PANCREATIC HORMONES & ANTIDIABETIC AGENTS

A. Insulin
1. Structure and synthesis a. Insulin is a polypeptide hormone produced by the pancreatic b cell. Insulin consists of two
chains, A and B, linked by two disulfide bridges.
b. Human insulin contains 51 amino acids. Bovine insulin differs from human insulin at three amino acid sites; porcine
insulin differs in only one amino acid.
c. Insulin is stored as a complex with Zn2+; two molecules of zinc complex six molecules of insulin.
d. Insulin synthesis and release are modulated by the following:
(1) The most important stimulus is glucose. Amino acids, fatty acids, and ketone bodies also stimulate release.
(2) The islets of Langerhans contain several cell types besides b cells that synthesize and
release peptide humoral agents (including glucagon and somatostatin) that can modulate insulin secretion.
(3) a-Adrenergic pathways inhibit secretion of insulin; this is the predominant inhibitory mechanism.
e. b-Adrenergic stimulation increases insulin release.
f. Elevated intracellular Ca2+ acts as an insulin secretagogue.
2. Mechanism of action

a. Insulin binds to specific high-affinity receptors with tyrosine kinase activity located in the plasma membrane. Specific
tyrosine residues of the insulin receptor become phosphorylated (autophosphorylation); other substrates for
phosphorylation include IRS-14 (insulin receptor substrates-1 to -4). The increase in glucose transport inmuscle and
adipose tissue is mediated by the recruitmentof hexose transport molecules (GLUT-1 andGLUT-4) into the plasma
membrane.
b. Insulin alters the phosphorylation state of key metabolic enzymes, leading to enzymatic activation or inactivation.
c. Insulin induces the transcription of several genes involved in increasing glucose catabolism and specifically inhibits
transcription of other genes involved in gluconeogenesis
.
3. Actions. Insulin promotes systemic cellular K+ uptake.
a. Liver
(1) Inhibits glucose production and increases glycolysis
(2) Inhibits glycogenolysis and stimulates glycogen synthesis
(3) Increases the synthesis of triglycerides
(4) Increases protein synthesis
b. Muscle
(1) Increases glucose transport and glycolysis
(2) Increases glycogen deposition
(3) Increases protein synthesis
c. Adipose tissue
(1) Increases glucose transport
(2) Increases lipogenesis and lipoprotein lipase
(3) Decreases intracellular lipolysis
4. Pharmacologic properties
a. Insulin has a t1/2 of 510 minutes.
b. Insulin is degraded by hepatic glutathioneinsulin transhydrogenase, which reduces the di disulfide
linkages between the A and B chains, producing two biologically inactive peptides.
5. Insulin preparations
(1) Rapid acting 3 Insulin analogs :
Insulin lispro, insulin aspart , insulin glulisine
*rapid onset and early peaks
*Control of postprandial glucose levels
*Immediately injected after meals
*For treatment of uncomplicated diabetic ketoacidosis.
(2) Short acting. Regular insulin (IV) emergency/ SC ordinary
Control postprandial glucose concentrations.
1 h before meal
(3) Intermediate acting Neutral Protamin Hagedorn Insulin ( NPH)
Regular insulin + Protamine
Delayed onset and peak of action
(4) Long acting Insulin glargine and Insulin detemir
Peakless basal insulin level
Last > 20h : Control glucose level without producing hypoglycemia
Insulin Delivery systems
1) Pen devices containing prefilled regular, lispro, NPH, glargine, premixed lispro protamine-lispro, or premixed
aspart protamine-aspart
2) Jet injector systems
3) Insulin pumps (continuous SC insulin infusion devices, CSII)
Inhaled insulin: Afrezza

Is a rapid-acting inhaled insulin to be administered prior to meals or within 20 minutes of starting a meal
The most common ADRs associated with Afrezza in clinical trials were hypoglycemia, cough, and throat pain or
irritation
It is not a substitute for long-acting insulin and must be used in combination with long-acting insulin in patients
with type 1 diabetes
It is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or who have chronic
lung disease

Adverse Effects :
1. Hypoglycemia
2. Insulin allergy and resistance
a) Insulin allergy
b) Insulin resistance
3. Lipohypertrophy

NON INSULIN ANTIDIABETIC DRUGS
Insulin Secretogogues Biguanides Thiazolidinedones
Drugs :
Older:
Chloropromide
Tolbutamide
Intermediate:
Glimepride
Glipize
Glyburide
Fast acting:
Repaglinide
Nateglinide

MOA :
Stimulate the release of endogenous
insulin by promoting closure of K+
channels -> deplorization -> insulin
release


Drugs :
Metformin

MOA:
Reduces postprandial and fasting
glucose
*inhibit hepatic and renal
gluconeogenesis
Stimulation of glucose uptake and
glycolysis and slowing of glucose
absorption from GIT, Reduction of
glucagon
All thru activation of AMP stimulated
kinases.
Reduces endogenous insulin
production through enhanced insulin
sensitivity
Restore fertitlity in anovulatory
women with POCD.
MOA: binds to the PPAR-gamma
(peroxisome proliferators activated
receptor) in cell nuclei esp in
adipocytes transcription of
multiple genes affecting lipid
homeostasis ( lipolysis, TG
accumulation, plasma free fa
concs) glu uptake in muscle,
gluconeogensis & hepatic glu
output by insulin. sensitivity of
adipocytes to insulin pt will gain
wt
Uses:
Monotherapy (up to 8mg bd) in type
2 DM
Combine with metformin or
sulphonyurea if there is insufficient
in fasting bld glu

Toxicities :
*hypoglycemia
* rash/allergic reactions
*Weight gain

Toxicities :
Do not cause hypoglycemia
GIT distress
Lactic acidosis

SEs:
Hepatic impairment. Avoid in pts
with hx of liver impairment or if basal
ALT is >2.5x upper limit of normal. If
give drug & LFT >3x, stop drug.
Fluid retention monitor carefully
for HF in pt with cardiac problems
Hb & hematocrit & wbc cos of in
bld vol due to fluid retention
Ovulation may be induced in
premenopausal/anovulatory women
with insulin resistance. May need
contraception
LDL & HDL over time, but HDL
more improve lipid profile



@Glucosidase Inhibitors Pramlintide Exenatide Sitagliptin
MOA: binds to the PPAR-
gamma (peroxisome
proliferators activated
receptor) in cell nuclei
esp in adipocytes
transcription of multiple
genes affecting lipid
homeostasis ( lipolysis,
TG accumulation,
plasma free fa concs)
glu uptake in muscle,
gluconeogensis &
hepatic glu output by
insulin. sensitivity of
adipocytes to insulin
pt will gain wt
Uses:
o Monotherapy (up to
8mg bd) in type 2 DM
o Combine with
metformin or
sulphonyurea if there
is insufficient in
fasting bld glu
SEs:
a. Hepatic impairment.
Avoid in pts with hx of
liver impairment or if
basal ALT is >2.5x upper
limit of normal. If give
drug & LFT >3x, stop
drug.
b. Fluid retention monitor
Synthetic analog of amylin
(hormone produced by
pancreatic B cells)
Activates high affinity
receptors ( complex of
calcitonin and Receptor
activity modifying
receptor(RANK(
Suppresses glucagon
release
Slow gastric emptying
Reduce appetite.

Use to treat DM type 1
and type 2

SE:
GI Disturbances
Headache
hypoglycemia
Glucagon like peptide-1
Incretin family.

Agument glucose
stimulated insulin rease
From pancreatic B cells
Retard gastric emptying
Inhibit glucagon secretion
Feeling of satiety

GLP-1 increase cAMp
Ca2+

Exenatide :
*Used in combination with
metformin , sulfonylurea
for type 1 and 2

SE: GIT disturbances
Nausea
Hypoglycemia
Fata acute
pancreatitis(Rare)
Oral inhibitor of
dipeptidyl peptidase 4
(DPP40
Type 2 diabetes
Used with metformin or
thiazolidinedione.

Sitaglipti :
Insulin release
Inhibit glucagon secretion
Anorexic effect

SE:
Headache
Nasopharyngitis
Upper Resp Track
Infection.
carefully for HF in pt with
cardiac problems
c. Hb & hematocrit & wbc
cos of in bld vol due to
fluid retention
d. Ovulation may be
induced in
premenopausal/anovulat
ory women with insulin
resistance. May need
contraception
e. LDL & HDL over time,
but HDL more
improve lipid profile




Glucagon :
Glucagon
a. Structure and synthesis
(1) Glucagon is a single-chain polypeptide of 29 amino acids produced by the a cells of the pancreas.
(2) Glucagon shares a structural homology with secretin, VIP, and gastric inhibitory peptide.
(3) Secretion of glucagon is inhibited by elevated plasma glucose, insulin, and somatostatin.
(4) Secretion of glucagon is stimulated by amino acids, sympathetic stimulation, and sympathetic secretion.

b. Actions and pharmacologic properties
(1) Membrane-bound receptors are most abundant in the liver; response is coupled to an
increase in cAMP.
(2) Glucagon stimulates the use of glycogen stores and gluconeogenesis; in general, its
actions oppose those of insulin.
(3) Large doses produce marked relaxation of smooth muscle.
(4) Glucagon is extensively degraded in the liver and kidney and is also subject to hydrolysis
in plasma. Plasma t1/2 of glucagon is approximately 35 minutes.
c. Therapeutic uses
(1) Glucagon produces rescue from hypoglycemic crisis. Glucagon rapidly increases blood
glucose in insulin-induced hypoglycemia if hepatic glycogen stores are adequate.
(2) Glucagon provides intestinal relaxation prior to radiologic examination.
(3) Glucagon causes b-cell stimulation of insulin secretion; it is used to assess pancreatic
reserves.
d. Adverse effects. The adverse effects of glucagon are minimal; there is a low incidence of
nausea and vomiting.