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Chapter: 41
Pancreatic Hormones & Antidiabetic Drugs
Pancreas
The endocrine pancreas in the adult human consists of:
•
approximately 1 million islets of Langerhans
•
interspersed throughout the pancreatic gland (secrete peptide hormones)
2
Pancreatic Islet Cells and Their Secretory
Products
Diabetes Mellitus
• Definition:
– elevated blood glucose
– associated with absent or inadequate pancreatic insulin
secretion,
– with or without concurrent impairment of insulin action
• It is a heterogeneous
characterized:
group
of
disorders
– by abnormalities in CHO, protein, and lipid metabolism;
– and an increased risk of complications from vascular disease
• Hyperglycemia is a common end point for all types of
DM and is the parameter that is measured to:
– evaluate and manage the efficacy of diabetes therapy
4
Diabetes Mellitus
• The American diabetic association (ADA)
recognizes four clinical classifications of diabetes:
– Type 1: Formerly ‘insulin-dependent diabetes’
– Type 2: Formerly ‘non insulin-dependent
diabetes’
– Type 3: Other
• (e.g. genetic defects or medication induced)
– Type 4: Gestational diabetes mellitus
5
Type 4 :Gestational diabetes (GDM)
• Defined as
– any abnormality in glucose levels
– noted for the first time during pregnancy
• During pregnancy,:
– the placenta and placental hormones create an insulin
resistance
– that is most pronounced in the last trimester
• Risk assessment for diabetes is suggested starting at
the first prenatal visit
6
Type 3 Diabetes Mellitus
• The type 3 designation refers to multiple other specific
causes of an elevated blood glucose:
1) Pancreatectomy
2) Pancreatitis
3) Nonpancreatic diseases (e.g. Cushing’s syndrome
& acromegaly)
4) Drug therapy (e.g. anti-hypertensive vasodilator
diazoxide and corticosteroids)
7
Type 1 Diabetes Mellitus
• Type I diabetes mellitus constitutes about 10% of
cases of diabetes mellitus
• Selective β-cell destruction
– and severe or absolute insulin deficiency
• Most patients are younger than 30 years of age
at the time of diagnosis
• Pathogenesis include:
– immune
– and idiopathic causes
8
Type 2 Diabetes Mellitus
• It is influenced by genetic factors, aging, & obesity
• In obese individuals and in the majority (>80%) of type
2 diabetic subjects, there is an expanded fat cell mass
and the adipocytes are resistant to the antilipolytic
effects of insulin
• The pathogenesis of type 2 diabetes mellitus is
complex, Characterized by:
– tissue resistance to the action of insulin
– combined with a relative deficiency in insulin secretion
• In persons with type 2 diabetes, the sensitivity of the
cell to glucose is impaired, and there is also a loss of
responsiveness
9
Type 2 Diabetes Mellitus
• In Type 2 DM, the pancreas retains some β-cell
function,
– but variable insulin secretion is insufficient to maintain
glucose homeostasis and to overcome the resistance
• This results in:
– delayed secretion of insufficient amounts of insulin,
– allowing the blood glucose to rise dramatically after meals,
– and failure to restrain liver glucose release during fasting
• Hyperinsulinemia is an early finding in the
development of T2DM
• The β-cell mass may become gradually reduced in
Type 2 DM
10
Pathophysiology of Type 2 Diabetes
ogenesis of Type 2 Diabetes: Insulin
Resistance and -Cell Dysfunction
100
75
Defective
-Cell Secretion:
Pancreas
50
25
sfunction
N = 376
Insulin
Resistance
0
–10
–6
–2
2
6
Years After Diagnosis
FFAs
Insulin
Resistance:
eas
Liver
Excess
Glucose
Production
Liver
Fasting Hyperglycemia
Muscle
Reduced
Glucose
Uptake
Muscle
Postprandial Hyperglycemia
FFAs = free fatty acids.
Adapted from UK Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258.
DeFronzo RA. Diabetes. 1988;37:667-687.
Fat
Fat
• Beta-cells dysfunction in DM is progressive
• and contribute to worsening blood glucose control over
time
Normal
No
treatment
Impaired
glucose
tolerance
Diet
Type 2 diabetes
0-5 years
5-15 years
More
than 15
years
Diet plus
metformin
Combination
therapy
Multiple
injections
of insulin
Characteristic
Age
Onset
Body habitus
Type 1 DM
<30 years
Abrupt
Lean
Insulin resistance
Autoantibodies
Symptoms
Ketones at diagnosis
Need for insulin therapy
Acute complications
Absent
Often present
Symptomatic
Present
Immediate
Diabetic ketoacidosis
Microvascular complications at
diagnosis
Macrovascular complications at or
before diagnosis
No
Type 2 DM
>30 years
Gradual
Obese or history of
obesity
Present
Rarely present
Often asymptomatic
Absent
Years after diagnosis
Hyperosmolar
hyperglycemic state
Common
Rare
Common
Diabetes-Related Complications
• Diabetes can cause metabolic derangements
• or acute complications, such as the life-threatening
metabolic disorders of:
– diabetic ketoacidosis
– and hyperglycemic hyperosmolar state
• These require hospitalization for:
– insulin administration,
– rehydration with intravenous fluids,
– and careful monitoring of electrolytes and metabolic
parameters
14
Diabetes-Related Complications
• Chronic complications are commonly divided
into:
1) Microvascular complications:
– retinopathy,
– nephropathy
– and neuropathy
2) Macrovascular complications refer to increased
atherosclerosis-related events such as:
– myocardial infarction
– and stroke
15
Diagnosis of Diabetes
• American Diabetes Association (ADA) and the
World Health Organization (WHO) have adopted
criteria for the diagnosis of diabetes, based on:
1) The fasting blood glucose
2) The glucose value following an oral glucose
challenge
3) Level of hemoglobin A1c (HbA1c)
16
Criteria for the Diagnosis of Diabetes
A1C ≥6.5%
OR
Fasting plasma glucose (FPG)
≥126 mg/dL (7.0 mmol/L)
OR
2-h plasma glucose ≥200 mg/dL
(11.1 mmol/L) during an OGTT
OR
A random plasma glucose ≥200 mg/dL (11.1
mmol/L)
ADA. I. Classification and Diagnosis. Diabetes Care 2013;36(suppl 1):S13; Table 2.
Criteria for the Diagnosis of Diabetes
 Symptoms of diabetes plus random blood glucose
concentration ≥ 11.1 mM (200 mg/dL)
 Fasting plasma glucose ≥7.0 mM (126 mg/dL)
 Two-hour plasma glucose ≥ 11.1 mM (200 mg/dL)
during an oral glucose tolerance test (OGTT)
 HbA1c 6.5%
18
Insulin & its analogs
Chemistry
• Insulin is a small protein with a molecular weight in humans of
5808.
– It contains 51 amino acids (a.as)arranged in two chains (A and B) linked
by disulfide bridges;
– there are species differences in the amino acids of both chains.
• Proinsulin (86 a.a.), 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 (51aa)and a residual connecting
segment called C-peptide (31 aa)
– by removal of four amino acids (Figure 41–1).
20
Insulin Chemistry




Small protein
Mol. Wt. 5808
Two chains A and B linked by disulfide bridges
51 amino acids
21
Insulin Chemistry
• Insulin and C-peptide are secreted in equimolar amounts in
response to all insulin secretagogues;
• a small quantity of unprocessed or partially hydrolyzed
proinsulin is released as well.
• Although proinsulin may have some mild hypoglycemic
action,
• C-peptide has no known physiologic function.
•
Granules within the beta cells store the insulin in the form of
crystals consisting of :
– two atoms of zinc and six molecules of insulin.
23
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.
• Other stimulants such as:
– other sugars (eg, mannose),
– certain amino acids (eg, leucine, arginine),
– hormones such as:
•
•
•
•
glucagon-like polypeptide-1 (GLP-1),
glucose-dependent insulinotropic polypeptide (GIP),
glucagon,
cholecystokinin,
– and vagal activity are recognized.
• Inhibitory signals include somatostatin, leptin, and chronically
elevated glucose and fatty acid levels.
26
Circulating Insulin
• Basal insulin values of 5-15 uU/mL (30-90 pmol/L) are found
in normal humans,
• with a peak rise to 60-90 uU/mL (360-540 pmol/L) during
meals.
• Biphasic
27
Insulin Secretion
One mechanism of stimulated insulin release:
• hyperglycemia results in increased intracellular ATP levels,
– which close the ATP-dependent potassium channels.
• Decreased outward potassium efflux results in :
– depolarization of the beta cell
– and opening of voltage-gated calcium channels.
• The resulting increased intracellular calcium >>>>> triggers
secretion of the hormone.
• The insulin secretagogue drug group (sulfonylureas,
meglitinides, and D-phenylalanine) exploits parts of this
mechanism.
28
One model of control of insulin release
from the pancreatic beta cell by glucose
and by sulfonylurea drugs
11/2/2014
29
Glucose transporters
Transporter
Tissues
Function
GLUT 1
All tissues, especially
red cells, brain
Basal uptake of glucose;
transport across the BBB
GLUT 2
B cells of pancreas;
liver, kidney; gut
Regulation of insulin release,
other aspects of glucose
Homeostasis
GLUT 3
Brain, kidney, placenta,
other tissues
Uptake into neurons, other
Tissues
GLUT 4
Muscle, adipose
Insulin-mediated uptake of
glucose
GLUT 5
Gut, kidney
Absorption of fructose
The Insulin Receptor
• After insulin has entered the circulation, it diffuses into
tissues, where it is bound by specialized receptors that are
found on the membranes of most tissues.
• The biologic responses promoted by these insulin-receptor
complexes have been identified in the primary target tissues,
ie, liver, muscle, and adipose tissue. The receptors bind
insulin with high specificity and affinity in the picomolar
range.
31
The Insulin Receptor
• The full insulin receptor consists of two covalently linked
heterodimers, each containing:
– a subunit, which is entirely extracellular and constitutes the recognition site,
– and a subunit that spans the membrane.The subunit contains a tyrosine
kinase.
• The binding of an insulin molecule to the subunits at the outside
surface of the cell:
– activates the receptor and through a conformational change brings the
catalytic loops of the opposing cytoplasmic subunits into closer proximity.
– This facilitates mutual phosphorylation of tyrosine residues on
the subunits and tyrosine kinase activity directed at
cytoplasmic proteins.
32
Insulin Receptor
33
Katzung 8th edition
Insulin MOA
34
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 35-40% of the endogenous hormone.
• However, in insulin-treated diabetics receiving subcutaneous
insulin injections, this ratio is reversed,
– with as much as 60% of exogenous insulin being cleared by the kidney
– and the liver removing no more than 30-40%.
• The half-life of circulating insulin is 3-5 minutes.
36
Table 41-3.
Endocrine effects of insulin
Effect on liver:
Reversal of catabolic features of insulin deficiency
Inhibits glycogenolysis
Inhibits conversion of fatty acids and amino acids to keto acids
Inhibits conversion of amino acids to glucose
Anabolic action
Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits
phosphorylase)
Increases triglyceride synthesis and very low density lipoprotein formation
Effect on muscle:
Increased protein synthesis
Increases amino acid transport
Increases ribosomal protein synthesis
Increased glycogen synthesis
Increases glucose transport
Induces glycogen synthase and inhibits phosphorylase
Effect on adipose tissue:
Increased triglyceride storage
Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins
Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids
supplied by lipoprotein transport
Intracellular lipase is inhibited by insulin
Insulin Therapy
1) All patients
indications)
with
type
1
DM
(primary
2) Patients with type 2 DM that is not controlled
adequately by diet and/or oral hypoglycemic
agents
3) Patients with postpancreatectomy diabetes or
gestational diabetes
Insulin Therapy
•
Long-term treatment relies predominantly on Sc
injections in the:
–
–
–
–
•
abdomen,
buttock,
anterior thigh,
or dorsal arm
The goal of Sc 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
Insulin administration sites
Characteristics of Available Insulin Preparations
• Commercial insulin preparations differ in a number
of ways, such as
1. Origin (different recombinant DNA production
techniques),
2. amino acid sequence,
3. concentration,
4. solubility, and
5. time of onset and duration of their biologic action
 Unit of insulin!
47
Principal Types and Duration of Action of
Insulin Preparations
• Four principal types of injected insulin are
available:
1. Rapid-acting with very fast onset and short
duration
2. Short-acting with rapid onset of action
3. Intermediate-acting
4. Long-acting with slow onset of action
Comparison of Human Insulins & Analogues
Insulin
Preparations
Onset of
Action
Peak of
Action (h)
Duration of
Action (h)
30-60 min
15-30 min
15-30 min
15-30 min
2-3
1-2
1-2
1-2
4-6
3-4
3-5
5-6
Intermediate-acting
NPH
2-4 h
4-8
8-12
Long-acting
Glargine
Detemir
4-5 h
2h
None
None
22-24h
14-24 h
Short-acting
Regular human
Lispro
Aspart
Gluilisine
Extent and duration of action of various types of insulin
Principal Types and Duration of Action of
Insulin Preparations
• Injected rapid-acting 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.
• Injected intermediate-acting NPH insulins:
– have been modified to provide prolonged action
– and are dispensed as a turbid suspension at neutral pH
– with protamine in phosphate buffer (neutral protamine Hagedorn
[NPH] insulin).
• Insulin glargine and insulin detemir are:
– clear, soluble long-acting insulins
52
1. Rapid-acting insulin
• Analogs: insulin LISPRO, insulin ASPART, and insulin GLULISINE:
– ……rapid onsets
– and early peaks of activity
– to control of postprandial glucose levels
• The 3 rapid-acting insulins have small alterations in their primary
amino acid sequences that :
– speed their entry into the circulation
– without affecting their interaction with the insulin receptor
• Uses:
– Injected immediately before a meal.
– ......preferred insulin for continuous subcutaneous infusion devices
– Used also for emergency treatment of uncomplicated diabetic ketoacidosis
2. Short-acting insulin
• Regular insulin is used:
– IV in emergencies
– or administered s.c. in ordinary maintenance regimens,
• alone or mixed with intermediate- or long-acting preparations
• Before the development of rapid-acting insulins,
– it was the primary form of insulin used for controlling
postprandial glucose concentrations,
– but it requires administration 1 h or more before a meal
54
3. Intermediate-Acting
• Neutral protamine Hagedorn insulin (NPH insulin):
– is a combination of regular insulin and protamine (a highly basic
protein also used to reverse the action of unfractionated heparin),
– that exhibits a delayed onset and peak of action
• NPH insulin is often combined with regular and rapid-acting
insulins
55
Long-Acting
• Insulin glargine and insulin detemir :
– are modified forms of human insulin that provide a peakless basal
insulin level
– lasting more than 20 h,
– which helps control basal glucose levels
• without producing hypoglycemia.
56
Mixtures of insulins
• Various fixed-ratio mixtures of insulin preparations
exist
• Benefits include:
– reduced errors
– and improved dosing accuracy
– as well as the convenience of using a single vial
Mixtures of insulins
• They are not ideal regimens for most diabetics,
– who may achieve better control by separately mixing
their insulin preparations (acutely)
• Insulin glargine and detemir must be given as
separate injections
– b/c they are not miscible acutely with any other insulin
formulation
12
Glucose Infusion Rate
mg/kg/min
10
8
Lispro
6
NPL
4
2
0
0
4
Heise T, et al. Diabetes Care. 1998;21:800-803.
8
12
Hours
16
20
24
Table 41-4.
Insulin Delivery Systems
• The standard mode of insulin therapy is subcutaneous
injection
– with conventional disposable needles and syringes.
– More convenient means of administration are also available.
• Portable pen-sized injectors are used:
– to facilitate subcutaneous injection.
– Some contain replaceable cartridges,
– whereas others are disposable.
• Continuous subcutaneous insulin infusion devices:
– avoid the need for multiple daily injections
– and provide flexibility in the scheduling of patients' daily activities.
– Programmable pumps deliver a constant 24-h basal rate, and manual
adjustments in the rate of delivery can be made to accommodate
changes in insulin requirements (bolus)(eg, before meals or exercise)61
Insulin Pumps
•
Continuous subcutaneous insulin infusion (CSII)
•
Battery operated
•
Programmable computer
•
Basal insulin throughout day
•
Bolus insulin before meals
•
Needles/catheters changed every 2-3 days
•
Rapid-acting insulin
63
Adverse reactions
1. Hypoglycemia
•
Causes:
a)
b)
c)
d)
Inadequate carbohydrate consumption
Unusual physical exertion
Inappropriately large dose of insulin
Mismatch between the time of peak delivery of
insulin and food intake
e) Factors that increase sensitivity to insulin (e.g.,
adrenal or pituitary insufficiency)
Hazards of Insulin Use
• The most common complication is hypoglycemia.
– resulting from excessive insulin effect.
• Patients with advanced renal disease, the elderly, and
children younger than 7 years
– are most susceptible to the detrimental effects of hypoglycemia.
• S & S:
–
–
–
–
–
–
tachycardia, palpitation,
tremor, paresthesias
sweating,
hunger
and nausea
.....progress to convulsion and coma if untreated!
• Immunological reaction (now less, with human insulin
66
Hypoglycemia Tx.
•
To prevent the brain damage that may result from
hypoglycemia,
– prompt administration of glucose (sugar or candy by mouth, glucose
by vein)
– or of glucagon (by intramuscular injection) is essential.
a)
Oral CHOs: dextrose tablets, glucose gel, or any sugarcontaining beverage or food may be given
b) Unconsciousness or stupor: IV glucose(2–3 min.)
c)
If IV glucoase not available: Glucagon SC or IM may
restore consciousness within 15 minutes
d)
Alternative….small amounts of honey or syrup can be
inserted into the buccal pouch…note that oral feeding is
contraindicated in unconscious patients
Adverse reactions
2.
Immunopathology of insulin therapy
A. Insulin allergy:
•
•
•
IgE-mediated local cutaneous reactions
Human insulins have markedly reduced the incidence of
insulin allergy
Antihistamines may provide relief
B. Immune insulin resistance:
•
•
•
Circulating IgG anti-insulin antibodies that neutralize the
action of insulin
Human insulin preparations should be used
Glucocorticoids is used in resistant patients
Adverse reactions
•
Lipohypertrophy remains a problem
–
•
Enlargement of subcutaneous fat depots has
been ascribed to
–
•
if injected repeatedly at the same site
the lipogenic action of high local concentrations of
insulin
May be corrected by avoiding the specific
injection site or by liposuction
Insulin and Oral Hypoglycemic
Drugs
Overview
• Also known as oral hpoglycemic agents
• These agents are useful in the treatment of patients
who have Type 2 DM
– but who cannot be managed by diet or weight loss and
exercise
• Patients with long-standing type 2 DM may require:
– a combination of hypoglycemic drugs
– with or without insulin to control their hyperglycemia
• Oral hypoglycemic agents should not be given to
patients with Type 1 DM
71
Overview
•
Different categories of oral antidiabetic agents available
1.
Insulin secretagogues
–
–
–
sulfonylureas,
meglitinides,
D-phenylalanine derivatives
2.
Insulin senitizers (biguanides & thiazolidinediones)
3.
α-glucosidase inhibitors
4.
Amylin analog
5.
glucagon like polypeptide (GLP-1 )receptor agonist
6.
7.
8.
9.
dipeptidyl peptidase-4 (DPP-4) inhibitor
Dopamine D2-receptor agonists
Bile Acid Binding Resins
Sodium Glucose Transporter 2 inhibitor
1. Sulfonylurea
• In the presence of viable pancreatic β-cells,
– sulfonylureas directly enhance the release of
endogenous insulin, thereby reducing blood glucose
levels
• The sulfonylureas are ineffective
management of severe type II DM,
for
the
– since the number of viable β-cells in these forms of
diabetes is small
73
1. Sulphonylurea- Mechanism of action
1) Insulin Release from Pancreatic Beta Cells
• Sulfonylureas bind to a 140-kDa high-affinity
sulfonylurea receptor (SUR1)
–
•
Binding of a sulfonylurea inhibits the efflux of
potassium ions through the channel
–
•
……associated with the ATP-sensitive potassium channel
(KATP)
and results in depolarization
Depolarization opens a voltage-gated calcium
channel
–
and results in the release of preformed insulin
74
ATP gated
Voltage gated
Inhibits K efflux
GLUT2
Glucokinase
Glucose sensor
Rate limiting enzyme
One model of control of insulin release from pancreatic B cells by
glucose and sulfonylurea
75
1. Sulphonylurea- Mechanism of action
2. Extrapancreatic effects
•
Sulfonylureas may also reduce hepatic clearance
of insulin,
–
•
further increasing plasma insulin levels
Long-term administration of
reduces serum glucagon levels
–
sulfonylureas
due to enhanced release of both insulin and
somatostatin, which inhibit alpha-cell secretion
76
1. Sulphonylurea- Mechanism of action
• In the initial months of sulfonylurea treatment,
– fasting plasma insulin levels and insulin responses to oral
glucose challenges are increased
• With chronic administration,
– circulating insulin levels decline to those that existed before
treatment, but despite this reduction in insulin levels,
reduced plasma glucose levels are maintained.
• The absence of acute stimulatory effects of
sulfonylureas on insulin secretion during chronic
treatment is attributed to downregulation of cell
surface receptors for sulfonylureas on the pancreatic
cell
77
1. Sulfonylurea- Pharmacokinetics
• The sulfonylureas have similar spectra of
activities;
– thus their pharmacokinetic properties are their most
distinctive characteristics
• Sulfonylureas are readily absorbed from the GIT
following oral administration
• Food and hyperglycemia
absorption of sulfonylureas
can
reduce
the
78
1. Sulfonylurea- Pharmacokinetics
• Sulfonylureas in plasma are largely (90-99%) bound to
protein, especially albumin
• Are metabolized by the liver, and the metabolites are
excreted in the urine!!!! (active metabolites)
– Sulfonylureas should be administered with caution to patients
with either renal or hepatic insufficiency
• Most sulfonylureas cross the placenta and enter breast
milk;
– as a result, use of sulfonylureas is contraindicated in pregnancy
and in breast feeding
• Half lives?? Risk of hypoglycemia?
79
1. Sulfonylurea- First generation sulfonylurea
• Agents:
–
–
–
–
Acetohexamide,
chlorpropamide,
tolazamide,
& tolbutamide
• Are not frequently used in the management b/c of
their:
1)
2)
3)
4)
5)
Relatively low specificity of action
Delay in time of onset
Occasional long duration of action
Side effects
Potential drug-drug interactions
80
1. Sulfonylurea- First generation sulfonylurea
• Tolbutamide is the safest sulfonylurea for elderly
diabetics:
– prolonged hypoglycemia has been reported rarely,
– because it is relatively short-acting with an elimination halflife of 4–5 hours
•
Chlorpropamide:


Relative slow onset of action
Contraindicated in elderly,

•
Prolonged hypoglycemic reactions are more common in elderly
patient.
Tolazamide:
–

Shorter duration than chlorpropamide.
Metabolized to active metabolites
81
1. Sulfonylurea- Second generation sulfonylurea
• Agents: glyburide (GLIBENCLIMIDE), glipizide, &
glimepiride
• prescribed more than are the 1st-generation agents
– b/c they have fewer ADRs and drug interactions
• The second-generation agents are approximately 100
times more potent than the first generation), but their
maximum hypoglycaemic effect is not greater and
control of blood glucose not better than with
tolbutamide
• Their hypoglycemic effects are evident for 12 to 24
hours, and they often can be administered once daily
82
1. Sulfonylureas- Adverse reactions
1. Hypoglycemia:
•
The most common adverse effect
•
Can be severe and prolonged
•
Its incidence is related to the potency and duration of
action of the agent
•
This is a particular concern in:
–
–
•
elderly patients with impaired hepatic or renal function
who are taking longer-acting sulfonylureas
The highest incidence occurring with chlorpropamide and
glyburide and the lowest with tolbutamide (6-12 hr)
84
1. Sulfonylureas- Adverse reactions
2. Weight gain: they stimulate appetite
–
–
(probably via their effects on insulin secretion and blood
glucose).
This is a major concern in obese diabetic patients
3. Chlorpropamide:
–
–
flushing particularly when taken with alcohol
and hyponatremia
4. Others:
–
–
–
–
–
NV,
cholestatic jaundice,
agranulocytosis, aplastic and hemolytic anemias,
generalized hypersensitivity reactions,
and dermatological reactions
85
1. Sulfonylureas- Drug interactions
• The hypoglycemic effect of sulfonylureas may be enhanced
by various mechanisms:
– decreased hepatic metabolism
– Or decreased renal excretion,
– displacement from protein-binding sites
• Other drugs may decrease the glucose-lowering effect of
sulfonylureas by:
– increased hepatic metabolism,
– increased renal excretion,
– or inhibiting insulin secretion (β-blockers, CCBs, diazoxide,
estrogens, sympathomimetics, thiazide diuretics, and urinary
alkalinizers)
86
2. KATP Channel Modulators: Non-Sulfonylureas
MEGLITINIDES
• Glinides: REPAGLINIDE and NATEGLINIDE
• Like sulfonylureas, they stimulate insulin release
– by closing ATP-dependent potassium channels in
pancreatic β cells
• In contrast to sulfonylureas,
– they have rapid onset and a short duration of action
– and are much less potent than most sulfonylureas
87
Table 41-7.
benzoic acid
derivative
Postprandial GLU
regulators…..safer
phenylalanine
a.a. derivative
2. KATP Channel Modulators: Non-Sulfonylureas
• Because of their rapid onset,
– the glinides are categorized as postprandial glucose regulators
• and are potentially safer than long‐acting sulfonylurea
– in terms of reducing the risk of hypoglycemia
• and they may cause less weight gain than conventional
sulfonylureas
• Repaglinide
– is hepatically cleared by CYP3A4
– then renal exc.,
• nateglinide
• is metabolized primarily by hepatic CYP2C9 (70%) and
CYP3A4 (30%)
• and then in the bile (safer in renal dysfunction)
89
2. KATP Channel Modulators: Non-Sulfonylureas
• Drugs that inhibit CYP3A4 potentiate the action of
glinides e,g,
– ketoconazole, itraconazole,
– erythromycin, and clarithromycin
• Drugs that increase the levels of the enzyme may
have the opposite effect e.g.
– barbiturates,
– carbamazepine,
– and rifampicin
• Repaglinide has been reported to cause
hypoglycemia in patients who are also taking
severe
– the lipid-lowering drug gemfibrozil, and concurrent use is
contraindicated (inhibited CYP2C9 activity)
90
Insulin sensitizers
• Insulin sensitizers lower blood glucose by improving
target-cell response to insulin
– without increasing pancreatic insulin secretion
– Their effects do not depend upon functional islet cells
– and generally do not cause hypoglycemia
• Two classes of oral agents improve insulin action:
I. Biguanides
II. Thiazolidinediones
91
1. Biguanides
• Metoformin (Glucophage®)
– is the only currently available biguanide
• Phenformin was withdrawn in many countries
during the 1970s
– because of an association with lactic acidosis
• Because metformin is an insulin-sparing agent it
does not cause:
– hypoglycemia
– or weight gain
92
1. Biguanides..PK
• Metformin is absorbed mainly from the small
intestine.
• It has a half-life of 1.5–3 hours
• It does not bind to plasma proteins
• and is excreted unchanged in the urine
93
1. Biguanides
• The transport of metformin into cells is mediated in
part by organic cation transporters (OCTs):
1) OCT 1
–
–
is believed to carry the drug into cells such as
hepatocytes and myocytes
where it is pharmacologically active
2) OCT 2
–
is thought to transport metformin into renal tubules
for excretion
• There is recent evidence suggesting that genetic
variation in OCT 1 among humans
– may affect the response to metformin
94
1. Biguanides- Mechanism of action
• Metformin increases the activity of the AMPdependent protein kinase (AMPK)
• AMPK is activated by phosphorylation when cellular
energy stores are reduced (i.e., lower concentrations
of ATP and phosphocreatine)
• Activated AMPK stimulates:
–
–
–
–
fatty acid oxidation,
glucose uptake,
and nonoxidative metabolism,
and it reduces lipogenesis and gluconeogenesis
95
1. Biguanides- Mechanism of action
• The molecular mechanism by which metformin
activates AMPK is not known,
– it is thought to be indirect,
– possibly by reducing intracellular energy stores
• The net result of these actions is:
–
–
–
–
increased glycogen storage in skeletal muscle,
lower rates of hepatic glucose production,
increased insulin sensitivity,
and lower blood glucose levels
96
1. Biguanides- Mechanism of action
• Metformin also slows intestinal absorption of
sugars glucose
• Metformin modestly reduce hyperlipidemia:
– apparent 4-6 weeks of use
97
1. Biguanide- Clinical uses
• Metformin is currently the most commonly used oral
agent to treat type 2 diabetes
– and is generally accepted as the first-line treatment for this
condition
– Metformin is effective as monotherapy
– and in combination with nearly every other therapy for type
2 diabetes
• Metformin, however, is the only therapeutic agent
that has been demonstrated to reduce macrovascular
events in type 2 DM
98
1. Biguanide- Clinical uses
• Metformin is useful in the prevention of type 2
diabetes: metformin is efficacious in preventing
the new onset of type 2 diabetes in:
– middle-aged, obese persons with impaired glucose
tolerance and fasting hyperglycemia
• Epidemiologic studies suggest that metformin use
may dramatically reduce the risk of some cancers
99
1. Biguanide- Clinical uses
• Metformin has been used as a treatment for
infertility in women with the polycystic ovarian
syndrome:
– it improve ovulation
– and menstrual cyclicity
– and reduce circulating androgens and hirsutism
100
1. Biguanide- Adverse reactions
1. GIT
–
–
–
•
•
•
•
anorexia,
nausea, vomiting,
abdominal discomfort, and diarrhea):
dose-related,
tend to occur at the onset of therapy,
and are often transient.
Can be minimized by
–
–
increasing the dosage of the drug slowly
and taking it with meals
2. Intestinal absorption of vitamin B12 and folate often
is decreased during chronic metformin therapy
101
1. Biguanide- Contraindications
• Like phenformin, metformin has been associated with
lactic acidosis
– The estimated incidence of lactic acidosis attributable to
metformin use is 3-6 per 100,000 patient-years of treatment
• patients are predisposed to lactic acidosis because of
reduced drug elimination or reduced tissue
oxygenation. Patients with:
–
–
–
–
renal insufficiency,
alcoholism,
hepatic disease,
or conditions predisposing to tissue anoxia (eg, chronic
cardiopulmonary dysfunction)
102
Tzds )Thiazolidinediones/Glitazones)
• Agents: pioglitazone (Actos) and rosiglitazone
(Avandia)
• Troglitazone:
– was the first of these to be approved for the treatment
of Type 2 diabetic,
– but was withdrawn after a number of deaths due to
hepatotoxicity were reported
• They all act to:
– decrease insulin resistance
– and enhance insulin action in target tissues
103
Thiazolidinediones- Mechanism of action
• Tzds are selective agonists for nuclear peroxisome
proliferator-activated receptor-γ (PPARγ)
• PPARγ is a nuclear receptor that is:
– predominantly expressed in adipose tissue
– and to a lesser extent in :
•
•
•
•
•
•
•
liver,
in cardiac,
skeletal,
and smooth muscle cells,
β-islet cells,
macrophages,
and vascular endothelial cells
104
Thiazolidinediones- Mechanism of action
• These drugs bind to PPARγ, which activates:
– insulin-responsive genes that regulate lipid and glucose
metabolism,
– insulin signal transduction,
– and adipocyte and other tissue differentiation
• The principal response to PPARγ
adipocyte differentiation
activation is
• Along with adipocyte differentiation, PPARγ activity
promotes uptake of circulating fatty acids into fat
cells and shifts of lipid stores to adipose tissue
105
Thiazolidinediones-
Clinical uses
• Tzds are approved as:
– a monotherapy
– and in combination with metformin, sulfonylureas, and
insulin for the treatment of type 2 diabetes
• Because their mechanism of action involves gene
regulation,
– the Tzds have a slow onset and offset of activity
– over weeks or even months
106
Mechanism of Action
Thiazolidinediones
Chronic
Peroxisome Proliferator Activated
Receptor (PPAR-)
 Glucose uptake in
muscles and adipose
 Glucose metabolism in
muscles and adipose
 Hepatic
gluconeogenesis
 resistance
107
Thiazolidinediones- Pharmacokinetics
• Both (Rosiglitazone & pioglitazone) completely
absorbed….time to peak plasma concentration ~ 2 hrs
• (> 99%) bound to plasma proteins
• Rosiglitazone metabolized by hepatic CYP2C8 and
CYP2C9,
• whereas pioglitazone is metabolized by CYP3A4 and
CYP2C8
• The metabolites of rosiglitazone are eliminated
mainly in urine,
• and those of pioglitazone mainly in bile
Thiazolidinediones- Adverse reactions
• The most common adverse effects of
thiazolidinediones are weight gain and edema
the
• Treatment with Tzds causes:
– an increase in body adiposity and an average weight gain of
2-4 kg over the first year of treatment
• Tzds promote sodium ion reabsorption in renal
collecting ducts amiloride-sensitive sodium ion
reabsorption, explaining the adverse effect of fluid
retention
109
Thiazolidinediones- Adverse reactions
• Edema is more likely to occur when these agents are
combined with insulin or insulin secretagogues
• Both drugs increase the risk of heart failure due to:
– an increase in weight,
– an expansion of plasma volume
• following a reduction in renal sodium excretion,
• or a direct effect to increase vascular permeability
110
Thiazolidinediones- Adverse reactions
• Tzds may cause or exacerbate CHF; closely monitor
for signs and symptoms of CHF (eg, rapid weight gain,
dyspnea, edema), particularly after initiation or dose
increases
• Tzds are not recommended for use in any patient with
symptomatic heart failure
• Due to CV risks, the FDA chose to restrict access and
distribution of rosiglitazone-containing medications
are only available through the Avandia-Rosiglitazone
Medicines Access Program1
1Source: http://www.uptodate.com
Thiazolidinediones- Adverse reactions
• Liver function should be monitored in patients
receiving Tzds
• Tzds have been associated with osteopenia and
increased fracture risk in women,
– which is postulated to be due to decreased osteoblast
formation
• Rosiglitaonze: HDL-cholesterol increased, LDLcholesterol increased, total cholesterol increased
• Hypoglycemia is rare with Tzds monotherapy;
– however, these drugs may potentiate the hypoglycemic
effects of concurrent sulfonylurea or insulin therapy
112
Thiazolidinediones- Adverse reactions
• Hypoglycemia is rare with Tzds monotherapy;
however, these drugs may potentiate the
hypoglycemic effects of concurrent sulfonylurea
or insulin therapy
• Bladder cancer:
– clinical trial data suggest an increased risk of bladder
cancer in patients exposed to pioglitazone; risk may be
increased with duration of use 2
2 Source: http://www.uptodate.com
α-Glucosidase Inhibitors
• Acarbose, miglitol, are competitive inhibitors of the αglucosidases in the intestinal brush border:
–
–
–
–
sucrase,
maltase,
glucoamylase,
And dextranase
• Inhibition of this enzyme slows the absorption of
CHOs;
– the postprandial rise in plasma glucose is blunted in both
normal and diabetic subjects
• They do not stimulate insulin release, nor do they
increase insulin action in target tissues.
– Thus, as monotherapy, they do not cause hypoglycemia
116
α-Glucosidase Inhibitors
• They are approved for persons with type 2
diabetes as:
– monotherapy
– and in combination with sulfonylureas, in which the
glycemic effect is additive
• The drugs should be administered at the start of
a meal
117
α-Glucosidase Inhibitors- ADEs
• Dose-related
–
–
–
–
flatulence,
diarrhea,
and abdominal pain
from the appearance of undigested CHO in the colon that is
then fermented into short-chain fatty acids, releasing gas.
– These tend to diminish with ongoing use
• Patients should not use these drugs:
– with inflammatory bowel disease,
– colonic ulceration,
– or intestinal obstruction
118
α-Glucosidase Inhibitors- ADEs
• Hypoglycemia may occur with concurrent sulfonylurea
treatment.
– If hypoglycemia occurs glucose (dextrose) should be
administered
• α-glucosidase inhibitors should not be prescribed in
individuals with severe renal impairment
• Acarbose has been associated with reversible hepatic
enzyme elevation
– and should be used with caution in the presence of hepatic
disease
119
Amylin analogs: Pramlintide
• It 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
• MOA:
– reduces glucagon secretion, slows gastric emptying by a
vagally medicated mechanism,
– and centrally decreases appetite
• It is administered SC in addition to insulin in those
– who are unable to achieve their target postprandial blood
sugars
Amylin analog: Pramlintide
• Because of the risk of hypoglycemia,
– concurrent rapid- or short-acting mealtime insulin doses
should be decreased by 50% or more
– Concurrent insulin secretagogue doses also may need to be
decreased in persons with type 2 diabetes.
• Pramlintide should always be injected by itself with a
separate syringe; it cannot be mixed with insulin
• ADEs:
– hypoglycemia
– and GIT symptoms (nausea, vomiting, and anorexia)
• Pramlintide is contraindicated in patients with:
– diabetic gastroparesis
– or a history of hypoglycemic unawareness
Incretin-based therapies: In ● cre ● tin
Intestine Secretion Insulin
• An incretin is a compound which is responsible for the
– higher insulin release in response to an oral glucose load
compared to an equal intravenous glucose load (reaching
the same glucose level)
• The incretin effect is believed to be mediated by
mainly two intestinal derived peptides:
– Glucose-dependent insulinotropic polypeptide (GIP)
– and GLP-1 (glucagon-like peptide-1)
• The incretin effect, is responsible for
– 50–70% of total insulin secretion after oral glucose
administration
Incretin Effect
“gut derived hormones that stimulate
insulin secretion with nutrient
ingestion”
2.0
C-peptide (nmol/L)
Plasma Glucose (mg/dL)
200
Oral Glucose
Intravenous (IV) Glucose
1.5
100
Incretin Effect
1.0
0.5
0
0.0
0
60
60
120
180
Time (min)
Time (min)
N = 6; Mean ± SE; *P0.05
127
Source :Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
0
120
180
More recently, investigators have reported that impairments in the secretion levels
and/or the activity of key incretin hormones may also play a significant role in the
development and progression of hyperglycemia in T2DM
Control subjects (n=8)
80
80 People with Type 2 diabetes
(n=14)
60
Insulin (mU/l)
Incretin
effect
40
20
Insulin (mU/l)
60
40
20
0
0
0
60
120
180
Time (min)
Oral glucose load
Intravenous glucose infusion
0
60
120
Time (min)
128
180
Physiology of GLP-1 secretion and action on various
tissues
GLP-1 secreted upon the
ingestion of food
5.Brain:
promotes satiety and
reduces appetite4,5
2.α-cell:
suppresses
postprandial
glucagon secretion1
1.-cell:
enhances glucosedependent insulin
secretion in the pancreas1
1Nauck MA, et al. Diabetologia 1993;36:741–744
2Larsson H, et al. Acta Physiol Scand 1997;160:413–422
3Nauck MA, et al. Diabetologia 1996;39:1546–1553
4Flint A, et al. J Clin Invest 1998;101:515–520
5Zander et al. Lancet 2002;359:824–830.
3.Liver:
reduces hepatic glucose
output2
4.Stomach:
slows the rate of
gastric emptying3
Incretin-based therapies
• Two different approaches can be used:
1. GLP-1 receptor agonists:
– that directly stimulate GLP-1 receptors on the pancreas
and gut
– to give effects similar to those of endogenous GLP-1
– (e.g. Exenatide, & liraglutide)
2. Enhance endogenous incretins by inhibiting their
degradation (dipeptidyl peptidase-4 DPP-4
inhibitors):
– thereby extending the activity of endogenously
produced GLP-1 and GIP
– (e.g. Sitagliptin, saxagliptin, & linagliptin)
Exenatide (Exendin-4) was discovered in a lizard
(salivary gland venom of the Gila monster)
GLP-1 receptor agonist
• Agents: exenatide and liraglutide
• Exenatide:
– (t1/2 of 2-3 hrs)
– is given as a Sc injection twice daily,
– typically before the first and last meals of the day
• Liraglutide:
– has extended t1/2 (12-14 hrs)
– permitting once a day administration given as a SC injection
• Are approved for use as for adjunctive therapy in
patients not achieving glycemic control:
– with metformin, sulfonylurea, or the combination of
metformin/ sulfonylurea or metformin/ tzds
Exenatide
• In clinical studies, exenatide therapy was shown to have
multiple actions such as :
–
–
–
–
potentiation of glucose-mediated insulin secretion,
suppression of postprandial glucagon release
slowed gastric emptying,
and a central loss of appetite.
• The increased insulin secretion is speculated to be due in
part to an increase in beta-cell mass.
135
GLP-1 receptor agonist
• In the absence of other diabetes drugs that cause low
blood glucose, hypoglycemia associated with GLP-1
agonist treatment is rare
• Although they require injection, the GLP-1 receptor
ligands have gained popularity because of:
– the improved glucose control
– and associated anorexia and weight loss in some users
GLP-1 receptor agonist
• ADEs:
– nausea (about 44% of users) decreases with ongoing usage, vomiting
and diarrhea,
– weight loss (anorectic effect)
• The most commonly observed adverse transient nausea,
– which may be the result of delayed gastric emptying.
– Resolves within 6-8 weeks
• In some cases, fatal necrotizing and hemorrhagic pancreatitis
in patients using exenatide:
– should not be prescribed for patients with a history of pancreatitis
– or risk factors such as:
•
cholelithiasis, hypertriglyceridemia, or alcohol abuse
138
Dpp-4 Inhibitors
• Agents; sitagliptin, saxagliptin,
vildagliptin (EU), and alogliptin
linagliptin,
&
• DD4 inhibitors:
– increase circulating levels of GLP-1 and GIP when their
secretion is by a meal
– and ultimately decreases postprandial glucose
excursions
2. Dpp-4 Inhibitors
• Approved as:
– a monotherapy
– and as an add-on therapy to metformin, TZDs, sulfonylureas,
and insulin
• Hypoglycemia is not common with these agents
because:
– insulin secretion results from GLP-1 activation caused by
meal-related glucose detection and not from β cell
stimulation
2. Dpp-4 Inhibitors
• Common adverse effects include:
– nasopharyngitis,
headaches
upper
respiratory
infections,
and
• Both sitagliptin and saxagliptin are excreted renally,
– and lower doses should be used in patients with reduced
renal function
• Renal clearance of linagliptin is minor; therefore,
dosage adjustment is not necessary in patients with
renal impairment, although caution is advised
• The most concerning issue to arise with sitagliptin is
– acute pancreatitis including hemorrhagic and necrotizing
pancreatitis
NEW ANT-DIABETES DRUGS: SELF
READ
142
Bile Acid Binding Resins: colesevelam
•
•
Approved as an adjunctive treatment for patients
with T2DM to improve glycemic control in
conjucation with diet, exercise, insulin, & oral agents
Possible mechanism of action:
1) Interruption of the enterohepatic circulation
2) Decrease in farnesoid X receptor (FXR) activation
3) Impair glucose absorption
Bile Acid Binding Resins: colesevelam
•
Its has favourable effect on the concentrations of LDL
and HDL cholesterol
• Side effects:
a) GIT (most common): constipation, dyspepsia,
abdominal pain, and nausea affecting up to 10% of
treated patients
b) Increase plasma TGss in persons with an inherent
tendency to hypertriglyceridemia
•
Colesevelam may impair absorption of multiple other
medications including fat-soluble vitamins, glyburide,
levothyroxine, and oral contraceptives
Dopamine D2-receptor agonists: bromocriptine
•
Bromocriptine administered in the morning
improves insulin sensitivity and has no effect on
insulin secretion
•
Effects of bromocriptine on blood glucose may reflect
an action on the CNS: altering the activity of
hypothalamic neurons to reduce hepatic
gluconeogenesis through a vagally mediated route
•
Side effects: nausea, fatigue, dizziness, orthostatic
hypotension, vomiting, and headache
Sodium GLucose
Transporter 2 inhibitor (SGLT2i)
• Approved for the treatment of T2DM as an adjunct to
diet and exercise as monotherapy or in combination
therapy with other antidiabetic agents to improve
glycemic control
• Advantages: a relatively low hypoglycemia risk and
weight loss-promoting effects
• ADRs: urinary tract and genital infections, hypotension,
hyperkalemia, dose-related LDL-C elevation
147
Ipragliflozin (Japan)
Capaglifozin
Dapaglifozin
Empagliflozin
(Europe)
3
4
5
2013
148
6
7
8
9
10
11
12
1 2
2014
3
4
The kidney plays a critical role in filtration and
reabsorption of glucose
(180 L/day) (900 mg/L)=162 g/day
Glucose
SGLT2
S1
SGLT1
S3
90%
10%
No Glucose
Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32-43.
Glucagon
Chemistry, Mechanism, and Effects
• Glucagon is a 29 amino acids protein hormone secreted by
the A cells of the endocrine pancreas.
• Acting through G-protein-coupled receptors (Gs) in heart,
smooth muscle, and liver, glucagon:
– increases heart rate and force of contraction,
– increases hepatic glycogenolysis and gluconeogenesis,
– and relaxes smooth muscle.....(cAMP)
•
The smooth muscle effect is particularly marked in the gut.
151
Glucagon- Clinical uses
• Severe hypoglycemia:
– glucagon is used for the emergency treatment of severe
hypoglycemia in patients with type 1 DM when
unconsciousness (glycogenolysis)
– (i.v or i.m)…1-mg vials for parenteral use (Glucagon
Emergency Kit).
– Nasal sprays developed but not yet approved
• Radiology of the bowel:
– glucagon has been used extensively in radiology as an aid to
x-ray visualization of the bowel because of its ability to relax
the intestine
• β-Adrenoceptor Blocker Overdose:
• glucagon is sometimes useful for reversing the cardiac
effects of an overdose of β-blocking agents
Glucagon- Clinical uses
• Endocrine Diagnosis: in patients with type 1 diabetes
mellitus, a classic research test of pancreatic beta-cell
secretory reserve, uses
– 1 mg of glucagon administered as an IV bolus
• Because insulin-treated patients develop circulating
anti-insulin
antibodies
that
interfere
with
radioimmunoassays of insulin,
– measurements of C-peptide are used to indicate beta-cell
secretion
Glucagon- ADEs
• Transient Nausea and occasionally Vomiting
• These are generally mild, and glucagon is relatively
free of severe adverse reactions