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Physiopathology of Diabetes & DiagnosisPhysiopathology of Diabetes & DiagnosisCCContentsContents
Normal physiology of glucose controlNormal physiology of glucose control
Classification of diabetesClassification of diabetes
Type Type 2 2 diabetesdiabetes
Type Type 1 1 diabetesdiabetesypyp
Diagnosis of diabetesDiagnosis of diabetes
١
Insulin and Glucagon Regulate Normal Glucose Insulin and Glucagon Regulate Normal Glucose HomeostasisHomeostasis
GlGlucagon(alpha cell)
Fasting state Fed statePancreas
Fasting state Fed state
Release of gut hormones
Insulin(beta cell)
hormones —Incretins1,2
(GLP-1 & GIP)
Blood glucose
Glucose output Glucose uptake
Blood glucoseLiver MuscleMuscle
Adipose Adipose tissuetissue
٢Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
Insulin Action in Muscle and Fat CellsInsulin Action in Muscle and Fat CellsMobilization of GLUTMobilization of GLUT44 to the Cell Surfaceto the Cell Surface
I li
Plasma membrane
ob o o G Uob o o G U 44 o e Ce Su ceo e Ce Su ce
Insulin receptor Intracellular
signaling cascades
IntracellularGLUT4 vesicles
Insulin
cascades
GLUT4 vesicle mobilizationto plasma membrane
GLUT4 vesicle integration into plasma
٣
integration into plasma membrane Glucose entry into cell
via GLUT4GLUT4=glucose transporter 4
Classification of Diabetes MellitusClassification of Diabetes Mellitusb E i lb E i lby Etiologyby Etiology
Type 1 β-cell destruction—complete lack of yp β pinsulin
Type 2 β-cell dysfunction and insulin yp β yresistance
Gestational β-cell dysfunction and insulin Gestational β-cell dysfunction and insulin resistance during pregnancy
Oth ifi t G ti d f t f β ll f tiOther specific types • Genetic defects of β-cell function• Exocrine pancreatic diseases
• Endocrinopathies
۴
Endocrinopathies• Drug- or chemical-induced
• Other rare forms
Etiology of Type Etiology of Type 2 2 DiabetesDiabetesImpaired Insulin Secretion and Impaired Insulin Secretion and Insulin ResistanceInsulin Resistancepp
Genes and environment
I i d i liImpaired insulin secretion Insulin resistance+
Impaired glucose tolerancetolerance
۵
Type 2 diabetes
Natural History of TypeNatural History of Type 22 Diabetes ProgressionDiabetes ProgressionNatural History of Type Natural History of Type 22 Diabetes ProgressionDiabetes Progression
Years from 0 5-10 -5 10 15diagnosis
Insulin secretionInsulin resistance
Microvascular
Type 2 diabetes (T2DM)Pre-diabetes
complicationsMacrovascular complications
۶
yp ( )Onset Diagnosis
Pathogenesis of Type Pathogenesis of Type 1 1 DiabetesDiabetesO D fO D fOne DefectOne Defect
No hepatic No muscle/fat
Absentinsulin
secretionpinsulin effect insulin effect
Hyperglycemia
Unrestrainedglucose production
Impaired glucoseclearance
Less glucose entersi h l ti
٧Glycosuria
More glucose entersthe blood
peripheral tissues
Natural History Of “Pre”Natural History Of “Pre”––Type Type 11 DiabetesDiabetes
Putativetrigger
yy ypyp
trigger
Circulating autoantibodies (ICA, GAD65)
Cellular autoimmunityCellular autoimmunityβ-Cell mass 100%
Loss of first-phase insulin response (IVGTT)
Gl i t lClinicalonsetGlucose intolerance
(OGTT)onset—
only 10% ofβ-cells remainremain
“Pre”-diabetes
Geneticpredisposition
Insulitisβ-Cell injury Diabetes
٨
Time
Eisenbarth GS. N Engl J Med. 1986;314:1360-1368
Glucose Tolerance CategoriesGlucose Tolerance Categories
FPG 2-h PPG (OGTT)Plasma glucose 240 Plasma glucose
200
g(mg/dL) Diabetes
Mellitus
240
220
Plasma glucose(mmol/L)
11 1
160
180
200DiabetesMellitus IGT
11.1
126 120
140
160
IFG7.0
80
100 NormalNormal
IFG5.5
٩American Diabetes Association. Diabetes Care. 2007;30(suppl 1)
60
Criteria for the Diagnosis of Diabetes MellitusCriteria for the Diagnosis of Diabetes Mellitusgg
• Symptoms of diabetes plus random blood glucose• Symptoms of diabetes plus random blood glucose Symptoms of diabetes plus random blood glucose Symptoms of diabetes plus random blood glucose concentration concentration 1111..11mmol/L (mmol/L (200 200 mg/dL)mg/dL)
orororor• Fasting plasma glucose • Fasting plasma glucose 77..0 0 mmol/L (mmol/L (126 126 mg/dL)mg/dL)
orororor• Two• Two--hour plasma glucose hour plasma glucose 1111..1 1 mmol/L (mmol/L (140 140
mg/dL) during an oral glucose tolerance testmg/dL) during an oral glucose tolerance testccmg/dL) during an oral glucose tolerance testmg/dL) during an oral glucose tolerance testcc
١٠
Diabetes Mellitus Diabetes Mellitus ComplicationsComplicationspp
١١
Acute Complications of DMAcute Complications of DMpp
Diabetic Ketoacidosis (DKA)Diabetic Ketoacidosis (DKA)Diabetic Ketoacidosis (DKA)Diabetic Ketoacidosis (DKA)
Hyperglycemic Hyperosmolar State (HHS)Hyperglycemic Hyperosmolar State (HHS)
Both disorders are associated with absolute or Both disorders are associated with absolute or relative insulin deficiency, volume depletion, relative insulin deficiency, volume depletion,
and acidand acid--base abnormalitiesbase abnormalities
١٢
HyperglycemiaHyperglycemiaTh D fi i F f Di bTh D fi i F f Di bThe Defining Feature of DiabetesThe Defining Feature of Diabetes
Excessivel d ti
Impaired
Hyperglycemia
glucose production glucose clearance
١٣
Tissue injury1
Two Mechanisms of Tissue Injury Two Mechanisms of Tissue Injury b H l ib H l iby Hyperglycemiaby Hyperglycemia
HyperglycemiaGlycationpathway
Sorbitolpathwayp y p y
Sorbitol and fructoseGlycated proteins Advanced glycation Sorbitol and fructose Glycated proteins(eg, A1C)
g yend products (AGEs)
Oxidativeeffects
Osmoticeffects
Altered functionor turnover
Receptor-mediatedcytokine effects
١۴Brownlee M. Metabolism. 2000;49(suppl 1):9-13; Greene DA et al. N Engl J Med.1987;316:599-606; Sheetz MJ, King GL. JAMA. 2002;288:2579-2588
effectseffectsor turnover cytokine effects
Chronic Complications of DMChronic Complications of DM
MicrovascularMicrovascularMicrovascularMicrovascularMacrovascularMacrovascularO hO hOtherOther
GastrointestinalGastrointestinalG i iG i iGenitourinaryGenitourinaryDermatologicDermatologicInfectiousInfectiousInfectiousInfectiousCataractsCataractsGlaucomaGlaucoma
١۵
What are theWhat are theMicrovascular Complications ?Microvascular Complications ?
HyperglycemiaHyperglycemia
Microvascular Complications ?Microvascular Complications ?
Kidney NervesEye
NeuropathyPeripheral
RetinopathyM l d
NephropathyMi lb i i – Peripheral
– AutonomicMacular edema – Microalbuminuria
– Gross albuminuria
Blindness Kidney failure Amputation
١۶Death and/or disability
RetinopathyRetinopathyRetinopathyRetinopathy
Normal retina Proliferative retinopathy
١٧
What are theWhat are theMacrovascular Complications ?Macrovascular Complications ?
Metabolic injury to large vesselsMetabolic injury to large vessels
Macrovascular Complications ?Macrovascular Complications ?
Metabolic injury to large vesselsMetabolic injury to large vessels
Heart Brain Extremities
Coronary artery disease Cerebrovascular diseasePeripheral vascular Coronary artery disease– Coronary syndrome– MI– CHF
Cerebrovascular disease– TIA– CVA– Cognitive impairment
Peripheral vascular disease
– Ulceration– Gangrene
١٨
– CHF – Cognitive impairment – Gangrene– Amputation
Macrovascular disease at diagnosis Macrovascular disease at diagnosis in Typein Type 22 diabetesdiabetesin Type in Type 22 diabetesdiabetes
11%%Cerebrovascular
disease 7575% of all deaths in % of all deaths in l ith Tl ith T 22
1818%%Abnormal ECG
people with Type people with Type 2 2 diabetes are due to diabetes are due to
cardiovascular diseasecardiovascular disease
3535%%Hypertension
Absent foot pulses 1313%%
33%%Intermittent l di ti
١٩UKPDS Group. Diabetes Res 1990; 13: 1–11.
claudication
Risk of Microvascular Complications Risk of Microvascular Complications vs.vs. AA11C C in Typein Type 11 DiabetesDiabetes
Results From the DCCT
in Type in Type 11 DiabetesDiabetes
Retinopathy progressionNeuropathy progression
20
15
Relative risk
eu opat y p og ess oMicroalbuminuria progression
15
10
5
051 6 7 8 9 10 11 12
٢٠Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254
A1C (%)
Risk of Microvascular Events Risk of Microvascular Events vs.vs. AA11CCin Typein Type 22 DiabetesDiabetesin Type in Type 22 DiabetesDiabetes
Results From Epidemiologic Analysis of the UKPDS
8
10Hazardratio
6
4 37% change per 1% change in A1C
0
2
٢١
5 6 7 8 9 10A1C (%)
Stratton IM et al. BMJ. 2000;321:405-412
AA11C Predicts Myocardial Infarction C Predicts Myocardial Infarction in Type in Type 2 2 DiabetesDiabetes
UKPDSUKPDSUKPDSUKPDS
4585 Patients Followed for 10 Years*
2.5 2.4
3Relative risk
11.3
1.8 1.92
11
0<6 6 to <7 7 to <8 8 to <9 9 to <10 ≥10
٢٢*Adjusted for age, sex, and duration of diabetesStratton IM et al. BMJ. 2000;321:405-412
A1C (%)
TREATMENTTREATMENT
٢٣
Guidelines: LimitationsGuidelines: LimitationsGuidelines: LimitationsGuidelines: Limitations
D i id li f l iD i id li f l iDespite many current guidelines for glycaemic Despite many current guidelines for glycaemic control there is still a lack of consensus on ‘ideal’ control there is still a lack of consensus on ‘ideal’ target and intervention valuestarget and intervention valuesggIncorporation of guidelines into clinical practice Incorporation of guidelines into clinical practice can be difficultcan be difficult
largelarge--scale studies have shown the need for improved scale studies have shown the need for improved glycaemic control, but many patients fail to reach goals glycaemic control, but many patients fail to reach goals for glycaemic controlfor glycaemic controlg yg ythe complexity of the individual’s characteristics, risk the complexity of the individual’s characteristics, risk factors, needs and personal goals still need to be taken factors, needs and personal goals still need to be taken into accountinto account
٢۴
into account into account
Current guidelines recommend targets Current guidelines recommend targets for HbAfor HbA11c, FPG and PPBG levelsc, FPG and PPBG levels
IDFIDF44AACEAACE33ADAADA11HealthyHealthyGlucose controlGlucose control ADA/ ADA/
<<66..55≤≤66..55<<77..00HbAHbA11cc* (%)* (%)
IDFIDFAACEAACEADAADAHealthyHealthyGlucose controlGlucose control
<<66..0011 <<77..00
EASDEASD55
<<55..6622
(<(<100100))<<66..0 0
(<(<110110))≤≤66..0 0
((≤≤110110))55..00−−77..22
((9090−−130130))FBG, mmol/L FBG, mmol/L (mg/dL)(mg/dL)
33..8989−−77..22 22 ((7070−−130130))
<<77..88****22
(<(<140140))
(( 100100)) (( 110110))((≤≤110110))((9090 130130))(mg/dL)(mg/dL)
<<88..00** ** (<(<145145))
≤≤77..88** ** ((≤≤140140))
<<1010..00** ** (<(<180180))
PPBG, mmol/L PPBG, mmol/L (mg/dL)(mg/dL)
((7070 130130))
<<10 10 (<(<180180))
1 American Diabetes Association Diabetes Care 2006;29(suppl 1):S4–S42
*DCCT aligned; **1–2 hours postprandial
(<(<140140)) (<(<145145))((≤≤140140))(<(<180180))(mg/dL)(mg/dL) (<(<180180))
٢۵
1. American Diabetes Association. Diabetes Care 2006;29(suppl 1):S4 S42.2. American Diabetes Association. Diabetes Care 2006;29(suppl 1):S43–8.3. American Association of Clinical Endocrinologists. Endocr Pract 2002;8(suppl 1):40–82.4. International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005.
http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf5. Nathan D, et al. Diabetologia 2006;49;1711-21.
Insulin and Glucagon Regulate Normal Glucose Insulin and Glucagon Regulate Normal Glucose HomeostasisHomeostasis
GlGlucagon(alpha cell)
Fasting state Fed statePancreas
Fasting state Fed state
Release of gut hormones
Insulin(beta cell)
hormones —Incretins1,2
(GLP-1 & GIP)
Blood glucose
Glucose output Glucose uptake
Blood glucoseLiver MuscleMuscle
Adipose Adipose tissuetissue
٢۶Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
Treatment of DiabetesTreatment of DiabetesTreatment of DiabetesTreatment of Diabetes
NonNon--pharmacologicpharmacologicNonNon pharmacologicpharmacologicOral agentsOral agentsI liI liInsulinInsulin
٢٧
NonNon--pharmacologicpharmacologicNonNon pharmacologicpharmacologic
NutritionNutritionNutritionNutritionExerciseExerciseLifLif l Chl ChLifeLife--style Changestyle Change
٢٨
Treatment of T2DM Is Accomplished by Different Agents via Different Modes of Action
I liInsulinInhibitors of gluconeogenesisInhibitors of glucose absorption
Insulin secretagogues
Insulin sensitizers
↑ Insulin ↓ Insulin secretion resistance
↓ Liver/gut glucose delivery
↓ Bl d l↓ Glucose toxicity ↓ Glucose toxicity
٢٩
↓ Blood glucose
Oral AntiOral Anti--Diabetes AgentsDiabetes Agents
OADs
INSULIN SECRETAGOGUES
OTHERS α-Glucosidase Inhibitor
INSULIN SENSITIZERS
acarbose GLUCOBAY (Bayer)
S l h l N S l h lBi id Thi lidi di / Sulphonylureas Non-Sulphonylureas
chlorpropamide DIABENESE (Pfizer)
glibenclamide
repaglinide NOVONORM (Novo)
nateglinide
Biguanides Thiazolidinediones / Glitazone (TZD)
metforminroziglitazone
AVANDIA (GSK) glibenclamide DAONIL (Aventis)
nateglinide STARLIX (Novartis)
gliclazide DIAMICRON (Servier)
metformin GLUCOPHAGE (Merck)
AVANDIA (GSK)
pioglitazone ACTOS (Eli Lilly)
٣٠
glipizide MINIDIAB (Pfizer)
glimepiride AMARYL (Aventis)
How Different Agents Regulate How Different Agents Regulate Hyperglycemia in DiabetesHyperglycemia in Diabetesyp g yyp g y
Pancreatic beta cells
• Sulfonylureas• MeglitinidesStimulate insulin release
MuscleLiver
Amelioration of hyperglycemia
MuscleLiver
• PPARs (TZDs or glitazones)
Gut• PPARs
(TZDs or glitazones)• Biguanides
• Biguanides• InsulinStimulate glucose uptake
• Alpha-glucosidase inhibitorsRetard glucose reflux into circulation
Biguanides• InsulinInhibit glucose production
٣١
PPAR=peroxisome proliferator-activated receptor agonist.
Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, Ma: Blackwell Publishing, 2004; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders, 2003:1427–1483.Adapted from DeFronzo RA. Ann Intern Med. 1999;131:281–303.
Therapeutic Effects and LimitationsTherapeutic Effects and Limitations
Primary Primary ClassClass
yyEffectEffect LimitationsLimitations
SulfonylureasSulfonylureas HbAHbA11cc Hypoglycemia, weight gainHypoglycemia, weight gain
MeglitinidesMeglitinides PPGPPG Hypoglycemia, weight gainHypoglycemia, weight gainBiguanides (metformin)Biguanides (metformin) HbAHbA11cc GI adverse effects, lactic acidosis GI adverse effects, lactic acidosis
(rare)(rare)( )( )PPARsPPARs HbAHbA11cc Weight gain, edema, anemia, Weight gain, edema, anemia,
potential for liver toxicitypotential for liver toxicityAlphaAlpha glucosidaseglucosidase PPGPPG GI adverse effectsGI adverse effectsAlphaAlpha--glucosidase glucosidase inhibitorsinhibitors
PPGPPG GI adverse effectsGI adverse effects
InsulinInsulin HbAHbA11cc Injectable route, hypoglycemia, Injectable route, hypoglycemia, i h ii h iPPG=postprandial glucose; GI=gastrointestinal
٣٢
weight gainweight gainPPG postprandial glucose; GI gastrointestinal.DeFronzo RA. Ann Intern Med. 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, Ma: Blackwell Publishing, 2004; Holz GG, Chepurny OG. Curr Med Chem. 2003;10:2471–2483; Meneilly GS et al. Diabetes Care. 2003;26:2835–2841; Ahrén B et al. Diabetes Care. 2002;25:869–875; Moller DE. Nature. 2001;414:821–827.
Insulin Deficiency and ResistanceInsulin Deficiency and Resistance
Type Type 2 2 DMDM
Insulin resistanceInsulin resistancee e (%)
(%)
200200
250250
Rel
ativ
eR
elat
ive
Func
tion
(Fu
nctio
n (
100100
150150
1515 2020 2525 303010105500––55––1010
ββ--cellcell failurefailure Insulin levelInsulin levelFF
00
5050
Duration of Diabetes (years)Duration of Diabetes (years)
٣٣Adapted from Bergenstal RM. In: Adapted from Bergenstal RM. In: Endocrinology. Endocrinology. Philadelphia, Pa: W.B. Saunders CoPhiladelphia, Pa: W.B. Saunders Co; ; 20012001::810810--820820. .
The Number of Medications Taken Usually The Number of Medications Taken Usually Increases With Duration of DiseaseIncreases With Duration of Disease
100 Diabetesdiagnosed
Requiring insulin
Monotherapyfailure
ion
(%)
g
Dual-drugMonotherapy
80
ell f
unct
i
Insulin-based
regimens
Multidrugcombination
+/–insulin
Dual-drugregimens60
40
Bet
a-ce
20IGT
00 10 15–25
Approximate time (years)
٣۴
IGT=impaired glucose tolerance.UKPDS 16. Diabetes. 1995;44:1249–1258. Turner RC et al. JAMA. 1999;281:2005–2012; Warren RE. Diabetes Res Clin Pract. 2004;65:S3–S8; Lebovitz HE. Med Clin N Am. 2004;88:847–863.
Oral Monotherapy: Failure Is InevitableOral Monotherapy: Failure Is Inevitable
Failure rates for oral monotherapy in type Failure rates for oral monotherapy in type 2 2 diabetes*diabetes*11,,22
Type Type 2 2 DMDM
StudyStudy 3 3 Years Years 6 6 Years Years 9 9 YearsYearsUKPDS UKPDS 49 49 >>4545%% NSNS >>7575%%(N=(N=40754075))
UKPDS UKPDS 24 24 NSNS 5252%% NSNS(N=(N=458458))
*Failure rates defined as A*Failure rates defined as A11C concentration >C concentration >77% in UKPDS% in UKPDS 4949 and >and >88% in UKPDS% in UKPDS 2424
٣۵11. Turner RC et al. . Turner RC et al. JAMA. JAMA. 19991999;;281281::20052005--20122012..22. UKPDS . UKPDS 2424. . Ann Intern Med. Ann Intern Med. 19981998;;128128::165165--175175..
Failure rates defined as AFailure rates defined as A11C concentration >C concentration >77% in UKPDS % in UKPDS 49 49 and >and >88% in UKPDS % in UKPDS 2424..NS, not studied; UKPDS, United Kingdom Prospective Diabetes Study.NS, not studied; UKPDS, United Kingdom Prospective Diabetes Study.
Insulin TherapyInsulin TherapyInsulin TherapyInsulin Therapy
٣۶
Action of InsulinAction of Insulin
Time
٣٧
BreakfastBreakfast LunchLunch SupperSupper
Normal Insulin Secretion: Normal Insulin Secretion: The BasalThe Basal--Bolus Insulin ConceptBolus Insulin Concept
Endogenous InsulinEndogenous Insulin
ffect
ffect
Bolus InsulinBolus InsulinBasal InsulinBasal Insulin
gg
nsul
in E
fns
ulin
Ef
InIn
BB DDLL HSHSTime of AdministrationTime of Administration
٣٨
B, breakfast; L, lunch; D, dinner; HS, bedtime.B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:Adapted from:11.. Leahy JL. In: Leahy JL, Cefalu WT, eds. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; New York, NY: Marcel Dekker, Inc.; 20022002..22.. Bolli GB et al. Bolli GB et al. Diabetologia. Diabetologia. 19991999;;4242::11511151--11671167..
Comparison of Human Insulins Comparison of Human Insulins and Analoguesand Analogues
Insulin Insulin Onset ofOnset of Peak of Peak of Duration ofDuration ofPreparations Preparations Action Action Action (h)Action (h) Action (h)Action (h)ShortShort--actingactingR l hR l h 3030 6060 ii 22 4 64 6 88
gg
Regular human Regular human 3030--6060 min min 22--4 64 6--88Rapid ActingRapid ActingLispro/Aspart/GlulisineLispro/Aspart/Glulisine 55--15 15 minmin 11--2 2 33--44
IntermediateIntermediate actingactingIntermediateIntermediate--actingactingNPH NPH 11--3 3 hh 55--77 1313--1616LenteLente 11--3 3 hh 44--88 1313--2020
LongLong--actingactingLongLong actingactingGlargineGlargine 11--2 2 hh PeaklessPeakless >>24 24 Ultralente Ultralente 22--4 4 hh 88--14 14 <<2020
Ti f ti f i li i diff t l t diff t ti i thTi f ti f i li i diff t l t diff t ti i th
٣٩
Time course of action of any insulin can vary in different people or at different times in the Time course of action of any insulin can vary in different people or at different times in the same person; thus, time periods indicated here should only be considered general guidelines.same person; thus, time periods indicated here should only be considered general guidelines.
Leahy JL. In: Leahy JL, Cefalu WT, eds. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin TherapInsulin Therapy. New York, NY: Marcel Dekker, Inc.; y. New York, NY: Marcel Dekker, Inc.; 20022002..
Insulin Time Action CurvesInsulin Time Action CurvesEf
fect
Effe
ct Rapid (Lispro, Aspart/Glulisine)Rapid (Lispro, Aspart/Glulisine)
e In
sulin
e
Insu
lin
Intermediate (NPH)Intermediate (NPH)Prolonged Intermediate (Ultralente)Prolonged Intermediate (Ultralente)
Short (Regular)Short (Regular)
Rel
ativ
eR
elat
ive
Long (Glargine, Detemir)Long (Glargine, Detemir)
Prolonged Intermediate (Ultralente)Prolonged Intermediate (Ultralente)
0 2 4 6 8 10 12 14 16 18 20
۴٠
Time (Hours)Time (Hours)
Twice-daily pre-mixed insulins
Breakfast DinnerLunch Snack
Regular insulinNPH insulin
Normal endogenous insulin
Both insulins combined
Breakfast DinnerLunch Snack
s
Risk of hypoglycaemiaRisk of hyperglycaemia
asm
a le
vels
Pla
Time of dayNPH=neutral protamine Hagedorn.
۴١
Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; 2002:87-112.Bolli GB et al. Diabetologia. 1999;42:1151-1167.
Insulin Treatment RegimensInsulin Treatment RegimensOAD + Basal
7 13 19 22 37 13 19 22 3
OAD + Bolus
7 13 19 22 37 13 19 22 3
7 13 19 22 37 13 19 22 3
Premix
7 13 19 22 37 13 19 22 3
7 13 19
Mischinsulin 25/75
22 37 13 19
Mischinsulin 25/75
22 3
Premix
7 13 19
Mischinsulin 25/75
22 37 13 19
Mischinsulin 25/75
22 3
Basal + Bolus
7 13 19 22 37 13 19 22 37 13 19 22 37 13 19 22 3
Basal insulins: The choicesBasal insulins: The choices
Generic nameGeneric name Brand nameBrand nameGeneric nameGeneric name Brand nameBrand name
Insulin analoguesInsulin analogues
Insulin glargineInsulin glargine LantusLantus®®Insulin glargineInsulin glargine LantusLantus
Insulin detemirInsulin detemir LevemirLevemir®®
NPH [Neutral Protamine Hagedorn]NPH [Neutral Protamine Hagedorn] InsulatardInsulatard®® NovolinNovolin®® NNNPH [Neutral Protamine Hagedorn] NPH [Neutral Protamine Hagedorn] insulininsulin
InsulatardInsulatard , Novolin, Novolin N, N, ProtaphaneProtaphane®®
Human insulinHuman insulin
Lente insulin Lente insulin (zinc suspension)(zinc suspension)
Iletin Lente, Insulin Lente PorkIletin Lente, Insulin Lente Pork(Humulin(Humulin®® L*, NovolinL*, Novolin®® L*)L*)
Ul l i liUl l i li (H li(H li ®® U* Ul dU* Ul d®®*)*)Ultralente insulin Ultralente insulin ((extended zinc suspension) extended zinc suspension)
(Humulin(Humulin®® U*, UltratardU*, Ultratard®®*)*)
۴٣*Discontinued
Basal InsulinBasal Insulin
Long acting (e.g. glargine)Long acting (e.g. glargine) Intermediate acting (e.g. NPH, Intermediate acting (e.g. NPH, lente)lente)
-- Provides optimal basal insulinProvides optimal basal insulin
lente)lente)
-- Less optimal as a basal insulin, Less optimal as a basal insulin, Provides optimal basal insulin Provides optimal basal insulin coverage with a once daily coverage with a once daily dosingdosing
ppbecause it doesn’t have a flat because it doesn’t have a flat insulin release profileinsulin release profile
-- Lower risk of hypoglycemiaLower risk of hypoglycemia -- More hypoglycemic episodesMore hypoglycemic episodes
-- Flat release profile Flat release profile
۴۴
Prandial insulinPrandial insulin –– promotes total flexibility in promotes total flexibility in meal timingmeal timing
Ultra short/rapid acting insulin Ultra short/rapid acting insulin analogues (lispro)analogues (lispro)
Short acting insulin (regular insulin)Short acting insulin (regular insulin)
-- Rapid onset of actionRapid onset of action
F d h iF d h i
-- Less optimal profile as compared Less optimal profile as compared to rapid acting analoguesto rapid acting analogues
F h d h lF h d h l-- Forms monomers and thus is Forms monomers and thus is absorbed rapidlyabsorbed rapidly
D ti f ti l t fD ti f ti l t f 44
-- Forms hexamers and has slower Forms hexamers and has slower absorptionabsorption
S t i d d ti f tiS t i d d ti f ti-- Duration of action lasts for Duration of action lasts for 44hours regardless of the dose hours regardless of the dose givengiven
-- Sustained duration of action may Sustained duration of action may lead to postlead to post--prandial hypoglycemiaprandial hypoglycemia
-- Less hypoglycemiaLess hypoglycemia
۴۵
Limitations of Intermediate Insulins: NPHLimitations of Intermediate Insulins: NPH
Does not mimick basal insulin profileDoes not mimick basal insulin profile11,,22
Variable absorptionVariable absorptionVariable absorptionVariable absorptionPronounced peakPronounced peak1313--1616––hour durationhour duration1313 1616 hour duration hour duration Requires twiceRequires twice--daily administration to provide daily administration to provide 2424--hour basal hour basal insulin coverageinsulin coverage
Fear of hypoglycaemiaFear of hypoglycaemia33
Major factor limiting insulin adjustmentsMajor factor limiting insulin adjustmentsMajor factor limiting insulin adjustmentsMajor factor limiting insulin adjustments
1. Chan JL et al. Mayo Clin Proc. 2003;78:459-467.
۴۶
1. Chan JL et al. Mayo Clin Proc. 2003;78:459 467.2. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker,
Inc.; 2002.3. Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia,
Pa: WB Saunders Co.; 2001:821-835.
The Ideal Basal InsulinThe Ideal Basal Insulin
1 1 injection daily covers injection daily covers 24 24 hourshoursNo peaksNo peaksL i id f h l iL i id f h l iLow incidence of hypoglycaemiaLow incidence of hypoglycaemiaGood glycaemic controlGood glycaemic controlLess weight gainLess weight gaing gg gSafeSafePredictablePredictableEasy handlingEasy handlingEasy handlingEasy handling
Injection at different sitesInjection at different sitesInjection at different timesInjection at different timesN i i / l l iN i i / l l iNo mixing necessary/clear solutionNo mixing necessary/clear solution
High treatment satisfaction and acceptanceHigh treatment satisfaction and acceptance
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Characteristics of Insulin GlargineCharacteristics of Insulin Glargine
Recombinant human insulin analogueRecombinant human insulin analogue11
Basal (longBasal (long--acting) insulinacting) insulin11
Relatively constant peakless concentration over Relatively constant peakless concentration over 24 24 hourshours11,,22
OnceOnce--daily SC administrationdaily SC administration11
For adult and paediatric (aged For adult and paediatric (aged ≥≥6 6 years) patients with type years) patients with type 1 1 di b t nd d lt ith t pdi b t nd d lt ith t p 22 di b tdi b t 11 22diabetes and adults with type diabetes and adults with type 22 diabetesdiabetes11,,22
Lower risk of hypoglycaemia than with traditional basal insulinsLower risk of hypoglycaemia than with traditional basal insulins11
Flexible dosingFlexible dosing11Flexible dosingFlexible dosing11
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1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.2. Lantus® receives European approval for pediatric use. Aventis Pharma Web site. Available at:
http://www.aventis.no/nyheter/nyheter/nyheter_lantus_eu_approval_pediatric.shtml. Accessed March 19, 2003.
Diagnosis
ADA/EASD consensus algorithm for type 2 diabetes mellitus (2006)
g
Lifestyle intervention and metformin
HbA1 ≥7%No YesaHbA1c ≥7%No Yes
Add basal insulinc − most effective
Add sulfonylurea − least expensive
Add glitazone −no hypoglycemia
HbA1c ≥7% HbA1c ≥7% HbA1c ≥7%No YesaNo YesaNo Yesa
Add glitazonebIntensify insulinc Add basal insulin Add sulfonylureab
HbA1c ≥7% HbA1c ≥7%No Yesa No Yesa
Add basal or intensify insulinc
Intensive insulin + metformin +/− glitazone
a Check HbA1c every 3 months until HbA1c is <7%, and then at least every 6 months. b Although three oral agents can be used initiation and intensification of insulin therapy
Nathan D, et al. Diabetologia 2006;49:1711−21.
b Although three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense.
c See Nathan et al for initiation and adjustment of insulin.
ADA/EASD consensus algorithm ADA/EASD consensus algorithm
for typefor type 22 diabetes mellitusdiabetes mellitus ((20082008))for type for type 2 2 diabetes mellitus diabetes mellitus ((20082008))
Tier 1: well-validated therapies
At diagnosis:Lifestyle + Metformin
Lifestyle + Metformin+ Basal insulin
Lifestyle + Metformin+ Intensive insulin
MetforminLifestyle + Metformin+ Sulfonylureas
STEP 1 STEP 2 STEP 3Tier 2: Less well validated therapies
Lifestyle + Metformin+ PioglitazoneN h p l i
Lifestyle + metformin+ PioglitazoneNo hypoglycaemia
Oedema/CHFBone loss
Lifestyle + metformin+ GLP 1 agonist
+ Pioglitazone+ Sulfonylurea
Lifestyle + metformin+ GLP-1 agonistNo hypoglycaemiaWeight lossNausea/vomiting
+ Pioglitazone+ Basal insulin
Nathan DM, et al. Diabetes Care 2008;31:1–11.