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°¡ ÀÏ¾î³ 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¸¦ ¾ÇȽÃŲ´Ù. glycemic controlÀÌ È£ÀüµÇ¸é islet functionµµ
È£ÀüµÈ´Ù. ±×¿Ü¿¡ FFAÀÇ Áõ°¡µµ islet functionÀ» ¾ÇȽÃŲ´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