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Pancreas.ppt
1. Pancreatic Hormones & Antidiabetic
Drugs
By Dr. Usama Shah
BDS, RDS, C-endo, C-Implant
2. Diabetes Mellitus
Diabetes mellitus (DM) is a group of metabolic
disorders of fat, carbohydrate, and protein
metabolism that results from defects in insulin
secretion, insulin action (sensitivity), or both
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
3. 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
4. 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
5. Type 2 Diabetes Mellitus
The pathogenesis of type 2 diabetes mellitus is
complex
Type 2 diabetic individuals are characterized by:
1) Defects in insulin secretion
2) Insulin resistance involving muscle, liver, and
the adipocyte
6. Ramlo-Halsted BA, et al. Prim Care 1999;26:771–789.
Impaired insulin production
& secretion
Insulin resistance (IR)
- Hyperinsulinaemia
- Normal glucose tolerance
IR + declining insulin levels + impaired glucose tolerance
- Failure of β-cell to adapt to IR
Genetic
Predispositions
Impaired responsiveness
to insulin
↑FFA levels
Sedentary
lifestyle
Diet Obesity
Type 2 diabetes
Glucotoxicity
-cell dysfunction
Pathophysiology of Type 2 Diabetes
7. Insulin and Glucose Patterns: Normal and Type 2 Diabetes
Polonsky, et al. N Engl J Med. 1988;318:1231-1239.
100
200
300
400
Glucose Insulin
0600 1000 1800
1400 0200
2200 0600
Time of Day
0600 1000 1800
1400 0200
2200 0600
Time of Day
20
40
60
80
100
120
B L D
B L D
Normal
Type 2 Diabetes
mg/dL
U/mL
8. Relative
Activity
Glucose
Years from Diabetes Diagnosis
–10 –5 0 5 10 15 20 25 30
-10 -5 0 5 10 15 20 25 30
*Conceptual representation.
NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.
Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.; and Ramlo-Halsted et al. Prim Care. 1999;26:771–789.
Postprandial glucose
Fasting glucose
Insulin resistance —
hepatic and peripheral
Insulin level
Beta-cell function
9. Time (min)
Mixed Meal (With ~85 g Dextrose)
0 120 240 360 480
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
Grams
of
Glucose
(flux/min)
-30
Insulin-mediated
glucose uptake
Balance of
insulin suppression and
glucagon stimulation
Regulated by hormones:
GLP-1, amylin, CCK, etc.
Meal-Derived Glucose
Hepatic Glucose Production
Total Glucose Uptake
N = 5; Mean (SE)
Data from Pehling G, et al. J Clin Invest 1984;74:985-991.
10. 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)
11. 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
12. 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
13. 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
14. TNF=tumor necrosis factor; CRP=C-reactive protein; PAI-1=plasminogen-activator inhibitor-1; MI=myocardial infarction; PVD=peripheral vascular disease
Adapted from Inzucchi SE JAMA 2002;287(3):360–372; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philiadelphia: Saunders, 2003:1427–1483; Sheetz MJ, King GL JAMA
2002;288(20):2579–2588; Libby P, Plutzky J. Editorial Circulation 2002;106:2760–2763;
Kendall DM et al Coron Artery Dis 2003;14:335–348; DeFronzo RA Ann Intern Med 1999;131:281–303.
Impaired insulin release Insulin resistance
Increased
circulating
free fatty acids
Macrovascular risk
• MI
• Stroke
• PVD
Microvascular risk
• Nephropathy
• Retinopathy
• Neuropathy
TNF-alpha
CRP
PAI-1
Dyslipidemia
Increased platelet aggregation
Blood vessel wall
abnormalities
Decreased
glucose uptake
Increased
lipolysis
Hyperglycemia
Overproduction
of glucose
15. Characteristic Type 1 DM Type 2 DM
Age <30 years >30 years
Onset Abrupt Gradual
Body habitus Lean Obese or history of
obesity
Insulin resistance Absent Present
Autoantibodies Often present Rarely present
Symptoms Symptomatic Often asymptomatic
Ketones at diagnosis Present Absent
Need for insulin therapy Immediate Years after diagnosis
Acute complications Diabetic ketoacidosis Hyperosmolar
hyperglycemic state
Microvascular complications at
diagnosis
No Common
Macrovascular complications at
or before diagnosis
Rare Common
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.
18. Insulin
Insulin is a polypeptide hormone (mwt =5808
Da)
It contains 51 amino acids arranged in two
chains (A and B) linked by disulfide bridges;
there are species differences in the amino
acids of both chains
20. S
S
Connecting Peptide
A Chain
B Chain
S
S
S
S
Proinsulin is single-chain
precursor in which the A and
B chains are connected by
the C peptide (proinsulin)
S
S
C-peptide
A Chain
B Chain
S
S
S
S
Proinsulin is hydrolyzed into
insulin (51aa) and a residual
connecting segment called C-
peptide (31aa) by removal of
four amino acids
22. Insulin secretion
Insulin is released from pancreatic β cells at a low
basal rate during fasting and at a much higher
stimulated rate in response to a variety of stimuli,
especially glucose
Glucose-induced stimulation of insulin release
from cells is biphasic
The first phase of insulin secretion is often blunted
in diabetes
24. Insulin secretion
Glucose enters the β cell by facilitated
transport, which is mediated by GLUT2
Glucose is phosphorylated by glucokinase &
enhances ATP production
The rise in ATP levels causes a block of K+
channels, leading to membrane depolarization
and an influx of Ca2+, which results in pulsatile
insulin exocytosis
26. 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 with the kidney removing 35–40% of
the endogenous hormone
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%
27. Cellular actions of insulin
Some effects of insulin occur within seconds or
minutes, including the activation of glucose
transport systems
Other effects, such as those on protein synthesis
and gene transcription, may take a few hours
Effects of insulin on cell proliferation and
differentiation may take days
28. Mechanism of Insulin Action
Glucose
Glucose
Transporter
Insulin
Receptor
P
P
P
P
P
P
Translocation
of
Glucose
Transporters
Skeletal muscle
Adipose Tissue
Insulin
Tyrosine kinase
doamins
Tyr Tyr- P
MAPK pathway
PI
3
kinase pathway
Protein synthesis Glycogen synthesis
Cell growth,
Differentiation, survival
29. Effects of insulin on its target
The important target tissues for regulation of
glucose homeostasis by insulin are liver,
muscle, and fat
Insulin stimulates intracellular use and storage
of glucose, amino acids, and fatty acids and
inhibits catabolic processes such as the
breakdown of glycogen, fat, and protein
30. Overview of insulin action
Triglycerides
Adipose
Tissue
Glycogen
Liver
Protein
Muscle
Glucose Amino
Acids
Fatty
Acids
Stimulated by insulin
Increased by feeding
Inhibited by insulin
Increased by fasting and in diabetes
Fatty
Acids
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
31. Insulin Therapy
1) All patients with type 1 DM (primary
indications)
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
32. Insulin Therapy
Long-term treatment relies predominantly on
Sc injections in the abdomen, buttock,
anterior thigh, or dorsal arm
The goal of Ss 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
33. Characteristics of Available Insulin Preparations
Preparations of insulin can be classified according
to their duration of action into short, intermediate,
and long acting and by their species of origin-
human or porcine
Modifications of the amino acid sequence of
human insulin have produced insulins with
different PK properties
35. Characteristics of Available Insulin Preparations
Doses and concentrations of insulin are
expressed in units
Almost all commercial preparations of insulin
are supplied in solution or suspension at a
concentration of 100 units/ml (100U)
Insulin also is available in a more
concentrated solution (500 units/mL) for
patients who are resistant to the hormone
36. Principal types and Duration of Action of
Insulin Preparations
Four principal types of injected insulins 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
5) Ultra long-acting insulin
37. Hours
regular
NPH
lispro/aspart
detemir
glargine
Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491
Plank, J. et.al. Diabetes Care, May 2005; 28(5): 1107-12
Extent and duration of action of various types of insulin
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
38. 1. Rapid-acting insulin
Analogs: insulin lispro, insulin aspart, and insulin
glulisine
When injected subcutaneously, they quickly
dissociates into monomers and are rapidly
absorbed with onset of action within 5–15 minutes
and peak activity as early as 1 hour.Their duration
of action is rarely more than 3-5 hours
39. 1. Rapid-acting insulin
These agents offer more flexible treatment
regimens and may lower the risk of hypoglycemia
The rapid-acting insulins permit more physiologic
prandial (After meal) insulin replacement allowing
insulin to be taken immediately before the meal
without sacrificing glucose control
They have the lowest variability of absorption of
all available commercial insulins (approximately
5%)
40. 2. Short-acting insulin
Its effect appears within 30 minutes and peaks
between 2 and 3 hours after Sc injection and generally
lasts 5-8 hours
Typically, regular insulin is administered several
minutes (30-45 mins) before a meal and is designed to
control postprandial hyperglycemia
It is primarily used to supplement intermediate- & long-
acting insulin preparations
It is the only type that can be administered
intravenously: in the management of diabetic
ketoacidosis and when the insulin requirement is
changing rapidly (e.g. after surgery or during acute
infections)
42. 3. Intermediate-acting insulins
NPH insulin is formulated to dissolve more gradually
when administered subcutaneously; thus their
durations of action are longer
NPH insulin has an onset of approximately 2-5 hours
and duration of 4-12 hours
It is used for basal control and is usually mixed
with regular, lispro, aspart, or glulisine insulin
The action of NPH is highly unpredictable, and its
variability of absorption is over 50%
43. Long acting insulins
Insulin glargine
Insulin glargine has a slow onset of action (1-1.5
hours) and achieves a maximum effect after 4-6
hours. This maximum activity is maintained for 11-
24 hours or longer
It is used to provide reproducible, convenient,
background/ basal insulin replacement
Glargine is usually given once daily
Insulin glargine results in less hypoglycemia, has
a and provides a better once-daily 24-hour insulin
coverage than NPH insulin
44. b. Insulin detemir
Insulin detemir has a fatty-acid side chain ,whcih
prolongs the availability of the injected analog by
increasing both self-aggregation in SC tissue and
reversible albumin binding
Insulin detemir has a dose-dependent onset of
action of 1-2 hours and duration of action of more
than 24 hours
It is given twice daily to obtain a smooth
background insulin level
45. ultra long-acting
insulin: Insulin degludec
Insulin degludec produces a flat profile, producing a
stable glucose-lowering effect
The terminal half-life of insulin degludec is
approximately 25 h
The duration of action is reportedly in excess of 40 h
insulin degludec can be administered once daily, at
any time of the day, with little consequence from a
change in injection timing that may result from an
unexpected lifestyle event
45
46. Insulin degludec Insulin glargine
0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg
Half-life (hours) 25.9 27.0 23.9 11.8 14.0 11.9
Mean half-life 25.4 12.5
*Insulin glargine was undectable after 48 hours
Results from patients with type 1 diabetes
IDeg, insulin degludec; IGlar, insulin glargine
Heise et al. Diabetologia 2011;54(Suppl. 1):S425
*
IDeg 0.8 U/kg
IGlar 0.8 U/kg
47. Comparison of Human Insulins & Analogues
Insulin Onset of Peak of Duration of
Preparations Action Action (h) Action (h)
Short-acting
Regular human 30-60 min 2-3 4-6
Lispro 15-30 min 1-2 3-4
Aspart 15-30 min 1-2 3-5
Gluilisine 15-30 min 1-2 5-6
Intermediate-acting
NPH 2-4 h 4-8 8-12
Long-acting
Glargine 4-5 h None 22-24h
Detemir 2 h None 14-24 h
48. 5. Mixtures of insulins
1) Insulin lispro, aspart, and glulisine can be acutely
mixed (ie, just before injection) with NPH insulin
without affecting their rapid absorption
Limitations: mixing technique and inaccurate dosing
ratios, potentially reducing the effectiveness of the
short-acting insulin
2) 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
52. Inhaled insulin: Afrezza
Is a rapid-acting inhaled insulin to be administered
prior to meals or within 20 minutes of starting a meal
The most common ADRs associated with Afrezza in
clinical trials were hypoglycemia, cough, and throat
pain or irritation
It is not a substitute for long-acting insulin and must
be used in combination with long-acting insulin in
patients with type 1 diabetes
It is not recommended for the treatment of diabetic
ketoacidosis or in patients who smoke or who have
chronic lung disease
52
54. Amylin analogs: Pramlintide
Pramlintide 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 in patients with type 1 and type 2 diabetes
Because of the risk of hypoglycemia, concurrent rapid-
or short-acting mealtime insulin doses should be
decreased by 50% or more
56. 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
57. Categories of oral antidiabetic agents now available for
the treatment of persons with type 2 diabetes
• Insulin secretagogues
• Insulin senitizers
• α-glucosidase inhibitors
• Amylin analog
• GLP-1 receptor agonist
• Dpp-4 Inhibitors
• Dopamine D2-receptor agonists
• Bile Acid Binding Resins
• Sodium Glucose Transporter 2
inhibitor
59. 1. Sulfonylurea
In the presence of viable pancreatic β-cells,
sulfonylureas directly enhance the release of
endogenous insulin, thereby reducing blood
glucose levels
Sulfoylureas are used to treat T2DM in the
early stages, but b/c they require functional β-
cells, they are not useful un late stage T2DM
60. 1. Sulphonylurea- Mechanism of action
1) Insulin Release from Pancreatic Beta Cells: by
binding to a specific site on the β cell KATP
channel complex (the sulfonylurea receptor,
SUR) and inhibiting its activity
2) Extrapancreatic effects
Reduce hepatic clearance of insulin, further
increasing plasma insulin levels
Long-term administration of sulfonylureas reduces
serum glucagon levels due to enhanced release
of both insulin and somatostatin, which inhibit
alpha-cell secretion
61. Sulfonylurea- Mechanism of action
Ca
++
K
+
K
+
ATP-binding
site
Voltage-dependent
Ca++ channel closed
ATP-sensitive K+ channel
Sulfonylurea-binding site
Kir 6.2
ATP
From Ashcroft FM, Gribble FM. Diabetologia. 1999;42:903-909.
Berne R, Levy M. Physiology. Chapter 46;851-875.
ADP
ADP
ADP
ADP
ADP
62. Sulfonylurea- Mechanism of action
K
+
Ca++
Exocytosis of insulin-
containing granules
Sulfonylurea
K
IR
6.2
Ca++
depolarization
ATP
ATP
ATP
ATP
ADP
ATP-sensitive K+
channel closed
From Ashcroft FM, Gribble FM. Diabetologia. 1999;42:903-919.
Bryan J, Aguilar-Bryan L. Biochemica et Biophysica Acta. 1999;1461;285-303.
Berne R, Levy M. Physiology. Chapter 46;851-875.
64. 1. Sulfonylurea
The sulfonylureas are divided into two groups or
generations of agents
The first generation sulfonylureas (tolbutamide,
tolazamide, and chlorpropamide) are rarely used
now in the treatment of type 2 diabetes
The second, more potent generation of
hypoglycemic sulfonylureas includes glyburide
(glibenclamide, glipizide, and glimepiride
65. First generation Sulfonylureas
Drug Tolbutamid Acetohexamide Tolazamide Chlorpropamide
Absorption Well Well Slow Well
Metabolism Yes Yes Yes Yes
Metabolites Inactive Active Active Inactive
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of
action
Short
(6 – 8 hrs)
Intermediate
(12 – 20 hrs)
Intermediate
(12 – 18 hrs)
Long
( 20 – 60 hrs)
Excretion Urine Urine Urine Urine
Second generation sulfonylureas
Drug Glipizide Glibenclamide Glimepiride
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of
action
10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
Excretion Urine Urine Urine
66. 1. Sulfonylureas- Adverse reactions
1. Hypoglycemia:
The commonest adverse effect
Can be severe and prolonged
This is a particular concern in elderly patients
with impaired hepatic or renal function who are
taking longer-acting sulfonylureas
67. 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. Others: NV, cholestatic jaundice,
agranulocytosis, aplastic and hemolytic anemias,
generalized hypersensitivity reactions, and
dermatological reactions
68. 2. KATP Channel Modulators: Non-Sulfonylureas
Glinides: rapeglinide and nateglinide
Like sulfonylureas, they stimulate insulin
release by closing ATP-dependent potassium
channels in pancreatic β cells
In contrast to sulphonylureas, the glinides
have a rapid onset and a short duration of
action and are much less potent than most
sulfonylureas
69. 2. KATP Channel Modulators: Non-Sulfonylureas
Because of their rapid onset, the glinides are
categorized as postprandial glucose
regulators
They 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
They are to be taken 15 to 30 mins before a
meal
70. 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
71. 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
72. 1. Biguanides
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
73. 1. Biguanides- Mechanism of action
1) The liver:
• Metformin increases the activity of the AMP-
dependent protein kinase (AMPK)
• Activated AMPK stimulates fatty acid oxidation,
glucose uptake, and nonoxidative metabolism,
and it reduces lipogenesis and gluconeogenesis
2) Increase glucose uptake and utalization
in skeletal muscles
3) Reduce carbohydrate absorption
74. Metformin: Mechanism of action
74
Adapted from DeFronzo RA Ann Intern Med 1999;131:281–303; Kirpichnikov D et al Ann Intern Med 2002;137(1):25–33; Williams G, Pickup JC, eds.
Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Hundal RS et al Diabetes 2000;49(12):2063–2069.
Metformin
Enhanced muscle
glucose uptake
Reduced insulin
resistance
Reduced hepatic
glucose production
Precise mechanism of action is unknown
Reduced plasma glucose
75. Metformin
Adapted from Jackson, et al. Diabetes. 1987;36:632-640, with permission.
Baseline
Metformin
0
80
120
160
200
240
280
320
360
1 2 3
Oral
glucose
Oral
glucose
Time (h)
0
0
20
40
60
1 2 3
Time (h)
Plasma Glucose Serum Insulin
mg/dL
mU/L
76. 1. Biguanide
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 produces beneficial efects on serum
lipid: TG & LDL-C may be reduced as much as
18.6% and 12.06% respectively
It is the only therapeutic agent that has been
demonstrated to reduce macrovascular events in
type 2 DM
77. 1. Biguanide- Clinical uses
Metformin is effective as monotherapy and in
combination with nearly every other therapy
for type 2 diabetes
Fixed-dose combinations of metformin in
conjunction with glipizide, glyburide,
pioglitazone, repaglinide, rosiglitazone, and
sitagliptin are available
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
78. 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
79. 1. Biguanide: lactic acidosis
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
Biguanides inhibits the mitochondrial oxidation
of lactic acidosis, thereby increasing the
chance of lactic acidosis occurance
80. 1. Biguanide: lactic acidosis
Patients with renal insufficiency, alcoholism,
hepatic disease, or conditions predisposing to
tissue anoxia (eg, chronic cardiopulmonary
dysfunction)
Metformin is contraindicted in patients with
serum creatinin level ≥ 1.4mg/dl in women &
1.5mg/dl in men
It should be initiated in patients 80 years of
age or older unless normal renal function is
established
81. (
Tzds
)
2. Thiazolidinediones
Agents: pioglitazone and rosiglitazone
Tzds are selective agonists for nuclear
peroxisome proliferator-activated receptor-γ
)PPARγ(
The principal response to PPARγ activation is
adipocyte differentiation
Along with adipocyte differentiation, PPARγ
activity promotes uptake of circulating fatty
acids into fat cells and shifts of lipid stores to
adipose tissue
83. Dual PPARα/γ Agonists: Mechanism of Action
PPAR selectivity (alpha/gamma zone)
alpha/gamma
Improved lipid control
Fatty acid oxidation
Total cholesterol
TG
Improved glucose control
Insulin sensitivity
Glucose
Free fatty acids
Effects of
dual PPARs
O
N
H
O
S
N
H
O
O
F
F
F
Adapted from Doebber TW et al Biochem Biophys Res Comm 2004;318:323–328; Guo Q et al Endocrinology 2004;145(4):1640–1648; Hegarty BD
et al Endocrinology 2004;145(7):3158–3164.
Gamma
Alpha
fenofibrate pioglitazone rosiglitazone
84. Thiazolidinediones- Adverse reactions
The most common adverse effects of the
thiazolidinediones are weight gain and edema
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, explaining the adverse effect of fluid
retention
85. 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
86. Thiazolidinediones- Adverse reactions
Liver function should be monitored in patients
receiving Tzds
Rosiglitaonze: HDL-cholesterol increased,
LDL-cholesterol increased, total cholesterol
increased
Tzds have been associated with osteopenia
and increased fracture risk in women
87. 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
88. α-Glucosidase Inhibitors
Agents: Acarbose, miglitol, and voglibose
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
89. Acarbose
Dimitriadis, et al. Metabolism. 1982;31:841-843.
Normal absorption of CHO
Without Acarbose
With Acarbose
Acarbose blocks proximal
absorption
Duodenum
Jejunum Ileum
Time (min)
140
–30 0 60 120 180 240
120
100
80
*
*
Meal
Placebo
Acarbose
* P <.05
Plasma
Glucose
(mg/dL)
90. 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
91. 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 with IBD, colonic ulceration, or intestinal
obstruction should not use these drugs
92. 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 renal impairment
Acarbose has been associated with reversible
hepatic enzyme elevation and should be used
with caution in the presence of hepatic disease
94. 94
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)
Oral Glucose
Intravenous (IV) Glucose
N = 6; Mean ± SE; *P0.05
Source :Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
C-peptide
(nmol/L)
Time (min)
0.0
0.5
1.0
1.5
2.0
Incretin Effect
Plasma
Glucose
(mg/dL)
200
100
0
Time (min)
60 120 180
0
60 120 180
0
95. Incretin-based therapies
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
96. 96
Oral glucose load
Intravenous glucose infusion
Time (min)
Insulin
(mU/l)
80
60
40
20
0
180
60 120
0
Time (min)
Insulin
(mU/l)
80
60
40
20
0
180
60 120
0
Incretin
effect
Control subjects (n=8) People with Type 2 diabetes (n=14)
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
97. Microvascular changes
Macrovascular changes
Clinical
features
Kendall DM, et al. Am J Med 2009;122:S37-S50.
Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
IFG, impaired fasting glucose;
IGT, impaired glucose tolerance.
Years
Relative
Amount
-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
0
50
100
150
200
250
-15
β-cell failure
Onset
diabetes
Glucose
(mg/dL)
Diabetes
diagnosis
50
100
150
200
250
300
350
Fasting glucose
Prediabetes
(Obesity, IFG, IGT)
Postmeal Glucose
-10 -5 0 5 10 15 20 25 30
-15
Years
98. Physiology of GLP-1 secretion and action on
various tissues
GLP-1 secreted upon the
ingestion of food
1.-cell:
enhances glucose-dependent
insulin secretion in the pancreas1
3.Liver:
reduces hepatic glucose
output2
2.α-cell:
suppresses postprandial
glucagon secretion1
4.Stomach:
slows the rate of gastric
emptying3
5.Brain:
promotes satiety and
reduces appetite4,5
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.
99. Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.
Intestinal
GLP-1
release
GLP-1 (7-36)
active
Mixed
meal
GLP-1 (9-36)
inactive
(>80% of pool)
DPP-4
T
1/2
= 1 to 2 min
100. 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
2.Enhance endogenous incretins by
inhibiting their degradation (DPP-4
inhibitors): thereby extending the activity of
endogenously produced GLP-1 and GIP
101. GLP-1 receptor agonist
Agents: exenatide, liraglutide, albiglutide
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
long-acting release (LAR) exenatide formulation is
approved as a once-weekly injection
Liraglutide has extended t1/2 (12-14 hrs)
permitting once a day administration
Albiglutide is a recombinant protein fusion of GLP-
1 and albumin at is thadministered once-weekly
102. GLP-1 receptor agonist- MOA
1) Potentiation of glucose-mediated insulin
secretion
2) Suppression of postprandial glucagon
release
3) Slowed gastric emptying
4) Central loss of appetite
The increased insulin secretion is speculated to
be due in part to an increase in beta-cell mass
103. 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
104. GLP-1 receptor agonist
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
Albiglutide should not be used in patients with a
personal or family history of MTC
105. Dpp-4 Inhibitors
Agents; sitagliptin, saxagliptin, linagliptin, &
vildagliptin (EU), and alogliptin
DD4 inhibitors increase circulating levels of GLP-1
and GIP when their secretion is by a meal and
ultimately decreases postprandial glucose
excursions
107. 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
108. 2. Dpp-4 Inhibitors
Common adverse effects include nasopharyngitis,
upper respiratory infections, and headaches
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
109. Bile Acid Binding Resins: colesevelam
Approved as an adjunctive treatment for patients
with T2DM to improve glycemic control
Its has favourable effect on the concentrations of
LDL and HDL cholesterol
Side effects:
GIT (most common): constipation, dyspepsia,
abdominal pain, and nausea affecting up to 10%
of treated patients
Increase plasma TGss in persons with an
inherent tendency to hypertriglyceridemia
110. Dopamine D2-receptor agonists: bromocriptine
Broocriptine 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
111. 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
111
113. SGLT2
S1 segment of
proximal tubule
~90%
~10%
SGLT1
Distal S2/S3 segment
of proximal tubule
Reabsorption
~180 g/day
No glucose in
urine
SGLT2, sodium-glucose co-transporter-2.
Adapted from: Abdul-Ghani MA, et al. Endocr Pract 2008;14:782–90;
Gerich JE. Diabet Med 2010;27:136–42.
SGLT2 plays a crucial role in renal glucose
reabsorption in the proximal tubule
Glucose
The kidney plays a critical role in filtration and
reabsorption of glucose
114. SGLT2
S1 segment of
proximal tubule
~90%
~10%
SGLT1
Distal S2/S3 segment
of proximal tubule
Reabsorption
~180 g/day
SGLT2, sodium-glucose co-transporter-2.
Adapted from: Abdul-Ghani MA, et al. Endocr Pract 2008;14:782–90;
Gerich JE. Diabet Med 2010;27:136–42.
SGLT2 plays a crucial role in renal glucose
reabsorption in the proximal tubule
Glucose
The kidney plays a critical role in filtration and
reabsorption of glucose
Glycosuria
Maximum
reabsorptive
capacity
exceeded
Excess glucose
not reabsorbed
