pancreatic hormones & antidiabetic drugs. diabetes mellitus diabetes mellitus (dm) is a group...
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Pancreatic Hormones & Antidiabetic Drugs
Pancreatic Hormones & Antidiabetic Drugs
Diabetes MellitusDiabetes 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
Diabetes MellitusDiabetes 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
Type 1 Diabetes Mellitus 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
Type 2 Diabetes MellitusType 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
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 levelsSedentary
lifestyle
Diet Obesity
Type 2 diabetes
Glucotoxicity
-cell dysfunction
Pathophysiology of Type 2 Diabetes
Insulin and Glucose Patterns: Normal and Type 2 Diabetes 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 18001400 02002200 0600
Time of Day
0600 1000 18001400 02002200 0600
Time of Day
20
40
60
80
100
120
B L DB L D
Normal
Type 2 Diabetes
mg
/dL
U/m
L
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 peripheralInsulin level
Beta-cell function
Time (min)
Mixed Meal (With ~85 g Dextrose)
0 120 240 360 480-0.6
-0.4
-0.2
0
0.2
0.4
0.6G
ram
s o
f G
luc
os
e (
flu
x/m
in)
-30
Insulin-mediatedglucose 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.
Type 3 Diabetes MellitusType 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)
Type 4: Gestational diabetes (GDM) 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
Diabetes-Related ComplicationsDiabetes-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
Diabetes-Related ComplicationsDiabetes-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
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 uptakeIncreased
lipolysis
Hyperglycemia
Overproduction
of glucose
Characteristic Type 1 DM Type 2 DMAge <30 years >30 years Onset Abrupt GradualBody habitus Lean Obese or history of
obesityInsulin resistance Absent PresentAutoantibodies Often present Rarely presentSymptoms Symptomatic Often asymptomaticKetones at diagnosis Present Absent Need for insulin therapy Immediate Years after diagnosisAcute complications Diabetic ketoacidosis Hyperosmolar
hyperglycemic stateMicrovascular complications at diagnosis
No Common
Macrovascular complications at or before diagnosis
Rare Common
Criteria for the Diagnosis of DiabetesCriteria 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.
Insulin & its analogsInsulin & its analogs
InsulinInsulin
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
Glu
Thr
Lys
Thr
TyrPhe
Phe GlyArg
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
GlyCys
LeuHis Gln Asn ValPhe
Asn CysTyr
Asn
Glu
Leu
Gln
Tyr
LeuSer
CysIle SerThrCys
Cys
Gln
Glu
Val
Ile
Gly
Pro
S S
S S
SS
A Chain
B Chain1 21
1
30
SS
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)
SS
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
α-chain
β-chain
Zn++Zn++
Self-aggregation
in solution
Monomers
Dimers
Hexamers
(around Zn2+)
21 amino acids
30 amino acids
Insulin secretionInsulin secretionInsulin secretionInsulin 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
HGP=hepatic glucose production.
IncreasedIncreased
HGPHGP
IncreasedIncreased
HGPHGPDecreased GlucoseDecreased Glucose
UptakeUptake
Decreased GlucoseDecreased Glucose
UptakeUptake
Time (minutes)
1st Phase 2nd Phase
i.v. Glucose
Diabetes
Normal glucose tolerance
-5-10 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 10095
Ins
ulin
Se
cre
tio
n
Time (minutes)
1st Phase 2nd Phase
i.v. Glucose
T2DM
Normal glucose tolerance
-5-10 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 10095
Ins
uli
n S
ecr
eti
on
Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.
Biphasic Insulin Secretion
Insulin secretionInsulin secretionInsulin secretionInsulin 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
Metabolism
Free
Ca++
Glucose
K+
K+ATP
Channel ATP
Ca++
(+)
-Cell
Insulin Release
Depolarization
Hu S et al. J Pharmacol Exp Ther 2000;293:444–52
GLUT2
Exocytosis
Insulin Insulin DegradationDegradationInsulin Insulin DegradationDegradation
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%
Cellular actions of insulinCellular 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
Mechanism of Insulin ActionMechanism of Insulin Action
Glucose
GlucoseTransporter
InsulinReceptor
PP
P
PP
P
Translocation
of
Glucose
Transporters
Skeletal muscle
Adipose Tissue
Insulin
Tyrosine kinase
doamins
Tyr
IRS
Tyr- P
IRS
MAPK pathway PI
3 kinase pathway
Protein synthesis Glycogen synthesisCell growth,
Differentiation, survival
Effects of insulin on its targetEffects 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
Overview of insulin actionOverview of insulin action
Triglycerides
AdiposeTissue
Glycogen
Liver
Protein
Muscle
Glucose AminoAcids
FattyAcids
Stimulated by insulinIncreased by feeding
Inhibited by insulinIncreased by fasting and in diabetes
FattyAcids
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
Insulin TherapyInsulin 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
Insulin TherapyInsulin 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
Characteristics of Available Insulin PreparationsCharacteristics 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
Human Insulin
Lispro
Aspart
Glargine
Glulisine
Asp
Lys Glu
Lys Pro
Gly
Arg Arg
Characteristics of Available Insulin PreparationsCharacteristics 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
Principal types and Duration of Action of Insulin Preparations
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
Pla
sma
Insu
lin le
vels
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 insulinExtent 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
1 .Rapid-acting insulin 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
1 .Rapid-acting insulin 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%)
2 .Short-acting insulin 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)
400
350
300
250
200
150
100
Meal
SC injection
50
00
30 60
Time (min)
90 120 180 210150 240
Lispro
Regular
Human
500
450
400
350
300
250
150
50
200
100
00 50 100
Time (min)
150 200 300250
Aspart
Regular
Human
Pla
sma
Insu
lin (
pm
ol/L
)
Pla
sma
Insu
lin (
pm
ol/L
)
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.
3 .Intermediate-acting insulins 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%
Long acting insulinsInsulin glargine
Long acting insulinsInsulin 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
b. Insulin detemirb. 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
ultra long-actinginsulin: Insulin degludec
ultra long-actinginsulin: 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
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 hoursResults from patients with type 1 diabetesIDeg, insulin degludec; IGlar, insulin glargineHeise et al. Diabetologia 2011;54(Suppl. 1):S425
*
IDeg 0.8 U/kgIGlar 0.8 U/kg
Comparison of Human Insulins & AnaloguesComparison of Human Insulins & Analogues
Insulin Onset of Peak of Duration ofPreparations Action Action (h) Action (h)
Short-actingRegular human 30-60 min 2-3 4-6Lispro 15-30 min 1-2 3-4Aspart 15-30 min 1-2 3-5Gluilisine 15-30 min 1-2 5-6
Intermediate-actingNPH 2-4 h 4-8 8-12
Long-actingGlargine 4-5 h None 22-24hDetemir 2 h None 14-24 h
5 .Mixtures of insulins 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
00 44 88 1212 1616 2020 2424
00
22
44
66
88
1010
1212
Glu
cos
e In
fusi
on
Rat
eG
luco
se
Infu
sio
n R
ate
mg
/kg
/min
mg
/kg
/min
HoursHours
LisproLispro
NPLNPL
Heise T, et al. Diabetes Care. 1998;21:800-803.
Generic name Brand strenghtNeutal protamine Haagedorn and regular
Novolin 70 NPH/30 regular (Novo Nordisk)
U100
Humulin 70 NPH/30 regular (Lilly) U100Humulin 50 NPH/50 regular (Lilly) U100
Neutral protamine lispro and lispro
75/25 NPL, Lispro (Lilly) U100
Neutral protamine aspart and aspart
70/30 NPA, Aspart (Novo Nordisk) U100
Combination insulin products
Insulin Delivery systemsInsulin Delivery systems
1) Pen devices containing prefilled regular, lispro, NPH, glargine, premixed lispro protamine-lispro, or premixed aspart protamine-aspart
2) Jet injector systems
3) Insulin pumps (continuous SC insulin infusion devices, CSII)
Inhaled insulin: AfrezzaInhaled 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
Adverse reactionsAdverse reactions
1. Hypoglycemia
2. Insulin allergy and resistance
a) Insulin allergy
b) Insulin resistance
3. Lipohypertrophy
Amylin analogs: PramlintideAmylin 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
oral antidiabetic agents oral antidiabetic agents
OverviewOverview
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
Categories of oral antidiabetic agents now available for the treatment of persons with type 2 diabetes
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
Sulfonylureas
Repaglinide
Liver
Metformin
Rosiglitazone
Pioglitazone
Pancreas
Acarbose
Miglitol
Gut
Muscle
Rosiglitazone
Pioglitazone
Metformin
Hyperglycemia
Adipose
tissue Glucose
uptake
FFA outputRosiglitazone
Pioglitazone
Insulin
secretion
Glucose
absorption
Hepatic glucose
output
Glucose
uptake
Oral Therapy for Type 2 Diabetes Target Sites of Action
Oral Therapy for Type 2 Diabetes Target Sites of Action
Incretin
effect
Exenatide
Sitagliptin
1 .Sulfonylurea 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
1 . -SulphonylureaMechanism of action 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
Sulfonylurea- Mechanism of actionSulfonylurea- Mechanism of action
Ca++
K+
K+
ATP-binding
site
Voltage-dependent
Ca++ channel closed
ATP-sensitive K+ channel
SUR 1
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
Sulfonylurea- Mechanism of actionSulfonylurea- Mechanism of action
K+
Ca++Exocytosis of insulin-
containing granules SUR 1
Sulfonylurea
KIR
6.2
Ca++
depolarization
ATP
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.
SulfonylureaSulfonylurea
Shapiro, et al. J Clin Endocrinol Metab. 1989;69:571-576.
Baseline
Treatment (2 mo)
90
180
270
360
42.6
85.1
Clock Time (h)
Glucose Insulin
MealMeal MealMealMeal Meal
00600 1200 1800 06002400
Clock Time (h)
0600 1200 1800 240000600 1800 06002400
mg
/dL
mU
/mL
1. Sulfonylurea1. 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
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 sulfonylureasDrug 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
1. Sulfonylureas- Adverse reactions1. 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
1. Sulfonylureas- Adverse reactions1. 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
2 .KATPChannel Modulators: Non-Sulfonylureas 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
2 .KATPChannel Modulators: Non-Sulfonylureas 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
Insulin sensitizersInsulin 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
1 .Biguanides 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
1 .Biguanides 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
1 .Biguanides -Mechanism of action 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
Metformin: Mechanism of actionMetformin: 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
MetforminMetformin
Adapted from Jackson, et al. Diabetes. 1987;36:632-640, with permission.
BaselineMetformin
080
120
160
200
240
280
320
360
1 2 3
Oralglucose
Oralglucose
Time (h)
00
20
40
60
1 2 3
Time (h)
Plasma Glucose Serum Insulin
mg
/dL
mU
/L
1. Biguanide1. 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
1. Biguanide- Clinical uses1. 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
1. Biguanide- Adverse reactions1. 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
1. Biguanide: lactic acidosis1. 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
1. Biguanide: lactic acidosis1. 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
( Tzds )Thiazolidinediones .2 ( 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
PPARγ Agonists: Mechanism of ActionPPARγ Agonists: Mechanism of Action
Modify insulin-sensitizing
factor(s) (e.g., adiponectin)
Modify expression/action
of insulin-resistance factor(s)
(e.g., resistin/TNF)
Adipose
Tissue
PPARγ
Agonist
Modify fatty acid uptake
and lipolysis
Modify
free fatty acids
Small, insulin-
sensitive adipocytes
modify visceral adiposity
Modify gene
expression in
adipocytes
Modify
insulin
action
PPARγ = Peroxisome Proliferator-Activated Receptor Gamma
Adapted from Moller DE Nature 2001;414:821–828.
Liver
Skeletal
muscle
Dual PPARα/γ Agonists: Mechanism of ActionDual 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.
GammaAlpha
fenofibrate pioglitazone rosiglitazone
Thiazolidinediones- Adverse reactionsThiazolidinediones- 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
Thiazolidinediones- Adverse reactionsThiazolidinediones- 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 reactionsThiazolidinediones- 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
Thiazolidinediones- Adverse reactionsThiazolidinediones- 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 Inhibitorsα-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
AcarboseAcarbose
Dimitriadis, et al. Metabolism. 1982;31:841-843.
Normal absorption of CHO
Without Acarbose
With Acarbose
Acarbose blocks proximal absorption
DuodenumJejunum Ileum
Time (min)
140
– 30 0 60 120 180 240
120
100
80
*
*
MealPlacebo
Acarbose
* P <.05
Pla
sma
Glu
cose
(mg
/dL)
α-Glucosidase Inhibitorsα-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
α-Glucosidase Inhibitors- ADEsα-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
α-Glucosidase Inhibitors- ADEsα-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
Incretin-based therapiesIncretin-based therapies
In ● cre ● tin Intestine Secretion Insulin
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)
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-p
epti
de
(n
mo
l/L
)
Time (min)
0.0
0.5
1.0
1.5
2.0
Incretin Effect
Pla
sm
a G
luc
ose
(m
g/d
L)
200
100
0
Time (min)
60 120 180060 120 1800
Incretin-based therapiesIncretin-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
Oral glucose load
Intravenous glucose infusion
Time (min)
Ins
uli
n (
mU
/l)
80
60
40
20
0
18060 1200
Time (min)
Ins
uli
n (
mU
/l)
80
60
40
20
0
18060 1200
IncretinIncretin
effecteffect
Control subjects (n=8)Control subjects (n=8) People with Type 2 diabetes (n=14)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
Microvascular changes
Macrovascular changesClinical
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
Re
lati
ve A
mo
un
t
-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
0
50
100
150
200
250
-15
Incretin effect
β-cell function
β-cell failure
Onset
diabetes
Glu
cos
e (
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 30-15Years
Physiology of GLP-1 secretion and action on various tissues
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.
Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.
Intestinal
GLP-1
releaseGLP-1 (7-36)
active
Mixed
meal
GLP-1 (9-36)
inactive
(>80% of pool)
DPP-4
T1/2
= 1 to 2 min
Incretin-based therapiesIncretin-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
GLP-1 receptor agonistGLP-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
GLP-1 receptor agonist- MOA 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
GLP-1 receptor agonistGLP-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 agonistGLP-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
Dpp-4 InhibitorsDpp-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
GLP-1 (9-36)
inactive
Intestinal
GLP-1
release
Mixed
meal
GLP-1 (7-36)
active
DPP-4
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
DPP-4
inhibitor
GLP-1 (7-36)
active
2 .Dpp-4 Inhibitors 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 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
Bile Acid Binding Resins: colesevelamBile 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
Dopamine D2-receptor agonists: bromocriptineDopamine 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
Sodium GLucose Transporter 2 inhibitor (SGLT2i)
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
112
3 4 5 6 7 8 9 10 11 12
Capaglifozin
1 2 3 4
Dapaglifozin
Ipragliflozin (Japan)
Empagliflozin
(Europe)
2013 2014
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 tubuleGlucose
The kidney plays a critical role in filtration and reabsorption of glucose
The kidney plays a critical role in filtration and reabsorption of glucose
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 tubuleGlucose
The kidney plays a critical role in filtration and reabsorption of glucose
The kidney plays a critical role in filtration and reabsorption of glucose
Glycosuria
Maximum
reabsorptive
capacity
exceeded
Excess glucose
not reabsorbed