(Diabetes mellitus)

2
Insulin Counter regulatory hormones (Glucagon, Cortisol,
Norepinephrine, Epinephrine, Growth hormone, Thyroid hormone)
Insulin Glucagon
1

-cell Glucagon
glycogenolysis ( glycogen )
gluconeogenesis ( glycerol,
amino acid)

-cell Insulin
glycogenesis glycogen

2 Insulin -cell

Insulin GLUT
glucose
transporter 2 (GLUT2) glycolysis ATP ATP

KATP channel
membrane depolarization voltage-dependent Ca2+channel

 Ca2+
insulin granules (
2)
1 Glucose transporter
Glucose
transporter (GLUT)
GLUT 1

GLUT 2
GLUT 3
GLUT 4

red blood cell,

kidney blood
brain barrier,
colon
liver, pancreatic
-cell
neuron
,placenta
,testes
adipose tissue,
muscle cell

GLUT 1-3 insulin

GLUT 4 transporter

insulin
(insulin-stimulated glucose
uptake)
( 3)
Insulin

-cell islet of Langerhans

GLUT insulin-stimulated glucose
uptake 3
[1]

[3]

1. 1 (Type 1 diabetes mellitus, T1DM)

-cell
(cellularmediated autoimmune) -cell
insulin (insulin-dependent
diabetes)

insulin

2. 2 (Type 2 diabetes mellitus, T1DM)

(insulin resistant)
insulin

(non-insulin-dependent

diabetes) insulin
(insulin deficiency)
3.
(Gestational diabetes mellitus,
GDM)



2 3 insulin resistant
(estrogen, progesterone)
insulin
4. (Specific types)

steroid,
thiazide, nicotinic acid, thyroid hormone, dilantin, -adrenergic
agonist, -interferon
, ,
2 1 2
Type 1 diabetes
Type 2 diabetes

10-20% 80-90% > 35

cellular-mediated
autoimmune
polyuria

insulin resistant, insulin

deficiency
polyuria

( ) polydipsia

( ) polydipsia

( ), polyphagia

(), polyphagia

Diabetic ketoacidosis
(DKA)

Hyperosmolar
hyperglycemic state
(HHS)

(), ,

(), ,

American Diabetes
Association (ADA) 2015
4 HbA1C,
Fasting plasma glucose (FPG), Oral Glucose Tolerance Test (OGTT),

 Random plasma glucose

2557 HbA1C
standardization quality control

3

Diagnostic criteria
Normal
*HbA1C (%)
5.76.4%
*FPG (mg/dL)
< 100
*OGTT (mg/dL)
< 140
*Random plasma
glucose (mg/dL)

[2]
Pre-DM

DM
6.5

100-125 126
140-199 200
200

* hyperglycermia

1. Acute complication
1.1. Diabetic ketoacidosis (DKA) DM type 1

(lipolysis)

ketone body (-hydroxybutyrate

acetoacetate) (metabolic acidosis)

1.2. Hyperosmolar hyperglycemic state (HHS) DM type
2

(osmotic dieresis)
prerenal azotemia,

hyperosmolality,

DKA
2. Chronic complication
Macrovascular (CAD), (CVD),
(PAD)

Microvascular Retinopathy, Nephropathy, Neuropathy (

nerve)

[3]
4
ADA

guideline
2557
2015
HbA1C
< 7%
< 6.5%
FPG
80-130
70-110 mg/dL
mg/dL
Peak postprandial capillary < 180
< 140 mg/dL
plasma glucose
mg/dL
Blood pressure
< 140/90
< 140/80 mmHg
mmHg
Lipid profile
LDL-C*
< 100
< 100 mg/dL
TG
mg/dL
< 150 mg/dL
HDL-C
< 150
40 mg/dL
mg/dL
50 mg/dL
40
mg/dL,
50 mg/dL
*

LDL-C < 70 mg/dL

1.
2.
[3]


(Lifestyle modification)

1.

- : : 50% : 1520% : <30-35%

-

- / ( 3-6

)
- 2 /
1 /
2.
- 150 / 30-50
3-5

2-3

- 75 / 3
/

3.
[3]
2

.
1. insulin (Insulin secretagogue)
- Sulfonylurea (SU)
- Non-Sulfonylurea (NSU)
2. (Insulin sensitizers)
- Biguanides
- Thiazolidinedione (TZD)
3. alpha-glucosidase (Alpha-glucosidase inhibitor)
4. (Drug that enhance
gastrointestinal hormone action)
- DPP-4 inhibitor
- GLP-1 analogues

 insulin (Insulin secretagogue)

1. Sulfonylurea (SU)

HbA1C12% 2 generation
1st generation:
Acetohexamide, Chlorpropamide, Tolbutamide
nd
2 generation:
Glibenclamide, Gliclazide, Glipizide, Glimepiride (Potency,
Pharmacokinetics, Safety )

4 SU R duration
R1 activity, toxicity
Mechanism of action
KATP Channels -cell K+
membrane
depolarization voltage-dependent Ca2+channel Ca2+
insulin granules
Pharmacokinetic
5 2nd generation Sulfonylurea

 1st generation Tolbutamide Short-acting

sulfonylurea (T1/2 ~ 4.5 hr.) R methyl
oxidation
Chlorpropamide duration
(T1/2 ~ 48 hr.)
potency

2nd generation
2nd generation lipophilic group
entero-hepatic circulation recycling

1-2
Note:
- ac
Glipizide
- Chlorpropamide Glibenclamide T1/2 hypoglycemia
active metabolite

- (weight gain)
- Hypoglycemia (, )

Beta-blocker

* Rule (15-

15-15) . 15g 15 . 15g

- Chlorpropamide disulfiram-like effect
- SIADH


- 1

-
- Sulfa allergy ( cross )
- Severe hepatic failure, Severe renal failure
2. Non-Sulfonylurea (NSU)

HbA1C11.5%

Hypoglycemia Repaglinide, Nateglinide
Mechanism of action
Sulfonylurea KATP Channels -cell
Pharmacokinetic [4]
6 Non-Sulfonylurea
Dura
Maximu
Onset
(min)
tion
m

(hr)
dose(m
(mg)
g/day)

(/
Repagl 0.5inide
4

15-60

4-6

)
2-4

Nategl
inide

20-60

60120

16

CrCl 20-40

0.5 mg

Note:
-
15
SU
-
(one meal onedose, no meal no
dose)

- (weight gain)

- Hypoglycemia (, )

- 1
- Repaglinide
(Insulin sensitizers)
1. Biguanides

HbA1C
1-2% 2

hypoglycemia TG,
LDL VLDL HDL
Metformin
Mechanism of action
- (gluconeogenesis)

AMPK gene
PEPCK Glc-6-Pase
gluconeogenesis
- insulin

-
- glucagon
Pharmacokinetic [4]
7 Biguanides
Maximum
Time to
peak
dose

(hr)
(mg/day)
(mg)

(/
Metfor
min

5002550

2-3

)
2-3

2550

SCr > 1.5 mg/dL

Note:
-

-
-

- (Metabolic taste)

- vitamin B12 deficiency vit B12

- lactic acidosis (
)
(ex. COPD, HF) CKD,

- 1
- (SCr > 1.5 mg/dL )
-
COPD, HF lactic
acidosis
2. Thiazolidinediones (TZD)


HbA1C 0.5-1.4% 2 2



hypoglycemia
Pioglitazone

Mechanism of action
- nuclear transcription factor PPAR-gamma
gene adipose tissue, skeletal
muscle , liver, pancreatic beta cell, vascular endothelium
macrophages GLUT-1 GLUT-4
insulin
Pharmacokinetic [4]
8 Thiazolidinediones
Maximu
Time to

peak
m dose


(mg)

(hr)

(mg/day)

(/

Pioglit
azone

1530

)
1

45

Note:
- Rosiglitazone ( MI), Troglitazone (

) 2
-
-
3-4
(1 )
- (ALT) 2

- (ALT) 3

-
-

prostaglandin

-
- congestive heart failure
- 2.5-3
- 2
insulin
edema
- Polycystic ovarian
syndrome

alpha-glucosidase (Alpha-glucosidase
inhibitor)


HbA1C 0.5-0.8%





Acarbose, Voglibose
Mechanism of action
alpha-glucosidase

Oligosaccharide monosaccharide
acarbose alpha-amylase
polysaccharide Oligosaccharide
Pharmacokinetic
(BA 2%) metabolize

9 Alpha-glucosidase

(mg)

Acarbo
se
Voglib
ose

25-100

(/)
3

0.2-0.3

Note:
-
- (one meal onedose,
no meal no dose)

- Hypoglycemia ( hypoglycemia

glucose )
- GI disturbance ( )

-
(Bowel obstruction)

-
(Malabsorption)
- (cirrhosis)
(Drug that enhance
gastrointestinal hormone action)
1. DPP-4 inhibitor

HbA1C 0.8%


Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin
Mechanism of action
incretin enhancer incretin hormone
dipeptidyl peptidase-4 (DPP-4)

2 glucagon-like peptide (GLP-1)

glucose-dependent insulinotropic polypeptide (GIP)
2 insulin
glucagon

Pharmacokinetic
CYP
450
10 DPP-4 inhibitor

2. GLP-1 analogues
SC HbA1C 1%
Exenatide,
liraglutide
Mechanism of action
Human incretin hormone glucagon-like
peptide-1 (GLP-1) insulin
glucagon

-
- Hypoglycemia

- medullary thyroid
carcinoma
2
Sodium glucose co-transporter subtype 2 (SGLT2) inhibitors

SGLT2 receptor proximal

convoluted tubule
90

(sodium :
glucose coupling ratio = 1 : 1)
Glucuretic
Therapy


Canagliflozin, Dapagliflozin Empagliflozin
(12/06/2015) (European Medicines
Agency EMA) SGLT2 inhibitors

(diabetic ketoacidosis)[5]
SGLT2 inhibitors 101
(
1 )
Dapagliflozin Pioglitazone
48 [6]

(insulin)
(Insulin) amino acid

-cell
preproinsulin proinsulin insulin ( 5)
5,800 2
chain A B disulfide bonds A7-B7
A20-B19 disulfide bond chain A A6-A11

5 insulin
A

 6 A. insulin monomer
B. insulin hexamer
C.

Insulin 2
1. Basal insulin secretion 24 hr.
0.5-1 IU/hr
70-110 mg/dl (Pre-prandial
glucose)
2. First and second phase insulin secretion
(Post-prandial glucose)
2 ( 7)
2.1. First phase insulin secretion

5-10

Insulin
2.2. Second phase insulin secretion First
phase

glucose

insulin
insulin
basal insulin
insulin


(Post-prandial glucose)
insulin 4
11 pharmacokinetic

 1
insulin
1 0.5-0.6 IU/kg/day
2 0.7-2.5 IU/kg/day
: Onset: IV > IM > SC


(

2557 )
1. 2

2.

2.1 HbA1c ()

2.2 (
)
2.3

3.
1-4

HbA1c
2-6 3 (
2, ++)
4. 2 ( 1)
Metformin (
2, ++)

2 (combination therapy)
2

Metformin
2 sulfonylurea

( glibenclamide

) sulfonylurea

> 220

mg/dL HbA1c > 9% 2

( +)
5. 3 3
2
( 1) 2 3
5.1 Thiazolidinedione: 2 Metformin

( 2,

+) 3

5.2 DDP-4 inhibitor: 2 3

(

2,

+/-)
Metformin / Thiazolidinediones
5.3 Alpha-glucosidase inhibitor: 2

3
( 2, +)
5.4 Repaglinide: 2 3
sulfonylurea

(
+)

sulfonylurea

5.5 GLP-1 analog: 3

BMI 30 kg/m2

( 2,

+/-)
6. 2 Basal insulin


( 2, ++)
6.1 basal insulin
- Intermediate acting insulin NPH 21.0023.00 .
- Long acting insulin analog (LAA) insulin glargine
insulin detemir
insulin glargine

6.2 basal insulin

NPH 0.1 - 0.2 /./

2-4 3-7

NPH LAA
6.3 RI
basal insulin pre-mixed insulin

 1-2

insulin
analog
7. 2

3 / 3-7

( 2,

++) RI basal insulin

pre-mixed insulin 2
1


1. . . 3
. : ;
2555.
2. American Diabetes Association. Standards of medical care in
diabetes 2015. Diabetes care. 2015
3. .
.. 2557. : ; 2557.
4. William J.Dana , et al. Drug Information Handbook .22nd Ed.
United state.
5. European Medicines Agency. Review of diabetes medicines called
SGLT2 inhibitors started. http://www.ema.europa.eu/ema/index.jsp?
curl=pages/medicines/human/referrals/SGLT2_inhibitors/human_refe
rral_prac_000052.jsp&mid=WC0b01ac05805c516f (June12, 2015)
6. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of
dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and
hypoglycemia risk in patients with type 2 diabetes inadequately
controlled on pioglitazone monotherapy. Diabetes Care 2012 .