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