucose administration
Transport all patients on oral anti-hypoglycemic
agents who develop hypoglycemia
In general, give IV D50/W for any hypoglycemia <50
even if oral glucose given
Hypoglycemia:
treatment

33. Who need insulin
 Type I (insulin dependent) diabetes patients whose body
produces no insulin.
 Type 2 diabetes patients that do not always produce
enough insulin.
Treatment
 subcutaneous injection

34. Stage 1 Insulin was extracted from the glands of
cows and pigs. (1920s)
Stage 2 Convert pig insulin into human insulin by
removing the one amino acid that distinguishes them
and replacing it with the human version.
Insulin drug evolution

35.  Stage 3 Insert the human
insulin gene into E. coli and
culture the recombinant
E.coli to produce insulin
(trade name = Humulin®).
Yeast is also used to
produce insulin (trade
name = Novolin®) (1987).
Recombinant DNA technology has also made it possible to
manufacture slightly-modified forms of human insulin that
work faster (Humalog® and NovoLog®) or slower
(Lantus®) than regular human insulin.

36. Rapid-acting: Lispro, Aspart, Glulisine
Short-acting: Regular
Formulation
Intermediate-acting: NPH Humulin
Long-acting: Insuline detemer, Insuline glargine
Insulin formulation: Type
Depending on Source
•Human
•Procaine
•Bovine
Human peptide
sequence
Pig and beef insulin
differ by 1
(AlaB30Thr) and 2
(ThrA8Ala,
ileA10Val) amino
acids respectively.

37. Types of insulin
• Regular insulins
• Insulin analogs
• Pre-mixed insulin
• Short peptide mimics

38. Regular insulins:
 Human insulin: Humulin® (from E.coli),
Novalin® (from yeast)
 NPH - neutral protamine Hagedorn (NPH),
protamine mixed.
 Lente® insulin / Ultralente® insullin-
zinc added

39. Types of insulin
• Regular insulins
• Insulin analogs
• Pre-mixed insulin
Short peptide mimics

40. Insulin Analogs:
 Fatty Acid Acylated insulins
 Insulin Lispro (Humalog®) (1996)
 Insulin Aspart (NovoLog®) (2000)
 Insulin Glargine (Lantus®) (2002)
 Insulin Detemir (Levemir®) (Jun.,2005)
 Insulin Glulisine (Apidra®) (Jan., 2006)

41. Amino Acid Substitutons
A-
chai
n
Position
B- chain Position
Source/
Type
A21 B3 B28 B29 B30 B31
And
B32
Human Asn Asn Pro Lys Thr
Aspart Asn Aspartic
acid
Lys Thr
Lispro Asn Lys Pro Thr
Glulisine Asn Lys Pro Glu Thr
Glargine Gly Pro Lys Thr Arg
Detemir Lys Myristic
acid
rapid-acting
long-acting

44. Extent and duration of action of various types of Insulin
Unitage: One unit of insuline is equal to the amount required to reduce the
concentration of blood glucose in a fasting rabbit to 45 mg/dl (2.50mM).
Homogeneous preparations of insuline contain between 25 and 30 units/mg

45. CHOICE OF INSULIN PREPARATION
There are two types of regimen for patients requiring
insulin:
 Intensive/flexible therapy. This uses pens (or pumps)
to administer multiple injections of short-acting insulin
during the day to mimic prandial secretion of insulin by
the pancreas, and a single night-time dose of long-
acting insulin.
 Conventional therapy. This involves two injections a
day of biphasic insulin. Soluble insulin or one of the
rapid-acting analogues is given subcutaneously three
times a day. Soluble insulin is given 30 min before meals
whilst the analogues have the advantage of being given
immediately before, during or after the meal. Risk of
hypoglycaemic reaction is lower with the analogues.

46. NPH insulin or one of the long-acting analogues is given
at night. This mimics basal pancreatic insulin release. The
long-acting analogues do this more effectively over 24 h
than NPH insulin, and avoid risk of nocturnal
hypoglycaemia.
Biphasic insulins are a mixture of variable proportions of
soluble insulin with NPH insulin, or of short-acting
analogue with protamine insulin. The available mixtures
are listed in. The most commonly used is 30 : 70
(soluble:NPH).
All of the above are normally administered
subcutaneously. Soluble insulin may also be administered
by intravenous infusion. This is the preferred method of
delivery in diabetic ketoacidosis, in other critically ill
patients, and in perioperative management of diabetes.
CHOICE OF INSULIN PREPARATION

47. Complication of Insulin Therapy
•Hypoglycemia:
•Most common cmplication of insulin therapy
•Symptoms of hypoglycemia appears at plasma
glucose level of 60-80 mg/dl
•Sweating, hunger, paresthesias, palpitations,
tremor and anxiety first appears
•Difficulty in concentrating, confusion, weakness,
dizziness blurred vision and loss of cnsciousness.
•Insulin allergy and resistant:
•Lipoatrophy and lipohypertropy:
•Insuline edema

48. Diabetes – Oral Medications
 Sulfonylureas
 Biguanides
 Thiazolidinediones
 Alpha-glycosidase inhibitors
 Meglitinides
5 Classes :

49. Sulfonylureas : stimulate β cells to
produce more insulin
 1st generation
 (1) tolbutamide
 (3) tolazamide
 (6) chlorpropamide
 2nd generation
– (75) glipizide
– (150) glipizide)
– (150) glyburide
– (250) micronized glyburide
 3rd generation
– (350) glimepiride
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)
was used in treatment of typhoid fever in 1940’s  hypoglycemia
Currently > 12,000
Rel.Potency
bindtoprotein
 may become dislodged  delayed activity
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway
*Hydroxylated derivatives have much lower hypoglycemic activity

50. Mechanism of Action
 Sulfonylureas interact with receptors on
pancreatic -cells to block ATP-sensitive
potassium channels
 This, in turn, leads to opening of calcium
channels
 Which leads to the production of insulin

51. Oral Hypoglycemic agents: Sulfonylureas
Adverse effects:
•infrequent, occurring in about 4% patients
•It can cause hypoglycemic reaction, including coma
•Other adverse effect include
•GIT disturbances: nausea, vomiting, cholestatic jaundice
•Blood diorder: agranulocytosis, aplastic anemia and
hemolytic anemia
•Hypersensitivity reaction: transient rashes, which rarely
progress to erythema multiforme and exfoliative dermatitis,
fever and ajundice
•Others-headache, photosensitivity, weight gain

52. Biguanides : improves insulin’s ability
to move glucose into cells (esp. muscle)
 Metformin
- Glucophage®, Fortamet®,
Riomet®
*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a
large study of overweight patients with diabetes (UKPDS 1998).
NN
NN
N
R
R R
R
RR
R
N N
N
N
N
H
H
H
H H
+ HCl
Mechanism of action:
Metformin mechanism of action is complex and incompletely understood.
Currently proposed mechanisms of action include
• reduced hepatic and renal gluconeogenesis;
• lowering of glucose absorption from the gastrointestinal tract,
with increased glucose to lactate conversion by enterocytes;
• direct stimulation of glycolysis in tissues, with increased
glucose removal from blood; and
• reduction of plasma glucagon levels.

53. Oral Hypoglycemic agents: Biguanides
Adverse effect:
occur in up to 20% of patient including diarrhea, abdominal
discomfort, nausea, flatulence, metallic taste, anorexia,
indigestion. They are dose-related, tend to occur at the onset
of therapy, and are often transient. However, metformin may
have to be discontinued in 3–5% of patients because of
persistent diarrhea. Absorption of vitamin B12 appears to be
reduced during long-term metformin therapy. In the absence
of hypoxia or renal or hepatic insufficiency, lactic acidosis is
less common with metformin therapy than with phenformin
therapy.

54. Sulfonylurea & Biguanide
Combo drugs/ Cocktails
 Glucovance® (Glyburide & Metformine HCl)
NH
O
NH
S
O
O
O
O
NH
Cl
1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea
N N
N
N
N
H
H
H
H H
+ HCl
&
&

55. Thiazolidinediones (TZD’s) : make
cells more sensitive to insulin (esp. fatty
cells)
 Pioglitazone
- Actos®, Avandia®
- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ).
- PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue,
cardiac and skeletal muscle, liver and placenta
PPAR - γ
- upon activation of this nuclear receptor by a ligand such as a TZD,
PPARγ–ligand complex binds to a specific region of DNA and thereby
regulates the transcription of many genes involved in glucose and fatty
acid metabolism.
S
NH
O
O
ON
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
Adverse effect:
CNS: Fatigue, headach
GI: Diarrhea, tooth disorder
Respiratory: Pharyngitis, sinusitis, URTI
Miscellaneous: Anemia,back pain, edema, myalgia

56. Αlpha – glycosidase inhibitors :
Block enzymes that help digest starches 
slowing the rise in B.G.L.
 AGI’s
- acarbose,
- miglitol
N
OO
O
O
O
H
H H
H H
1-(2-Hydroxy-ethyl)-2-hydroxymethyl-
piperidine-3,4,5-triol
a-glucosidase inhibitors reduce
intestinal absorption of starch,
dextrin and disaccharides by
inhibiting the action a-
glucosidase in the intestinal
brush border. Acarbose and
miglitol are competitive
inhibitors of the intestinal a-
glucosidases and reduce the
postprandial digestion and
absorption of starch and
disaccharides
Prominent adverse effects
include flatulence, diarrhea, and
abdominal pain and result from
the appearance of undigested
carbohydrate in the colon that is
then fermented into short-chain
fatty acids, releasing gas.

57. Meglitinides :
Stimulate more insulin production ;
dependant upon level of glucose present
 Meglitinides
- repaglinide
- nateglinide
O
OHO
NH
N
O
2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
O
OH
NH
O
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

58. Oral Hypoglycemic agents: Meglilitinide
Repaglinide is an insulin secratogogue of meglitinide
Class. It stimulate insulin secretion by closing ATP-
dependent potassium channels in pancreatic -cells.
Adverse reaction:
CNS: Headache, paresthesia
GI: Constipation, Diarrhea, Dyspepsia, Nausea, vomiting
Musculoskeletal: Arthralgia, Back pain
Resepirotaory: Bronchitis, rhinities
CVS: chest pain, angina, abnormal EKG, MI, arrhythmia and
palpitation
DI
CYP-450 inhibitors like ketoconazole inhibit metabolism
Cyp 450 inducer rifampin increase metabolism

59. Oral Hypoglycemic agents: D-phenylalanine derivatives
Nateglinide is an insulin secratogogue derived from D-
phenylalanine. It stimulate insulin secretion by closing
ATP-dependent potassium channels in pancreatic -cells.
Nateglinide promotes a more rapid but less sustained
relese of insulin than other oral agents.
Adverse effect
Arthropathy, back pain, bronchitis, coughing, diarrhea, dizziness, flu
syndrome, Hypoglycemia, URTI
DI
Nateglinde is a inhibitor of CYP2C9 decrease metabolism of
tolbutamide
MAOI, NSAIDS, beta-blocker potetiate its action
Thiazide, corticosteroid, sympathomymetic decrease action

60. Oral Hypoglycaemic agents: Incretin mimetics
The L cells in the distal intestinal mucosa secrete GLP-1 in response to
mixed meals.
β-Cell signalling by glucagon-like peptide-1 (GLP-1), which binds to its
receptor on the cell surface and elicits intracellular signaling by
activating the coupled G proteins, mainly the Gs type. In turn, Gs
activates adenylate cyclase to produce cAMP from ATP. This process
results in activation of cAMP-dependent protein kinase A (PKA), which
increases calcium uptake. Interacting with calmodulin, PKA stimulates
exocytosis on insulin-containing granules.

61. Exenatide is a GLP-1 receptor agonist (incretin mimetic).
Exenatide binds to the GLP-1 receptor, resists DPP-IV
degradation, and has produced effects similar to those of
endogenous GLP-1. Its plasma half-life is about 2.5 hours,
requiring a twice-daily SC dosing schedule. Nausea is one
disadvantage of exenatide; this side effect is mild or moderate in
40% of patients, severe in 5%, and causes medication termination
in approximately 3%. Nausea tends to subside over time but
remains problematic for some patients. Beside dizziness, feeling
jittery, headache, diarrhea, dyspepsia may occur
Oral Hypoglycemic agents: Incretin mimetics
Sitagliptin
Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), the
enzyme that degrades incretin and other GLP-1-like molecules.

62. Pramlintide
Pramlintide suppresses glucagon release via
undetermined mechanisms, delays gastric emptying,
and has central nervous system-mediated anorectic
effects. It is rapidly absorbed after subcutaneous
administration; levels peak within 20 minutes, and the
duration of action is not more than 150 minutes.
Hypoglycemic agents: amylin analog
Adverse Effect
CNS: Dizziness, fatigue, headach
GI: abdominal pain, anorexia, nausea, vomiting
Respiratory: Coughing, pharyngitis
Miscellaneous: Allergic reaction, arthralgia,

63.  Animation showing overview of diabetes:
 http://www.healthscout.com/animation/1/34/main.html
 Animation showing mechanism of action of insulin:
 http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancr
eas/insulin_phys.html

64. References:
http://www.webmd.com/content/article/59/66840
http://hms.harvard.edu/public/disease/diabetes/diabetes.html
http://focus.hms.harvard.edu/2005/May20_2005/immunology.sht
ml
http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pan
creas/insulin_struct.html
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pan
creas/insulin.html
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/moa
ction/surface.html
http://www.cancure.org/insulin_potentiation_therapy.htm
http://www.diabetes.org/about-diabetes.jsp
http://en.wikipedia.org/wiki/Actos
http://www.answers.com/topic/peroxisome-proliferator-activated-
receptor
http://www.mja.com.au/public/issues/176_08_150402/omo10828_f
m.html
http://www.univgraph.com/bayer/inserts/precose.pdf
http://www.drugs.com/pdr/ACARBOSE.html
http://www.pfizer.com/pfizer/download/uspi_glyset.pdf
http://www.rxlist.com/cgi/generic2/miglitol.htm
http://en.wikipedia.org/wiki/Prandin
http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-
bin/getCard.cgi?CARD=APRD00593.txt