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Diabetes Mellitus

1. ºÐ·ù Tab 333-1

1) type 1 DM(¥â cell destruction)

A= immune-mediated B= idiopathic

2) type 2 DM: predominantly insulin resistance with relatively insulin deficiency

predominantly insulin deficiency with relatively insulin resistance

3) other specific types

MODY, endocrinopathy...

cf. Endocrinopahy: acromegaly, cushing's syndrome, glucagonoma,

pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronism

* Gestational DM

¹Ì±¹¿¡¼­ Àӽſ©¼ºÀÇ 4%¿¡¼­ ¹ß»ýÇÏ¸ç ´ëºÎºÐ ºÐ¸¸ÈÄ Á¤»ó glucose tolerance¸¦ ȸº¹

ÇÑ´Ù. ³ªÁß¿¡ ´ç´¢º´ ¹ß»ý°¡´É¼ºÀÌ ³ô´Ù(30-60%).

24-28ÁÖ¿¡ screening(50g OGTT 1hr>140mg/dL)ÇÏ¿© ¾ç¼ºÀ¸·Î ³ª¿À¸é 100g OGTT½ÃÇà

fasting 105 mg/dL, 1h 190 mg/dL, 2h 165 mg/dL, 3h 145 mg/dLÁß 2°³ ÀÌ»óÀ̸é Áø´ÜµÊ.

2. Áø´Ü Tab 333-2

i) FPG(mg/dL) <110 : nomal

110-125 : IFG

¡Ã126 : DM

ii) plasma glucose(2hr) <140 : normal

140-200 : IGT

¡Ã200 : DM

IFG¿Í IGT µÑ´Ù type 2 DM¹ß»ý À§Ç輺ÀÌ ÀÖÀ¸¸ç cardiovascular ds¹ß»ý À§Ç輺ÀÌ ÀÖ´Ù.

3. Insulin biosynthesis, secretion, and action(Tab 333-3, 333-4 ÂüÁ¶)

4. º´ÀÎ

1) type 1 DM (Fig 333-5)

genetic, environmental, and immunologic factorÀÇ synergistic effect¿¡ ÀÇÇØ pancreatic ¥â

cellÀÌ ÆÄ±«µÊÀ¸·Î½á ¹ß»ýÇÑ´Ù.

genetic susceptibility°¡ ÀÖ´ø »ç¶÷ÀÌ Ãâ»ý½Ã¿¡´Â Á¤»ó ¥â cell mass¸¦ °¡Áö°í ÀÖÁö¸¸

infection or environmental stimulus¿¡ ÀÇÇØ À¯¹ßµÈ autoimmune process¿¡ ÀÇÇØ ¥â cell loss

°¡ ÀϾ±â ½ÃÀÛÇÑ´Ù. triggering event°¡ ÀϾ ÈÄ¿¡ ´ëºÎºÐ immunologic marker°¡ ³ªÅ¸

³­´Ù. ¥â cellÀÇ ´ëºÎºÐ(¡­80%)ÀÌ ÆÄ±«µÉ ¶§±îÁö ´ç´¢º´ÀÇ Æ¯Â¡Àº ³ªÅ¸³ªÁö ¾ÊÁö¸¸ 20% Á¤µµ

³²Àº ¥âcellÀÌ glucose tolerance¸¦ À¯ÁöÇϱ⿣ ºÒÃæºÐÇÏ´Ù. À̶§ insulin ¿ä±¸·®À» Áõ°¡½ÃŰ´Â

event(infection or puberty)°¡ ÀÖÀ¸¸é Çö¼º ´ç´¢º´ÀÌ »ý±â°Ô µÈ´Ù. type 1A DMÀÌ »ý±äÈÄ

"honeymoon" phase°¡ µÚµû¶ó ¿ÀÁö¸¸ °á±¹Àº insulinÀÌ ¿ÏÀüÈ÷ °í°¥µÇ°Ô µÈ´Ù.

¨ç genetic considerations

type 1A DMÀÇ concordance : 30-40%

ÀÌ´Â ´ç´¢º´ ¹ß»ý¿¡¼­ ´Ù¸¥ ÀÎÀÚ°¡ °ü¿©ÇÔÀ» ÀǹÌÇÑ´Ù.

* major susceptibility for type 1A DM : HLA region on chromosome 6

-> class II MHC molecules encode

-> helper T cell¿¡ ´ëÇÑ Ag¹ßÇö

-> immune response½ÃÀÛ

type 1A DMȯÀÚ ´ëºÎºÐ HLA DR3 and/or DR4 haplotypeÀÌ ¾ç¼ºÀÌ´Ù.

DQA1, B1 : strongest association with type 1A DM

= type 1A DM ¾î¸°ÀÌÀÇ 40%¿¡¼­ Á¸Àç

Á¤»ó ¹Ì±¹Àο¡¼­´Â 2%¿¡¼­¸¸ Á¸Àç

ºñ·Ï type 1A DMÀÌ Æ¯Á¤ genotype°ú ºÐ¸í °ü·ÃÀÌ ÀÖÀ¸³ª ÀÌ·± haplotypeÀ» °®´Â ¸ðµç

»ç¶÷¿¡¼­ ´ç´¢º´ÀÌ ¹ß»ýÇÏ´Â °ÍÀº ¾Æ´Ï´Ù. type 1A DMȯÀÚ ´ëºÎºÐÀÇ 1ÃÌ Á÷°è°¡Á·¿¡¼­ ´ç´¢

º´Àº ¾ø´Ù.

±×·¯³ª ÀÌ·¯ÇÑ Ä£Ã´ÀÇ type 1A DM¹ß»ý À§ÇèÀº ÀϹÝÀκ¸´Ù´Â ÈξÀ ³ô´Ù.

¨è autoimmune factors

´ç´¢º´ ȯÀÚÀÇ ÃéÀåÁ¶Á÷À» º¸¸é pancreatic islet cell¿¡ lymphocyte infiltration(=insulitis)

µÇ¾î ÀÖ´Ù. insulitis¿Í autoimmune process¿¡ ´ëÇÑ ¿¬±¸´Â ´ÙÀ½°ú °°Àº immune systemÀÇ

humoral & cellular armÀÇ ÀÌ»óÀ» º¸¿©ÁØ´Ù.

i) islet cell autoAb

ii) islet, peripancreatic LN, systemic circulation¿¡¼­ lymphocyte activation

iii) islet proteinÀ¸·Î ÀÚ±ØÇÒ ¶§ Áõ½ÄÇÏ´Â T lymphocyte

iv) insulitis³»¿¡ cytokines release: ¥â cellÀº ƯÁ¤ cytokine(TNF-¥á, INF-¥ã, IL-1)¿¡ ´ëÇØ

ƯÈ÷ susceptibleÇÏ´Ù.

¥â cell deathÀÇ Á¤È®ÇÑ ±âÀüÀº ¾Ë·ÁÁ® ÀÖÁö¸¸ ´ÙÀ½ »çÇ×°ú °ü·ÃÀÖ´Ù.

i) NO metabolite formation

ii) apoptosis

iii) direct CD8+ T cell cytotoxicity

* autoimmune process¿¡¼­ targetÀ¸·Î ÇÏ´Â pancreatic islet molecules

: insulin, GAD, ICA512/IA-2(tyrosine phosphatase¿Í homology), phogrin(insulin secretory

granular protein)

¨é immunologic markers

ICA : GAD, insulin, IA-2/ICA 512, islet ganglioside¿Í °°Àº pancreatic islet molecules¿¡

´ëÇÑ Ab·Î type 1 DMÀÇ autoimmune process marker·Î ÀÌ¿ëµÈ´Ù.

DM typeÀ» ºÐ·ùÇϴµ¥ ÀÌ¿ëÇÒ¼ö ÀÖ°í, type 1A DMÀ¸·Î ¹ßÀüÇÒ À§Ç輺À» ÀÎÁöÇϴµ¥

ÀÌ¿ëÇÒ¼öµµ ÀÖ´Ù.

»õ·ÎÀÌ type 1A DMÀ¸·Î Áø´ÜµÈ ´ëºÎºÐÀÇ È¯ÀÚ(>75%)¿¡¼­ Á¸ÀçÇÑ´Ù.

type 2 DM¿¡¼­´Â ±Ø¼Ò¼ö¿¡¼­¸¸ Á¸ÀçÇϰí, GDM¿¡¼­´Â °£È¤(<5%) Á¸ÀçÇÑ´Ù.

type 1A DMÀÇ Á÷°è°¡Á·¿¡¼­´Â 3-4%¿¡¼­ ¾ç¼ºÀÌ´Ù.

IV glucose intolerance test¿¡¼­ impaired insulin secretionÀÌ ÇÔ²² ÀÖÀ» ¶§ 5³â³» type

1A DMÀ¸·Î ¹ßÀüÇÒ °¡´É¼ºÀº 50% ÀÌ»óÀÌ´Ù.

insulin secretionÀÌ»óÀÌ ¾øÀ»¶§´Â <25%

¿©±â¼­ º¸¸é Á÷°è°¡Á·¿¡¼­ type 1A DMÀ¸·Î ¹ßÀüÇÒ °¡´É¼ºÀº ±ØÈ÷ ³·À¸¸ç ICA ¾ç¼ºÀÏÁö

¶óµµ Ç×»ó ´ç´¢·Î ¹ßÀüÇÏ´Â °ÍÀº ¾Æ´Ï´Ù.

ÇöÀç ICA´Â ¿¬±¸¸ñÀûÀ¸·Î ÁÖ·Î »ç¿ëµÈ´Ù.

¨ê environmental factors

ÃßÁ¤µÇ´Â ȯ°æ ÀÎÀÚ : virus(coxsackie & rubella virus most prominently), bovine milk

proteinÁ¶±â³ëÃâ, nitrosourea compounds

¨ë type 1A DMÀÇ ¿¹¹æ

µ¿¹°½ÇÇè¿¡¼­ ¼º°øÀûÀ¸·Î ½ÃµµµÇ¾ú´Ù. ¸é¿ª¾ïÁ¦, selective T cell subset deletion, islet

protein¿¡ ´ëÇÑ immunologic toleranceÀ¯µµ¿Í °°ÀÌ immune system¿¡ ´ëÇÑ Á÷Á¢Àû ½Ãµµ°¡

ÀÖ¾ú°í ¶Ç´Ù¸¥ ¿¬±¸¿¡¼­´Â cytotoxic cytokineÀ» block½ÃŰ°Å³ª destructive process¿¡

´ëÇÑ islet resistance¸¦ Áõ°¡½ÃŰ´Â ÂÊÀ¸·Î ½ÃµµµÇ¾ú´Ù. µ¿¹°½ÇÇè¿¡¼­´Â Èñ¸ÁÀûÀ̾úÀ¸³ª

»ç¶÷¿¡¼­´Â ¼º°øÀûÀÌÁö ¸øÇß´Ù.

2) type 2 DM

type 2 DM¹ß»ýÀÇ Áß½ÉÀû ±âÀüÀº insulin resistance & abnormal insulin secretionÀÌ´Ù.

primary defect¿¡ ´ëÇØ ³íÀïÀÇ ¿©Áö°¡ ÀÖÀ¸³ª ´ëºÎºÐÀÇ ¿¬±¸¿¡¼­´Â insulin resistance°¡

insulin secretory defectº¸´Ù ¼±ÇàÇÑ´Ù°í ÇÏ¿´´Ù.

¨ç genetic considerations

strong genetic compounds¸¦ °¡Áö°í ÀÖ´Ù.

ºñ·Ï ƯÁ¤ À¯ÀüÀÚ´Â ¾Ë·ÁÁ® ÀÖÁö ¾ÊÁö¸¸, ÀÌ º´ÀÌ polygenic & multifactorialÇÏ´Ù´Â °ÍÀº

¸í¹éÇÏ´Ù. °¨¼ö¼º ÀÖ´Â »ç¶÷ÀÌ È¯°æÀû ÀÎÀÚ(nutrition & physical activity)¿¡ ÀÇÇØ ¹ßÇöµÈ´Ù.

identical twin¿¡¼­ type 2 DMÀÇ concordance: 70-90%

type 2 DMºÎ¸ð¸¦ °¡Áø ÀÚ³à´Â ´ç´¢º´ ¹ß»ý À§ÇèÀÌ ³ô´Ù.

¿¹> ¾çÂÊ ºÎ¸ð ¸ðµÎ ´ç´¢º´ÀÌ ÀÖÀ» ¶§ 40%

type 2 DMÀÇ non-diabetic, first-degree relatives¿¡¼­ insulin resistance(=skeletal muscle

glucose utilization°¨¼Ò)°¡ ÀÖ´Ù.

¨è pathophysiology

* 3 pathophysiologic abnormalities

i) impaired insulin secretion

ii) peirpheral insulin resistance

iii) excessive hepatic glucose production

insulin resistance´Â obesity¿Í ÈçÈ÷ °ü·ÃÀִµ¥, adipocyte°¡ insulin resistance¸¦

ÀÏÀ¸Å°´Â ¸¹Àº biologic product(leptin, TNF-¥á, free fatty acid)¸¦ ºÐºñÇÑ´Ù.

* ÀÓ»ó 3 ´Ü°è

i) Ãʱ⿣ insulin resistance¿¡µµ ºÒ±¸Çϰí glucose tolerance´Â Á¤»óÀÌ´Ù: pancreatic ¥â

cellÀÌ insulin outputÀ» Áõ°¡½ÃÅ´À¸·Î½á compensationÇÑ´Ù.

ii) insulin resistance & compensatory hyperinsulinemia°¡ ÁøÇàÇÔ¿¡ µû¶ó pancreatic islet

Àº hyperinsulinemic state¸¦ Áö¼ÓÇÒ¼ö ¾ø°Ô µÈ´Ù. À̶§ ½ÄÈÄ °íÇ÷´çÀ» Ư¡À¸·Î ÇÏ´Â IGF

°¡ »ý±ä´Ù.

iii) insulin secretionÀÌ ´õ¿í °¨¼ÒÇϰí hepatic glucose productionÀÌ ´õ¿í Áõ°¡Çϸé overt

diabetes°¡ µÇ¸ç fasting hyperglycemia°¡ µÈ´Ù. °á±¹ ¥â cell failure°¡ µÚÀ̾î ÀϾ´Ù.

¨é metabolic abnormalities

i) insulin resistance

insulinÀÌ peripheral target tissue(ƯÈ÷ muscle & liver)¿¡ È¿°úÀûÀ¸·Î ÀÛ¿ëÇÏÁö ¸øÇÏ¿©

»ý±ä´Ù.

insulin¿¡ ´ëÇÑ ÀúÇ×À¸·Î glucose utilizationÀÌ ¼Õ»óµÇ°í hepatic glucose outputÀº Áõ°¡

Çϸç hepatic glucose outputÀÇ Áõ°¡°¡ FPG levelÁõ°¡ÀÇ ÁÖ ¿øÀÎÀÌ´Ù. ¹Ý¸é peripheral

glucose usage°¨¼Ò´Â ½ÄÈÄ °íÇ÷´çÀ» ÀÏÀ¸Å²´Ù.

skeletal muscle¿¡¼­ glycolysis¸¦ ÅëÇÑ oxidative glucose metabolismº¸´Ù nonoxidative

glucose usage(glycogen formation)¿¡ ´õ Å« Àå¾Ö°¡ ÀÖ´Ù. insulin resistance¿¡ ´ëÇÑ

Á¤È®ÇÑ ºÐÀÚÇÐÀû ±âÀüÀº ¹àÇôÁöÁö ¾Ê¾Ò´Ù. skeletal muscle¿¡¼­ insulin receptor level &

tyrosine kinase activity°¡ °¨¼ÒµÇ¾î ÀÖÁö¸¸ À̰ÍÀº ´ëºÎºÐ hyperinsulinemia¿¡ ´ëÇÑ 2Â÷Àû

¹ÝÀÀÀ̸ç primary defect´Â ¾Æ´Ï´Ù. ±×·¯¹Ç·Î postreceptor defect°¡ insulin resistanceÀÇ

ÁÖ ±âÀüÀ¸·Î »ý°¢µÈ´Ù.

IRS-1 polymorphismÀÌ glucose intolerance¿Í °ü°èÀִµ¥ ÀÌ·¯ÇÑ postreceptor molecule

ÀÇ polymorphismÀº insulin-resistant state¿Í combineµÈ´Ù. insulin resistance

pathogenesis¿¡ °üÇÑ ÇöÀçÀÇ ÃÊÁ¡Àº PI-3 kinase signaling defect¿¡ ¸ÂÃçÁ® ÀÖ´Ù.

* PI-3 kinase signaling defect

: GLUT4 -> plasma membraneÀ¸·ÎÀÇ translocationÀ» °¨¼Ò½ÃŲ´Ù.

FFAÀÇ Áõ°¡(obesity)°¡ type 2 DM º´Àο¡ °ü¿©ÇÑ´Ù´Â À̷еµ ÀÖ´Ù.

FFA´Â skeletal muscle¿¡¼­ glucose utilizationÀ» ¼Õ»ó½Ã۰í, liver¿¡¼­ glucose

productionÀ» Áõ°¡½ÃŰ¸ç ¥â cell functionÀ» ¼Õ»ó½ÃŲ´Ù.

ii) impaired insulin secretion

óÀ½¿£ normal glucose tolerance¸¦ À¯ÁöÇϱâ À§ÇØ insulin secretionÀÌ Áõ°¡ÇÏ¿©

glucose-stimulated insulin secretionÀÌ Ä§¹üµÈ´Ù. À̶§ arginine°ú °°Àº ´Ù¸¥ nonglucose

secretagogues´Â À¯ÁöµÈ´Ù. ±×·¯³ª °á±¹Àº insulin secretory defect°¡ ÁøÇàµÈ´Ù.

insulin secretory capacity°¡ °¨¼ÒÇÏ´Â ÀÌÀ¯´Â ¸íÈ®ÇÏÁö´Â ¾Ê´Ù. second genetic defect

°¡ ¥â cell failure¸¦ ÀÏÀ¸Å²´Ù´Â °¡Á¤¿¡µµ ºÒ±¸Çϰí ÇöÀç±îÁöÀÇ ¿¬±¸¿¡¼­ ¹àÇôÁø °ÍÀº ¾ø´Ù.

islet amyloid polypeptide or amylinÀÌ ¥â cell¿¡¼­ ÇÔ²² ºÐºñµÇ¾î isletÁÖÀ§¿¡ amyloid

fibrillar depositÀ» Çü¼ºÇÑ´Ù. metabolic environment¶ÇÇÑ islet functionÀ» ¼Õ»ó½ÃŲ´Ù.

¿¹¸¦ µé¸é chronic hyeprglycemia´Â paradoxicÇϰԵµ islet functionÀ» ¼Õ»ó½ÃÄÑ("glucose

toxicity") hyperglycemia¸¦ ¾ÇÈ­½ÃŲ´Ù. glycemic controlÀÌ È£ÀüµÇ¸é islet functionµµ

È£ÀüµÈ´Ù. ±×¿Ü¿¡ FFAÀÇ Áõ°¡µµ islet functionÀ» ¾ÇÈ­½ÃŲ´Ù("lipotoxicity").

iii) increased hepatic glucose production

liver´Â glycogenolysis¿Í gluconeogenesis¿¡ ÀÇÇØ °øº¹Ç÷´çÀ» À¯ÁöÇÑ´Ù.

insulinÀº hepatic glycogenÀÇ ÇüÅ·Π´çÀÇ ÀúÀåÀ» ÃËÁøÇϰí gluconeogenesis¸¦ ¾ïÁ¦

ÇÑ´Ù.

insulin resistance´Â hyperinsulinemiaÀÇ gluconeogensis suppression failure¸¦ À¯¹ß

ÇÑ´Ù. ±× °á°ú fasting hyperglycemia & postprandial glucose storage°¨¼Ò¸¦ À¯¹ßÇÑ´Ù.

¨ê insulin resistance syndromes

i) syndrome X

insulin resistance, hypertension, dyslipidemia, central or visceral obesity, endothelial

dysfunction, accelerated cardiovascular disease

ii) acanthosis nigricans, hyperandrogenism signs(hirsutism, acne, oligomenorrhea)

* 2 distinct syndrome of severe insulin resistance in adults

type A : young women, severe hyperinsulinemia, obesity, hyeprandrogenism

type B: middle-aged women, severe hyperinsulinemia, hyperandrogenism, autoimmune

disorder

iii) polycystic ovarian syndrome

: premenopausal women, chronic anovulation, hyperandrogenism, insulin resistance

type 2 DM ¹ß»ý À§ÇèÀÌ ³ô´Ù.

metformin & thiazolidinedionsÀÌ hyperinsulinemia¸¦ ÁõÁø½Ã۰í, hyperandrogenÀ» È£Àü

½Ã۸ç ovulationÀ» À¯µµÇÏÁö¸¸ ÀûÀÀÁõÀ¸·Î ÀÎÁ¤µÇÁö´Â ¾Ê´Â´Ù.

6. MODY

ÀüÇüÀûÀ¸·Î 10-25¼¼¿¡ ¹ß»ýÇÏ´Â autosomal domiant disorder

islet cell transcription factor or glucokinase gene muation¿¡ ÀÇÇÑ´Ù.

5 vaiants°¡ Àִµ¥ ±×Áß MODY2°¡ most common variant(glucokinse gene mutation)

glucose -----------------> G-6-P

glucokinase

: liver¿¡¼­ glucose utilization¿¡ Áß¿äÇÑ ¹ÝÀÀ

glucokinase mutationÀ¸·Î ÀÎÇÏ¿© glucose levelÀÌ Áõ°¡ÇÑ´Ù.

MODY 1 = HNF(hepatocyte nuclear transcription factor)-4¥á

MODY 3 = HNF-1¥á

MODY 5 = HNF-1¥â mutation