Anti-Diabetic

THE ENDOCRINE PANCREAS

The endocrine pancreas in the adult human
consists of approximately 1 million islets of
Langerhans
interspersed
throughout
the
pancreatic gland
-

Their hormone products include insulin,

the storage and anabolic hormone of the
body

islet amyloid polypeptide (IAPP, or

amylin), which modulates appetite, gastric
emptying, and glucagon and insulin
secretion

glucagon, the hyperglycemic factor that

mobilizes glycogen stores

somatostatin,
secretory cells

universal

inhibitor

of

gastrin, which
secretion

pancreatic peptide, a small protein that

facilitates
digestive
processes
by
mechanism not yet clarified.

stimulates

gastric

acid

Diabetes mellitus is defined as an elevated

blood glucose associated with absent or
inadequate pancreatic insulin secretion, with or
without concurrent impairment of insulin action.
four categories:
1,
2,
3,
4,

insulin-dependent diabetes
noninsulin-dependent diabetes
other
gestational diabetes mellitus

Type 1 Diabetes Mellitus

The hallmark of type 1 diabetes is selective beta
cell (B cell) destruction and severe or absolute
insulin deficiency.
-

Interruption of the insulin replacement

therapy can be life-threatening and can
result in diabetic ketoacidosis or death.

Diabetic ketoacidosis is caused by insufficient or

absent insulin and results from excess release of
fatty acids and subsequent formation of toxic
levels of ketoacids.
Type 2 Diabetes Mellitus

type
type
type
type

subdivided into immune and idiopathic

causes:

immune form is the most common form of type 1

diabetes.
Pharmacologic insulin is administered by injection
into the subcutaneous tissue using a manual
injection device or an insulin pump that
continuously infuses insulin under.

Type 2 diabetes is characterized by tissue

resistance to the action of insulin combined with a
relative deficiency in insulin secretion.
-

A given individual may have more

resistance or more beta-cell deficiency, and
the abnormalities may be mild or severe.

The impaired insulin action also affects fat

metabolism, resulting in increased free
fatty acid flux and triglyceride levels and
reciprocally low levels of high-density
lipoprotein (HDL).

Although persons with type 2 diabetes ordinarily

do not develop ketosis, ketoacidosis may occur as
the result of stress such as infection or the use of
medication
that
enhances
resistance,
eg,
corticosteroids.
Dehydration in individuals with untreated or poorly
controlled type 2 diabetes can lead to a lifethreatening
condition
called
nonketotic
hyperosmolar coma
Type 3 Diabetes Mellitus
The type 3 designation refers to multiple other
specific causes of an elevated blood glucose:
pancreatectomy, pancreatitis, nonpancreatic
diseases, drug therapy
Type 4 Diabetes Mellitus
Gestational diabetes (GDM) is defined as any
abnormality in glucose levels noted for the first
time during pregnancy.
Screening may be deferred in lower-risk women
until the 24th to 28th week of gestation.

INSULIN

Proinsulin, a long single-chain protein molecule, is

processed within the Golgi apparatus of beta cells
and packaged into granules, where it is hydrolyzed
into insulin and a residual connecting segment
called C-peptide by removal of four amino acids.
-

Granules within the beta cells store the

insulin in the form of crystals consisting of
two atoms of zinc and six molecules of
insulin.

Insulin Secretion
Insulin is released from pancreatic beta cells at a
low basal rate and at a much higher stimulated
rate in response to a variety of stimuli especially
glucose.
-

Stimulatory
drugs
are
sulfonylureas,
meglitinide and nateglinide, isoproterenol,
and acetylcholine.

Inhibitory signals are hormones, including

insulin itself and leptin, -adrenergic
sympathetic activity, chronically elevated
glucose, and low concentrations of fatty
acids.

Inhibitory
drugs
include
diazoxide,
phenytoin, vinblastine, and colchicine.

Insulin Degradation
The liver and kidney are the two main organs that
remove insulin from the circulation.
The
liver
normally
clears
the
blood
of
approximately 60% of the insulin released from the
pancreas by virtue of its location as the terminal
site of portal vein blood flow, with the kidney
removing 3540% of the endogenous hormone.
Circulating Insulin
Basal insulin values of 515 U/mL (3090 pmol/L)
are found in normal humans, with a peak rise to
6090 U/mL (360540 pmol/L) during meals.
The Insulin Receptor
The biologic responses promoted by these insulinreceptor complexes have been identified in the
primary target tissues, ie, liver, muscle, and
adipose tissue.
The first proteins to be phosphorylated by the
activated receptor tyrosine kinases are the docking
proteins, insulin receptor substrates (IRS).

Characteristics
Preparations

of

Available

Insulin

A. Principal Types and Duration of Action of

Insulin
Preparations
Four principal
available:

types

of

injected

insulins

are

(1) rapidacting, with very fast onset and short

duration
(2) short-acting, with rapid onset of action
(3) intermediate-acting; and (4) long-acting, with
slow onset of action
Injected rapidacting and short-acting insulins are
dispensed as clear solutions at neutral pH and
contain small amounts of zinc to improve their
stability and shelf life.
The goal of subcutaneous insulin therapy is to
replicate normal physiologic insulin secretion and
replace the background or basal (overnight,
fasting, and between-meal) as well as bolus or
prandial (mealtime) insulin.

Intensive regimens involving multiple daily

injections (MDI) use long-acting insulin analogs to
provide basal or background coverage, and rapidacting insulin analogs to meet the mealtime
requirements.

Rapid-acting insulin Three injected

rapid-acting insulin analogs insulin
lispro, insulin aspart , and insulin
glulisine are commercially available.

The rapid-acting insulins permit more

physiologic prandial insulin replacement
because their rapid onset

Their duration of action is rarely more than

45 hours, which decreases the risk of late
postmeal hypoglycemia.

Insulin lispro, the first monomeric insulin analog

to be marketed.
-

To enhance the shelf life of insulin in vials,

insulin lispro is stabilized into hexamers by
a cresol preservative.

When injected subcutaneously, the drug

quickly dissociates into monomers and is
rapidly absorbed with onset of action within
515 minutes and peak activity as early as
1 hour.

Insulin aspart is created by the substitution of

the B28 proline with a negatively charged aspartic
acid
-

it is more reproducible than regular insulin,

but it has binding properties, activity, and
mitogenicity characteristics similar to those
of regular insulin in addition to equivalent
immunogenicity.

Insulin glulisine is formulated by substituting a

lysine forasparagine at B3 and glutamic acid for
lysine at B29
-

After high-dose insulin glulisine interaction

with the insulin receptor, there may be
downstream differences in IRS-2 pathway
activation relative to human insulin.
Short-acting insulin Regular insulin is a
short-acting soluble crystalline zinc insulin
that is now made by recombinant DNA
techniques to produce a molecule identical
to that of human insulin.
Its effect appears within 30 minutes, peaks
between 2 and 3 hours after subcutaneous
injection, and generally lasts 58 hours.
Intermediate-acting
insulins

and

long-acting

a. NPH (neutral protamine Hagedorn, or

isophane) insulin

NPH insulin is an intermediate-acting insulin whose

absorption and onset of action are delayed by
combining appropriate amounts of insulin and
protamine so that neither is present in an
uncomplexed form (isophane).
The action of NPH is highly unpredictable, and its
variability of absorption is over 50%.
b. Insulin glargine Insulin glargine is a
soluble, peakless (ie, having a broad
plasma concentration plateau), long-acting
insulin analog.
c. c. Insulin detemir This insulin is the most
recently developed long-acting insulin
analog
- most
reproducible
effect
of
the
intermediate- and long-acting insulins,
- associated with less hypoglycemia than
NPH insulin.
- has a dose-dependent onset of action of 1
2 hours and duration of action of more than
12 hours BID.
4. Mixtures of insulins
- intermediate-acting NPH insulins require several
hours to reach adequate therapeutic levels their
use in diabetic patients usually requires
supplements or rapid- or short-acting insulin
before meals.
- often mixed together in the same syringe before
injection
- Insulin lispro, aspart, and glulisine can be acutely
mixed
with NPH insulin without affecting their rapid
absorption
- To remedy this, intermediate insulins
composed of isophane complexes of
protamine with insulin lispro and insulin
aspart have been developed.
- These intermediate insulins have been
designated as NPL (neutral protamine
lispro) and NPA (neutral protamine aspart)
and have the same duration of action as
NPH insulin.
B. Insulin Production
- Mass production of human insulin and insulin
analogs
C. Concentration
- All insulins in the USA and Canada are available
in a concentration of 100 U/mL (U100).
Insulin Delivery Systems
A. Standard Delivery
- subcutaneous injection
B. Portable Pen Injectors
- To facilitate multiple subcutaneous injections of
insulin, particularly during intensive insulin
therapy, portable pen-sized injectors
C. Continuous Subcutaneous Insulin Infusion
Devices
(CSII, Insulin Pumps)

Continuous subcutaneous insulin infusion

devices are external open-loop pumps for
insulin delivery
Boluses are used to correct high blood
glucose levels and to cover mealtime
insulin
requirements
based
on
the
carbohydrate content of the food and
concurrent activity.
dynamically
programmed
or
use
preprogrammed
algorithm;
the
user
calculates the dose based on the amount of
carbohydrate consumed and the current
blood glucose level

Insulin Regimens
A. Intensive Insulin Therapy
Generally,
the
total
daily
insulin
requirement in units is equal to the weight
in pounds divided by four, or 0.55 times the
persons weight in kilograms.
In intensive insulin regimens, the meal or
snack and high blood sugar correction
boluses are prescribed by formulas.
The patient uses the formulas to calculate
the rapid-acting insulin bolus dose by
considering how much carbohydrate is in
the meal or snack, the
current plasma glucose, and the
target glucose. The formula for the
meal or snack bolus is expressed as
an
insulin-to-carbohydrate
ratio,
which refers to how many grams of
carbohydrate will be
disposed of by 1 unit of rapid-acting
insulin.
high blood sugar correction formula is
expressed as the predicted fall in plasma
glucose (in mg/dL) after 1 unit of rapidacting insulin.
Continuous subcutaneous insulin infusion most sophisticated and physiologic insulin
replacement.
B. Conventional Insulin Therapy
usually prescribed only type 2 diabetes who
are
felt not to benefit from intensive
glucose control.
one injection/day to many injections per
day, using intermediate- or long-acting
insulin alone or with short- or rapid-acting
insulin or premixed insulins.
Insulin Treatment of Special Circumstances
A. Diabetic Ketoacidosis
life-threatening medical emergency caused
by
inadequate
or
absent
insulin
replacement, occurs in people with type 1
diabetes
The fundamental treatment for DKA
includes aggressive intravenous hydration
and insulin therapy and maintenance of
potassium and other electrolyte levels
Close attention has to be given to hydration
and renal status, the sodium and potassium

levels, and the rate of correction of plasma

glucose and plasma osmolality.
Fluid therapy generally begins with normal
saline. Regular human insulin should be
used for intravenous therapy with a usual
starting dose of about 0.1 IU/kg/h.

B. Hyperosmolar Hyperglycemic Syndrome

is diagnosed in persons with type 2
diabetes and is characterized by profound
hyperglycemia and dehydration.

associated with inadequate oral hydration,

especially in elderly patients, with other
illnesses, the use of medication that
elevates the blood sugar or causes
dehydration, such as phenytoin, steroids,
diuretics, and blockers, and with
peritoneal dialysis and hemodialysis. The
diagnostic hallmarks are declining mental
status and even seizures, a plasma glucose
of over 600 mg/dL, and a calculated serum
osmolality higher than 320 mmol/L.

Persons with HHS are not acidotic unless

DKA is also present.
Complications of Insulin Therapy
A. Hypoglycemia
1. Mechanisms and diagnosis
most common complication of insulin
therapy.
2. Treatment of hypoglycemia
All the manifestations of hypoglycemia are
relieved by glucose administration
If more severe hypoglycemia has produced
unconsciousness or stupor, the treatment
of choice is to give 2050 mL of 50%
glucose solution by IV infusion over a period
of 23 minutes
If intravenous therapy is not available, 1
mg of glucagon injected either SQ or IM
may restore consciousness within 15
minutes to permit ingestion of sugar.

If the patient is stuporous and glucagon is

not available, small amounts of honey or
syrup can be inserted into the buccal pouch
B. Immunopathology of Insulin Therapy
1. Insulin allergyanaphylaxis results
2. Immune insulin resistance
- A low titer of circulating IgG anti-insulin
antibodies that neutralize the action of
insulin to a negligible extent develops in
most insulin-treated patients.
- Rarely, the titer of insulin antibodies leads
to insulin resistance and maybe associated
with other systemic autoimmune processes
such as lupus erythematosus.
C. Lipodystrophy at Injection Sites
- Hypertrophy of subcutaneous fatty tissue
remains a problem if injected repeatedly at
the same site.
D. Increased Cancer Risk

An increased risk of cancer attributed to

insulin resistance , hyperinsulinemia has
been reported in individuals with insulin
resistance, prediabetes, and type 2
diabetes.
Treatment
with
insulin
and
sulfonylureas, which increase circulating
insulin levels, but not metformin possibly
exacerbates that risk.

ORAL ANTIDIABETIC AGENTS

Binding of a sulfonylurea inhibits the efflux

of potassium ions through the channel and
results in depolarization.

Depolarization opens a voltage-gated

calcium channel and results in calcium
influx and the release of preformed insulin.

B. Reduction of Serum Glucagon

Concentrations
-

Long-term administration of sulfonylureas

to type 2 diabetics reduces serum glucagon
levels, which may contribute to the
hypoglycemic effect of the drugs.

involve indirect inhibition due to enhanced

release of both insulin and somatostatin,
which inhibit alpha-cell secretion.

oral antidiabetic agents are now available in

the USA for the treatment of persons with type 2
diabetes:

insulin secretagogues (sulfonylureas,

meglitinides, D-phenylalanine
derivatives),biguanides, thiazolidinediones,
-glucosidaseinhibitors, incretin-based
therapies, an amylin analog, and a bile
acidbinding sequestrant.
The sulfonylureas and biguanides have
been available the longest and are the
traditional treatment choice for type 2
diabetes.
Novel classes of rapid-acting insulin
secretagogues, the meglitinides and Dphenylalanine derivatives, are
alternatives to the short-acting
sulfonylureas

Insulin secretagogues increase insulin

secretion from beta cells.
The amylin analog also decreases postmeal glucose levels and reduces appetite.
Alpha-glucosidase inhibitors slow the
digestion and absorption of starch and
disaccharides.

INSULIN SECRETAGOGUES:
SULFONYLUREAS
Mechanism of Action
The major action of sulfonylureas is to increase
insulin release from the pancreas
Two additional mechanisms of action have been
proposed:
-

a reduction of serum glucagon levels

closure of potassium channels in
extrapancreatic tissue

FIRST-GENERATION
SULFONYLUREAS
Tolbutamide is well absorbed but rapidly
metabolized in the liver. Its duration of effect is
relatively short, with an elimination half-life of 45
hours
-

Chlorpropamide has a half-life of 32 hours and is

slowly metabolized in the liver to products that
retain some biologic activity.
-

Sulfonylureas bind to a 140-kDa highaffinity sulfonylurea receptor

Dosages higher than 500 mg daily increase

the risk of jaundice.

Tolazamide is comparable to chlorpropamide in

potency but has a shorter duration of action
-

Tolazamide is more slowly absorbed than

the other sulfonylureas, and its effect on
blood glucose does not appear for several
hours.

SECOND-GENERATION
SULFONYLUREAS
The second-generation sulfonylureas are
prescribed more frequently in the USA than are the
first-generation agents because they have fewer
adverse effects and drug interactions.
Glyburide is metabolized in the liver into products
with very low hypoglycemic activity
-

Glyburide is contraindicated in the presence

of hepatic impairment and in patients with
renal insufficiency

the FDA recommends careful monitoring to

re-titrate dosage when switching from

A. Insulin Release from Pancreatic Beta

Cells
-

it is the safest sulfonylurea for elderly

diabetics.

standard glyburide doses or from other

sulfonylurea drugs.
Glipizide has the shortest half-life (24 hours) of
the more potent agents
-

this agent should be ingested 30 minutes

before breakfast because absorption is
delayed when the drug is taken with food.

Glimepiride is approved for once-daily use as

monotherapy or in combination with insulin.

INSULIN SECRETAGOGUE:
MEGLITINIDE
Repaglinide is the first member of the meglitinide
group of insulin secretagogues
-

These drugs modulate betacell insulin

release by regulating potassium efflux
through the potassium channels

Repaglinide is indicated for use in

controlling postprandial glucose excursions

Repaglinide is approved as monotherapy or

in combination with biguanides.
There is no sulfur in its structure, so
repaglinide may be used in type 2 diabetics
with sulfur or sulfonylurea allergy.

reduce hepatic glucose production through

activation of the enzyme AMP-activated protein
kinase (AMPK).
-

impairment of renal gluconeogenesis

slowing of glucose absorption from the
gastrointestinal tract, with increased
glucose to lactate conversion by
enterocytes
direct stimulation of glycolysis in tissues
increased glucose removal from blood, and
reduction of plasma glucagon levels.

As a consequence of metformins blockade of

gluconeogenesis, the drug may impair the hepatic
metabolism of lactic acid.

Clinical Use
recommended as first-line therapy for type 2
diabetes.
The UKPDS reported that metformin therapy
decreases the risk of macrovascular as well as
microvascular disease
-

Biguanides are also indicated for use in

combination with insulin secretagogues or
thiazolidinediones in type 2 diabetics in
whom oral monotherapy is inadequate.
The dosage of metformin is from 500 mg to a
maximum of 2.55 g daily, with the lowest effective
dose being recommended.

INSULIN SECRETAGOGUE:
D-PHENYLALANINE
DERIVATIVE

The most common toxic effects of metformin are

gastrointestinal (anorexia, nausea, vomiting,
abdominal discomfort, and diarrhea), which occur
in up to 20% of patients

Nateglinide, a D-phenylalanine derivative, is the

latest insulin secretagogue to become clinically
available

THIAZOLIDINEDIONES

Nateglinide stimulates very rapid and transient

release of insulin from beta cells through closure of
the ATP-sensitive K + channel.
It also partially restores initial insulin release in
response to an intravenous glucose tolerance
test. This may be a significant advantage of the
drug because type 2 diabetes is associated with
loss of this initial insulin response.

BIGUANIDES
The structure of metformin
Phenformin (an older biguanide) was discontinued
in the USA because of its association with lactic
acidosis

Mechanisms of Action

Thiazolidinediones (Tzds) act to decrease insulin

resistance. Tzds are ligands of peroxisome
proliferator-activated receptor gamma
(PPAR-f), part of the steroid and thyroid
superfamily of nuclear receptors.
The Tzd oncogenic effects are complex and may
be both tumorigenic and antitumorigenic.
a major site of Tzd action is adipose tissue, where
the drug promotes glucose uptake and utilization
and modulates synthesis of lipid hormones or
cytokines and other proteins involved in energy
regulation
Two thiazolidinediones are currently available:
pioglitazone and rosiglitazone
Pioglitazone has PPAR- as well as PPAR-gamma
activity. It is absorbed within 2 hours of ingestion
-

Pioglitazone is metabolized by CYP2C8 and

CYP3A4 to active metabolites.

Pioglitazone is approved as a monotherapy and in

combination with metformin, sulfonylureas, and
insulin for the treatment of type 2 diabetes.
Rosiglitazone is rapidly absorbed and highly
protein-bound.
-

It is metabolized in the liver to minimally

active metabolites, predominantly by
CYP2C8 and to a lesser extent by CYP2C9.
For those restricted populations,
rosiglitazone is approved for use in type 2
diabetes as monotherapy, in double
combination therapy with a biguanide or
sulfonylurea, or in quadruple combination
with a biguanide, sulfonylurea, and insulin.
An adverse effect common to both Tzds is
fluid retention, which presents as a mild
anemia and peripheral edema, especially
when the drugs are used in combination
with insulin or insulin secretagogues

ALPHA-GLUCOSIDASE
INHIBITORS

AMYLIN ANALOG
Pramlintide , a synthetic analog of amylin, is an
injectable antihyperglycemic agent that modulates
postprandial glucose levels and is approved for
preprandial use in persons with type 1 and type 2
diabetes.
Pramlintide suppresses glucagon release via
undetermined mechanisms, delays gastric
emptying, and has central nervous
systemmediated anorectic effect

GLUCAGON-LIKE
POLYPEPTIDE-1 (GLP-1)
RECEPTOR AGONISTS
In type 2 diabetes, the release of glucagon-like
polypeptide is diminished postprandially, which
leads to inadequate glucagon suppression and
excessive hepatic glucose output.
Two synthetic analogs of glucagon-like
polypeptide, exenatide and liraglutide
to help restore GLP-1 activity

Acarbose and miglitol are competitive inhibitors

of the intestinal -glucosidases and reduce
postmeal glucose excursions by delaying the
digestion and absorption of starch and
disaccharides

Exenatide , a derivative of the exendin-4 peptide

in Gila monster venom, was the first incretin
therapy to become available for thetreatment of
diabetes.

Miglitol differs structurally from acarbose and is six

times more potent in inhibiting sucrose

Liraglutide is a long-acting synthetic GLP-1

analog with 97% homology to native GLP-1 but has
a prolonged half-life that permits once-daily dosing

Although the binding affinity of the two compounds

differs, acarbose and miglitol both target the glucosidases: sucrase, maltase, glucoamylase, and
dextranase.
The STOP-NIDDM trial demonstrated that glucosidase
therapy in prediabetic persons successfully
prevented a significant number of new cases of
type 2 diabetes.

BILE ACID SEQUESTRANTS

Initially developed as a bile acid sequestrant and
cholesterol-lowering drug.
Colesevelam hydrochloride is now approved as
an antihyperglycemic therapy for persons with
type 2 diabetes who are taking other medications
or have not achieved adequate control with diet
and exercise.
In clinical trials, it lowered the hemoglobin A
(HbA 1c ) concentration about 0.5%, and LDL
cholesterol by 15% or more.

1c

It is not recommended as a first-line therapy or for

use with insulin.

develops. Because rodents exposed to liraglutide

developed thyroid C-cell tumors, there is an FDA
mandated black box warning that
liraglutide is contraindicated in individuals with a
personal or family history of medullary cancer or
multiple endocrine neoplasia type 2.

DIPEPTIDYL PEPTIDASE-4
(DPP-4) INHIBITORS
Sitagliptin, saxagliptin, and linagliptin are
inhibitors of DPP-4, the enzyme that degrades
incretin hormones.
These drugs increase circulating levels of native
GLP-1 and glucose-dependent insulinotropic
polypeptide (GIP)
which ultimately decreases postprandial glucose
excursions by increasing glucose-mediated insulin
secretion and decreasing glucagon levels.

Sitagliptin has an oral bioavailability of over 85%,

achieves peak concentrations within 14 hours,
and has a half-life of approximately 12 hours
-

Common adverse effects include

nasopharyngitis, upper respiratory
infections, headaches, and hypoglycemia
when the drug is combined with insulin
secretagogues or insulin.

Saxagliptin is given orally as 2.55 mg daily. The

drug reaches maximal concentrations within 2
hours (4 hours for its active metabolite)
Linagliptin is the most recently introduced drug
in this class and appears to have properties similar
to sitagliptin and saxagliptin. It is approved for use
as monotherapy and in combination with
metformin, glimepiride, and pioglitazone.

COMBINATION THERAPY
ORAL
ANTIDIABETIC AGENTS &
INJECTABLE MEDICATION
Combination Therapy in Type 2
Diabetes
Mellitus
The second-line drug can be an insulin
secretagogue,
Tzd, incretin-based therapy, amylin analog, or a
glucosidase inhibitor
- preference is given to sulfonylureas or
insulin because of cost, adverse effects,
and safety concerns.
Third-line therapy can include metformin, multiple
other oral medications, or a noninsulin injectable
and metformin and intensified insulin therapy.
Recommended fourth-line therapy is intensified
insulin management with or without metformin or
Tzd.
A. Combination Therapy with GLP-1 Receptor
Agonists
Exenatide and liraglutide are approved for use in
individuals who fail to achieve desired glycemic
control on metformin, sulfonylureas, metformin
plus sulfonylureas, or (for liraglutide) metformin
plus sulfonylureas and Tzds.
B. Combination Therapy with DPP-4
Inhibitors
Sitagliptin, saxagliptin, and linagliptin are
approved for use in individuals who fail to achieve
desired glycemic control on metformin,
sulfonylureas, or Tzds.
C. Combination Therapy with Pramlintide
Pramlintide is approved for concurrent mealtime
administration in individuals with type 2 diabetes
treated with insulin, metformin, or a sulfonylurea

who are unable to achieve their postprandial

glucose targets.
D. Combination Therapy with Insulin
Bedtime insulin has been suggested as an adjunct
to oral antidiabetic therapy in patients with type 2
diabetes who have not responded to maximal oral
therapy.

Combination Therapy in Type 1

Diabetes
Mellitus
Insulin secretagogues (sulfonylureas, meglitinides,
or D-phenylalanine derivatives), Tzds, metformin,
-glucosidase inhibitors, GLP-1 receptor agonists,
DPP-4 inhibitors, or bile acid sequestrants are not
approved for use in type 1 diabetes.
Combination Therapy with Pramlintide
Pramlintide is approved for concurrent mealtime
administration in individuals with type 1 diabetes
who have poor glucose control after eating despite
optimal insulin therapy

GLUCAGON
Glucagon is synthesized in the alpha cells of the
pancreatic islets of Langerhans
One of the precursor intermediates consists of a
69-aminoacid peptide called glicentin, which
contains the glucagon sequence interposed
between peptide extensions

Gut Glucagon
Glicentin immunoreactivity has been found in cells
of the small intestine as well as in pancreatic alpha
cells and in effluents of perfused pancreas.
The intestinal cells secrete enteroglucagon, a
family of glucagon-like peptides, of which glicentin
is a member, with glucagon-like peptides 1 and 2
(GLP-1 and GLP-2).

Glucagon-like Peptide 1 (GLP-1)

A derivative of the 37-amino-acid form of GLP-1
that lacks the first six amino acids (GLP-1[737]) is
a potent stimulant of insulin synthesis and release
and beta-cell mass.
-

it inhibits glucagon secretion, slows gastric

emptying, and has an anorectic effect

GLP-1 represents the predominant form of

GLP in the human intestine and has been
termed insulinotropin .

Pharmacologic Effects of Glucagon

B.Metabolic Effects
This leads to an increase in cAMP, which facilitates
catabolism of stored glycogen and increases
gluconeogenesis and ketogenesis.
B. Cardiac Effects
Glucagon has a potent inotropic and chronotropic
effect on the heart, mediated by the cAMP
mechanism described above
C. Effects on Smooth Muscle
Large doses of glucagon produce profound
relaxation of the intestine. In contrast to the above
effects of the peptide, this action on the intestine
may be due to mechanisms other than adenylyl
cyclase activation

Clinical Uses

A. Severe Hypoglycemia
The major use of glucagon is for emergency
treatment of severe hypoglycemic reactions in
patients with type 1 diabetes when
unconsciousness precludes oral feedings and
intravenous glucose reatment is not possible.

ISLET AMYLOID
POLYPEPTIDE IAPP, AMYLIN
The physiologic effect of amylin may be to
modulate insulin release by acting as a negative
feedback on insulin secretion.
Amylin reduces glucagon secretion, slows gastric
emptying by a vagally medicated mechanism, and
centrally decreases appetite.
An analog of amylin, pramlintide (see previous
section), differs from amylin by the substitution of
proline at positions 25, 28, and 29