Pancreatic Hormones and Antidiabetic Drugs

Subclass, Drug Mechanism of Action Effects Clinical Applications P, T, I

Insulin Analogs: Activate insulin receptor Reduce circulating glucose Type 1 and type 2 DM Hypoglycemia, weight gain,
Rapid-acting insulin: Can be taken immediately Allow insulin to be taken Preferred insulin for use in lipodystrophy
before meal immediately before meal continuous subcutaneous
Insulin Lispro Lowest variability of without sacrificing glucose insulin infusion devices
(Humalog), absorption control

Insulin Aspart
(Novolog),
Insulin Glulisine
(Apidra)
Short-acting insulin: Activates insulin receptor Reduces circulating glucose Type 1 and type 2 DM Same
Available as U100 and U500 Injected 30-45 minutes or IV tx for diabetic ketoacidosis
both SC and IV more before meals Management for rapidly
Regular Insulin Soluble crystalline zinc insulin changing insulin
requirements
Intermediate-acting insulin: Activate insulin receptor Reduce circulating glucose Type 1 and type 2 DM Same
Mixture of 30% semilente
Lente Insulin, with 70% ultralente insulin
Neutral Protamine (lente insulin)
Provides a combination of
Hagedorn (NPH), relatively rapid absorption
Isophane Insulin with sustained long action
(lente insulin)
Long-acting insulin: Activates insulin receptor Reduces circulating glucose Type 1 and type 2 DM Same
Soluble peakless insulin
analog
Insulin Glargine Designed to provide
reproducible, convenient
Activates insulin receptor Type 1 and type 2 DM Same
Most recently developed
Insulin Detemir long-acting insulin analog
Associated with less

1
 hypoglycemia than NPH
solution
Ultra long-acting basal insulin Additional of hexadecanoic Type 1 and type 2 DM Same
analog acid allows the formation of Improves HbA1C
Insulin Degludec Active at a physiologic Ph SC depot that results in the
slow insulin release into the
systemic circulation
Oral Antidiabetic Older sulfonylureas, lower Increase insulin secretion Type 2 DM Skin rash, hypoglycemia,
Agents: potency, greater toxicity from beta cells weight gain
Rarely used (sulfonylureas, meglitinides,
Insulin Secretagogues: d-phenylalanine)
Sulfonylureas: Promotes insulin release for
st
1 generation: pancreatic beta cells
Serum glucagon
concentration reduction
Tolbutamide Possible potentiation of
insulin action at target
tissues
Same Same Hyperemic flush, jaundice,
Chlorpropramide hypoglycemia, transient
(Diabinese) leukopenia,
thrombocytopenia
Same Same Hypoglycemia
Tolazamide
(Tolinase)
Same Same
Acetohexamide
nd
2 generation: Insulin secretagogues: close Reduce circulating glucose in Type 2 DM Hypoglycemia, weight gain,
potassium channels in beta patients with functioning flushing
Glyburide cells beta cells (all)
Increase insulin release (all)
Hypoglycemia
Glipizide
rd
3 generation: Approved for once-daily use Type 2 DM Hypoglycemia
as monotherapy or in
Glimepiride combination with insulin
Not available
Gliclazide
Meglitinides:

2
 Similar to sulfonylureas with
Repaglinide some overlap in binding sites
First member of the
meglitinide group of insulin
secretagogues
CYP3A4
A benzylsucrinic acid
derivative that binds to the
Mitiglinide sulfonylurea receptor and is
similar to repaglinide in its
clinical effects
D-Phenylalanine Stimulates very rapid and
Derivative: transient release of insulin
from beta cells through the
Nateglinide closure of ATP-sensitive
potassium channel
Biguanide: Activates AMP kinase
Reduces hepatic and renal
gluconeogenesis
Metformin Fist line therapy for type 2
diabetes
Refractory obesity
Thiazolidinediones Regulates gene expression by
(Tzds): binding to PPAR-y and PPAR-
a tissue
Increases the sensitivity of
muscle, fat, and liver to
Pioglitazone endogenous and exogenous
insulin
Excessive number of heart
attack and congestive heart
Rosiglitazone failure
Worsening of CV risk
Alpha-Glucosidase
Inhibitors:
In patients with functioning
beta cells, reduce circulating
glucose
May be used in type 2 DM
with sulfur or sulfonylureas
allergy
Safe in those with reduced
renal function
Decreases circulating glucose
Reduces hepatic glucose
production through
activation of the enzyme
AMP-activated protein kinase
(AMPK)
Reduces insulin resistance
Major site of action: adipose
Reduces insulin resistance
Type 2 DM
Controlling postprandial
glucose excursions
Type 2 DM
Slowing of glucose
absorption from the GIT with
increased glucose to lactate
conversion by enterocytes
Reduction of plasma
glucagon levels
Type 2 DM
Type 2 DM
Hypoglycemia
Hypoglycemia
GIT symptoms, decreases
B12, lactic acidosis
*Lowers risk of
macrovascular and
microvascular disease
*Decreases risk of cancers
Fluid retention, edema,
anemia, weight gain, macular
edema, bone fractures in
women, hypoglycemia in
combination
Slight increase in HDL and
LDL
3
 Inhibit intestinal alpha-
Voglibose, glucosidases
Acarbose, Reduce the postprandial
digestion and absorption of
Miglitol starch and disaccharides
Bile Acid Sequestrant: Bile acid binder: lowers
glucose through unknown
mechanisms
Colesevelam Antihyperglycemic therapy
for persons with type 2 DM
Hydrochloride who are taking other
medications
Islet Amyloid Analog of amylin: binds to
Polypeptide Analog: amylin receptors
Suppresses glucagon release,
delays gastric emptying and
has CNS-mediated anorectic
Pramlintide effects
The Incretin Agents: Analog of GLP-1: binds to
GLP-1 Receptor GLP-1 receptors
A derivative of the exendin-4
Agonists: peptide in Gila monster
Synthetic: venom
Exenatide
A soluble fatty acid-acylated
GLP-1 analog
Liraglutide Long-acting
Once daily dosing
A human GLP-1 dimer fused
Albiglutide to human albumin
Consists of 2 GLP-1 analog
molecules covalently linked
Dulaglutide to an Fc fragment of human
IgG4
DPP-4 Antagonists:
Reduce conversion of starch
and disaccharides to
monosaccharides
Reduce postprandial
hyperglycemia
Reduces glucose levels
Related to deceasing hepatic
glucose output
Reduces post-meal glucose
excursions: lowers glucagon
levels, slows gastric
emptying, decreases appetite
Reduces post-meal glucose
excursions: increases
glucose-mediated insulin
release, lowers glucagon
levels, slows gastric
emptying, decreases appetite
(all)
Increase insulin and decrease
glucagon release
st
Not recommended as 1 line
therapy
Type 2 DM GIT symptoms, flatulence,
diarrhea, abdominal pain
Type 2 DM Constipation, indigestion,
Lowers LDL flatulence, impairs
Reduces HbA1c in type 2 DM absorption of fat-soluble
Increases GLP-1 secretion vitamins
Type 1 and type 2 DM Nausea, anorexia,
Modulates postprandial hypoglycemia, headache,
glucose levels type 2 and vomiting
type 2 DM
Type 2 DM Necrotizing and hemorrhagic
Injectable, adjunctive pancreatitis (serious adverse
therapy in type 2 DM with effects) nausea, headache,
metformin or metformin + vomiting, anorexia, mild
sulfonylureas weight loss, c-cell tumors in
rodents
Type 2 DM Same
Type 2 DM Same
Type 2 DM Same
4
 Given orally as 100 mg once Reduce post-meal glucose Type 2 DM Rhinitis, URTI, headaches,
daily excursions: increase glucose- Adjunctive therapy to diet pancreatitis, rare allergic
Sitagliptin Blocks degradation of GLP-1, mediated insulin release and exercise in type 2 reactions
raises circulating GLP-1 levels diabetic individuals who have
(all) failed to achieve glycemic
goals
Given orally as 2.5-5mg daily Same Type 2 DM Same
Saxagliptin
Lowers HbA1c by 0.4-0.6% Same Type 2 DM Same
when added to metformin,
Linagliptin sulfonylurea, or pioglitazone
Lowers HbA1c by 0.5-1% Same Type 2 DM Same
when added to the
Vildagliptin therapeutic regimen of
patients with type 2 DM
Not available
Sodium Glucose Blocks renal glucoe Increases glycosuria, lowers Type 2 DM Genital and urinary tract
Transport (SGLT2) resorption (all) plasma glucose levels (all) infections, polyuria, pruritus,
Reduces the threshold for Advantages: low risk of thirst, osmotic diuresis,
Inhibitors: glycosuria from plasma hypoglycemia, increase constipation
Canagliflozin glucose threshold of weight loss, reduction in BP
approximately 180 mg/Dl
Reduces HbA1c by 0.5-0.8% Type 2 DM Same
when used alone or in *Vaginal candidiasis, weight
Dapagliflozin combination with other oral loss = good adverse effect
agents or insulin
Reduces HbA1c by 0.5-0.7% Type 2 DM Same
when used alone or in
Empagliflozin combination with other oral
agents or insulin
Type 2 DM Same
Sergliflozin
Type 2 DM Same
Remogliflozin
Others: A key enzyme in glucose-
sensing tissues that regulates
glucose hemostasis
GKAs Rate-limiting enzyme in

5
 glucose stimulated insulin
release
Blockade of the effect of Low hypoglycemic potential
Glucagon glucagon in the liver to
Receptor stimulate hepatic glucose
production
Antagonists
Affects appetite regulation
Cannabinoid-1 Reduces lipogenesis and
Receptor improves insulin sensitivity
Not approved because of
Antagonists potential for suicide
Dopamine agonist, in placebo Improves glucose tolerance
randomized controlled and insulin resistance
Bromocriptine studies lowered HbA1c by 0- Patient with type 2 DM
0.2% compared with baseline should take the drug within 2
and by 0.4-0.5% compared to hours of waking in the
placebo morning
Synthesized in the alpha cells (+) inotropic and Transient nausea/vomiting
Glucagon of pancreatic islets of chronotropic
Langerhans