(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 3 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 red blood cell, kidney blood brain barrier, colon

GLUT 2liver, pancreatic -cell

GLUT 3neuron ,placenta ,testes

GLUT 4adipose 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 (cellular-mediated 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 2Type 1 diabetesType 2 diabetes

10-20% 80-90% > 35

cellular-mediated autoimmuneinsulin resistant, insulin deficiency

polyuria () polydipsia (), polyphagia (), , polyuria () polydipsia (), 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 [2]Diagnostic criteriaNormalPre-DMDM

*HbA1C (%)5.7-6.4% 6.5

*FPG (mg/dL)< 100100-125 126

*OGTT (mg/dL)< 140140-199 200

*Random plasma glucose (mg/dL) 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, DKA2. Chronic complication Macrovascular (CAD), (CVD), (PAD)Microvascular Retinopathy, Nephropathy, Neuropathy ( nerve)

[3] 4 ADA guideline 2015 2557

HbA1C< 7%< 6.5%

FPG80-130 mg/dL70-110 mg/dL

Peak postprandial capillary plasma glucose< 180 mg/dL< 140 mg/dL

Blood pressure< 140/90 mmHg< 140/80 mmHg

Lipid profileLDL-C*TGHDL-C< 100 mg/dL< 150 mg/dL 40 mg/dL, 50 mg/dL< 100 mg/dL< 150 mg/dL 40 mg/dL 50 mg/dL

* LDL-C < 70 mg/dL

1. 2. [3] (Lifestyle modification) 1. - : : 50% : 15-20% : 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(mg)Time to peak(hr)(/)Maximum dose (mg/day)

Pioglitazone15-302145

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)(/)

Acarbose 25-1003

Voglibose0.2-0.33

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, liraglutideMechanism 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 B C

6 A. insulin monomerB. insulin hexamerC.

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 7 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 1 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 / Thiazolidinediones5.3 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 21.00-23.00 .- 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 analog7. 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. 20153. . .. 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_referral_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.