Insulin and oral hypoglycemic drugs. Endogenous insulin is secreted from cells in the pancreas Islet of Langerhans Alpha cell: 20%, glucagon Beta cell:

Insulin and oral Insulin and oral hypoglycemic drugshypoglycemic drugs

Endogenous insulin is secreted from Endogenous insulin is secreted from cells in the pancreas cells in the pancreas

Islet of Langerhans Alpha cell: 20%, glucagonBeta cell: 75%, insulinDelta cell: 5%, somatostatinD1 cell: VIPPP cell: pancreatic polypeptide

Glucose metabolism aGlucose metabolism and the regulation by ind the regulation by insulin and glucogannsulin and glucogan

Diabetes mellitus:Diabetes mellitus:

Insulin Insulin or its or its responses responses

blood glucose blood glucose

Acute or chronic Acute or chronic symptomssymptoms

A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both

100 million people worldwide 85-90% cases are Type II

Diabetes MellitusDiabetes Mellitus

CLASSIFICATION

TYPE 1 (IDDM,10%) Deficiency of insulin secretion Genetic predisposition and possible links to

viral infections and environmental factors Possible autoimmune process with destruct

ion of beta pancreatic cells Require insulin supplementation, prone to

develop DKA ( 酮症酸中毒）

CLASSIFICATION

TYPE 2 Resistance to action of insulin on target organs Decrease in insulin production Increased risk with obesity high fat, high caloric di

ets Stronger genetic predisposition Variety of initial presentations: HHNKS ( 高血糖高渗性非酮症综合征 ), nephropathy, retinopathy, neuropathies

Disease can be delayed or prevented with life style changes

Natural History of Type 2 Natural History of Type 2 DiabetesDiabetes

150200250

-10 -5 0 5 10 15 20 25 30

Years of DiabetesYears of Diabetes

Glucose(mg/dL)

Relative Function

Insulin Resistance

Insulin Level“Beta-cell failure”

*IGT = impaired glucose tolerance

50100150200250300350

Fasting Glucose

Post-meal Glucose

Adapted from International Diabetes Center (IDC)Minneapolis, Minnesota

Obesity IGT Diabetes Uncontrolled hyperglycemiaObesity IGT Diabetes Uncontrolled hyperglycemia

CLASSIFICATION

SECONDARY CAUSES Exocrine pancreas disease: pancreatitis Genetic syndromes: Downs, Turners Infections: CMV, Congenital rubella Drugs: Glucocorticoids, Dilantin, beta

agonists Endocrinopathies: Cushing's, Acromegaly

Classification

Gestational Presents only during pregnancy 135,000 cases annually Increased risk of developing diabetes post

partum Tight glycemic control required to prevent

macrosomia, fetal cardiac and CNS abnormalities

CLINICAL FEATURES

PolyuriaPolydipsiaPolyphagiaWeight loss

TYPE 1 DM-- acute, severeTYPE 2 DM-- chronic, less severe

正常人正常人糖尿病糖尿病尿崩症尿崩症

Complications of diabetes mellitusComplications of diabetes mellitus

Acute complicationsAcute complications Diabetic ketoacidosis Diabetic ketoacidosis Hyperosmotic nonketotic comaHyperosmotic nonketotic coma Chronic complicationsChronic complications Cardiovascular diseasesCardiovascular diseases Renal damageRenal damage Retinal damageRetinal damage Nerve degenerationNerve degeneration Myopathy Myopathy Infection Infection

Rhinocerebral Mucormycosis

Therapy of Diabetes Mellitus

DietDietExerciseExerciseInsulin and its enhancers Insulin and its enhancers Oral hypoglycemic drugsOral hypoglycemic drugs

Insulin and its enhancersInsulin and its enhancers

Structure of insulinStructure of insulin

InsulinInsulin1. 1. Pharmacological effectsPharmacological effects(1)(1) Carbohydrate metabolism:Carbohydrate metabolism: reducing blood glucose levels by glycogenreducing blood glucose levels by glycogen

olysis olysis , glycogen synthesis , glycogen synthesis , gluconeogenesis , gluconeogenesis (ketone badies (ketone badies ))

(2) Lipid metabolism: (2) Lipid metabolism: fat synthesis fat synthesis , lipolysis , lipolysis , plasma free fatty acids , plasma free fatty acids

(3) Protein metabolism: (3) Protein metabolism: active transport of amino acids active transport of amino acids , incorporation of , incorporation of amino acids into protein amino acids into protein , protein catabolism , protein catabolism

(4)(4) HR HR ,, myocardial contractility, renal blood flowmyocardial contractility, renal blood flow

Mechanism of insulin actionsMechanism of insulin actions Interacting with insulin receptorInteracting with insulin receptor

Insulin promotes glucose utilizationInsulin promotes glucose utilization

(2) Lipid metabolism:(2) Lipid metabolism: fat synthesis fat synthesis , lipolysis , lipolysis , plasma free fatty acids , plasma free fatty acids

(3) Protein metabolism: (3) Protein metabolism: active transport of amino acids active transport of amino acids , incorporation of , incorporation of amino acids into protein amino acids into protein , protein catabolism , protein catabolism

(2) Lipid metabolism:(2) Lipid metabolism: fat synthesis fat synthesis , lipolysis , lipolysis , plasma free fatty acids , plasma free fatty acids

(3) Protein metabolism:(3) Protein metabolism: active transport of amino acids active transport of amino acids , incorporation of , incorporation of amino acids into protein amino acids into protein , protein catabolism , protein catabolism

Interaction betwInteraction between insulin and iteen insulin and its receptors receptorIRS:IRS: insulin receptor insulin receptorsubstrate substrate

tyr:tyr: tyrosine tyrosine

P:P: phosphate phosphate

Insulin promotes the Insulin promotes the translocation of glucose translocation of glucose transporters into the transporters into the membranemembrane

2.2. Clinical uses Clinical uses(1)(1) Insulin-dependent patients with diabetes mellitInsulin-dependent patients with diabetes mellit

us us (type 1 diabetes mellitus) (type 1 diabetes mellitus)

(2) Insulin-independent patients:(2) Insulin-independent patients: failure to other drugsfailure to other drugs

(3) Diabetic complications:(3) Diabetic complications: diabetic ketoacidosis (diabetic ketoacidosis ( 酮症酮症酸中毒酸中毒 ), hyperosmotic nonketotic coma), hyperosmotic nonketotic coma （（高渗性非酮症性昏高渗性非酮症性昏迷迷））

(4) Critical situations of diabetic patients:(4) Critical situations of diabetic patients: fever, sevfever, severe infection, pregnancy, trauma, operationere infection, pregnancy, trauma, operation

(5) Others:(5) Others: promotion of Kpromotion of K++ uptake into the cells, pshychia uptake into the cells, pshychiatric disorders tric disorders

3.3. Preparations Preparations

PropertiesProperties PreparationsPreparations OnsetOnset PeakPeak DurationDuration

Fast-actingFast-acting Regular insulinRegular insulin 0.5-1 0.5-1 hh

2-3 h2-3 h 6-8 h6-8 h

Intermmediate-aIntermmediate-actingcting

Neutral protamine hagNeutral protamine hagedornedorn

2-4 h2-4 h 6-10 h6-10 h 12-18 h12-18 h

Long-actingLong-acting Protamine zinc insulin Protamine zinc insulin suspensionsuspension

3-6 h3-6 h 6-10 h6-10 h 24-36 h24-36 h

Hirsch IB NEJM 352:174, 2005

Rapid Acting Insulin AnaloguesRapid Acting Insulin Analogues Current agents include lispro, aspart, and glulisine.Current agents include lispro, aspart, and glulisine. Remain monomeric after injection, resulting in rapid absorption, Remain monomeric after injection, resulting in rapid absorption,

and relatively rapid onset and offset.and relatively rapid onset and offset. Onset of action is 5-15 minutes, with peak action at 60-90 Onset of action is 5-15 minutes, with peak action at 60-90

minutes and duration of ~3-5 hours.minutes and duration of ~3-5 hours. Advantages include: Advantages include:

increased convenience- can take just prior to meal.increased convenience- can take just prior to meal. better postprandial glycemic control. better postprandial glycemic control.

Disadvantages include: Disadvantages include: short duration of action- can be problematic in Type 1 diabetic short duration of action- can be problematic in Type 1 diabetic

without basal insulinization, as with bedtime NPH.without basal insulinization, as with bedtime NPH. more expensive than regular insulin (~double the cost).more expensive than regular insulin (~double the cost).

Holleman and Hoekstra, NEJM, 337:176-83, 1997Holleman and Hoekstra, NEJM, 337:176-83, 1997Hirsch, NEJM, 352:174-83, 2005 Hirsch, NEJM, 352:174-83, 2005

Actions of different insulin preparationsActions of different insulin preparations

4.4. Adverse effects Adverse effects

(1) Hypersensitivity: (1) Hypersensitivity: treated with Htreated with H11 receptor antagonist, receptor antagonist,

glucocorticoids glucocorticoids

(2) Hypoglycemia:(2) Hypoglycemia: adrenaline secretion (sweating, hungeadrenaline secretion (sweating, hunger, weakenss, tachycardia, blurred vision, headache, r, weakenss, tachycardia, blurred vision, headache, etc.etc.), tre), treated with 50% glucoseated with 50% glucose

(3) Lipoatrophy: (3) Lipoatrophy: localized in injection siteslocalized in injection sites

(4) Insulin resistance: (4) Insulin resistance: Acute: stress induced, need large dose of insulinAcute: stress induced, need large dose of insulinChronic: need >200U/d and no complicationChronic: need >200U/d and no complication

Insulin action enhancersInsulin action enhancers

Thiazolidinediones (TDs) Thiazolidinediones (TDs) 噻唑烷酮类化合物噻唑烷酮类化合物

Rosiglitazone Rosiglitazone 罗格列酮罗格列酮

Pioglitazone Pioglitazone 吡格列酮吡格列酮

Troglitazone Troglitazone 曲格列酮曲格列酮

Rosiglitazone Rosiglitazone 罗格列酮罗格列酮

Pioglitazone Pioglitazone 吡格列酮吡格列酮

Insulin action enhancersInsulin action enhancers

1.1. Pharmacological effects Pharmacological effects

Selective agonists for nuclear peroxisome proliferatoSelective agonists for nuclear peroxisome proliferator-activated receptor-r-activated receptor- ( (PPARPPAR, , 过氧化物酶增殖体激活受体过氧化物酶增殖体激活受体 ).).

(1) Lowering insulin resistance(1) Lowering insulin resistance(2) Lipid metabolism regulation: (2) Lipid metabolism regulation: TG, free fatty acid TG, free fatty acid (3) Antihypertensive effects(3) Antihypertensive effects(4) Effect on vascular complications in type 2 patients(4) Effect on vascular complications in type 2 patients

2.2. Clinical uses Clinical uses

Used for treatment of insulin-resistant diUsed for treatment of insulin-resistant diabetic patients or type 2 patientsabetic patients or type 2 patients

Edema, headache, myalgia, GI reactions, heEdema, headache, myalgia, GI reactions, hepatic damage (troglitazone)patic damage (troglitazone)

Oral hypoglycemic Oral hypoglycemic drugs drugs

SulfonylureasSulfonylureas （磺酰脲类）（磺酰脲类）

BiguanidesBiguanides （双胍类）（双胍类）

-Glucosidase inhibitors-Glucosidase inhibitors （（葡萄糖苷酶抑制药）葡萄糖苷酶抑制药）

OthersOthers

Oral hypoglycemic drugs Oral hypoglycemic drugs

SulfonylureasSulfonylureas （磺酰脲类）（磺酰脲类）

Tolbutamide Tolbutamide (D860)(D860) 甲磺丁脲甲磺丁脲Chlorpropamide Chlorpropamide 氯磺丙脲氯磺丙脲Glibenclamide Glibenclamide 格列本脲格列本脲 (( 优降优降糖糖 )) Glipizide Glipizide 格列吡嗪格列吡嗪Gliclazide Gliclazide 格列齐特格列齐特 (( 达美康达美康 ))

SulfonylureasSulfonylureas

(1)(1)Hypoglycemic effect:Hypoglycemic effect: blocking ATP-sensitive Kblocking ATP-sensitive K++ channel: Ca channel: Ca2+2+ inflow inflow , ins, ins

ulin release ulin release , stimulating insulin secretion, stimulating insulin secretion increasing insulin sensitivity (long-term use)increasing insulin sensitivity (long-term use) inhibit glucagon releaseinhibit glucagon release

(2) Antidiuretic effect(2) Antidiuretic effect

(3) Effect on coagulation function (3) Effect on coagulation function

Action of sulfonylureasAction of sulfonylureas

(1)(1)Hypoglycemic effect:Hypoglycemic effect: blocking Kblocking K++ channel: Ca channel: Ca2+2+ inflow inflow , insulin release , insulin release , ,

stimulating insulin secretionstimulating insulin secretion increasing insulin sensitivity (long-term use)increasing insulin sensitivity (long-term use) inhibit glucagon releaseinhibit glucagon release

(2) Antidiuretic effect(2) Antidiuretic effect

(3) Effect on coagulation function (Gliclazide)(3) Effect on coagulation function (Gliclazide)

2.2. Clinical uses Clinical uses

(1) Insulin-indenpedent diabetic patients (type 2): (1) Insulin-indenpedent diabetic patients (type 2): aloalone or combined with insulinne or combined with insulin

(2) Diabetes insipidus (2) Diabetes insipidus (( 尿崩症尿崩症 )): : Chlorpropamide (Chlorpropamide ( 氯磺丙脲氯磺丙脲 ): antiuretic hormone (ADH) ): antiuretic hormone (ADH)

(1) GI reactions(1) GI reactions

(2) CNS reactions(2) CNS reactions

(3) Hypoglycemia:(3) Hypoglycemia: especially in elderly, hepatic or reespecially in elderly, hepatic or renal insufficiencies nal insufficiencies

(4) Others:(4) Others: cholestatic jaundice, hepatic damage (Chlocholestatic jaundice, hepatic damage (Chlorpropamide),rpropamide), leukopenia.leukopenia.

4.4. Drug interactions Drug interactions

(1) Potentiation of hypoglycemic effects(1) Potentiation of hypoglycemic effects replacement in plasma protein binding:replacement in plasma protein binding: salicylic acid, sulfates, isalicylic acid, sulfates, indomethacin, penicillin, warfarin, ndomethacin, penicillin, warfarin, etc.etc. inhibition of hepatic microsomal enzymes:inhibition of hepatic microsomal enzymes: chloramphenicol, w chloramphenicol, warfarinarfarin

(2) Attenuation of hypoglycemic effects(2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes:induction of hepatic microsomal enzymes: phenytoin, phenoba phenytoin, phenobarbital, rbital, etc.etc.

interactions in pharmacodynamics:interactions in pharmacodynamics: glucagon, thiazides, glucagon, thiazides, etc.etc.

BiguanidesBiguanides （双胍类）（双胍类）

Metformin Metformin 二甲双胍（甲福明）二甲双胍（甲福明） Phenformin Phenformin 苯乙双胍（苯乙福明）苯乙双胍（苯乙福明）

BiguanidesBiguanides

1.1. Pharmacilogical effects Pharmacilogical effects increasing glucose uptake in fat tissues and increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut and gludecreasing glucose absorption in gut and glucagon releasecagon release

2.2. Clinical uses Clinical uses mild insulin-independent patients with obesitymild insulin-independent patients with obesity

3.3. Adverse effects Adverse effects severe lactic acidosissevere lactic acidosis ( (less for metforminless for metformin), m), m

alabsorption of vitamin Balabsorption of vitamin B1212 and folic acid and folic acid

-Glucosidase inhibitors-Glucosidase inhibitors （（葡萄糖苷酶抑制葡萄糖苷酶抑制药）药）

AcarboseAcarbose 阿卡波糖阿卡波糖

Reducing intestinal absorption of starch (Reducing intestinal absorption of starch ( 淀粉淀粉 ), ), dextrin (dextrin ( 糊精糊精 ), and disaccharides (), and disaccharides ( 二糖二糖 ) by inhib) by inhibiting the action of intestinal brush border iting the action of intestinal brush border -glu-glucosidasecosidase

OthersOthers

RepaglinideRepaglinide 瑞格列奈瑞格列奈

Oral insulin secretagogueOral insulin secretagogue

Pharmacological effectsPharmacological effects Repaglinide lowers blood glucose by stimulating the r

elease of insulin from the pancreas. It achieves this by closing ATP-dependent potassium

channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion

Clinical usesClinical uses Type2 DM, diabetic nephropathy, elder DM patient

Repaglinide Repaglinide (( 餐时血糖调节剂餐时血糖调节剂 ))

Incretin MimeticsIncretin Mimetics

Mechanism of Action:Mechanism of Action: Act as an incretinAct as an incretin enhance insulin secretion in response enhance insulin secretion in response

to an oral glucose load.to an oral glucose load. Suppress post-prandial glucagon secretion in a glucose-dSuppress post-prandial glucagon secretion in a glucose-d

ependent mannerependent manner Delay gastric emptyingDelay gastric emptying Centrally suppress appetiteCentrally suppress appetite Preserve beta cell mass by reducing apoptosis and increaPreserve beta cell mass by reducing apoptosis and increa

sed neogenesis (animal models).sed neogenesis (animal models).

Keating, Drugs. 65(12):1681-92, 2005.Keating, Drugs. 65(12):1681-92, 2005.Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.

Incretin MimeticsIncretin Mimetics Exenatide (Byetta) is first Exenatide (Byetta) is first incretin mimetic on market. incretin mimetic on market. Synthetic version of salivary protein found in the Gila monsterSynthetic version of salivary protein found in the Gila monster53% o53% o

verlap with human GLP-1.verlap with human GLP-1.

Must be taken as a BID injection w/in 60 mins prior to mealMust be taken as a BID injection w/in 60 mins prior to meal Major side effects: nausea, vomiting, diarrhea. Increases the risk of AcMajor side effects: nausea, vomiting, diarrhea. Increases the risk of Ac

ute pancreatitis. ute pancreatitis. Use not recommended in severe renal impairment. Use not recommended in severe renal impairment. Not recommended as monotherapyNot recommended as monotherapy

To be used as add on therapy with SU, metformin, or TZD’sTo be used as add on therapy with SU, metformin, or TZD’s Increases the risk of Hypoglycemia when added to SU treatment.Increases the risk of Hypoglycemia when added to SU treatment.

Major advantage is weight loss (~5 kg) as well as maintained effect (?Major advantage is weight loss (~5 kg) as well as maintained effect (?preserved beta cell function).preserved beta cell function).

Efficacy: decreases A1C ~1.0%.Efficacy: decreases A1C ~1.0%.

Keating, Drugs 2005 65(12):1681-92Keating, Drugs 2005 65(12):1681-92

Site of DPP-IV Inactivation

Exenatide

A SYL GQ AKE RVKAH G F VEA T TSD S SY LE GQAA KE F I AW LVKGR -NH2GLP-1Human

Dipeptidylpeptidase IV (DPP-IV) InhibitorsDipeptidylpeptidase IV (DPP-IV) Inhibitors Mechanism of Action:Mechanism of Action:

Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal GLP-1 levelsGLP-1 levels

Acts as an incretinActs as an incretin enhances insulin secretion in response to an oral enhances insulin secretion in response to an oral glucose load.glucose load.

Suppresses post-prandial glucagon secretion in a glucose-dependent Suppresses post-prandial glucagon secretion in a glucose-dependent mannermanner

Preserves beta cell mass by reducing apoptosis and increased Preserves beta cell mass by reducing apoptosis and increased neogenesis (animal models).neogenesis (animal models).

Sitagliptin (Januvia) is first DPP-IV inhibitor on market.Sitagliptin (Januvia) is first DPP-IV inhibitor on market. Effective as monotherapy or when used in conjunction with Effective as monotherapy or when used in conjunction with

metformin or a thiazolidinedione.metformin or a thiazolidinedione. Appears to maintain efficacy (?preserved beta cell fxn).Appears to maintain efficacy (?preserved beta cell fxn). Efficacy: decreases A1C ~0.8%.Efficacy: decreases A1C ~0.8%.

Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.

Case 150y/o, Chinese Male, CC: Hyperglycemia found ×2 mPE: BMI 29 Kg/m2 WC: 102cmLab Findings: FBG 155mg/dl, 2hPG:

276mg/dl, HbA1c: 7.5%Which DRUG or DRUGS will we order?

Treatment Strategies Beyond LifestyleTreatment Strategies Beyond Lifestyle

In general, try to initiate pharmacotherapy with an oraIn general, try to initiate pharmacotherapy with an oral agent in newly diagnosed type 2 diabetics unless:l agent in newly diagnosed type 2 diabetics unless:

Fasting plasma glucose is >300 mg/dl with ketonemia or ketFasting plasma glucose is >300 mg/dl with ketonemia or ketonuriaonuria

Markedly symptomaticMarkedly symptomatic

In patients who need insulin initially, often can be switIn patients who need insulin initially, often can be switched to oral agents after 6-8 weeks when glucose toxched to oral agents after 6-8 weeks when glucose toxicity resolvesicity resolves

Answer to Case 1 ( A newly diagnosed type 2 DM patient with obesity)

Lifestyle interventionMetformin 500mg q.d.-t.i.d

““Failure” of a Single Oral AgentFailure” of a Single Oral Agent Type 2 diabetes is a Type 2 diabetes is a

progressive disease, with progressive disease, with ’d ’d loss of beta cell function over loss of beta cell function over time. time.

Need to progress to multi-drug Need to progress to multi-drug therapy or add insulin in order to therapy or add insulin in order to maintain a similar level of maintain a similar level of glycemic control. glycemic control.

If glycemic goals are not met If glycemic goals are not met with agent in one class, we must with agent in one class, we must add second agent with different add second agent with different mechanism of action or add mechanism of action or add insulininsulin

22Nathan et al. Diabetes Care. 29:1963-1972, 2006.Nathan et al. Diabetes Care. 29:1963-1972, 2006.

• ADA consensus algorithm recommends addition of a ADA consensus algorithm recommends addition of a SU, thiazolidinedione, or insulin if metformin therapy is SU, thiazolidinedione, or insulin if metformin therapy is not effective in getting patients to goal A1C.not effective in getting patients to goal A1C.22

11Kahn et al. N Engl J Med, 355:2427, 2006Kahn et al. N Engl J Med, 355:2427, 200611Kahn et al. N Engl J Med, 355:2427, 2006Kahn et al. N Engl J Med, 355:2427, 2006

Algorithm for the management of T2DMAlgorithm for the management of T2DM

From: China Guideline for Type 2 Diabetes (CDS,2007)From: China Guideline for Type 2 Diabetes (CDS,2007) From: China Guideline for Type 2 Diabetes (CDS,2007)From: China Guideline for Type 2 Diabetes (CDS,2007)

Add insulin

Add one or several agents below: Sulfonylurea or Meglitinide (one of the two), Glitazones , Alp

ha-Glucosidase Inhibitor

Diet,exercise,weight loss

+Metformin

3 month later HbA1c 6.5% ﹥

3 month later HbA1c > 6.5%

Overweight orobese patients

(BMI >=24Kg/m2)

Algorithm for the management of T2DM (Cont’)Algorithm for the management of T2DM (Cont’)

Non-obese Patients(BMI 24kg/m﹤ 2)

Diet, exercise, weight loss +One or several agents below: Metformin, Sulfonylurea or Meglitinide (one of the two), Thiazolidinedione,

Alpha-Glucosidase Inhibitor

Add insulin

3 month later HbA1c > 6.5%

From: China Guideline for Type 2 Diabetes From: China Guideline for Type 2 Diabetes (CDS,2007)(CDS,2007)From: China Guideline for Type 2 Diabetes From: China Guideline for Type 2 Diabetes (CDS,2007)(CDS,2007)

Use of Oral Agents to Optimize Glycemic Use of Oral Agents to Optimize Glycemic Control: ConclusionsControl: Conclusions

Choice of oral agents needs to be matched with patient Choice of oral agents needs to be matched with patient characteristics (thin vs. obese) as well as concurrent characteristics (thin vs. obese) as well as concurrent medical issues (renal, hepatic, cardiopulmonary status).medical issues (renal, hepatic, cardiopulmonary status).

Diabetes is a progressive disease, and will require an Diabetes is a progressive disease, and will require an increasing number of agents and/ or addition of insulin as increasing number of agents and/ or addition of insulin as the duration of diabetes increases.the duration of diabetes increases.

Each oral agent can only improve A1C a maximum of 2%, Each oral agent can only improve A1C a maximum of 2%, so if poor control persists on multiple agents, insulin is so if poor control persists on multiple agents, insulin is needed.needed.

Use Of Insulin In Type 2 DiabetesUse Of Insulin In Type 2 Diabetes

Indications Indications When glycemic control deteriorates despite combiWhen glycemic control deteriorates despite combi

nation oral agents. nation oral agents. Surgery in patients with type 2 DM (transient)Surgery in patients with type 2 DM (transient) PregnancyPregnancy

Method:Method: Start with bedtime intermediate (NPH) or long actiStart with bedtime intermediate (NPH) or long acti

ng (glargine, detemir) insulin in addition to oral ageng (glargine, detemir) insulin in addition to oral agents.nts.

If doesn’t work, switch to basal-bolus therapy as uIf doesn’t work, switch to basal-bolus therapy as used in conventional type 1 DM treatmentsed in conventional type 1 DM treatment

• Can continue metformin.Can continue metformin.• Stop insulin secretagogues.Stop insulin secretagogues.

4:004:00

16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

n µµ

Basal/Bolus Insulin Absorption Pattern w/Basal/Bolus Insulin Absorption Pattern w/Standard Insulin PreparationsStandard Insulin Preparations

8:008:0012:0012:008:008:00

TimeTime

REG REGREG

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

8:008:0012:0012:008:008:00

TimeTime

Glargine

Basal-Bolus Treatment withBasal-Bolus Treatment withRapid and Long Acting AnaloguesRapid and Long Acting Analogues

lin Lispro Lispro Lispro

or or or

Aspart Aspart Aspart

or oror

Glulisine Glulisine GlulisineGlulisine Glulisine Glulisine

Insulin Pump and Glucose Monitoring

Insulin Pump – “Open Loop”Patient sets basal infusion rate and w/ superimposedboluses

Continuous Glucose Monitor

“Closed Loop” insulin pump system is ultimate goal… infusion rate adjusted based on input from continuous glucose monitor.

Case 2

64y/o, Chinese Male.CC:polydipsia,polyuria,polyphagia × 12y lower limb edema × 3 mMetformin 500mg bid + Glipizide 80mg tidPE: BMI 22kg/m2, WC 78cm, decreased sensati

on and medium pitting edema in both lower limbs

Lab Findings: UA: PRO 3+,GLU 2+ ; FBG 188mg/dl, 2hPG 266 mg/dl HbA1c 8.3%;

Case2 (Cont’)

Liver function tests: nl transaminase, Alb 28g/l

SCr:1.5mg/dl, CCr: 52ml/minWhich DRUG or DRUGS should we Pre

scribe?

Answer to case 2 (long diabetes history with diabetic Nephropathy and Chronic renal insufficiency )

Should start with insulin treatment Regimen:

1. Regular insulin or rapid acting insulin analogs tid pre-meal + NPH or long acting insulin analog at bedtime

2. Insulin Pump

Insulin and oral hypoglycemic drugs. Endogenous insulin is secreted from cells in the pancreas Islet of Langerhans Alpha cell: 20%, glucagon Beta cell:

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