Anti-Diabetic Drugs

Diabetes Mellitus
The incidence of diabetes is increasing at
an alarming rate in the US.
 Pancreatic
axis
Insulin
cells secrete due
to high blood
glucose levels
Glucose uptake
into tissues
increases
Glucagon
cells secrete
when blood
glucose is low
Glucose is
 Glucose homeostasis
Body
cells
Insulin take up more
glucose

Beta cells
of pancreas stimulated
to release insulin into
the blood Liver takes Blood glucose level
up glucose declines to a set point;
High blood and stores it as stimulus for insulin
glucose level glycogen release diminishes

STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal) Homeostasis: Normal blood glucose level
(about 90 mg/100 mL) STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)

Blood glucose level

rises to set point; Alpha
stimulus for glucagon cells of
release diminishes pancreas stimulated
to release glucagon
into the blood
Liver
breaks down
glycogen and Glucagon
releases glucose
Figure 26.8 to the blood
 Normal
Insulin

Glycerol
Lipolysis

Free fatty acids

Triglyceride
Synthesis
Free fatty acids

LPL Glucose

Insulin
Normal Glucose Control
In the post-absorptive period of a normal individual,
low basal levels of circulating insulin are
maintained through constant cell secretion. This
suppresses lipolysis, proteolysis and glycogenolysis.
After ingesting a meal a burst of insulin secretion
occurs in response to elevated glucose and amino
acid levels. When glucose levels return to basal
levels, insulin secretion returns to its basal level.
Type I DM: Lack of functional -cells prevents
mitigation of elevated glucose levels and
associated insulin responses. The onset and
progression of neuropathy, nephropathy and
retinopathy are directly related to episodic
hyperglycemia.
Type II DM: The pancreas retains some -cell
function but effective insulin response is
inadequate for the glucose level. Actual insulin
levels may be normal or supra-normal but it is
ineffective (insulin resistance).
Diabetes mellitus
Type I
Childhood diabetes
Loss of pancreatic cells
Decreased insulin
Type II
Adult diabetes
Defective signal reception in insulin pathway
Decreased insulin
Both cause hyperglycemia, glycosuria,
lipid breakdown because tissues are
deficient in glucose, ketone bodies
 Diabetes Mellitus
This is a disease caused by elevated glucose levels
2 Types of diabetes:
Type I diabetes (10% of cases)
Develops suddenly, usually before age 15.
Caused by inadequate production of insulin because T
cell-mediated autoimmune response destroys beta cells.
Controlled by insulin injections.
Type II diabetes (90% of cases)
Usually occurs after age 40 and in obese individuals, but
genetics, aging, and peripheral insulin resistance also.
Insulin levels are normal or elevated but there is either a
decrease in number of insulin receptors or the cells
cannot take it up.
Controlled by dietary changes and regular exercise.
 Type 1 Diabetes Mellitus

Glycerol
Lipolysis

Free fatty acids

Triglyceride
Synthesis

Free fatty acids

LPL Glucose
 Type 2 Diabetes: Pathophysiology

Exxagerated lipolysis

e I
co s G
Glu I
Cell G I
Dysfunction Insulin G

I
G
Pancreas I G
G
I
I G
G
I Decreased
G
I
G

Increase Glucose
d Uptake
splanchni
c glc
output Insulin Resistance
 FOOD

Storage In Fat Depots

Inhibition of Lipolysis
e I
co s G
Glu I
Insulin G I
Secretion Insulin G

I
G
Pancreas I G
G
I
I G
G
Restrain I
of HGO G Uptake of
I
G

glucose

Insulin Effects
Insulin and Oral
Hypoglycemics
The peptide hormones directly involved in responding to and
controlling blood glucose levels are located in the islets of
Langerhans in the pancreas; insulin is secreted by -cells
and glucagon by 2 cells. Diabetes is a disorder of
inadequate insulin activity it is associated with episodes of
both hyper- and hypo-glycemia. It is the episodes of
hyperglycemia that are associated with long-term
complications.
Long term complications
 Diabetes is a
heterogeneous
group of syndromes
characterized by the
elevation of glucose
levels due to a
relative or absolute
deficiency of insulin;
frequently
inadequate insulin
release is
complicated by
excess glucagon
release.
The long term complications of diabetes
may be divided into two large groups:
1. Macrovascular: These complications are
associated with pathology of the large and
medium-sized vessels; this includes CHD,
stroke, PVD
2. Microvascular: These complications are
due to vascular pathology of the small
vessels and include neuropathy,
nephropathy, retinopathy
Treatment:
Type I: Type 1s depend on exogenous insulin to
prevent hyperglycemia and avoid ketoacidosis.
The goal of type 1 therapy is to mimic both the
basal and reactive secretion of insulin in response
to glucose levels avoiding both hyper- and hypo-
glycemic episodes.
Type II: The goal of treatment is to maintain
glucose concentrations within normal limits to
prevent long term complications. Weight
reduction, exercise (independent of weight
reduction) and dietary modification decrease
insulin resistance and are essential steps in a
treatment regimen. For many this is inadequate
to normalize glucose levels, the addition of
hypoglycemic agents is often required, often
insulin therapy is required.
Insulin secretion:
Insulin secretion is regulated by glucose levels,
certain amino acids, hormones and autonomic
mediators.
Secretion is most commonly elicited by elevated
glucose levels; increased glucose levels in -cells
results in increased ATP levels, this results in a
block of K+ channels causing membrane
depolarization which opens Ca2+ channels.
The influx of Ca2+ results in a pulsatile secretion
of insulin; continued Ca2+ influx results in
activation of transcription factors for insulin.
Oral glucose elicits more insulin secretion than IV
glucose; oral administration elicits gut hormones
which augment the insulin response.
Insulin is normally catabolized by insulinase
produced by the kidney.
Mechanism of Insulin Release in the
Pancreas
INSULIN

Insulin is a peptide hormone synthesized

as a precursor (pro-insulin) which
undergoes proteolytic cleavage to form a
dipeptide; the cleaved polypeptide
remnant is termed protein C.
Both are secreted from the -cell, normal
individuals secrete both insulin and (but
much less) pro-insulin.
Type 2s are found to secrete high levels of
pro-insulin (pro-insulin is inactive)
measuring the level of C-protein is a more
accurate estimation of normal insulin
secretion in type 2s.
Insulin
Human insulin consists of
51 aa in two chains
connected by 2 disulfide
bridges (a single gene
product cleaved into 2
chains during post-
translational modification).
T1/2 ~5-10 minutes,
degraded by glutathione-
insulin transhydrogenase
(insulinase) which cleaves
the disulfide links.
Bovine insulin differs by 3
aas, pork insulin differs by
1 aa.
Insulin is stored in a
complex with Zn2+ ions.
The synthesis and release of
insulin is modulated by:
1. Glucose (most
important), AAs, FAs
and ketone bodies
stimulate release.
2. Glucagon and
somatostation inhibit
relases
3. -Adrenergic
stimulation inhibits
release (most
important).
4. -Adrenergic
stimulation promotes
Insulin secretion - Insulin secretion in beta cells
release. is triggered by rising blood glucose levels.
5. Elevated intracellular Starting with the uptake of glucose by the GLUT2
Ca2+ promotes transporter, the glycolytic phosphorylation of
release. glucose causes a rise in the ATP:ADP ratio. This
rise inactivates the potassium channel that
depolarizes the membrane, causing the calcium
channel to open up allowing calcium ions to flow
inward. The ensuing rise in levels of calcium
 Mechanism of Insulin Action
Insulin binds to specific
high affinity membrane
receptors with tyrosine
kinase activity
Phosphorylation cascade
results in translocation of
Glut-4 (and some Glut-1)
transport proteins into the
plasma membrane.
It induces the transcription
of several genes resulting
in increased glucose
catabolism and inhibits the
transcription of genes
involved in
gluconeogenesis.
Insulin promotes the
uptake of K+ into cells.
The Goal of Insulin Therapy
Administration of insulins are arranged to mimic the
normal basal, prandial and post-prandial secretion of
insulin. Short acting forms are usually combined
with longer acting preparations to achieve this effect.
Rapid Onset and Ultrashort-acting
Preparations
1. Regular insulin: short acting, soluble, crystalline zinc insulin is
usually given subcutaneously; it rapidly lowers glucose levels. All
regular insulin is now made using genetically engineered bacteria;
cow and pig no longer used.
2. Lispro, Aspart & Glulisine preparations are classified as ultrashort
acting forms with onset more rapid than regular insulin and a
shorter duration. These are less often associated with
hypoglycemia. Lispro insulin is given 15 minutes prior to a meal
and has its peak effect 30-90 minutes after injection (vs. 50-120
minutes for regular insulin).
3. Glulisine can be given anywhere from 15 minutes prior to 20
minutes after beginning a meal.
 Intermediate acting Insulin
Preparations
1. Lente insulin: This is a
amorphous precipitate of
insulin with zinc ion
combined with 70%
ultralente insulin. Onset is
slower but more sustained
than regular insulin. It
cannot be given IV ( this
has not been produced
since 2005).
2. Isophane NPH insulin:
Neutral protamine
Hagedorn insulin is a
suspension of crystalline
zinc insulin combined with
protamine (a polypeptide).
The conjugation with
protamine delays its onset
of action and prolongs it
effectiveness. It is usually
given in combination with
Prolonged-acting insulin
preparations
1.Ultralente: a Pump vs. Standard Insulin
suspension of zinc Therapy
insulin forming large
particles which
dissolve slowly,
delaying onset and
prolonging duration
of action.
2.Insulin glargine:
Precipitation at the
injection site
extends the duration
of action of this
preparation.
3. Detemir insulin: has
a FA complexed with
insulin resulting in
slow dissolution.
 Insulin Preparations and Treatment
Various types of insulin are characterized
by their onset and duration of action
Insulin
Combinations
Various premixed
combinations of
various preparations
of insulin are
available to ease
administration.
Standard combination
use should follow
establishment of an
acceptable regime of
individual
preparations.
Action of Insulin on Various Tissues

Liver Muscle Adipose

glucose production Glucose transport glucose transport

glycolysis glycolysis lipogenesis&

lipoprotein lipase
activity
TG synthesis glycogen deposition intracellular lipolysis

Protein synthesis protein synthesis

Adverse Effects of Insulin
1. Hypoglycemia may occur due to insulin
overdose, insufficient caloric intake (missed
meal, improper meal content, delayed meal,
etc.). Ethanol consumption promotes
hypoglycemic response. Symptoms: HR,
diaphoresis, MS changes, anything (diabetics are
usually really good at recognizing hypoglycemic
symptoms).
2. Hypokalemia: insulin draws K+ into the cell with
glucose (hyperglycemia with normal K+).
3. Anaphylaxis: when sensitized to non-human
insulin gets non-human insulin (now rare).
4. Lipodystrophy at injection site
5. Weight gain
6. Injection complications
Oral Hypoglycemics
These agents are useful in the treatment of
type 2s who do not respond adequately to
non-medical interventions (diet, exercise and
weight loss).
Newly diagnosed Type 2s (less than 5 years)
often respond well to oral agents, patients
with long standing disease (often diagnosed
late) often require a combination of agents
with or without insulin.
The progressive decline in -cell function
often necessitates the addition of insulin at
some time in Type II diabetes. Oral agents are
never indicated for Type Is.
Sulfonylureas
These agents promote the
release of insulin from -cells
(secretogogues); tolbutamide,
glyburide, glipizide and
glimepiride.
Mechanism:
These agents require
functioning -cells, they
stimulate release by blocking
ATP-sensitive K+ channels
resulting in depolarization
with Ca2+ influx which
promotes insulin secretion.
They also reduce glucagon
secretion and increase the
binding of insulin to target
tissues.
They may also increase the
number of insulin receptors
Pharmacokinetics: These
agents bind to plasma
proteins, are metabolized in
the liver and excreted by the
liver or kidney. Tolbutamide
has the shortest duration of
action (6-12 hrs) the other
agents are effective for ~24
Sulfonylureas
Adverse Effects: These agents tend to
cause weight gain, hyperinsulinemia
and hypopglycemia. Hepatic or renal
insufficiency causes accumulation of
these agents promoting the risk of
hypoglycemia. There are a number of
drug-drug interactions. Elderly patients
appear particularly susceptible to the
toxicities of these agents.
Tolbutamide is asociated with a 2.5X
in cardiovascular mortality.
Onset and Duration
Short acting: Tolbutamide (Orinase)
Intermediate acting: Tolazamide
(Tolinase), Glipizide (Glucotrol),
Glyburide (Diabeta)
Long acting: Chloropropamide,
Glimerpiride
Meglitinide analogs
These agents (repaglinide (Prandin) and nateglinide
(Starlix)) act as secretogogues.
Mechanism: These agents bind to ATP sensitive
K+channels like sulfonylureas acting in a similar
fashion to promote insulin secretion however
their onset and duration of action are much
shorter. They are particularly effective at
mimicking the prandial and post-prandial release
of insulin. When used in combination with other
oral agents they produce better control than any
monotherapy.
Pharmacokinetics: These agents reach effective
plasma levels when taken 10-30 minutes before
meals. These agents are metabolized to inactive
products by CYP3A4 and excreted in bile.
Adverse Effects: Less hypoglycemia than
sulfonylureas; drugs that inhibit CYP3A4
(ketoconozole, fluconazole, erythromycin, etc.)
prolong their duration of effect. Drugs that
Insulin Sensitizers
Two classes of oral hypoglycemics work by
improving insulin target cell response; the
biguanides and thiazolidinediones.
Biguanides:
Metformin is classified as an insulin sensitizer, it
increases glucose uptake and utilization by target
tissues. It requires the presence of insulin to be
effective but does not promote insulin secretion.
The risk of hypoglycemia is greatly reduced.
Mechanism: Metformin reduces plasma glucose
levels by inhibiting hepatic gluconeogenesis. It
also slows the intestinal absorption of sugars. It
also reduces hyperlipidemia (LDL and VLDL
cholesterol and HDL). Lipid lower requires 4-6
weeks of treatment. Metformin also decreases
appetite. It is the only oral hypoglycemic shown
to reduce cardiovascular mortality. It can be used
in combination with other oral agents and insulin.
Adverse effects: Hypoglycemia occurs only when
Insulin Sensitizers
Thiazolidinedion
es
(Glitazones)
These agents are
insulin sensitizers,
they do not promote
insulin secretion
from -cells but
insulin is necessary
for them to be
effective.
Pioglitazone and
rosiglitazone are the
two agents of this
group.
 Mechanism of Action: These agents act through the
activation of peroxisome proliferator-activated receptor-
(PPAR-). Ligands for PPAR- regulate adipocyte
production, secretion of fatty acids and glucose
metabolism. Agents binding to PPAR- result in increased
insulin sensitivity is adipocytes, hepatocytes and skeletal
muscle. Hyperglycemia, hypertriglyceridemia and
elevated HbA1c are all improved. HDL levels are also
elevated. Accumulation of subcutaneous fat occurs with
these agents.
 In the liver: glucose output
In muscle: glucose uptake
In adipose: glucose uptake , FA release
Only pioglitazone may be used in combination
with insulin; the insulin dose must be modified.
Rosiglitazone may be used with other
hypoglycemic but severe edema occurs when
combined with insulin.
Pharmacokinetics: Both are extensively bound to
albumin. Both undergo extensive P450
metabolism; metabolites are excreted in the urine
the primary compound is excrete unchanged in
the bile.
Adverse Effects: Fatal hepatotoxicity has
occurred with these agents; hepatic function must
be monitored. Oral contraceptives levels are
decreased with concomitant administration, this
has resulted in some pregnancies.
-Glucosidase Inhibitors
This enzyme hydrolyses
oligosaccharides to
monosaccharides
which are then
absorbed. Acarbose
also inhibits pancreatic
amylase. The normal
post-prandial glucose
rise is blunted, glucose
levels rise modestly
and remain slightly
elevated for a
prolonged period, less
of an insulin response
is required and
hypoglycemia is
avoided; use with other
agents may result in
hypoglycemia. Sucrase
is also inhibited by
these drugs.
-Glucosidase Inhibitors
Acarbose and miglitol are two agents of this class
used for type 2 diabetes.
Mechanism of action: These agents are oligosaccharide
derivatives taken at the beginning of a meal delay
carbohydrate digestion by competitively inhibiting -
glucosidase, a membrane bound enzyme of the
intestinal brush border.
Pharmacokinetics: Acarbose is poorly absorbed remaining
in the intestinal lumen. Migitol is absorbed and excreted
by the kidney. Both agents exert their effect in the
intestinal lumen.
Adverse Effects: GUESS (flatulence, diarrhea, cramping).
Metformin bioavailability is severely decreased when
used concomitantly. These agents should not be used in
diabetics with intestinal pathology.
Type 2
An easy (and over-
simplified) way to
approach type 2
diabetics is their
glucostat is set at a
higher level.
Glucagon remains
higher than normal to
maintain the higher
glucose level, but the
insulin response is less
pronounced.
Post Prandial Glucose
Regulation
Incretin Therapy
Incretins are naturally occurring hormones
that the gut releases throughout the day;
the level of active incretins increases
significantly when food is ingested.
Endogenous incretins GLP-1 (glucagon-like
peptide 1) and GIP (glucose-dependent
insulinotropic peptide) facilitate the
response of the pancreas and liver to
glucose fluctuations through their action on
pancreatic cells and cells.
GIP and GLP-1 are the 2 major incretin
hormones in humans: 1
GIP is a 42-aa peptide derived from a larger
protein (ProGIP) and is secreted by endocrine K
cells mainly present in the proximal
gastrointestinal (GI) tract (duodenum and
proximal jejunum).
GLP-1 is a 30- or 31-aa peptide derived from a
larger protein (proglucagon) and is secreted by
Incretin Therapy
Januvia (sitagliptin)
These incretins are released from the gut in
response to ingestion of food and
collectively contribute to glucose control
by:
Stimulating glucose-dependent insulin release
from pancreatic beta cells (GLP-1 and GIP):
Decreasing glucagon production from pancreatic
alpha cells (GLP-1) when glucose levels are
elevated.
The combination of increased insulin
production and decreased glucagon
secretion reduces hepatic glucose
production when plasma glucose is
elevated.
The physiologic activity of incretins is limited
by the enzyme dipeptidyl peptidase-4 (DPP-
4), which rapidly degrades active incretins
after their release.
The Incretin Effect Is Diminished in Type 2
Diabetes
Levels of GLP-1 are decreased.
Standard vs. Intensive
Treatment

The trade off between standard and intensive therapy is

more frequent hypoglycemic events (hypoglycemic events,
seizures and coma) for a marked delay in the onset of
diabetic complications both microvascular and
macrovascular.
HbA1c = Hemoglobin A1c is a useful measure of glucose
control over the prior 3-6 months, hyperglycemic episodes
result in the nonspecific glycosylation of various proteins.
Symptomatic Hypoglycemia
A note on the treatment of hypoglycemia: Oral
glucose/carbohydrate administration results in a more rapid
rise in blood glucose than IV administration; this is due to
the involvement of gastrointestinal hormones.