Current Diagnosis and Mechanisms of Current Diagnosis and Mechanisms of Glucose DysregulationGlucose Dysregulation

Dr. Josephine Carlos-RabocaDr. Josephine Carlos-RabocaChief, Section of Endocrinology, Diabetes & MetabolismChief, Section of Endocrinology, Diabetes & Metabolism

Makati Medical CenterMakati Medical CenterImmediate Past President, PSEMImmediate Past President, PSEM

OutlineOutline

Overview of glucose regulation Overview of glucose regulation Stages of Dysglycemia (glucose dysregulation)Stages of Dysglycemia (glucose dysregulation) Current Diagnostic Criteria for dysglycemiaCurrent Diagnostic Criteria for dysglycemia Mechanisms of Glucose DysregulationMechanisms of Glucose Dysregulation SummarySummary

Glucose MetabolismGlucose MetabolismTightly regulated to maintain adequate plasma levelsTightly regulated to maintain adequate plasma levels

Major hormonesMajor hormones insulininsulin glucagonglucagon incretinsincretins

Major organsMajor organs islet cells of pancreasislet cells of pancreas insulin sensitive organs: liver, muscle, fatinsulin sensitive organs: liver, muscle, fat intestinesintestines KidneysKidneysModulatorModulator Endocannabinoid SystemEndocannabinoid System

Islet as an Organ:Islet as an Organ:

Role of Pancreatic Islets in NormalRole of Pancreatic Islets in NormalGlucose HomeostasisGlucose Homeostasis

~ 3,000 cells75% Beta cells25% non-Beta cells

200 µm

Micrograph: Lelio Orci, Geneva

Islet of LangerhansIslet of Langerhans

Beta and Alpha Cells in the Pancreas of Beta and Alpha Cells in the Pancreas of Normal IndividualsNormal Individuals

Beta CellsBeta Cells Alpha CellsAlpha Cells

• Comprise about 50% Comprise about 50% of the endocrine mass of of the endocrine mass of the pancreasthe pancreas11

• Comprise about 35% of Comprise about 35% of the endocrine mass of the endocrine mass of the pancreasthe pancreas11

• Produce insulin and Produce insulin and amylinamylin22

• Produce glucagonProduce glucagon22

• Insulin released in Insulin released in response to elevated response to elevated blood glucose levelsblood glucose levels22

• Glucagon released in Glucagon released in response to low blood response to low blood glucose levelsglucose levels2 2 leading to leading to increase in glucoseincrease in glucose

1. Cabrera O et al. PNAS. 2006;103:2334–2339.2. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21–39.

Insulin ProductionInsulin Production

Primary regulators for insulin biosynthesisPrimary regulators for insulin biosynthesis glucoseglucose glucagonglucagon incretins- GLP-1, GIPincretins- GLP-1, GIP

Inhibits insulin biosynthesisInhibits insulin biosynthesis catecholaminecatecholamine somatostatinsomatostatin

GlucagonGlucagon

Main regulator- glucoseMain regulator- glucose amino acidsamino acids

incretinsincretins InsulinInsulin fatty acidsfatty acids ketonesketones

Insulin and Glucagon Regulate Insulin and Glucagon Regulate Normal Glucose HomeostasisNormal Glucose Homeostasis

Porte D Jr et al. Clin Invest Med. 1995;18:247–254.Adapted from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Blood glucose

Glucose output Glucose uptake

Glucagon(Alpha cell)

Insulin(Beta cell)

Pancreas

Liver

(+)

(–) (+)

(+)

(–)(–)

Muscle and adipose tissue

GUT and GUT HormonesGUT and GUT Hormones

Na ATP channels – absorption of glucoseNa ATP channels – absorption of glucose IncretinsIncretins

Decreasedhepatic glucose output

Increased peripheral glucose uptakeGI tract Pancreas

Incretins Regulate Glucose Homeostasis Incretins Regulate Glucose Homeostasis Through Effects on Islet-Cell FunctionThrough Effects on Islet-Cell Function

Glucagon in glucose-

dependent way from αα

cells (GLP-1)

α cells

Insulinin glucose-dependent way

from β cells(GLP-1 and GIP)

β cells

Ingestion of food

Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653-2659;Zander M et al. Lancet. 2002;359:824-830; Ahrén B. Curr Diab Rep. 2003;3:365-372; Buse JB et al. In Larsen PR et al, eds.: Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: Saunders; 2003:1427-1483.

InactiveGLP-1 (9-36)

and GIP (3-42)

↓ GLUCAGON

INSULIN Bloodglucose

control

Release of

incretin gut

hormones

Active GLP-1 and

GIP

Bloodglucose

control

The endocannabinoid system is a The endocannabinoid system is a modulatory systemmodulatory system

Endocannabinoids:Endocannabinoids: Synthesized on Synthesized on

demand from lipid demand from lipid precursors in precursors in postsynaptic cellpostsynaptic cell

CBCB11 receptors: receptors: Play a key role in Play a key role in

energy balance and energy balance and lipid and glucose lipid and glucose metabolismmetabolism

Di Marzo V et al, 2005; Di Marzo V et al, 1998;Wilson R et al, 2002

Bensaid M et al, 2003; Pagotto U et al, 2005; Osei-Hyiaman D et al, 2005;

Di Marzo V et al, 2005; Liu YL et al, 2005

Adipose tissue

MuscleLiverGI tract

Increased food intakeIncreased fat storage

Insulin resistanceHDL-cholesterolTriglyceridesGlucose uptakeAdiponectin

Hypothalamus: hunger

Nucleus accumbens: motivation to eat ^

^

^^

Brain Peripheral tissues

Central and peripheral targets of Central and peripheral targets of the endocannabinoid systemthe endocannabinoid system

HDL: high-density lipoprotein

Regulation of glucose HomeostasisRegulation of glucose Homeostasis

Na dependent transporters in proximal tubules of Na dependent transporters in proximal tubules of kidneys cotransport glucose with sodium kidneys cotransport glucose with sodium maintained by Na+/K+-ATPase ion pumpmaintained by Na+/K+-ATPase ion pump

Glucose homeostasisGlucose homeostasis

Is a balance of glucose appearance and Is a balance of glucose appearance and disappearancedisappearance

Glucose appearance:Glucose appearance: endogenous glucose production (liver, endogenous glucose production (liver,

muscle and kidneys)muscle and kidneys) exogenous sources (GIT) affected by feeding exogenous sources (GIT) affected by feeding

signalssignals Glucose disappearanceGlucose disappearance peripheral uptake from liver, muscle and fatperipheral uptake from liver, muscle and fat

Current Diagnosis ofCurrent Diagnosis of

Prediabetes and DiabetesPrediabetes and Diabetes

Definition of DDefinition of Diabetesiabetes

A metabolic dysregulation A metabolic dysregulation Hallmark: hyperglycemiaHallmark: hyperglycemia Basic defects: Basic defects: Islet cell dysfunctionIslet cell dysfunction

Insulin insensitivityInsulin insensitivity Impaired action of insulin on target tissues Impaired action of insulin on target tissues

Definition of DiabetesDefinition of Diabetes

Chronic hyperglycaemia associated with long-Chronic hyperglycaemia associated with long-term damage to:term damage to: EyesEyes KidneysKidneys NervesNerves Heart and blood vesselsHeart and blood vessels

Hyperglycemia

Impaired Glucose Tolerance or

Impaired Fasting Glucose(Pre-Diabetes)

Diabetes Mellitus

Not insulin requiring

Insulin requiring for control

Insulin requiring for survival

Normal Glucose

Regulation

Stages

Type

Type 1 *

Type 2

Other Specific Type *

Gestational Diabetes **

Diagnostic Criteria For DMDiagnostic Criteria For DMFPGFPG 2 hours PG (after 75 g 2 hours PG (after 75 g

OGTT)OGTT)

NORMOGLYCEMIANORMOGLYCEMIA < 110 mg/dL< 110 mg/dL < 140mg/dL(7.8mmol/l)< 140mg/dL(7.8mmol/l)

IMPAIRED FASTING IMPAIRED FASTING GLYCEMIA (IFG)GLYCEMIA (IFG)

110 and < 126 mg/dL110 and < 126 mg/dL ------

IMPAIRED GLUCOSE IMPAIRED GLUCOSE TOLERANCE (IGT)TOLERANCE (IGT)

------ 140mg/dl(7.8mmol/l) 140mg/dl(7.8mmol/l) and < 200 and < 200

mg/dL(11.1mmol/l)mg/dL(11.1mmol/l)

DIABETES MELLITUSDIABETES MELLITUS 126 mg/dL(7.0 126 mg/dL(7.0

mmol/l)mmol/l) 200 mg/dL 200 mg/dL (11.1mmol/l)(11.1mmol/l)

Symptoms of diabetes and casual plasma glucose Symptoms of diabetes and casual plasma glucose of of 200 mg/dl(11.1mmol/l) 200 mg/dl(11.1mmol/l)

American Diabetes Association American Diabetes Association 20032003

<100mg/dL (5.6mmol/l)

100mg/dl(5.6mmol)and< 126 mg/dL(7.0)

ADA, Diabetes Care 2009

Hba1cHba1c

Integrated summary of circadian blood glucose in Integrated summary of circadian blood glucose in the preceding 6-8 weeksthe preceding 6-8 weeks

Not used as diagnostic test for diabetesNot used as diagnostic test for diabetes Lack of standardized analytical method and Lack of standardized analytical method and

therefore lack of a uniform non diabetic therefore lack of a uniform non diabetic reference level between laboratoriesreference level between laboratories

Insensitive in the low range Insensitive in the low range Normal aic cannot exclude diabetes or IGTNormal aic cannot exclude diabetes or IGT

Issues on current diagnostic cut offIssues on current diagnostic cut off

3 studies on which FPG of 7.0 cutoff was based for 3 studies on which FPG of 7.0 cutoff was based for diagnosis of diabetes used direct ophthalmoscopic diagnosis of diabetes used direct ophthalmoscopic examination and one retinal photographexamination and one retinal photograph

Diabetes Prevention Program showed substantial Diabetes Prevention Program showed substantial prevalence of retinopathy below FPG of 7.0prevalence of retinopathy below FPG of 7.0

Cardiovascular complications occur at lower glucose Cardiovascular complications occur at lower glucose levelslevels

Definition and classification of diabetes and pre states Definition and classification of diabetes and pre states should be based on the level of subsequent risk of should be based on the level of subsequent risk of cardiovascular complications class 1 level B ESC,EASD cardiovascular complications class 1 level B ESC,EASD 20072007

Relation between FPG and retinopathyRelation between FPG and retinopathy

BMES AusDiab MESABMES AusDiab MESA FPG FPG 5.3 6.5 5.9 5.3 6.5 5.9 (Mean) (Mean)

Number 364 Number 364 210 959210 959

(%) with (%) with (11.5) (9.3) (15.8) (11.5) (9.3) (15.8) Retinopathy Retinopathy

Lancet 2008Lancet 2008

0

10

20

30

40

50

60

< 4.6 4.7 - 5.4 5.5 - 6.2 6.3 - 7.0 7.1 - 7.8 7.9 - 8.6 8.7 - 9.4 9.5 - 10.2 > 10.3

Any retinopathy

Blue Mountains Eye Study (5-year incident retinopathy)Pe

rcen

tage

Number with Number with any retinopathyany retinopathy

4040 100100 2424 1212 33 77 33 22 55

TotalTotal 545545 996996 241241 5656 2121 1515 99 55 1515

Relation between baseline FPG and incident retinopathy, BMES

Fasting plasma glucose (mmol/L)

RecommendationRecommendation

Current diagnostic criteria remain the bestCurrent diagnostic criteria remain the best tools for now.tools for now.

Mechanisms of Glucose Mechanisms of Glucose Dysregulation and Development Dysregulation and Development

of Type 2 Diabetesof Type 2 Diabetes

GeneticsGenetics

39% of patients with type 2 diabetes have at least 39% of patients with type 2 diabetes have at least one parent with the diseaseone parent with the disease

Among monozyzgotic twin pairs with one Among monozyzgotic twin pairs with one affected twin, approximately 90% of unaffected affected twin, approximately 90% of unaffected twins eventually develop the diseasetwins eventually develop the disease

First degree relative of patients with type 2 First degree relative of patients with type 2 diabetes frequently have impaired nonoxidative diabetes frequently have impaired nonoxidative glucose metabolism long before they develop glucose metabolism long before they develop type 2 diabetestype 2 diabetes

Ethnic predilectionEthnic predilection

EnvironmentEnvironment

Low birth weightLow birth weight Gestational diabetesGestational diabetes PrematurityPrematurity Sedentary lifestyleSedentary lifestyle High fat dietHigh fat diet

Physiologic & Molecular basis of DiabetesPhysiologic & Molecular basis of Diabetes

PhysiologicPhysiologicislet cell dysfunctionislet cell dysfunctioninsulin resistanceinsulin resistance

MolecularMolecular insulin receptorinsulin receptor Insulin signal transductionInsulin signal transduction

Beta-Cell Function Is Abnormal Beta-Cell Function Is Abnormal in Type 2 Diabetesin Type 2 Diabetes

A range of functional abnormalities is presentA range of functional abnormalities is present Abnormal oscillatory insulin release Abnormal oscillatory insulin release Increased proinsulin levels Increased proinsulin levels Abnormal insulin responseAbnormal insulin response Progressive loss of beta-cell functional massProgressive loss of beta-cell functional mass

Adapted from Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Polonsky KS et al N Engl J Med 1988;318:1231–1239; Quddusi S et al Diabetes Care 2003;26:791–798; Porte D Jr, Kahn SE Diabetes 2001;50(suppl 1):S160–S163.

First-Phase Insulin Response to IV Glucose First-Phase Insulin Response to IV Glucose Is Lost in Type 2 DiabetesIs Lost in Type 2 Diabetes

Normal Type 2 Diabetes

n=9 normal; n=9 type 2 diabetes.Adapted from Pfeifer MA et al. Am J Med. 1981;70:579–588.

0

20

40

60

80

100

120

–30 0 30 60 90 120

Time (min)

0

20

40

60

80

100

120

–30 0 30 60 90 120

Time (min)

Pla

sma

insu

lin

(µ

U/m

L)

Pla

sma

insu

lin

(µ

U/m

L)

33Adapted from Rhodes CJ. Science. 2005;307:380–384.

Fewer Pancreatic Islets in Type 2 Diabetes

Normal

CompensationMore islets

Larger isletsMore beta cells/islet

Larger beta cells

Nondiabetic Obesity

DecompensationFewer islets

Fewer beta cells/isletAmyloidosis

Type 2 diabetes

Increased Beta-Cell Apoptosis Occurs Increased Beta-Cell Apoptosis Occurs in Type 2 Diabetesin Type 2 Diabetes

*

0.0

0.5

1.0

1.5

2.0

2.5

Control Type 2 diabetes

Apo

ptos

is (a

rbitr

ary

units

)

*p<0.05. Islet cell death was assessed by an ELISA method, which evaluates the cytoplasmic histone-associated DNA fragments. After incubation absorbance of samples was read spectrophotometrically.Data obtained from pancreatic islets isolated from 6 T2DM organ donors and 10 nondiabetic cadaveric organ donors.Adapted from Marchetti P et al. J Clin Endocrinol Metab. 2004;89:5535–5541.

AmylinAmylin

Amylin co-secreted with insulinAmylin co-secreted with insulin Low amylin levels in type 2 diabetesLow amylin levels in type 2 diabetes cause or effect is unclearcause or effect is unclear

Insulin and Glucagon Response to a Large Insulin and Glucagon Response to a Large Carbohydrate Meal in Type 2 Diabetes Carbohydrate Meal in Type 2 Diabetes

Insu

lin

(µU

/ml)

Glu

cag

on

(µµ

g/m

l)G

lucose

(mg

/100 m

l)

*Insulin measured in five patientsAdapted from Müller WA et al N Engl J Med 1970;283:109–115.

Type 2 diabetes mellitus (n=12)*Nondiabetic controls (n=11)

150

0

140

90

360

80

240

–60

Time (minutes)

30

60

90

120

110

270300330

100

110

120

130

Meal

Nonsuppressed glucagon

0 60 120 180 240

Depressed/delayed insulin response

37

Incretin Function in Type 2 DiabetesIncretin Function in Type 2 Diabetes

Secretion of GLP-1 impairedSecretion of GLP-1 impaired Beta-cell sensitivity to GLP-1 decreasedBeta-cell sensitivity to GLP-1 decreased Secretion of GIP normal (or slightly impaired)Secretion of GIP normal (or slightly impaired) Effect of GIP abolished or grossly impairedEffect of GIP abolished or grossly impaired

Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723; Kjems LL et al. Diabetes. 2003;52:380–386; Vilsbøll T et al. Diabetologia. 2002;45:1111–1119; Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88:4897–4903.

Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Saunders, 2003:1427–1483; Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. McGraw-Hill, 2005:2152–2180; Rhodes CJ. Science. 2005;307:380–384.Adapted from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Glucose outputGlucose uptake

Glucagon(Alpha cell)

Insulin(Beta cell)

Pancreas

Liver

HyperglycemiaMuscle and adipose tissue

The Pathophysiology of Type 2 Diabetes Includes The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin ResistanceIslet Cell Dysfunction and Insulin Resistance

Insulin ResistanceInsulin Resistance

GeneticsGenetics AgeAge WeightWeight adipokinesadipokines

Intra-abdominal adiposity is a Intra-abdominal adiposity is a major contributor to insulin major contributor to insulin

resistanceresistance

Kershaw EE et al, 2004; Lee YH et al, 2005; Boden G et al, 2002

Associated withinflammatory markers(C-reactive protein)

Free fattyacids

Inflammation

Insulinresistance

Dyslipidaemia

DM2Increased

cardiometabolicrisk

IAA = high risk fat

Secretion ofadipokines(↓ adiponectin)

IAA: intra-abdominal adiposity

Visceral fat

Weight

endocannabinoid system endocannabinoid system dysregulationdysregulation

FFA=free fatty acidsCETP=cholesterol ester transfer protein

Feeding

Modified from: Lam TKT, 2003; Carr DB, 2004; Eckel R, 2005;

Pagotto U, 2005; Di Marzo V et al, 2005

Weight-dependentWeight IndependentEndocannabinoid system

CB-1 blockade CB-1 blockade

CB-1 blockade

Hepatic insulinresistance

Hepaticglucoseoutput

Portal circulation Liver

FFAFFA

TG-richVLDL-C

Small,denseLDL-C

LowHDL-C

Lipolysis

CETP,lipolysis

Peripheral insulinresistance

Adiponectin

Type 2 diabetesDyslipidaemia

Insulin ActionInsulin Action

decrease in number of insulin receptorsdecrease in number of insulin receptors any disruption in the transcription or any disruption in the transcription or

transduction of insulin signaling pathwaytransduction of insulin signaling pathway

SummarySummary

Glucose metabolism is tightly regulated to maintain Glucose metabolism is tightly regulated to maintain desirable glucose levelsdesirable glucose levels

Glucose dysregulation leads to progressive dysglycemia Glucose dysregulation leads to progressive dysglycemia from prediabetes to frank diabetesfrom prediabetes to frank diabetes

The pathophysiology of type 2 diabetes is complex.The pathophysiology of type 2 diabetes is complex. Involves multiple physiologic and molecular disturbances Involves multiple physiologic and molecular disturbances

influenced by multiple genes and environmental factorsinfluenced by multiple genes and environmental factors This offers multiple target sites for therapy and explains This offers multiple target sites for therapy and explains

the complexity of treatment of DM2the complexity of treatment of DM2