Anti-Diabetic Drugs
Diabetes Mellitus
• The incidence of diabetes is increasing at an alarming
rate in the US.
Pancreatic axis
• Insulin
– β cells secrete due to
high blood glucose
levels
– Glucose uptake into
tissues increases
• Glucagon
– α cells secrete when
blood glucose is low
– Glucose is released
from tissues back into
blood
• Glucose homeostasis
Insulin
Beta cells
of pancreas stimulated
to release insulin into
the blood
High blood
glucose level
STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal)
Body
cells
take up more
glucose
Liver takes
up glucose
and stores it as
glycogen
Homeostasis: Normal blood glucose level
(about 90 mg/100 mL)
Blood glucose level
rises to set point;
stimulus for glucagon
release diminishes
Figure 26.8
Blood glucose level
declines to a set point;
stimulus for insulin
release diminishes
Liver
breaks down
glycogen and
releases glucose
to the blood
STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)
Alpha
cells of
pancreas stimulated
to release glucagon
into the blood
Glucagon
Normal
Insulin
Glycerol
Lipolysis
Free fatty acids
Synthesis
Free fatty acids
LPL
Glucose
Insulin
Triglyceride
Normal Glucose Control
• In the post-absorptive period of a normal individual, low basal
levels of circulating insulin are maintained through constant β
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 β-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 β-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 β 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
I
I
β Cell
Dysfunction
Insulin
Pancreas
I
Increased
splanchnic
glc
output
Decreased Glucose
Uptake
Insulin Resistance
FOOD
Storage In Fat Depots
Inhibition of Lipolysis
I
I
Insulin
Secretion
Insulin
Pancreas
Restrain of
HGO
I
Insulin Effects
Uptake of glucose
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 β-cells and glucagon by α2 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.
Table 24-8. Type 1 Versus Type 2 Diabetes Mellitus (DM)
Clinical
Type 1 DM
Onset: <20 years
Normal weight
Markedly decreased blood
insulin
Anti-islet cell antibodies
Ketoacidosis common
Genetics
30-70% concordance in twins
Linkage to MHC Class II HLA
genes
Pathogenesis Autoimmune destruction of βcells mediated by T cells and
humoral mediators (TNF, IL-1,
NO)
Islet cells
Absolute insulin deficiency
Insulitis early
Marked atrophy and fibrosis
β-cell depletion
Type 2 DM
Onset: >30 years
Obese
Increased blood insulin
(early);normal to moderate
decreased insulin (late)
No anti-islet cell antibodies
Ketoacidosis rare;
nonketotic hyperosmolar
coma
50-90% concordance in
twins
No HLA linkage
Linkage to candidate
diabetogenic genes
(PPARγ, calpain 10)
Insulin resistance in
skeletal muscle, adipose
tissue and liver
β-cell dysfunction and
relative insulin deficiency
No insulitis
Focal atrophy and amyloid
deposition
Mild β-cell depletion
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 β-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 β-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 Cprotein 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. α-Adrenergic
stimulation inhibits
release (most
important).
4. β-Adrenergic
stimulation promotes
release.
5. Elevated intracellular
Ca2+ promotes release.
Insulin secretion - Insulin secretion in beta cells is triggered
by rising blood glucose levels. Starting with the uptake of
glucose by the GLUT2 transporter, the glycolytic
phosphorylation of 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 leads to the exocytotic release of insulin
from their storage granule.
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 regular
insulin.
Prolonged-acting insulin preparations
1.Ultralente: a suspension of
zinc 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.
Pump vs. Standard Insulin Therapy
• 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 nonhuman 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 β-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 β-cells (secretogogues);
tolbutamide, glyburide, glipizide and
glimepiride.
• Mechanism:
– These agents require functioning βcells, 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
hrs.
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 drugdrug 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 promote
CYP3A4 (barbiturates, carbamazepine and rifampin) decrease
their effectiveness. The combination of gemfibrozil and
repaglinide has been reported to cause severe hypoglycemia.
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 combined
with other agents. Rarely severe lactic acidosis is associated
with metformin use particularly in diabetics with CHF. Drug
interactions with cimetidine, furosemide, nifedipine and
others have been identified.
Insulin Sensitizers
Thiazolidinediones
(Glitazones)
• These agents are insulin
sensitizers, they do not
promote insulin secretion
from β-cells but insulin is
necessary for them to be
effective. Pioglitazone
and rosigglitazone are the
two agents of this group.
• Mechanism of Action: These agents act through the activation of
peroxisome proliferator-activated receptor-γ (PPAR-γ). Ligands for PPAR-γ
regulate adipocyte production, secretion of fatty acids and glucose
metabolism. Agents binding to PPAR-γ 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.
α-Glucosidase Inhibitors
This enzyme hydrolyses
oligosaccharides to
monosaccharides which are
then absorbed. Acarbose
also inhibits pancreatic
amylase. The normal postprandial 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.
α-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 αglucosidase, 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 oversimplified) 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 β cells and α 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 L cells located
predominantly in the distal GI tract (ileum and colon). This
protein was first isolated from salivary gland venom of the
Gila monster (investigating how these lizards are able to
tolerate long periods between meals).
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.
The insulinotropic response to GIP is diminished but not
absent.
Defective GLP-1 release and diminished response to GIP may
be important factors in glycemic dysregulation in type 2
diabetes.
Standard vs. Intensive Treatment
Type
Normal
Standard
Intensive
Glucose Goal
110mg/dl
225-275 mg/dl
150 mg/dl
HbA1c Goal
6%
8-9%
7%
Treatments
-----------Insulin BID
3 or more
BG Monitoring
-------------2-3 per day
4-6 per day
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.