Type II DiabetesType II Diabetes

Heidi Chamberlain Shea, MDHeidi Chamberlain Shea, MD

Endocrine Associates of Endocrine Associates of DallasDallas

Points of DiscussionPoints of DiscussionType II DiabetesType II Diabetes

BackgroundBackground DiagnosisDiagnosis PathophysiologyPathophysiology Oral treatmentsOral treatments Office visitsOffice visits

Type II DiabetesType II Diabetes Epidemic Epidemic

Increase intakeIncrease intake Decreased activityDecreased activity

Parallels the rise in Parallels the rise in obesityobesity

GeneticsGenetics Obesity causes earlier Obesity causes earlier

diseasedisease High risk ethnic groupsHigh risk ethnic groups

Indian, African American Indian, African American and Hispanicand Hispanic

19961991

2003

Obesity Trends* Among U.S. Adults(*BMI 30, or about 30 lbs overweight for 5’4” person)

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Insulin resistance Insulin resistance ß-Cell secretory ß-Cell secretory

dysfunctiondysfunction Relative insulin Relative insulin

deficiencydeficiency Onset in pubertyOnset in puberty Acanthosis Acanthosis

NigricansNigricans FemaleFemale

Type II DiabetesType II Diabetes

Diagnosis of DiabetesDiagnosis of DiabetesADA Expert CommitteeADA Expert Committee

NORMALNORMAL IMPAIREDIMPAIRED DIABETESDIABETES

FASTING FASTING (8 hrs)(8 hrs)

< < 110110 mg/dlmg/dl

(6.1 mM)(6.1 mM)

110-125 110-125 mg/dlmg/dl

>= >= 126126 mg/dlmg/dl

(7 mM)(7 mM)

ORAL ORAL GTT*GTT*

< < 140140 mg/dlmg/dl

(7.8 mM)(7.8 mM)

140-199 140-199 mg/dlmg/dl

>=>=200200 mg/dlmg/dl

(11.1 mM)(11.1 mM)

*Not recommended for routine clinical useExpert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2002;25 Suppl 1

Symptoms of diabetes plus a random plasma glucose concentration of 200 mg/dL, regardless of the timesince last meal

Impaired insulin Impaired insulin secretionsecretion

IncreasedIncreased HepaticHepatic

Glucose ProductionGlucose Production

Decreased Decreased Muscle Muscle Glucose Glucose uptakeuptake

Insulin Resistanc

e

Metabolic Consequences in Type 2 DM

Etiology of Type 2 DiabetesEtiology of Type 2 Diabetes Impaired Insulin Secretion and Impaired Insulin Secretion and

Insulin ResistanceInsulin ResistanceGenes and environment

Type 2 diabetes

Impaired glucose tolerance

Impaired insulin secretion

Insulin resistance+

Weyer C et al. Diabetes Care. 2001;24:89-94

0

10

20

30

40

Low HighHigh

Low

Early-phase insulin secretion

Cumulative diabetes incidenceover 4 years

Low Insulin Secretion and Sensitivity Low Insulin Secretion and Sensitivity

Both Predict Progression from IGT Both Predict Progression from IGT to Type 2 Diabetesto Type 2 Diabetes

IGT=impaired glucose tolerance

Insulin sensitiv

ity

-cell function(% of normal by HOMA)

Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;UKPDS. Diabetes. 1995;44:1249-1258

Years

0

20

40

60

80

100

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6

Time of diagnosis

?

HOMA=homeostasis model assessment

Decline of Decline of -Cell Function in -Cell Function in the UKPDS Illustrates the UKPDS Illustrates

Progressive Nature of DiabetesProgressive Nature of Diabetes

Pancreatic function= 50% of normal

InsulinInsulin + fat infusion

Glucose Measurements During High Insulin Levels

0

100

Glucose uptake or output (mg/dL fat-free mass/min)

Peripheral glucose uptake

Hepatic glucose output

*

*

High FFA Levels CauseHigh FFA Levels CausePeripheral and Hepatic Insulin Peripheral and Hepatic Insulin

ResistanceResistance

*P<0.05200

300

400

500

Boden G, Chen X. J Clin Invest. 1995;96:1261-1268

FFA=free fatty acid

Glucose FFA

FFA

Increasedglucosamine

Otherpathways

Otherpathways

Glucose

Impaired insulinsecretion from -cell

Insulin resistancein muscle and fat

Mechanism of Glucotoxicity and Mechanism of Glucotoxicity and Lipotoxicity Lipotoxicity

The Glucosamine HypothesisThe Glucosamine Hypothesis

Hawkins M et al. J Clin Invest. 1997;99:2173-2182; Rossetti L. Endocrinology. 2000;141:1922-1925

FFA=free fatty acid

Etiology of Type 2 DiabetesEtiology of Type 2 Diabetes Impaired Insulin Secretion and Impaired Insulin Secretion and

Insulin ResistanceInsulin Resistance

Type 2 diabetes

Genes and environment

Impaired insulin secretion

Insulin resistance

Impaired glucose tolerance

Progressive hyperglycemiaand high free fatty acids

Kosaka K et al. Diabetologia. 1980;18:23-28

Plasma insulin(U/mL)

0

50

25

Dietn=17

0 1 2 3

Sulfonylureasn=26

0 1 2 3

After

Before

0

Insulinn=7

*

**

*

**

* *

*

*

*

***

*

*

*

1 2 3

*P<0.05

Better Insulin SecretionBetter Insulin SecretionAfter Improved Metabolic After Improved Metabolic

ControlControlResponse to Oral Glucose Before and After 3 Therapies

Hours

• Hepatic glucose production is a primary factor determining fasting plasma glucose

• Fasting hepatic glucose production is regulated by– Fasting (basal) plasma insulin – Hepatic sensitivity to insulin– Fasting substrate availability

• In type 2 diabetes– Basal insulin secretion is impaired – Hepatic sensitivity to insulin is decreased

Regulation of Fasting Regulation of Fasting GlucoseGlucose

*

0

50

100

0 50 100 150

*

*

Groop LC et al. J Clin Invest. 1989;84:205-213

Calculated portal plasma insulin (U/mL)

Glucose output (mg/m2/min)

*

NormalType 2 diabetes

*P<0.05

Hepatic Resistance to Hepatic Resistance to InsulinInsulin

in Type 2 Diabetesin Type 2 Diabetes

•

•

••

• •

Hepatic Glucose Output During Graded Insulin Infusion

•

•

•

• ••

Byrne MM et al. Am J Physiol. 1996;270(4 pt 1):E572-E579

Plasma glucose (mg/dL)

NormalIGTType 2 diabetes

100 150 200 250 300

30

25

20

15

10

5

0

Secretion/BMIpmol x m2/(min x kg)

Insulin Secretion Rate During Graded Glucose Infusion

Impaired Basal Insulin Impaired Basal Insulin Secretion in Secretion in

Type 2 DiabetesType 2 Diabetes

IGT=impaired glucose toleranceBMI=body mass index

• A meal contains 6 to 20 times the glucose content of the blood

• Normally, postprandial hyperglycemia is regulated by– Clearance of ingested glucose by the liver– Suppression of hepatic glucose production– Peripheral clearance of glucose

Regulation of Postprandial Regulation of Postprandial GlucoseGlucose

• In impaired glucose tolerance or diabetes, glucose regulation is impaired by – Delayed and reduced insulin secretion– Lack of suppression of glucagon – Hepatic and peripheral insulin resistance

Impaired Regulation ofImpaired Regulation ofPostprandial GlucosePostprandial Glucose

Abnormal Acute Insulin Response Abnormal Acute Insulin Response to to

Intravenous Glucose in Type 2 Intravenous Glucose in Type 2 DiabetesDiabetes

Robertson RP, Porte D Jr. J Clin Invest. 1973;52:870-876

Plasma insulin(U/mL)

Minutes

300– 300

40

20

60

80

100

0

40

20

60

80

100

Normal Type 2 Diabetes

GlucoseGlucose

300– 30

Insulin release(IR/G [pM/mM])

Kahn SE et al. Diabetes. 1998;47:640-645

OGTT-Stimulated Insulin OGTT-Stimulated Insulin Release in IGT and Type 2 Release in IGT and Type 2

DiabetesDiabetes

0

20

40

60

80

100

120

NGTn=56

IGTn=10

Type 2 diabetesn=28

OGTT=oral glucose tolerance testNGT=normal glucose toleranceIGT=impaired glucose tolerance

Patterns of Glucose, Insulin, and Patterns of Glucose, Insulin, and Glucagon Glucagon

After Oral Glucose in Type 2 After Oral Glucose in Type 2 DiabetesDiabetes

–60 0 60 120 180 240 300

60

30

45

400

Type 2 Diabetes

Normal

0

120

240

360

–60 0 60 120 180 240 300

Delayed and reducedHigh and not suppressed

Postprandial hyperglycemia

Minutes Minutes

–60 0 60 120 180 240 300

Minutes

300

200

100

Mitrakou A et al. Diabetes. 1990;39:1381-1390

Insu

lin (p

mol

/L)

Glu

cago

n (fm

ol/L

)

Glu

cose

(mg/

dL)

Kolterman OG et al. J Clin Invest. 1981;68:957-969

Glucosedisposal rate(mg/m2/min)

Insulin Resistance in IGT Insulin Resistance in IGT and and

Type 2 DiabetesType 2 Diabetes

IGT=impaired glucose tolerance

360

270

180

90

0Normal IGT Type 2 diabetes

0 1 2 3 4 5 6 7 8 9 1011

300

250

200

150

100

50

0

Peripheral Insulin Sensitivity Peripheral Insulin Sensitivity Decreases Decreases

With Intra-abdominal FatWith Intra-abdominal Fat

Cefalu WT et al. Metabolism. 1995;44:954-959

Insulin sensitivity (x 10-4 min-1 • U-1 • mL-1)

Femalesr = -0.44P=0.0024

Malesr= -0.68P=0.005

Males

Females

Intra-abdominalfat (cm3)

Polonsky KS et al. Polonsky KS et al. N Engl J Med.N Engl J Med. 1988;318:1231-1239 1988;318:1231-1239

NormalType 2 on diet only

Glucose(mg/dL)

Insulin(U/mL)

Abnormal Glucose and Insulin Abnormal Glucose and Insulin ProfilesProfiles

in Type 2 Diabetesin Type 2 Diabetes

100

200

300

400

0600 1000 18001400 02002200 0600 0600 1000 18001400 02002200 0600

Time of day

20

40

60

80

100

120

B L D B L D

B=breakfast; L=lunch; D=dinner

• Type 1 diabetes– The main abnormality is insulin deficiency

• Type 2 diabetes– Both insulin deficiency and insulin resistance

contribute–Free Fatty Acids–Increased Glucagon

• Glucotoxicity and lipotoxicity– Poor metabolic control worsens insulin

deficiency and insulin resistance

Summary of Summary of PathophysiologyPathophysiology

Basal hyperglycemiaBasal hyperglycemia Basal insulin levels Basal insulin levels Hepatic response determine fasting plasma glucoseHepatic response determine fasting plasma glucose

Postprandial hyperglycemiaPostprandial hyperglycemia Early insulin release Early insulin release Glucagon suppressionGlucagon suppression Hepatic and muscle responses to insulin determine Hepatic and muscle responses to insulin determine

postprandial glucosepostprandial glucose

Summary of Summary of PathophysiologyPathophysiology

Pharmacologic Pharmacologic TreatmentTreatment

Insulin Insulin SecretagoguesSecretagogues SulfonylureasSulfonylureas MeglitanidesMeglitanides

Insulin SensitizersInsulin Sensitizers MetforminMetformin ThiazolidinedionesThiazolidinediones

α-Glucosidase inhibitorα-Glucosidase inhibitor Acarbose, miglitolAcarbose, miglitol

InsulinInsulin

SulfonylureasSulfonylureas

Glyburide Glyburide Micronase, DiabetaMicronase, Diabeta

Glyburide Glyburide GlynaseGlynase

Glipizide Glipizide GlucotrolGlucotrol Glucotrol XLGlucotrol XL

Glimepiride Glimepiride AmarylAmaryl

ChlorpropamideChlorpropamide DiabenaseDiabenase

TolazamideTolazamide AcetohexamideAcetohexamide

DymelorDymelor TolbutamideTolbutamide

Newer Older

Glucose entry

GLUT2 glucosetransporter

Glucokinase

ADP/ATP

Potassium (KATP) channel

K+

Ca2+

Calcium channel

SUR 1

Insulin Secretion by the Insulin Secretion by the -Cell-Cell

Roles of Glucose, KRoles of Glucose, K++, and , and CaCa2+2+

Glucose metabolism

ADP/ATP

K+K+

Ca2+

Ca2+

Kir 6.2

Insulin secretory granules

opens

Ca2+

Ca2+

Insulin secretion

K+

KATP channel subunits:SUR 1=regulatory subunit;Kir 6.2=inward rectifying channel

closes

Insulin SecretagoguesInsulin Secretagogues Sulfonylureas, Repaglinide, and Sulfonylureas, Repaglinide, and

NateglinideNateglinide

Riddle MC. Am Fam Physician. 1999;60:2613-2620; Wolffenbuttel et al. Drugs. 1995;50:263-288; Horton ES et al. Diabetes Care. 2000;23:1660-1665; Hanefeld M et al. Diabetes Care. 2000;23:202-207;Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: ADA; 1998

Mechanism of actionMechanism of action Increase basal and/or postprandialIncrease basal and/or postprandialinsulin secretioninsulin secretion

Efficacy depends uponEfficacy depends upon Functioning Functioning -cells-cells

PowerPower Sulfonylureas, repaglinide: decrease A1C Sulfonylureas, repaglinide: decrease A1C 1%–2%1%–2% Nateglinide: decreases A1C 0.5%–1%Nateglinide: decreases A1C 0.5%–1%

DosingDosing Sulfonylureas: 1 or 2 times dailySulfonylureas: 1 or 2 times daily Repaglinide, nateglinide: Repaglinide, nateglinide:

3 or 4 times daily with meals3 or 4 times daily with meals

Side effectsSide effects Weight gain, allergy (rare)Weight gain, allergy (rare)

Main riskMain risk HypoglycemiaHypoglycemia

BiguanidesBiguanidesMetforminMetformin

Riddle MC. Am Fam Physician. 1999;60:2613-2620; Cusi K et al. Diabetes Rev. 1998;6:89-131

Primary mechanismPrimary mechanism Decreases hepatic glucoseDecreases hepatic glucose of actionof action productionproduction

Efficacy depends uponEfficacy depends upon Presence of insulinPresence of insulin

PowerPower Decreases A1C 1%–2%Decreases A1C 1%–2%DosingDosing 2 or 3 times daily 2 or 3 times daily

(metformin)(metformin)1 or 2 times daily 1 or 2 times daily

(metformin XR)(metformin XR)

Side effectsSide effects Diarrhea, nauseaDiarrhea, nausea

Main riskMain risk Lactic acidosisLactic acidosis

αα-Glucosidase Inhibitors-Glucosidase InhibitorsAcarbose and MiglitolAcarbose and Miglitol

Mechanism of actionMechanism of action Delay carbohydrate Delay carbohydrate absorptionabsorption

Efficacy depends uponEfficacy depends upon Postprandial hyperglycemiaPostprandial hyperglycemia

PowerPower Decrease A1C 0.5%–1%Decrease A1C 0.5%–1%

Dosing Dosing 3 times daily3 times daily

Side effectsSide effects FlatulenceFlatulence

Main riskMain risk Liver enzyme elevation (rare)Liver enzyme elevation (rare)

Riddle MC. Am Fam Physician. 1999;60:2613-2620; Lebovitz HE. Endocrinol Metab Clin North Am. 1997;26:539-551

Glitazones (TZDs)Glitazones (TZDs)Pioglitazone and RosiglitazonePioglitazone and Rosiglitazone

Mechanism of actionMechanism of action Enhance tissue response to Enhance tissue response to

insulininsulinEfficacy depends uponEfficacy depends upon Presence of insulin and Presence of insulin and resistanceresistance

to its actionto its action

PowerPower Decrease A1C 0.9%–1.6%Decrease A1C 0.9%–1.6%

DosingDosing Once dailyOnce daily

Side effectsSide effects Edema, weight gain, anemiaEdema, weight gain, anemia

Main riskMain risk Congestive heart failureCongestive heart failure

Riddle MC. Am Fam Physician. 1999;60:2613-2620; Zinman B. Diabetes Obesity Metab. 2001;3(suppl 1):S34-S43; Actos (pioglitazone hydrochloride) package insert; Avandia (rosiglitazone maleate) package insert

Antihyperglycemic AgentsAntihyperglycemic AgentsMajor Sites of ActionMajor Sites of Action

Carbohydrate absorption

Glucose production

Insulin secretion

Secretagogues

Glucose uptake

Injected insulin

Glitazones-Glucosidase inhibitors

–

+

+

+

Pancreas

Metformin

Muscle/Fat

–

–

–

+

GI tract

Liver

Plasma glucose

Glucose Profiles in Type 2 Glucose Profiles in Type 2 DiabetesDiabetes

Effects of Correcting Effects of Correcting Basal vs Postprandial Basal vs Postprandial

HyperglycemiaHyperglycemia

100

200

300

Normal—A1C 5%

Plasma glucose(mg/dL)

0800 1200 1800 0800

Time of day

A1C 7%

A1C 9%

A1C 6%

Jeppesen J et al. Diabetes Care. 1994;17:1093-1099

Glipizide aloneGlipizide + metformin

Effects of Metformin Added to a Effects of Metformin Added to a SulfonylureaSulfonylurea

Glucose and Insulin ProfilesGlucose and Insulin Profiles

Insulinpmol/L

0

100

200

300

400

0800 1200 1800 2400

500Glucose

Time of day

mg/dL

0

100

200

300

0800 1200 1800 2400

Meal Meal Meal Meal

Oral Antihyperglycemic Oral Antihyperglycemic MonotherapyMonotherapy

Maximum Therapeutic Effect Maximum Therapeutic Effect on A1Con A1C

-0.50 -1.0 -1.5 -2.0

Nateglinide

Reduction in A1C (%)

Glipizide GITS

Glimepiride

Repaglinide

Pioglitazone

Acarbose

Metformin

Rosiglitazone

Diabetes Care. 2000;23:202-207; Precose (acarbose) package insert; Drugs. 1995;50:263-288; J Clin Endocrinol Metab. 2001;86:280-288; Diabetes Care. 2000;23:1605-1611; Diabetes Care. 1996;19:849-856; Diabetes Care. 1997;20:597-606; Am J Med. 1997;102:491-497

Treatment of Postprandial Treatment of Postprandial GlycemiaGlycemia

Conclusions From StudiesConclusions From Studies

Most oral agents control mainly fasting Most oral agents control mainly fasting

(basal) hyperglycemia(basal) hyperglycemia

Acarbose, miglitol, and nateglinide have the Acarbose, miglitol, and nateglinide have the

greatest effect on postprandial increments greatest effect on postprandial increments

and the least ability and the least ability

to reduce A1Cto reduce A1C

Time Course of Action ofTime Course of Action ofOral AntihyperglycemicsOral AntihyperglycemicsEffect on Fasting Plasma Effect on Fasting Plasma

GlucoseGlucose

DeFronzo RA et al. N Engl J Med. 1995;333:541-549; Fonseca V et al. JAMA. 2000;283:1695-1702; Goldberg RB et al. Diabetes Care. 1996;19:849-856

0 4 8 12 16

Weeks of treatment

0

-20

-40

-60

2

FPG(mg/dL) Glimepiride (4 mg)

Rosiglitazone (8 mg) added to metformin

Metformin (up to 2550 mg)

Selected Insulin Selected Insulin SecretagoguesSecretagogues

Dosing InformationDosing InformationRecommendedRecommended Usual Usual

Generic NameGeneric Name Dose StrengthsDose Strengths Dose RangeDose Range Maximal Maximal EffectEffect

GlimepirideGlimepiride 1, 2, or 4 mg1, 2, or 4 mg 1–8 mg1–8 mg 4 mg qd4 mg qd

Glipizide GITSGlipizide GITS 2.5, 5, or 10 mg2.5, 5, or 10 mg 2.5–20 mg2.5–20 mg 5 or 10 mg qd5 or 10 mg qd

GlyburideGlyburide 1.25, 2.5, or 5 mg1.25, 2.5, or 5 mg 1.25–20 mg1.25–20 mg 5 or 10 mg bid5 or 10 mg bid

NateglinideNateglinide 60 or 120 mg60 or 120 mg 180–360 mg180–360 mg 120 mg tid120 mg tid

RepaglinideRepaglinide 0.5, 1, or 2 mg0.5, 1, or 2 mg 1–16 mg1–16 mg 4 mg qid4 mg qid

Metformin, Metformin, -Glucosidase -Glucosidase Inhibitors, Inhibitors, GlitazonesGlitazones

Dosing InformationDosing InformationRecommendedRecommended UsualUsual

Generic NameGeneric Name Dose StrengthsDose Strengths Dose RangeDose Range Maximal EffectMaximal EffectMetforminMetformin 500, 850, or500, 850, or 500 mg qd to 1000 mg bid500 mg qd to 1000 mg bid

1000 mg1000 mg 850 mg tid850 mg tid

Metformin XRMetformin XR 500 mg500 mg 500 mg qd to 1000 mg bid500 mg qd to 1000 mg bid1000 mg bid1000 mg bid

AcarboseAcarbose 25, 50, or 100 mg25, 50, or 100 mg 25–100 mg tid25–100 mg tid 50 mg tid50 mg tid

MiglitolMiglitol 25, 50, or 100 mg25, 50, or 100 mg 25–100 mg tid25–100 mg tid 50 mg tid50 mg tid

PioglitazonePioglitazone 15, 30, or 45 mg 15, 30, or 45 mg 15–45 mg qd15–45 mg qd 45 mg qd45 mg qd

RosiglitazoneRosiglitazone 2, 4, or 8 mg2, 4, or 8 mg 4–8 mg daily4–8 mg daily 4 mg bid4 mg bid

Metabolic Effects of Metabolic Effects of Oral AntihyperglycemicsOral Antihyperglycemics

Sulfonylureas Acarbose Pioglitazone Meglitinides Metformin MiglitolRosiglitazone

Weight or

LDL cholesterol or

HDL cholesterol or

Triglycerides or

Medical BenefitsMedical BenefitsSubstantiated in Published Substantiated in Published

Clinical TrialsClinical TrialsMicrovascular Cardiovascular

Insulin Yes Yes?

Sulfonylureas Yes No

Metformin Yes Yes?

-Glucosidase inhibitors No No

Glitazones (TZDs) No No

Repaglinide, nateglinide* No No

* Recently available agents with few trials documenting long-term outcomes

Severe Adverse EffectsSevere Adverse Effects

Hypoglycemia CV

Insulin Yes No No

Sulfonylureas Yes No No

Metformin No No Yes

Lactic acidosis

-Glucosidase inhibitors No No No

Glitazones (TZDs) No Yes (CHF) No

Repaglinide, nateglinide* Yes No No

* Recently available agents with few trials documenting long-term outcomes CV=cardiovascular; CHF=congestive heart failure

Efficacy of Oral Efficacy of Oral AntihyperglycemicsAntihyperglycemicsDeclines With TimeDeclines With Time

A1C rises at ~0.2% to 0.3% yearly on stable therapyA1C rises at ~0.2% to 0.3% yearly on stable therapy This rate is the same as for diet alone, sulfonylureas, This rate is the same as for diet alone, sulfonylureas,

and metforminand metformin -Cell function declines at the same rate with all -Cell function declines at the same rate with all

these treatmentsthese treatments Combination treatments are routinely neededCombination treatments are routinely needed

UKPDS Group. Diabetes. 1995;44:1249-1258; Turner RC et al. JAMA. 1999;281:2005-2012

Secondary Failure of Secondary Failure of MonotherapyMonotherapy

Overweight Patients in the Overweight Patients in the UKPDSUKPDS

Turner RC et al. UKPDS 49. JAMA. 1999;281:2005-2012

Percent with A1C <7% on monotherapy

Diet 23 12 11

Sulfonylureas 45 28 21

Metformin 44 34 13

3 years 6 years 9 years

Insulin TherapyInsulin Therapy Who should be on Who should be on

insulin?insulin? Insulin DeficientInsulin Deficient

DKADKA Weight lossWeight loss

Patient on maximal Patient on maximal oral therapy oral therapy A1c not at goalA1c not at goal

Insulin TherapyInsulin Therapy

Basal insulin plus Basal insulin plus secretagoguesecretagogue Lantus HS (10 units)Lantus HS (10 units) NPH HS (10 units)NPH HS (10 units)

Bolus and BasalBolus and Basal 75/2575/25

Novolog or Humalog Novolog or Humalog with NPHwith NPH

70/3070/30 Regular with NPH Regular with NPH

New TherapiesNew Therapies Fat absorption blocker─orlistat (XenicalFat absorption blocker─orlistat (Xenical®®))

Oral intestinal lipase inhibitorOral intestinal lipase inhibitor Approved for obesity, proposed for diabetesApproved for obesity, proposed for diabetes

Amylin analogue─pramlintide (Symlin™)Amylin analogue─pramlintide (Symlin™) Slows gastric emptying, suppresses glucagon, increases Slows gastric emptying, suppresses glucagon, increases

satietysatiety Requires injectionRequires injection

GLP-1 analogues/agonists─exendin-4 (ByettaGLP-1 analogues/agonists─exendin-4 (ByettaTMTM) ) Potentiate insulin secretion, suppress glucagonPotentiate insulin secretion, suppress glucagon May promote May promote -cell neogenesis-cell neogenesis Require injectionRequire injection

GLP-1=glucagon-like peptide

Summary ofSummary ofOral Antihyperglycemic AgentsOral Antihyperglycemic Agents

Four major classesFour major classes of oral agents acting at different sites of oral agents acting at different sites

are availableare available Fasting and preprandial glucoseFasting and preprandial glucose are reduced by are reduced by

sulfonylureas, repaglinide, metformin, and glitazones sulfonylureas, repaglinide, metformin, and glitazones (TZDs), with lesser effects on postprandial increments(TZDs), with lesser effects on postprandial increments

Postprandial glucosePostprandial glucose increments are reduced best by increments are reduced best by -glucosidase inhibitors and nateglinide-glucosidase inhibitors and nateglinide

A1C reductionsA1C reductions are similar using sulfonylureas, are similar using sulfonylureas, metformin, and glitazonesmetformin, and glitazones

Secondary failureSecondary failure to monotherapy and oral therapies to monotherapy and oral therapies routinely occursroutinely occurs

Complications of Complications of DiabetesDiabetes

Type I and IIType I and II AtherosclerosisAtherosclerosis

StrokeStroke Heart diseaseHeart disease

RetinopathyRetinopathy Leading cause of Leading cause of

blindnessblindness NeuropathyNeuropathy

Peripheral Peripheral AutonomicAutonomic

NephropathyNephropathy Leading cause of end Leading cause of end

stage renal diseasestage renal disease One out of every 3 One out of every 3

patients on dialysis or patients on dialysis or transplant programtransplant program

Relative Risk

15

13

11

9

7

5

3

1

HbA1c %7 8 9 10 11 12

Diabetic retinopathyNephropathyNeuropathyMicroalbuminuria

Risk of Progression of Risk of Progression of Complications: DCCT Complications: DCCT

StudyStudy

Skyler JF. Endocrinol Metab Clin North Am. 1996;25:243-254.

Treatment of DiabetesTreatment of Diabetes

Treatment goalsTreatment goals Type I A1c < 7.0Type I A1c < 7.0 Type II A1c < 6.0Type II A1c < 6.0

Minimize hypoglycemiaMinimize hypoglycemia Maximize participation Maximize participation

in usual activitiesin usual activities

Goals of Diabetes Goals of Diabetes TreatmentTreatment

Early detection of Early detection of complications:complications: Annual retinal examAnnual retinal exam Annual renal examAnnual renal exam

(microalbuminuria, (microalbuminuria, Creatinine)Creatinine)

Frequent lower extremity Frequent lower extremity examinationsexaminations

Diabetes ManagementDiabetes Management

Home blood glucose Home blood glucose monitoringmonitoring 4 times daily4 times daily Periodically check at 3 AMPeriodically check at 3 AM

PM insulinPM insulin

Every yearEvery year TSH TSH Lipid panelLipid panel

Office visit Q3-4 Office visit Q3-4 monthsmonths Monitor HgbAMonitor HgbA1c1c Adjustment of Adjustment of

medicationmedication Examine injection sites Examine injection sites

HypertrophyHypertrophy LipoatrophyLipoatrophy

Blood pressureBlood pressure WeightWeight

ConclusionsConclusions Type II Diabetes is Type II Diabetes is

multifactorialmultifactorial Metabolic syndromeMetabolic syndrome Fatty acid excessFatty acid excess

TherapyTherapy Multiple agents neededMultiple agents needed With time insulin is neededWith time insulin is needed

Tight control prevents Tight control prevents complicationscomplications Silent diseaseSilent disease Assume 10 years of disease Assume 10 years of disease

and vascular damage at and vascular damage at time of diagnosistime of diagnosis

ConclusionsConclusions TherapyTherapy

Multiple agents neededMultiple agents needed With time insulin is neededWith time insulin is needed

Diet therapyDiet therapy Exercise Exercise Medical therapyMedical therapy

InsulinInsulin Oral agentsOral agents Adjunctive therapiesAdjunctive therapies

EducationEducation Diabetes Team Diabetes Team MD, RN CDE, Dietitian, Social MD, RN CDE, Dietitian, Social

work and Psychiatrywork and Psychiatry

Diet Therapy Lose weightLose weight

1 pound per week1 pound per week Decreased intake of 500-Decreased intake of 500-

1000 calories per day1000 calories per day 3500-7000 calories per 3500-7000 calories per

weekweek Decrease portion sizeDecrease portion size

Decrease carbohydrate Decrease carbohydrate intakeintake

Lower fat intakeLower fat intake Increase activityIncrease activity

Walk the dog Walk the dog (even if you don’t have (even if you don’t have one)one)

Pramlintide Reduces A1C and Pramlintide Reduces A1C and WeightWeight

Combination With Insulin for Type Combination With Insulin for Type 2 Diabetes2 Diabetes

Placebo + insulinPramlintide 150 g tid + insulin

Ratner RE et al. Diabetes Technol Ther. 2002;4:51-61

Week

A1C Placebo-subtracted difference 0.4%

WeightPlacebo-subtracted difference 2.5 kg

kg

-1.5

-1.0

-0.5

0

0.5

1.0

1.5

0 13 26 39 52

-0.8

-1.0

-0.6

-0.4

-0.2

0

0 13 26 39 52

A1C %

**PP<0.01<0.01

**PP<0.01<0.01

****

**

****

****

**

**

Synthetic Exendin-4 Reduces A1C Synthetic Exendin-4 Reduces A1C and Weightand Weight

28-Day Treatment of Type 2 Diabetes28-Day Treatment of Type 2 Diabetes

Fineman MS et al. Diabetes 2002;51:A85

A1C % 0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

P0.006

-1.1%

-0.3%

-1.0

0

1.0

2.0

lb

-2.0

3.0

A1CPlacebo-subtracted difference -0.8%

WeightPlacebo-subtracted difference -2.9 lb

PlaceboAC2993 bid

109 Patients With Continued Treatment on Sulfonylurea, Metformin, or Both

-0.9

2.0

Orlistat Reduces A1C and Orlistat Reduces A1C and WeightWeight

Treatment of Patients With Treatment of Patients With Type 2 DiabetesType 2 Diabetes

A1C (%)

Week

-4 0 12 24 3648

0

-2

-4

-6

Hanefeld M et al. Diabetes Obes Metab. 2002;4:415-423

% bodyweightchange

-4 0 12 24 3648

9.0

8.5

8.0

7.5

7.0

PlaceboOrlistat 120 mg tid

P=P=0.0060.006PP=0.0003=0.0003

Insulin receptor

Plasma membrane

GLUT4 vesicle mobilization to plasma membrane

Insulin

Intracellular signaling cascades

Insulin Action in Muscle and Fat Insulin Action in Muscle and Fat CellsCells

Mobilization of GLUT4 to the Cell Mobilization of GLUT4 to the Cell SurfaceSurface

GLUT4 vesicle integration into plasma

membrane Glucose entry into cell via GLUT4

IntracellularGLUT4 vesicles

GLUT4=glucose transporter 4