Insulin in Type 2 DM

8/12/2019 Insulin in Type 2 DM

1/80

INSULIN THERAPY IN TYPE 2

DIABETES


2/80

Presentation Point of View

Background

Pathogenesis of Type 2 DM

Insulin choices Rationality of Insulin Therapy for Type 2 DM

INSULIN TREATMENT ON OUTPATIENT


3/80

Normal islet cell

Deposition of amyloid

in T2DM


4/80

0 10 20 30

Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota

Years of Diabetes

-cell

function

Plasma

glucose

Insulin resistance

Insulin secretion

Fasting glucose

Post-prandial

glucose

Insulin Rx

Natural History of Type 2 Diabetes

Timing of Intervention(Window of Opportunity)

OADs

TLCOADACEIAIIA


5/80

Successful Insulin Therapy

Simple insulin initiation

Comfortable injections

Peralatan suntik sederhana & mudah

Emotional support

Education in diabetes management

Pasien taat / patuh menjalani


6/80

Persentation Point of View

Background


Insulin choices & KINETICS Rationality of Insulin Therapy for Type 2 DM

INSULIN REGIMEN


7/80


8/80

Insulin

secretion

time

Type 2diabetic

Non-diabetic

IV Glucose stimulus

Loss of the early peak of insulin

secretion


9/80

Four biochemical pathways that are sensitive to glucose and produce ROS. The islet is

particularly at risk for chronic oxidative stress when exposed to long-term hyperglycemia

because it expresses very low levels of antioxidant mRNA, protein, and activityRobertson et al, 2003


10/80


11/80


Background


Insulin choices & Kinetics Rationality of Insulin Therapy for Type 2 DM

INSULIN REGIMEN


12/80

INDICATION OF INSULIN THERAPY

Type 2 DM in certain condition DM + secondary failure

DM + Celulitis/Gangren/Infeksi lainnya

DM + underweight

DM + Fracture DM + Chronic Hepatitis / Cirrhosis

DM + Pulmonary TBC

DM + Graves Disease

DM + Cancer DM + Severe liver dysfunction

DM + Late stage Nephropaty

Type 2 DM with Early Insulin Therapy


13/80

Insulin Therapy for Type 2

Diabetes:

Augmentation Supplemental or corrective

Replacement of Beta-Cell Function Short Term Rescue Therapy


14/80

Selecting a Regimen

Provide adequate control

Simple

Flexible

Suit patient needs

KISS = Keep It Safe and Simple

(Keep It Simple and Stupid)

N l I li S i


15/80

B DL HS

Insulin

Effect

Bolus Insulin

Basal Insulin

Endogenous Insulin

B, breakfast; L, lunch; D, dinner; HS, bedtime.Adapted from:

1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.

Normal Insulin Secretion

The Basal-Bolus Insulin Concept

Time of Administration


16/80

Menurunkan produksi glukosaantar makan dan malam (overnight)

Bervariasi per individu

5060 % dari kebutuhan harian

Basal Insulin


17/80

Mengatasi hiperglikemia setelah makan

Meningkat segera dan mencapai puncakdalam 1 jam

10-20% dari total insulin tiap kali makan

Bolus Insulin

(Mealtime or Prandial)


18/80

Preparations Onset(h) Peak(h) Duration(h)

Lispro/Aspart < 0.25 1 - 2 3 - 4

Regular 0.5 - 1 2 - 4 6 - 8

NPH 1 - 3 5 - 7 13 - 16

Ultralente 2 - 4 8 - 14 < 20Glargine 1 - 2 - > 24

Action Profiles

Modified after Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.


19/80

Insulin Left At 1, 2, 3, and 4 Hours After

A Dose Of Humalog Or Novorapid, Apidra

Dose Given

Units Left To Work After:

1 Hr 2 Hr 3 Hr 4 Hr 5 Hr

1 unit 0.80 u 0.60 u 0.40 u 0.20 u 0

2 units 1.60 u 1.20 u 0.80 u 0.40 u 0

3 units 2.40 u 1.80 u 1.20 u 0.60 u 0

4 units 3.20 u 2.40 u 1.60 u 0.80 u 0

5 units 4.00 u 3.00 u 2.00 u 1.00 u 0

6 units 4.80 u 3.60 u 2.40 u 1.20 u 0

7 units 5.60 u 4.20 u 2.80 u 1.40 u 0

8 units 6.40 u 4.80 u 3.20 u 1.60 u 0

9 units 7.20 u 5.40 u 3.60 u 1.80 u 0

10 units 8.00 u 6.00 u 4.00 u 2.00 u 0

20% of a dose will be used each hour after it is given


20/80

A chainGly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn

1 5 10 15 21

S S

1 5 10 15 20

25

30

B chainS

S S

S

Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly

Phe

PheTyr

Thr

LysPro

The

Phe

HUMAN INSULIN

Regular : Poor prandial, poor basal

NPHL: Poor prandial, fair basal (better w ith smal l do se QID,small at daytim e, large at night)

Ultralente: Fair basal


21/80

HUMAN INSULIN

A chain

Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Asn

1 5 10 15 21

S S

1 5 10 15 20

25

30

B chainS

S S

S


Phe

PheTyr

Thr

LysPro

The

Phe

A chain


1 5 10 15 21

S S

1 5 10 15 20

25

30

B chainS

S S

S


Phe

Phe

TyrThr

Pro

Lys

The

Phe

INSULIN LISPRO

Lispro

Excellent prandial, excellent basal ifused in a CSII program


22/80

HUMAN INSULIN

A chain


1 5 10 15 21

S S

1 5 10 15 20

25

30

B chainS

SS

S


Phe

PheTyr

Thr

Lys

Pro

The

Phe

INSULIN ASPART

A chain


1 5 10 15 21

S S

1 5 10 15 20

25

30

B chainS

S S

S


Phe

PheTyr

Thr

Lys

Asp

The

Phe

Aspart

Excellent prandial, excellent basal if

used in a CSII program


23/80

Human insulinA chain 21 amino acids

B chain 30 amino acids

HUMAN INSULINA chain


1 5 10 15 21

S S

1 5 10 15 20

25

30

B chain S

S S

S


Phe

PheTyr

Thr

LysPro

The

Phe

INSULIN GLARGINE

A chain

Gly IIe Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Glu Leu Glu Asn Tyr Cys Gly

1 5 10 15 21

S S

1 5 10 15 20

25

30

B chain S

S S

S


Phe

PheTyr

Thr

LysPro

The

Phe

ArgArg

32 31Glargine, Detemir

Promise to be excellent basal insulin


24/80

Figure. Pharmacokinetincs on various insulin drugs, and insulin frompancreas http://www.medscape.com/viewarticle/501976_6


25/80

HumaPenLUXURAHumaPenErgo II


26/80


27/80

Insulin Glargine versus NPH-Insulin

clear solution vs. suspension

NPH Glargine NPH NPH


28/80

Factors that speed insulin

absorption

Injecting into an exercised area such asthe thigh

High temperatures, for example, shower,

bath, hot water bottle, spa or sauna Massaging the area around the injection

site

Injecting into musclethe deeper theinjection into muscle, the faster the insulinwill be absorbed


29/80

Factors that delay insulin

absorption

Cigarette smoking.

Over-use of the same injection site, which

causes the flesh to become hard, lumpy or

scarred, and leads to erratic absorption of

insulin.

Cold insulin, for example, injecting

immediately after taking the insulin from

the fridge.


30/80


31/80

Persentation Point of View Background


Insulin choices & KINETICS

Rationality of Insulin Therapy for T2DM INSULIN REGIMEN


32/80

KAPAN INSULIN

DIPERLUKAN?

UKPDS Study data

50% DMT2 perlu insulin setelah 6 tahun

Lowest B-cell function at diagnosis

greatest risk of OAD failure

Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30


33/80

Rationale for Early insulin therapy

UKPDS demonstrated that early intervention toachieve tight glycemic control (A1C 7.0%)resulted in 25% reduction (P=.0099) in the riskfor microvascular complications and a 16% risk

reduction (P=.052) for mycocardial infarction.

During the first 6 years of UKPDS, slightly more

than half (53%) of the patients treated withmaximal sulfonylurea therapy could not maintainglucose control


34/80

Rationale for Early insulin therapy

The addition of insulin to sulfonylurea therapyresulted in significantly improved glycemiccontrol. Without an increased incidence ofhypoglycemia or weight gain

These data underscore a critical concept in type2 diabetes: Given the progressive decline inbeta-cell function, combination therapy, such as

oral agent(s) with insulin, is often necessary toachieve treatments goals

UKPDS Lancet 1998: 837-853

I li I U il D l d


35/80

Insulin Is Unnecessarily Delayed

Hayward de Sonnaville de Grauw Rosendal Vahataloet al.30 et al.31 et al.32 et al.33 et al.34

USA Netherlands Netherlands Netherlands Finland

Initiation of insulin in Type 2 diabetes. Data from retrospective or prospectivelongitudinal surveys where the glycaemic level of initiation of insulin is notprotocol driven.

Davies M. Int J Obesity (2004) ; 28 (Suppl. 2) : S14-S22

N=735

N=883

N=31N=52

N=272

5

6

7

8

9

1011

MeanHbA1c(%HB)

Before insulin initiation After insulin initiation (1-4y)

I li I t ifi ti Eff t BG


36/80

Insulin Intensification -Effects on BG

Knight Mohrie Howorka Reichard Schifferdeckeret al.37 et al.38 et al.39 et al.40 et al.35

Intensification of insulin therapy. Data from Schifferdecker et al.

Davies M. Int J Obesity (2004) ; 28 (Suppl. 2) : S14-S22

5

6

7

8

9

10

11

12

HbA1c(%)

Before intensification After intensification


37/80

7

8

9

10

11

12

0 1 2 3 4 5 6

Time (months)

HbA1c

(%) Two injections daily

(Mix Insulin)

Morning insulin(Insulin NPH) + SU

Evening insulin(Insulin NPH) + SU

Twice-daily insulin therapy, or combination therapy with asulphonylurea (SU) markedly improved metabolic control in

patients where OADs had failed.Marre M. Int J Obesity (2002) ; 26 (Suppl. 3) : S25-S30

Insulin Improved Glycaemic Control


38/80

7

8

9

10

0 3 6 9 12

Time (months)

HbA1

c(%)

Sulphonylurea group

Insulin group

Long-Term Control With Insulin

Insulin therapy can improve and maintain glycaemic control more effectively thansulphonylurea treatment. Patients had an HbA1cof 8-10% on entry and were stablycontrolled at that level.

Marre M. Int J Obesity (2002) ; 26 (Suppl. 3) : S25-S30


39/80

Figure 1. ADA consensus on therapy for type 2 diabetes. Adapted with

permission from the American Diabetes Association. Diabetes Care.

1995;18:1516.2


40/80


Background


Insulin choices & KINETICS Rationality of Insulin Therapy for Type 2 DM

INSULIN REGIMEN


41/80

Insulin regimens

No insulin injection regimen satisfactorily

mimics normal physiology

The choice will depend on many factors:

age,

duration of diabetes,

lifestyle (dietary patterns, exercise schedules, school,

work commitments, etc),

targets of metabolic control and,

particularly, individual patient/family preferences


42/80

Selecting a Regimen

Provide adequate control

Simple

Flexible

Suit patient needs

KISS = Keep It Safe and Simple

(Keep It Simple and Stupid)


43/80

Insulin Treatment in

Type 2 Diabetes

Options:

Terapi oral + Suntik NPH atau Glarginesebelum tidur

NPH + short acting insulin BID

Multiple daily injections (MDI)

Meltzer et al. CMAJ 1998;159(Suppl 8):S1-S29.


44/80

DERAJAT KEPARAHAN DM

DMT2 ringan: GDP < 126 mg/dl (Jarang

perlu insulin)

DMT2 sedang: GDP 126200 mg/dl

(Insulin basal)

DMT2 berat: GDP > 200 mg/dl

(Insulin premixed 2 x)

DMT2 sangat berat: GDP > 250300 mg/dl

(Insulin dosis multipel)

Skyler, 2004

R d d St t i f I iti ti


45/80

Recommended Strategies for Initiating

Insulin in Type 2 Diabetes*A1C Threshold Therapeutic

Strategy

Suggested

Initial Dose

Follow-up

7.0% to 10.0%

despite 2 oral

medications

Initiate basal

insulin

10 U every day

for insulin

glargine

Advance insulin dose

weekly until FPG is

within target

Continue oral

medications

10 U every day

or twice daily for

NPH

If A1C remains >

7.0% and PPG is

elevated, add

prandial insulin

starting with largest

daily meal

Monitor A1C every 3

months until < 7.0%;

every 6 months

thereafter

Hirsch, 2005


46/80

Pagi Siang Malam Sebelumtidur

Terapi Kombinasi Oral Insulin Glargine

Suntik Insulin Glargine

Oral


47/80

Sample Plan for Bedtime Basal Insulin Dosing in T2DM

FBG target is 70 100 mg/dl, plans should be individualized

Start 10 unitsbedtime basal insulin, adjust the dose weekly

If mean FBG during the previous 4 days is > 180mg/dl

Increase the dose with 8 unit

If mean FBG during the previous 4 days is 140 - 180mg/dl




Maintain current dose

Return to the previous dose

Reduce the dose by 24 units






Sk ler 2004



48/80


Insulin in Type 2 Diabetes*A1C

Threshold

Therapeutic

Strategy

Suggested Initial

Dose

Follow-up

> 10.0%

despite 2

oral

medications

Initiate

basal-

prandial

insulin

Basal, as above Optimize prandial

doses for each meal

Discontinueoral

secretagogu

es

Prandial: 5-10 U ateach meal

(Approximately 1 U for

every 10-15 g of

carbohydrate to start)

Advance insulin doseweekly until PPG and

FPG are within target

Premixed insulin is notusually recommended,

but can consider 10 U

before breakfast and

dinner

Monitor A1C every 3

months until < 7.0%;

every 6 months

thereafter

Hirsch 2005


49/80

SAMPLE MIXED-SPLIT INSULIN REGIMEN (1)

Meals

B L S HS B

Regular Insulin

NPH/Lente NPH/Lente


50/80

SAMPLE MIXED-SPLIT INSULIN REGIMEN (2)

Meals

B L S HS B

Regular Insulin

NPH/Lente NPH/Lente

SAMPLE MULTIPLE COMPONENT INSULIN


51/80


REGIMEN (1)

Meals

B L S HS B

Regular Insulin

NPH/Lente



52/80


REGIMEN (2)

Meals

B L S HS B

Regular Insulin

NPH/Lente



53/80


REGIMEN (3)

Meals

B L S HS

Regular Insulin

Glargine


54/80

http://www.medscape.com/viewarticle/501976_6


55/80

INJECTION DEVICE DEVELOPMENT IN THE 80S


56/80

INJECTION DEVICE DEVELOPMENT IN THE 80SAND 90S HAS ADDRESSED THESE ISSUES

From syringes to safe

and convenient portablepens with insulin

cartridges

1925

1960

1920s

1985

1989

1990sMore insulin pen introductions in the


57/80

FUTURE INSULIN TREATMENT


58/80

NON INJECTABLE INSULIN DELIVERIES


59/80

Transdermal insulin delivery

Oral insulin delivery

Buccal insulin deliveryPulmonary insulin delivery

NON INJECTABLE INSULIN DELIVERIES
http://www.generex.com/images/rapidmistrollover


60/80

Treatment Options

Bedtime Insulin and Daytime OHA

Replacement Insulin Therapytwice dailyinsulin

Intensive therapy QID (rarely indicated)

ALGORITMA KOMBINASI INSULIN DAN OHO


61/80

Jika jml Ins > 30 U/hari, hentikanOHO

OHO + 10 U Insulin (kerja menengah/panjang)

OHO* (TT & TK)

STT**

- Insulin Kombinasi (basal + bolus)

- Insulin Campuran (2/3 pagi dan 1/3 malam)

OHO stop jk

nyaman

Sesuiakan dosis

2-4 U dlm 3-4

hari

ALGORITMA KOMBINASI INSULIN DAN OHO

Konsensus Perkenii 2006

*: obat hipo- oral, terapi tunggal,

kombinasi

**: sasaran tak tercapai


62/80

Dose titration schedule

Mean of self-monitored FPG

values from preceding 2 days

Increase in

insulin dosage (IU/day)

>10 mmol/L (180 mg/dl) 8

>7.810.0 mmol/L (140180

mg/dl)

6

>6.77.8 mmol/L (120140mg/dl)

4

>5.66.7 mmol/L (100120

mg/dl)

2

Riddle M et al. Diabetes Care2003;26(11):30806.

Start with 10 IU/day bedtime basal insulin doseand adjust weekly in addition to current oral therapy

Smaller dose reductions allowed in the event that FPG drops below 3.0 mmol/L (56 mg/dl) or of a severe hypoglycaemic episode


63/80

Target

Improve BG controltarget :

HbA1C< 6.5%

Fasting sugar of < 108 mg/dL

PP sugars of < 144 mg/dL

Initiating Insulin in Type 2 DM


64/80

If more than 30-36 IU of insulin necessaryto obtain good metabolic control, considerstopping insulin secretagogues and

continue on same total dose of insulin +metformin or TZD

Divide the dose into 2 daily injections:

2/3 before breakfast

1/3 at bedtime

Sepuluh Langkah Untuk Mencapai Sasaran


65/80

p g p

Glikemik Penderita Diabetes

1. Sasaran Kendali Glikemik yg baik adalahA1C < 6,5%

2. Pantau A1c setiap 3 bln disamping

pemeriksaan glukosa darah

3. Pengelolaan agresif hiperglikemia,dislipidemia dan hipertensi dengan intensitas

yang sama untuk mencapai luaran penderitayang terbaik

4. Rujuk semua penderita diabetes baru ke unit

perawatan diabetes bila memungkinkan

Sepuluh Langkah Untuk Mencapai


66/80

p g p

Sasaran Glikemik Penderita Diabetes

5. Pengobatan ditujukan kepada dasarpatofisiologinya termasuk resistensi insulin

6. Obati penderita secara intensif hinggamencapai sasaran A1C < 6,5% dalam waktu 6bulan setelah didiagnosis

7. Setelah 3 bulan, jika sasaran A1C < 6,5% tidaktercapai pertimbangkan terapi kombinasi

8. Mulai dengan terapi kombinasi atau insulinsegera untuk semua penderita dengan A1C 9% pada saat diagnosis



67/80


Sasaran Glikemik Penderita Diabetes

9. Gunakan kombinasi obat oral denganmekanismekerja yang saling melengkapi

10. Lakukan pendekatan tim multidisiplindalam pengelolaan diabetes untukmeningkatkan pemahaman penderita

meliputi edukasi, perawatanmandiri,tanggung jawab bersama untukmencapai sasaran glukosa yang baik

A1C


68/80

A1C

Patients average glycemia over the preceding 2-3 months

First at initial assessment and then as a part of continuing care

At least two times a year (stable glycemic control)

Mean plasma glucose

A1C (%) mmol/l mg/dl

4

56

7

8

9

10

11

12

3.5

5.57.5

9.5

11.5

13.5

15.5

17.5

19.5

65

100135

170

205

240

275

310

345

Table. MPG as estimated from the regression line and approximate

MPG (based on MPG change of 35 mg/dl or 2 mmol/l per 1%

change in A1C) at different A1C levels (assessed in the DCCT)

Rohlfing et al. Diabetes Care 25: 275-278, 2002


69/80

CARA PEMBERIAN INSULIN

Pasien rawat jalan :

dapat dimulai dgn insulin kerja menengah

dosis rendah pagi hari

Penyesuaian : 24 unit setiap 34 hari

Bila dosis dibutuhkan tinggi : dapat dibagi

pagi malam, perbandingan 2:1


70/80


Pasien rawat inap :

Makanan tidak selalu dalam bentuk padat

dosis insulin basal dan insulin nutrisional

Insulin nutrisional :

Jumlah insulin yang dibutuhkan untuk mengatasi

glukosa yg diberikan lewat intravena, TPN, sonde

lambung, nutrisi tambahan dan makanan bebas

Bila hanya makan makanan padat : kebutuhan

insulin nutrisional setara (equivalen) dengan

insulin prandial


71/80


Pasien rawat inap :

Kebutuhan insulin meningkat akibat pengaruh

hormon kontrainsulin (respons thd stres) o.k:

tindakan operasi, kortikosteroid,pressor agent,obat diabetogenik, dll.

Tambahan kebutuhan = insulin koreksi

(supplement)

Komponen insulin utk rawat inap tdd.: Insulin basal

Insulin prandial (nutrisional)

Insulin koreksi (supplemental)


72/80


Dosis insulin basal dan insulin prandial dicatat sebagaiinsulin program (scheduled insulin)

Dosis insulin koreksi dicatat sebagai algoritme untukditambah pada insulin program

Tujuan algoritme koreksi : mengatasi hiperglikemia yangmelampaui target dan sering tak terduga pada pasiendgn stres

Jenis insulin koreksi : insulin kerja cepat dan insulin kerjapendek

Dosis insulin koreksi : berdasarkan glukosa preprandialdan kebutuhan insulin total perhari

ALGORITME INSULIN KOREKSI PREPRANDIAL


73/80

Glukosa

preprandial

(mg/dl)

Dosis insulin koreksi (unit)

Algoritmedosis rendah Algoritmedosis sedang Algoritmedosis tinggi

150199

200249250299

300349

> 349

1

23

4

5

1

35

7

8

2

47

10

12

Catatan :

Gunakan algortime dosis rendah bila pasien membutuhkan < 40 unit insulin/hari

Gunakan algortime dosis sedang bila pasien membutuhkan 40-80 unit insulin/hari

Gunakan algortime dosis tinggi bila pasien membutuhkan > 80 unit insulin/hari


74/80


Dosis insulin perhari : 0,31,5 U/kgBB

Dua per tiga dari total dosis dalam bentuk insulin kerja pendek

diberikan setengah jam sebelum makan Sepertiga dari total dosis

Dalam bentuk insulin kerja menengah atauinsulin kerja panjang

Diberikan malam hari Insulin program dan insulin koreksidinaikkan bertahap untuk mencapaikebutuhan tertinggi dari insulin basal daninsulin prandial


75/80

MENYUNTIK INSULIN

Kebanyakan diberikan subkutan

Semua insulin suspensi : kocok secara lembut

sebelum disuntikkan

Untuk mencampur insulin kerja cepat / pendekdengan insulin kerja menengah / panjang :

insulin kerja cepat / pendek harus disedot

lebih dahulu baru insulin kerja menengah /

panjang


76/80

MENYUNTIK INSULIN

Bila area suntikan cukup bersihtidak

perlu dibersihkan lagi dengan alkohol

Suntikan intramuskuler mempercepatabsorbsisecara rutin tidak dianjurkan

Melakukan pijatan / pemanasan pada

tempat suntikanmempercepatabsorbsi insulin


77/80

TEKNIK MENYUNTIK SUBKUTAN

Jepit kulit dengan dua jaritusukkanjarum dengan posisi 90 derajat

lepaskan jepitan sambil disuntik

tunggu + 5 detik baru jarum dicabut

Untuk pasien kurus : arahkan jarum 45derajat agar insulin tidak masuk ke otot

Ketika jarum sudah berada di subkutan,sebelum disuntikkan tidak perludilakukan penyedotan


78/80

TEMPAT SUNTIKAN

Abdomen : 2 inchi di sekeliling pusat

Sisi lateral lengan atas

Sisi anterolateral paha

Untuk menghindari variasi absorbsi

rotasi suntikan pada 1 tempat saja,

misalnya di abdomen

EFEK SAMPING DAN


79/80

EFEK SAMPING DAN

KOMPLIKASI SUNTIKAN INSULIN

Hipoglikemia

Reaksi alergi (lokal, sistemik)

Lipohipertrofi (penebalan lemak subkutan

pada tempat suntikan)

Lipoatrofi (penipisan lemak subkutan pada

tempat suntikan)


80/80

Insulin in Type 2 DM

Documents

Transcript of Insulin in Type 2 DM