Al-Bayan University / College of Pharmacy

Pharmacology & Toxicology Dept. 2019-2020

Fourth stage / Pharmacology III - Lecture 3 / By Dr. Atheer S. Alsabah

Pancreatic Hormones and Antidiabetic Drugs

 Pancreatic Hormones
• Pancreas is the source of 2 types of hormones include exocrine hormones
(digestive hormones) & endocrine hormones (peptide hormones). Endocrine
hormones are the secretory products of pancreatic islets cells which include:
1. A-cell (alpha cell): secret glucagon (appose many actions of insulin by ↑ blood
glucose through activation of hepatic glycogenolysis & gluconeogenesis), &
incretins (GLP-1 & GLP-2 "glucagon-like peptides"), where GLP-1 stimulates
insulin release.
2. B-cell (beta cell): secret insulin (the storage & anabolic hormone of the body),
C-peptide, proinsulin, & amylin (neuroregulatory peptide modulates appetite,
gastric emptying, glucagon & insulin secretion).
3. D-cell (delta cell): secret somatostatin "GIF" (GH release inhibitory factor), a
universal inhibitor of secretory cells; also found in GIT & CNS.
4. F-cell (PP cell): secret pancreatic polypeptide "PP", a small protein facilitates
digestive processes.

 Glucagon
- Single chain polypeptide consist of 21 a.a with structure similar to secretin,
vasoactive peptide "VAP", & gastric inhibitory peptide "GIP". It is produced by
pancreatic islets A-cells & act as physiologic antagonist to insulin.
- Glucagon secretion stimulated by amino-acids esp. arginine, cortisol, gastrin,
theophylline, stress, & hypoglycemia. While inhibited by glucose, ketone bodies,
free fatty acids, secretin, somatostatin, & phenytoin.

• MOA: glucagon stimulates production of cAMP from ATP in the liver & activate
phosphorylase which is 2nd messenger.

• Pharmacological actions:
1. Catabolic hormone stimulates glycogenolysis, lipolysis, gluconeogenesis, &
protein catabolism; Therefore resulting in elevation of blood glucose level.
2. Stimulates release of EP from adrenal medulla, insulin from pancreatic B-cells,
calcitonin from thyroid gland, GH & ACTH from pituitary gland.
3. Inhibits GI motility (relax intestines).
4. Promotes water & electrolytes secretion.
5. +ve inotropic & chronotropic effects related to ↑cAMP production.

• Uses:
1. In management of hypoglycemic coma.
2. As an antidote for β-Blockers toxicity.
3. As a diagnostic agent in pheochromocytoma, medullary CA of thyroid, & anterior
pituitary function test.
4. In radiology of bowel.
5. In management of 1st episode of HF (clinically not useful).

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 Insulin
- Polypeptide consist of 51 a.a arranged in 2 chains (A of 21 a.a & B of 30 a.a)
linked by disulfide bridges. It is produced by pancreatic islets B-cells.
- Proinsulin, a long single-chain protein molecule is hydrolyzed into insulin & a
residual connecting segment called C-peptide by removal of 4 a.a.
- Although proinsulin may have some mild hypoglycemic action, C-peptide has no
known physiologic function (some studies state that C-peptide has a role in
prevention of angiopathy), but it is used as indicator for endogenous release of
insulin & important in pts develop antibodies to insulin (after long usage).
- Insulin secretion stimulated by glucose, amino-acids esp. leucine & arginine,
ketone bodies, glucagon, gastrin, secretin, pancaroenzymes, vagal stimulation, GH
& ACTH. While inhibited by thiazides, CCBs, diazoxide, clonidine, oral
contraceptives, serotonin, somatostatin, & phenytoin.
- Oral glucose drink stimulates insulin release more than IV inj. of glucose! Why?

- Hyperglycemia lead to ↑IC ATP which close ATP-dependent K+ channels,

resulting in ↓ outward K+ efflux causing depolarization of B-cell & opening of
voltage-gated Ca2+ channels. The resulting ↑ IC Ca2+ triggers hormone secretion.

• Pharmacokinetics: insulin is destroyed in GIT, thus given parenterally (Sc, IM,

IV "crystalline zinc insulin"). Pulmonary absorption occurs & inhalation of an
aerosol is a new route of administration. Once absorbed, insulin has an elimination
half-life of approx. 10 min, it is inactivated enzymatically in liver & kidney.

• MOA: Insulin acts via receptors that are trans-membrane glycoproteins. Each
receptors has 2 insulin binding sites. Receptor occupancy results in:
1. Activation of insulin-dependent glucose transport processes in adipose tissue &
muscles.
2. Inhibition of adenylyl cyclase-dependent processes e.g. lipolysis, proteolysis, &
glycogenolysis.
3. Intracellular accumulation of potassium & phosphate (which are linked to glucose
transport in some tissue).
4. Increased cellular amino acid uptake, DNA & RNA synthesis.
5. Increased oxidative phosphorylation.

• Insulin actions: insulin have anabolic & metabolic effects, it promotes storage of
glucose & fat (energy sources) within specialized target cells & influences cell
growth & metabolic functions of a wide variety of tissues.

A. Effects on Liver: insulin increase storage of glucose as glycogen in the liver by

insertion of additional GLUT2 glucose transporter in cell membrane, increase
synthesis of the enzymes pyruvate kinase, phosphofructokinase, & glucokinase;
and suppression of several other enzymes.
- ↑Glycogenesis (↑ glycogen formation from glucose).
- ↑Glycolysis (↑ glucose conversion to ATP).
- ↑Lipogenesis (↑ lipid formation).
- ↓Gluconeogenesis (↓ glucose formation).
- ↓Glycogenolysis (↓ glycogen degradation to glucose).
- ↓Lipolysis (↓ oxidation of FFA "glucose precursor").
- ↓Protein breakdown (↓ a.a release "glucose precursor").

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B. Effects on skeletal muscles: insulin stimulates glycogen & protein synthesis by
insertion of additional GLUT4 glucose transporter in cell membrane.
- ↑Glycogenesis (↑ glycogen formation from glucose).
- ↑Glycolysis (↑ glucose conversion to ATP).
- ↑Glucose uptake.
- ↑Amino acid uptake.
- ↑Protein synthesis

C. Effects on adipose tissue: insulin facilitates TG storage by activating plasma

lipoprotein lipase, increasing glucose transport into cells via GLUT4 transporters,
and reducing intracellular lipolysis.
- ↑TG synthesis.
- ↑Fatty acid synthesis
- ↑Glycerol synthesis.
- ↑Glucose uptake.
- ↓Lipolysis

• Insulin sources: insulin is obtained from different origin e.g. human, beef, or
pork. Pork insulin is slightly more rapid onset & shorter acting than beef insulin, it
is differ in 1 a.a from human insulin while beef insulin differ in 4 a.a from human
insulin.
• Human insulin is prepared from enzymatic modification of pork insulin, or
produced by recombinant DNA technology by inserting human proinsulin gene
(DNA) into special strain of E. coli or yeast; then extracted to form human insulin
molecules.
• Human insulin differ from animal insulin in that:
- Onset, human insulin is slightly more rapid.
- DOA, human insulin is slightly shorter acting.
- Antibodies, human insulin is less immunogenic.
- Hypoglycemia, human insulin causes frequent & severe attacks of hypoglycemia.
- Adverse effects, human insulin causes less adrenergic symptoms e.g. flushing,
sweating, tremor, palpitation, & tachycardia.

• Insulin preparations: they differ in purity, solubility, concentration, a.a

sequences, production technique, onset & duration of action.

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1. Rapid-acting: involves 3 injectable insulin analogs (aspart, lispro, & glulisine),
and inhaled human insulin. They have rapid onset & early peak of activity that
permit control of postprandial glucose levels.
- They injected immediately before a meal & they are preferred for continuous Sc
infusion devices. Also can be used for emergency treatment of uncomplicated
diabetic ketoacidosis "DKA".

2. Short-acting: involves regular "soluble crystalline zinc" insulin, the only one
used IV in emergency. Also used Sc in ordinary maintenance regimens, alone or
mixed with intermediate or long acting preparations. Given 1hr before meal.

3. Intermediate-acting: involves NPH "neutral protamine Hagedorn" (isophan),

which is a combination of regular insulin and protamine (highly basic protein also
used to reverse the action of unfractionated heparin). NPH exhibit delayed onset
& peak of action, and often combined with regular & rapid-acting insulin.

- Lente insulin: is an amorphous ppt of insulin with zinc, combined with 70% of
ultralente insulin, it is not suitable for IV administration.

4. Long-acting: involves glargine & detemir, they are modified form of human
insulin that provide a peak less basal insulin level lasting more than 20hrs, which
helps control basal glucose levels without producing hypoglycemia.

- Ultralente insulin: is a suspension of zinc crystals in acetate buffer, this produce

large particles that are slow to dissolve resulting in a slow onset of action & long
lasting hypoglycemic effects.

• Insulin time action curves:

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• Insulin delivery systems:
1. The standard mode of insulin therapy is Sc injection with disposable needles &
syringes.
2. Portable pen-sized injections are used to facilitate Sc injection.
3. Continuous Sc insulin infusion devices avoid the need for multiple daily injections
and provide flexibility in scheduling of pts daily activity.
4. Programmable pump deliver a constant 24hrs basal rate, made to accommodate
change in insulin requirement.
5. An inhaled formulation of insulin can be used to cover mealtime insulin
requirement.

• Clinical uses of insulin:

1. Type I DM "IDDM", requires long-term maintenance treatment with insulin
(intermediate-acting often combined with a short-acting taken before meals).
2. Diabetic ketoacidosis "DKA", emergency hyperglycemia requires IV soluble
insulin.
3. Many pts with Type II DM "NIDDM", ultimately require insulin.
4. Short-term treatment of pts with Type II DM "NIDDM" or impaired glucose
tolerance during inter current events e.g. surgery, infections, & MI.
5. Emergency treatment of hyperkalemia, where insulin is given with glucose to
lower EC K+ via redistribution into cells.

• Adverse effects of insulin:

1. Hypoglycemia, most common complication result from excessive insulin effect
since long term diabetics often do not produce adequate amounts of counter-
regulatory hormones (glucagon, EP, cortisol, & GH), which normally provide an
effective defense against hypoglycemia. It is ccc by hunger, weakness, sweating,
tachycardia, tremor, anxiety, convulsion, & may lead to brain damage.

• Treatment of hypoglycemia include:

a. For mild case, any glucose containing beverage even sugar or candy by mouth.
b. For severe case, DOC is 20-50ml of 50% glucose by IV infusion over 2-3min.
- If IV treatment not available, 1mg glucagon Sc or IM.
- If glucagon not available, small amount of honey or syrup inserted into mouth.

2. Lipid dystrophy at site of injection & formation of lipomata (all insulin types
cause lipodystrophy).
3. Immunological complications especially formation of antibodies to insulin or to
non-insulin protein content which result in an insulin resistance & allergic
reactions e.g. rash, urticaria, & anaphylaxis (use of purified human insulin
↓chance of immunological reactions).
4. Hypokalemia may occur in pts with acidosis using a lot of insulin & glucose, it
causes death with abnormal heart beat.
5. Weight gain due to increased caloric storage of glucose by insulin, & some is due
to renal sodium retention resulting in fluid retention & edema. These effects can
synergize with oral agents that are often co-administered with insulin, particularly
thiazolidinediones.

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 Diabetes Mellitus (DM)
• Is a multifactorial chronic metabolic disorder ccc by a high blood glucose level
(fasting plasma glucose "FBS" >126mg/dL [>7mmol/L], or random plasma
glucose "RBS" "postprandial glucose level" >200 mg/dL [>11.1mmol/L]), mainly
caused by insulin deficiency often combined with insulin resistance.
• Hyperglycemia occurs because of uncontrolled hepatic glucose output & reduced
glucose uptake by skeletal muscles with reduced glycogen synthesis. When the
renal threshold for glucose reabsorption is exceeded [>180mg/dL]), glucose spills
over into the urine (glycosuria) & causes an osmotic diuresis (polyuria), which in
turn, results in dehydration, thirst & increased drinking of water (polydipsia).

• Types of DM:
1. Type I DM, or Insulin-dependent DM "IDDM", or Juvenile type: It is involves
destruction of pancreatic B-cells, as a result of an autoimmune process.
2. Type II DM, or Non-Insulin-dependent DM "NIDDM", or Maturity onset type: It
is results from a combination of insulin resistance & altered insulin secretion.
3. Gestational DM "GDM": glucose intolerance during pregnancy.
4. Mody DM: It is related to multiple causes e.g. drug-induced.

• Monitoring of DM:

1. Fasting plasma glucose "FBS" 70-126mg/dl

[3.9-7mmol/L].
2. Random plasma glucose "RBS" "Postprandial
glucose level" <200mg/dl [<11.1mmol/L].
3. Oral glucose tolerance test "OGTT" "2hrs-
after 75gm anhydrous glucose" <200mg/dl
[<11.1mmol/L].
4. Glycosylated Hb "HbA1c" 1-4% of total Hb,
but <7% is accepted to confirm DM control in
the last 3 months.

• Treatment of type I DM:

- Therapy involves dietary instruction, & parenteral insulin (to maintain control of
basal & postprandial glucose level, avoid ketoacidosis, & maintain acceptable
level of glycosylated Hb "Hb A1c" which serve as marker of glycemia). Also
pramlintide is possibly given to improve control of postprandial glucose level.

- Careful attention by the pt to factors that change insulin requirements e.g.

exercise, infections, stress, & deviation from regular diet.

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• Treatment of type II DM:
- Therapy involves weight reduction, dietary control, monotherapy with metformin,
& a 2nd generation sulfonylureas.
- After 5yrs, secondary failure is common, where non-insulin antidiabetic drugs are
being used in combination with each other or with insulin to achieve better
glycemic control. Usually combination of agent that augment insulin action
"insulin sensitizers" (e.g. metformin, thiazolidinediones, or α-glucosidase
inhibitors) with agent that augment insulin supply "insulin secretagogues" or
insulin itself are applied.

• Complications of DM:
1. Acute complications: include diabetic ketoacidosis "DKA" (>22mmol/L),
hyperosmolar non-ketotic hyperglycemia "HONKH" (>55.5mmol/L), &
hypoglycemia.
2. Chronic complications: include
a. Micro-vascular complications e.g. nephropathy, retinopathy, & neuropathy.
Because high blood glucose level cause binding between glucose & protein lead to
glycosylation process result in advanced glycosylated end product (AGEP)
associated with free radical formation as a result of oxidative stress that cause
damage to nephrons, retina, & nerve endings.
- DM associated with micro-albuminuria due to damage of renal tissue (like
hypertension), therefore ACEIs provide renal protection in DM.

b. Macro-vascular complications e.g. atherosclerosis, angiopathy, & gangrene.

Because hyper-osmolarity of blood due to high blood glucose level lead to
↑atheroma formation & endothelium dysfunction causing ↓NO. release resulting
in vasoconstriction & IHD.

• Insulin therapy:
1. Standard therapy involves given insulin Sc. inj. twice daily, to ↓glucose level
about 225 -275mg/dL with HbA1c 8-9% of total body Hb.
2. Intensive therapy involves given insulin 3 or more times daily, to ↓glucose level
about 150mg/dL.
- Normalization of blood glucose level cannot be achieved even with intensive
insulin therapy since glucose level of 150mg/dL still more than normal glucose
level (70-126mg/dL), & that give chance for DM complications.

- Insulin resistance considered in a pts requiring >200IU insulin daily, since daily
insulin requirements > secreted insulin & concerned with insulin receptors
response. Insulin resistance either acute concerned with stress, emotion, surgery,
infection, fever, coma, thyrotoxicosis, & pregnancy. Or chronic concerned with
presence of large amount of plasma insulin binding antibodies.

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 Classification of oral antidiabetic drugs (former name oral hypoglycemic drugs)

1. Insulin sensitizers: drugs that sensitize the body to insulin &/or control hepatic
glucose production.
• Biguanides e.g. metformin (Glucophage®), buformin (less likely used), &
phenoformin (fatal lactic acidosis).
• Thiazolidinediones "TZDs" e.g. pioglitazone (Actos®), rosiglitazone (cardiotoxic),
& troglitazone (hepatotoxic).

2. Insulin secretagogues: drugs that stimulate the pancreas to make more insulin.
• Sulfunylureas e.g. glibenclamide "glyburide" (Daonil®), glimepiride (Amaryl®),
gliclazide (Diamicron®), glipizide (Clucotrol®), chlorpropamide & tolbutamide.
• Meglitinides e.g. repaglinide (Novonorm®), & nateglinide.

3. Carbohydrate absorption delayers: drugs that slow absorption of starch.

• α-glucosidease inhibitors e.g. acarbose & miglitol.

4. New drugs targeting endogenous regulators of glucose hemostasis: unlike

above drugs, this group some given parenterally (Sc) & others given orally.
• Amylin mimetics: (Sc)
- Amylin receptor agonists e.g. pramlintide (Symlin®) (amylin analog).

• Incretin mimetics: (Sc & oral)

- Incretin "GLP-1" receptor agonists e.g. exenatide (incretin "GLP-1" analog),
liraglutide (Victoza® or Saxenda®), & dulaglutide.
- Dipeptidyl peptidase-4 "DPP-4" inhibitors e.g. sitagliptin (Januvia®), saxagliptin
(Onglyza®), vildagliptin(Calvus®), linagliptin (Tradjenta®), & alogliptin.

• Glucose excretion enhancers: (oral)

- Sodium- glucose cotransporter -2 (SGLT-2) inhibitors e.g. canagliflozin
(Invokana®), dapagliflozin (Farxiga®), & empagliflozin (Jardiance®).

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 Biguanides e.g. metformin.
- Metformin is euglycemic agent not provoke hypoglycemia, now considered a
1st -line drug for the treatment of type II DM.
• MOA:
1. Direct stimulation of glycolysis in tissues, with ↑glucose removal from blood.
2. Reduced hepatic & renal gluconeogenesis.
3. Slowing GI absorption of glucose, with ↑glucose to lactate conversion by
enterocytes.
4. Reduction of plasma glucagon level.

• Pharmacokinetics:
- Metformin has t1/2 1.5–3hrs, not bound to plasma protein, not metabolized, &
excreted unchanged in urine as active compound.
- As a consequence of metformin's blockade of gluconeogenesis, the drug may
impair the hepatic metabolism of lactic acid. In patients with renal insufficiency,
biguanides accumulate and thereby increase the risk of lactic acidosis.

• Clinical use:
1. 1st line therapy in type II DM.
- It offers obvious advantages over insulin or sulfonylureas in treating
hyperglycemia due to ineffective insulin action (insulin resistance syndrome), also
it decreases the risk of macro-vascular & micro-vascular complications (↓LDL
&VLDL, & ↑HDL). Used in combination with insulin secretagogues or TZDs in
type II diabetics in whom oral monotherapy is inadequate.
- It is efficacious in prevention of new onset of type II DM in middle-aged, obese
individuals with impaired glucose tolerance & fasting hyperglycemia.
2. In obesity.
3. In polycystic ovarian syndrome (PCOS).

• S/E:
1. Commonest dose-related GI disturbances e.g. metallic taste, N, V, D, & anorexia.
2. Rare dose-dependent lactic acidosis (potentially fatal toxic effect).
3. Long-term use may interfere with absorption of vitamin B12.

• C/I: renal failure, hepatic disease, alcoholism, anoxia as in pt with chronic

cardiopulmonary dysfunction.

 Thiazolidinediones (TZDs) e.g. pioglitazone.

• MOA: ligand to PPAR-γ (activating peroxisome proliferator-activated receptor-γ)

at muscle, fat, & liver; lead to nuclear modulation of genes involved in glucose &
lipid metabolism, insulin signal transduction, & adipocyte differentiation.
Resulting in ↓insulin resistance, improve lipid profile, & improve glucose
peripheral uptake & utilization.

- In addition, pioglitazone activates PPAR-α resulting in TG lowering effect. Thus

long-term therapy associated with significant drop in TG level & slight rise in
HDL & LDL values (possible cardiac protective effect in MI & stroke pts).

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• Pharmacokinetics:
- TZDs are euglycemics & efficacious in about 70% of new users.
- They are well absorbed, highly protein binding, cleared renally & can be used in
pts with renal dysfunction.
- Because their MOA involves gene regulation, TZDs have a slow onset & offset of
activity over weeks or even months.
- Individuals experiencing secondary failure to other oral agents should benefit
from the addition (rather than substitution) of a TZDs.

• S/E:
1. Fluid retention, manifested as peripheral edema & mild anemia esp. when
combined with insulin or insulin secretagogues.
2. Combination therapy with insulin & sulfonylureas can lead to hypoglycemia &
may require dosage adjustment.
3. Dose-related weight gain (average 1-3kg), which may be fluid-related.
4. Increase risk of fractures in females.

• C/I: pregnancy, liver disease, CHF, & osteoporosis in females.

 Sulfonylureas
- 1st-generation Sulfonylureas e.g. chlorpropamide & tolbutamide.
- 2nd-generation Sulfonylureas e.g. glibenclamide "glyburide", glimepiride,
gliclazide, & glipizide.

• MOA:
1. Stimulate insulin release from B-cell of pancreas by blocking ATP-dependent K+
channels inhibiting K+ efflux & depolarization resulting in opening of voltage
gated Ca2+ channels & Ca2+ influx with release of preformed insulin.
2. Increase sensitivity of target tissues to insulin.
3. Reduce glucagon plasma level by unclear mechanism involves indirect inhibition
by enhancing release of both insulin & somatostatin that inhibit A-cells secretions.
4. K+ channels closure in extra-pancreatic tissues & potentiation of insulin action.

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• Pharmacokinetics:
- Sulfonylureas are well absorbed, high plasma protein binding, cause
hyponatremia, & all have same MOA. But differ in t1/2, duration, & S/Es.

• S/E:
1. weight gain.
2. Hypoglycemia.
- SU are C/I in renal & hepatic insufficiency because delayed excretion of SU
resulting in accumulation & may cause hypoglycemia. Renal impairment is a
particular problem in agents with active metabolites e.g. glyburide & glimepiride.
- They cross the placenta causing depletion of insulin from fetal pancreas, so
pregnant with type II DM should be given insulin.
3. Secondary failure & tachyphylaxis to sulfonylureas i.e. failure to maintain a good
response to sulfonylurea therapy over the long term caused by:
- A progressive decrease in B-cell mass.
- Reduction in physical activity.
- Decline in lean body mass.
- Increase in ectopic fat deposition in chronic type II diabetes.

• C/I: renal failure, hepatic failure, & pregnancy.

• D/I:
1. They depresses I131 uptake, thus not given at doing radioactive I131 therapy.
2. Antagonized by thiazide diuretics & corticosteroids that causing hyperglycemia.
3. Potentiated by drugs displaced it from protein binding sites e.g. clofibrate,
salicylates, & sulphonamides.
4. Potentiated by drugs reduced its renal elimination e.g. allopurinol, & salicylates.
5. Interference with hepatic metabolism either inducers e.g. rifampicin, & phenytoin.
Or inhibitors e.g. cimetidine.

▲ Chlorpropamide
- Has long t1/2 about 32hrs & slowly metabolized in liver to products that retain
some biologic activity.
- It is has antidiuretic effect thus used in diabetes insipidus.
- Produces prolonged hypoglycemia in elderly, & interact with alcohol causing
hyperemic flushing (due to genetic factors).

▲Tolbutamide
- Has short t1/2 6-12hrs, therefore it is the safest sulfonylurea for elderly diabetics.
- It is well absorbed, strongly bind plasma protein, & rapidly metabolized in liver.
- It is has +ve inotropic effect due to cAMP activation.
- Produces rare prolonged hypoglycemia in elderly.

▲ Glibenclamide "glyburide"
- T1/2 18-24hrs, can be given in single dose.
- 50% is excreted unchanged in feces.
- Inhibit platelets aggregation & enhance free water clearance.
- The active metabolites accumulated in case of renal failure causing hypoglycemia.

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▲ Glimepiride
- T1/2 5hrs, & DOA 12-24hrs.
- It is completely metabolized in liver to inactive products & the only sulfonylurea
excreted completely in feces.
- A single daily dose of 1mg has been shown to be effective & achieves blood
glucose lowering with the lowest dose of any sulfonylurea compound.

▲ Gliclazide
- T1/2 10hrs, & DOA 48hrs.
- The only sulfonylurea selective to SU1-receptors.
- It has fibrinolytic activity, thus used for elderly pts with CV disease.

▲ Glipizide
- It has shortest t1/2 2-4hrs & more potent agent.
- At least 90% of glipizide is metabolized in liver to inactive products, & 10% is
excreted unchanged in urine..
- It cause less hypoglycemia than glyburide, but high risk of hypoglycemia in pts
with significant hepatic or renal impairment.

 Meglitinides e.g. repaglinide & nateglinide.

- Insulin secretagogues not related to sulfonylureas but act by the same MOA. They
have rapid onset "t1/2 1hr" & short DOA "4-5hrs".
- They are particularly effective in early release of insulin that occur after meal,
thus categorized as postprandial glucose regulator (↓postprandial hyperglycemia).
- They are excreted via bile, thus safe in pts with very reduced renal function.
- They are metabolized in liver by CYP3A4. Therefore enzyme inhibitors e.g.
erythromycin will enhance the glucose lowering ability of repaglinide & the
opposite in case of enzyme inducers e.g. rifampin, carbamazepine, & phenytoin.
- Dose titration not required since lowest incidence of hypoglycemia & weight gain
than sulfonylureas.
- Partially restores initial insulin release in response to IV GTT, & this is significant
advantage because type II DM associated with loss of this initial insulin response.
Also have specific role in treatment of isolated postprandial hyperglycemia but
minimal effect on overnight or fasting glucose levels.

 α-Glucosidase Inhibitors e.g. acarbose & miglitol.

• MOA: competitive inhibitors of the intestinal α-glucosidases (sucrase, maltase,

glycoamylase, & dextranase that broken down complex starch, oligosaccharides,
& disaccharides into individual monosaccharides) reducing postprandial digestion
& absorption of starch & disaccharides.
- Miglitol structurally unrelated to acarbose & 6 times more potent in inhibiting
sucrase.
- Acarbose ↓ macro-vascular complications of DM, & it is cautioned in hepatic
disease since it associated with reversible hepatic enzyme elevation.
• C/I: in pts with inflammatory bowel disease, renal impairment, & ketosis.

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 New drugs targeting endogenous regulators of glucose hemostasis:

▲ Pramlintide
- Injectable synthetic analog of amylin (pancreatic B-cells hormone contribute to
glycemic control by activating complex of calcitonin receptor & receptor activity
modifying receptor "RANK").
• Effects: it suppresses glucagon release, slows gastric emptying, & centrally
suppresses appetite (satiety feeling).
- After Sc injection, it is rapidly absorbed & has shorter DOA. Arm administration
is less reliable & given immediately before meal.
- It cleared renally but no change in bioavailability even at low creatinine clearance
& not required dose adjustment.
• Use: in type I & type II DM (combined with insulin to control postprandial
glucose level).
• S/E: hypoglycemia & GI upset.

▲ Exenatide
- Injectable synthetic analog of incretin "GLP-1" (peptide hormone released from
endocrine cells of gut in response to food. Also from pancreatic A-cells), which is
not destroyed easily by dipeptidyl peptidase-4 (DPP-4).
• Effects: it potentiates "augment" glucose mediated insulin secretion, suppresses
glucagon release, slows gastric emptying (vagally-mediated), & centrally
suppresses appetite (satiety feeling).
- It is absorbed equally from arm, abdomen, or thigh; & given 60min before meal.
- It cleared renally & require dose adjustment when creatinine clearance<30ml/min.
• Use: in type II DM in order to increase insulin release.
• S/E: hypoglycemia, GI upset (esp. nausea 44%), & acute fatal pancreatitis.

▲ Sitagliptin
- Oral inhibitor of dipeptidyl peptidase-4 "DPP-4" (enzyme degrades incretins &
other GLP-1 molecules), so endogenous incretins will act longer. .
• Effects: like exenatide + facilitates weight loss.
- It is absorbed equally from arm, abdomen, or thigh; & given 60min before meal.
- It cleared renally & require dose adjustment in pts with renal impairment.
• Use: in type II DM in order to increase insulin release.
• S/E: rare hypoglycemia, headache, nasophyrangitis, & URT infection.

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Note: Incretin Therapy:

- Incretins are naturally occurring hormones released from gut throughout the day;
the level of active incretins increases significantly when food is ingested.
- Endogenous incretins GLP-1 (glucagon-like peptide 1) & GIP (gastric inhibitory
peptide) are the 2 major incretin hormones in human, where GIP is a 42-aa
peptide secreted by proximal GIT (duodenum & proximal jejunum); while GLP-1
is a 30- or 31-aa peptide secreted by distal GIT (ileum & colon).

- These incretins are released from the gut in response to ingestion of food &
collectively contribute to glucose control by:
1. Stimulating glucose-dependent insulin release from pancreatic B-cells.
2. Decreasing glucagon release from pancreatic A-cells when glucose level elevated.
3. Decreasing gastric emptying.
4. Decreasing appetite (increase satiety).

- Physiologic activity of incretins limited by dipeptidyl peptidase-4 "DPP-4", which

rapidly degrades active incretins after their release.

- Incretin effect is diminished in type II diabetes because levels of GLP-1 are

decreased & the insulinotropic response to GIP is diminished but not absent.
Therefore defective GLP-1 release & diminished response to GIP may be
important factors in glycemic dys-regulation in type II diabetes.

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