ʻO Pioglitazone i ka mālamaʻana i ka maʻi diabetes type 2

• KEKAHI MEA: ka maʻi maʻamau, ka hyperglycemia, nā mokupuni o Langerhans, hepatotoxicity, troglitazone, rosiglitazone, pioglitazone, Baeta

ʻO ke kī nui o ka pathogenesis o ke ʻano type diabetes 2 he kū i ka insulin (IR), ka mea e alakaʻi nei ʻaʻole wale nō i ka hyperglycemia wale nō, akā ua hoʻonāukiuki hoʻi i nā mea pili i ke ʻano o ka hoʻomohala ʻana o nā maʻi cardiovascular e like me ka hypertension arterial a me dyslipidemia. Ma kēia noʻonoʻo ʻana, hana a me ka hoʻohana i ka mālama ʻana o nā maʻi me ka lāʻau lapaʻau e pili pono ana i ka IR he ʻōlelo hoʻohiki i ka mālama ʻana i kēia maʻi maʻi.

Mai ka makahiki 1996, i ka mālama ʻana i nā poʻe maʻi me ka maʻi diabetes type 2, ua hoʻohana ʻia kahi papa hou o ka lāʻau lapaʻau, i hui pū ʻia e ka ʻano o kā lākou hana i ka hui o thiazolidinediones (TZD) a i ʻole sensitifers insulin (ciglitazone, rosiglitazone, darglitazone, troglitazone, pioglitazone, ka ʻoihana nui o ka hana nā kiko i ka insulin. ʻOiai ke ʻano o nā hoʻopuka nui o nā 80-90 o ke kenekulia hope i hoʻolaʻa ʻia no ka hoʻopaʻa mua ʻana o ka palekana a me ka hana pono ʻana o kēia mau pūhui, ʻekolu wale nō huina mai kēia pūʻulu i hoʻoili ʻia i loko o ka hana lapaʻau - troglitazone, rosiglitazone a me pioglitazone. ʻO ka mea kaumaha, ma hope o ka troglitazone ua pāpā ʻia no ka hoʻohana ʻia ma muli o ka hepatotoxicity i hōʻike ʻia i ka wā o ka hoʻohana lōʻihi.

I kēia manawa, ua hoʻohana ʻia ʻelua mau lāʻau mai ka hui TZD: pioglitazone a me rosiglitazone.

Ke hana o ka hana o ka thiazolidinediones

ʻO ka hopena nui o ka hopena TZD i ka maʻi diabetes type 2 ke hōʻemi nei i ka pale ʻana i ka insulin ma o ka hoʻonui ʻana i ka naʻau o nā ʻolua peripheral i insulin.

Kūʻē ka hoʻonāukiuki (IR) ma mua o ka hōʻike ʻana o ke haukaʻi o nā maʻi maʻi 2. ʻO ka emi iki o nā cell momona i ka hopena antilipolytic o ka insulin e alakaʻi i kahi hoʻonui koʻikoʻi i ka waihona o nā momona momona free (FFA) i loko o ke koko koko. ʻO ka FFA, a me ka hoʻonui ʻana i ka pale o ka insulin i ka pae o nā maemae a me nā māhā o ka iwi, e alakaʻi ai i ka glucoseoneogenesis e hoʻonui i ka hoʻohiolo ʻana i ka glucose i kēia mau kiko. I lalo o kēlā ʻano hanana, nā ʻōpū momona e hana i ka nui o nā cytokine (factor necrosis tumor a - TNF-a), interleukin (IL-6 a me resistin), kahi e hoʻonāukiuki i ka pale ʻana i ka insulin a hoʻōla i ka atherogenesis. ʻO ka hana ʻana e nā momona momona o kahi cytokine ʻokoʻa - adiponectin, e hoʻonui ai i ka ʻike o nā ʻili i ka insulin, ua hoʻemi ʻia.

ʻO Thiazolidinediones nā agonist affinity kiʻekiʻe o nā mea ulu o ka nīkini i hoʻomoʻa ʻia e ka peroxisome proliferator - PPARg (peroxisome proliferators-activated receptor), nona nā ʻohana o nā mea transkrip i ke kāohi i ka hōʻike o nā huaʻāina i hoʻoponopono i nā kao kalepa a me ka lipid metabolism i loko o ka adipose a me ka hoʻonaninani. Nui nā isoforms PPAR i ʻike ʻia: PPARa, PPARg (subtypes 1, 2) a me PPARb / PPARd. ʻO PPARa, ʻo PPARg a me PPARd, he hana nui i ka hoʻoponopono o ka adipogenesis a me IR. ʻO ka hua gen PPARγ i kekahi mau mammals, me nā kānaka, aia ma ka 3 chromosome (locus 3p25). Hoʻomaʻamaʻa ʻia ka mea hoʻokele PPARg i nā momona momona a me nā monocytes, hōʻemi i ka pūhaka skeletal, nā ʻōpū a me nā pēpē. ʻO ka hana koʻikoʻi o PPARg ka ʻokoʻa o nā ʻāpana sela adipose. Hāʻawi ʻo PPARg agonists (TZD) i ka hoʻokumu ʻana o nā adipocytes liʻiliʻi e ʻoi aku ka naʻau i ka insulin, e hoʻoikaika nui ana i ka FFA a me ka hoʻoponopono i ka hoʻolaʻa ʻana i nā momona ma ka subcutaneous a ʻaʻole i nā kiko momona visceral (3). Eia kekahi, hoʻoneʻe ʻia ka hoʻolaʻa ʻana o PPARg i ka nui o ka hōʻike a me ka unuhi ʻana o nā mea lawe aku i ka glucose (GLUT-1 a me GLUT-4) i ka membrane o ka cell, e ʻae ana i ka glucose e halihali ʻia i nā ʻukā a me nā mākau a me ka hōʻemi i ka glycemia. Ma lalo o ka mana o nā agonist PPARg, e hoʻoneʻe ana ka hana o TNF-a me ka hoʻonui ʻana o ka hōʻike o ka adiponectin, e hoʻonui ai hoʻi i ka hoʻololiʻana i nā kolo peripheral i insulin (4).

No laila, hoʻomaikaʻi nui ka thiazolidinediones i ka hoʻoliʻi ʻana o ka ʻiole i ka insulin, ka mea i hōʻike ʻia e ka hoʻohaʻahaʻa ʻana i ka gluconeogenesis i loko o ka ate, ka pale ʻana o ka lipolysis ma ka pā adipose, kahi i hoʻemi ʻia o ka FFA i ke koko, a me ka hoʻomaikaʻi ʻana i ka hoʻohana ʻana o ka glucose i nā ʻōpū (Figure 1).

ʻAʻole hiki i nā Thiazoldinediones ke hoʻoikaika pololei i ka huna ʻana o ka insulin. Eia naʻe, ʻo ka hōʻemi o ka glucose o ke koko a me ka FFA i ke koko i ka wā e lawe ai i ka TZD e hōʻemi i ka hopena o ka glucose a me ka lipotoxic i nā b-cells a me nā lipolipo peripheral a, i ka hala ʻana o ka manawa, ke alakaʻi nei i ka hoʻonui ʻia o ka insulin a nā b-cells (5). Nā haʻawina e Miyazaki Y. (2002) a me Wallace T.M. (2004), ʻo ka hopena kūpono o ka TZD ma ka hana o nā hana o nā selela i ke ʻano o ka hoʻēmi ʻana i ka apoptosis a me ka piʻi ʻana o kā lākou hoʻomaʻamaʻa ua hōʻoia ʻia (6, 7). Ma ka noiʻi a Diani A.R. (2004) ua hōʻike ʻia ka hoʻokele ʻana o ka pioglitazone i nā holoholona kahu ʻai me ka maʻi diabetes type 2 i kōkua i ka mālama ʻana i ke ʻano o nā mokupuni o Langerhans (8).

ʻO ka emi ʻana o ka pale ʻana i ka insulin ma lalo o ka mana o ka pioglitazone ua hōʻoiaʻiʻo ʻia i loko o kahi hōʻike noiʻi ma o ka loiloi ʻana i ka hoʻohālikelike NOMA homeostasis (9). Hōʻike ʻo Kawamori R. (1998) i kahi hoʻomaʻamaʻa ʻana i ka huehue olakolapa a peripheral e kū'ē i ka waiʻumua o ka pule o ka pioglitazone ma kahi o 30 mg / lā. hoʻohālikelike me ka papa hana (1.0 mg / kg × min. vs. 0.4 mg / kg × min, p = 0.003) (10). He haʻawina ma Benett S.M. et al. (2004), i ka manawa i hoʻohana ʻia ai ʻo TZD (rosiglitazone) i nā wiki he 12 i loko o nā poʻe me ka hoʻohaʻomaʻi ʻole i ka glucose i hoʻomaʻamaʻa ʻia, ua hoʻonui ʻia ka ʻatikala ʻana o ka insulin e 24,3%, aʻo ke kūpaʻa ʻana i ka pletebo, i hōʻemi ʻia e 18. 3% (11). Ma kahi noiʻi hoʻomalu i hoʻomoe ʻia e TRIPOD, ka hopena o ka troglitazone ma ka hopena o ka maʻi type type 2 i nā wahine ʻAmelika Latin me ka mōʻaukala o ke ʻano maʻi gestational i aʻo ʻia (12). Hōʻike nā hopena o ka hana i ka ʻoiaʻiʻo ma ka wā e hiki mai ana ka hopena pili i ka hoʻomohala ʻana i ka maʻi type 2 no kēia ʻāpana o nā mea maʻi ma ka 55%. Pono e hoʻolilo i ka hōʻemi o ka maʻi diabetes type 2 i kēlā me kēia makahiki he 5.4% hoʻohālikelike ʻia me 12,1% kūlike i ka placebo. Ma kahi noi ʻo PIPOD wehe, he hoʻomau ia o ka noiʻi TRIPOD, i pili pū ka pioglitazone me kahi hōʻemi o ka hoʻomohala ʻana i ka maʻi type 2 (ʻo ke alapine o nā hihia maʻamau hou o ka maʻi maʻamau ʻo 2 ka 4.6% i kēlā me kēia makahiki) (13).

ʻO ka hopena hoʻohaʻahaʻa gula i ka pioglitazone

He nui nā noiʻi o ka hoʻohana ʻana i ka pioglitazone i hōʻike i kona pono i ka mālama ʻana i nā mea maʻi me ka maʻi maʻi 2.

Hōʻike nā hualoaʻa o nā noi hoʻokele plope multicenter i ka pioglitazone me ka hoʻohaʻahaʻa nui ʻana i ka glycemia ma ka monotherapy a me ke ʻano pū me nā lāʻau lapaʻaka hypoglycemic waha, i ka maʻi maʻamau me nā metformin a me ka sulfonylurea i hoʻohana nui ʻia i ka mālama ʻia ʻana o nā mea maʻi me ka maʻi type 2 (14, 15, 16, 17).

Mai Pepeluali 2008, ʻaʻole ʻia ka TZD, rosiglitazone e hoʻohana ʻia no ka hoʻohana pū ʻana me ka insulin ma muli o ka hopena hiki i ka puʻuwai māhaʻi. Ma kēia mea, ke hōʻike nei ke kūlana o nā maʻi maʻi maʻi i ka USA a me ʻEulopa, i ka "A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes" no ka makahiki i kēia manawa, he mea kūpaʻa ʻole ia, no ka mea ae ʻae i ka hoʻohana hoʻohui ʻana o insulin a me pioglitazone. E akakaʻa, ua pili kēia ʻōlelo i ka ikepili mai nā noiʻi koʻikoʻi koʻikoʻi. No laila, he pālua ʻelua makapō, randomized, placebo-control control e Matoo V. ma 2005 me 289 nā mea maʻi me ka maʻi type type 2 i hōʻike mai i ka hoʻohui ʻana o ka pioglitazone i ka hoʻomehana insulin e alakaʻi i ka emi nui o ka hemoglobin glycated (HbA1c) a me ka wikiwiki i ka glycemia (18) . ^ E Ha yM. Eia nō naʻe, ke pīhoihoi nei ia, ke kūpaʻa ʻana o ka loiloi o ka hui ʻana i nā maʻi i nā maʻi, ua hōʻike pinepine ʻia nā manawa epoglycemia. Eia kekahi, ʻo ka hoʻonui ʻana o ka paona o ke kino ma ke kaila o ka monotherapy insulin i ka haʻahaʻa ma lalo o ka wā e hui pū ai me ka pioglitazone (0.2 kg vs. 4.05 kg). I ka manawa like, ʻo ka hui pū ʻana o ka pioglitazone me ka insulin e hele pū ʻia me ka dinamics maikaʻi i loko o ke kikoo lipid pae a me nā pae o nā māka o ka hopena cardiovascular (PAI-1, CRP). ʻAʻole ʻae ʻia ka manawa pōkole o kēia noi (6 mau mahina) i kahi loiloi o nā hopena cardiovascular. Ke hāʻawi nei i kekahi pilikia e pili ana i ka hoʻomohala ʻana i ka puʻuwai naʻau congestive me ka hui pū ʻana o ka rosiglitazone me ka insulin, i kā mākou hana ʻana ʻaʻole mākou e pilikia i ka hoʻohui ʻana i ka hopena me ka pioglitazone a hiki i ka ʻike paʻa mau e pili ana i ka palekana piha o ka mālama ʻia.

ʻO ka hopena o ka pioglitazone ma nā mea koʻikoʻi no ka maʻi cardiovascular

Hoʻopili i nā hopena hypoglycemic, hiki i ka TZD ke loaʻa kahi hopena maikaʻi loa i ka nui o nā mea kūlohelohe no ka hoʻomohala ʻana o nā maʻi cardiovascular. ʻO ka mea nui ka hopena o ka lāʻau lapaʻau ma ka lipid spra o ke koko. I hoʻokahi mau haʻawina i hana ʻia i loko o nā makahiki i hala iho nei, ua hōʻike ʻia ka pioglitazone ua loaʻa ke hopena maikaʻi i nā pae lipid. No laila, noiʻi ʻia e Goldberg R.B. (2005) a me Dogrell S.A. (2008) hōʻike i ka pioglitazone lowers triglycerides (19, 20). Eia kekahi, hoʻonui ka pioglitazone i ka pae o ka anti-atherogenic hapa o ka momona lipoprotein kiʻekiʻe (HDL). Hoʻopili kēia mau ʻike ma nā hualoaʻa o ka hōʻike ʻoihana Proactive (PROspective pioglitAzone Clinical Trial In macroVascular Events), ma kahi o 5238 nā mea maʻi me nā maʻi maʻi type 2 a me kahi mōʻaukala o nā maʻi macrovascular i komo i 3 mau makahiki. ʻO ka hui pū ʻana o ka pioglitazone me nā mea ʻai a me nā waha hypoglycemic a ʻoi loa ma hope o 3 mau makahiki nānā ke alakaʻi i ka 9% i nā pae HDL a me ka hōʻemi he 13% i ka triglycerides hoʻohālikelike i ka mea mua. ʻO ka make holoʻokoʻa, ʻo ka hopena o ka hoʻomohala ʻana i ka maʻi myocardial non-fatal a me kahi ulia cerebrovascular ʻoi aku me ka hoʻohana ʻana i ka pioglitazone i hoʻohaʻahaʻa nui. ʻO ka hopena holoʻokoʻa o kēia mau hanana i ka poʻe e loaʻa ana i ka pioglitazone i hōʻemi ʻia e 16%.

Nā hopena o ka noi ʻana o CHICAGO (2006) a me ka hana a Langenfeld M.R. et al. (2005) (21), i hōʻike ʻia me ka hoʻokele ʻana o ka pioglitazone, ua emi ana ka mānoanoa o ka paia vascular a pēlā pū nō hoʻi ka hoʻomohala ʻana o ka ulu ʻana o ka atherosclerosis. Ua hōʻike ʻia kahi hoʻokolohua hoʻokolohua e Nesto R. (2004) i ka holomua o nā hana o ka hana hou ʻana o ka ventricle hema a me ka hoʻihoʻi ma hope o ischemia a reperfusion me ka hoʻohana ʻana o TZD (22). ʻO ka mea pōʻino, ua ʻike ʻia ka hopena o kēia mau loli morphological i ka hopena o ka hopena o ka maʻi cardiovascular i ka wā lōʻihi.

Hiki i nā hopena kūpono ke pioglitazone

I nā noiʻi lapaʻau āpau, pioglitazone, a me TZD ʻē aʻe, ua ukali ʻia e ka piʻi ʻana o ka nui o ke kino ma ka 0.5-3.7 kg, ʻoi aku ka 6 mau mahina o ka mālama ʻana. Ma hope aku, ua kūpaʻa ka nui o nā mea maʻi.

ʻO kaʻoiaʻiʻo, ʻo ka loaʻaʻana o ke kaumaha he hopena kūpono ʻole loa o kekahi lāʻau lapaʻau ma ka mālama ʻana i nā mea maʻi me ka maʻi type 2, no ka mea ka nui loa o ka maʻi o ka poʻe maʻi e ʻoi a kaumaha paha. Eia naʻe, pono e hoʻohālikelike ʻia ka hui ʻana o ka pioglitazone, ka mea nui, ma ka hoʻonui ʻana o ka nui o ka momona subcutaneous, ʻoiai ka nui o ka momona visceral i nā maʻi e loaʻa ana i ka TZD. I nā huaʻōlelo, ʻoiai ke loaʻa ʻana o ka paona i ka wā e lawe ai i ka pioglitazone, ʻaʻole i hoʻonui i ka ulu ʻana a me / a i ʻole e holomua ana ka maʻi cardiovascular (23). He mea nui ia e hoʻomaopopo i ka kiʻekiʻe o ka hoʻonui ʻana i ke kaupaona kino e hoʻopili pono me ka concomitant sugar-lowing therapy, i.e. ke kiʻekiʻe ka nui o ke kaupaona i nā mea maʻi e loaʻa ana i kahi hui pū me TZD me ka insulin a i ka sulfonylureas, a i lalo me ka metformin

E kūʻē i ke kūpaʻa o ka mālama ʻana me ka pioglitazone, 3-15% o nā mea maʻi e ʻike i ka mālama wai ʻana, nā kumu kumu i maopopo ʻole ai. No laila, aia kahi wahi o ka manaʻo e like me ka hopena o ka hoʻohaʻahaʻa i ka sodium excretion a me ka hoʻonui ʻana i ka mālama wai, e hoʻonui ana i ka nui o ke koko e hele nei. Eia kekahi, hiki iā TZD ke hana i ka vasodilation arterial me ka piʻi o ka hopena i loko o ka wai extracellular fluid (22). ʻO ia me kēia hopena hopena o TZD e pili ana ka maʻi naʻau congestive. No laila, ma ka nui o ka noiʻi PROactive nui, ʻo ka nui o nā maʻi hou i hōʻike ʻia i ka hopena o ka puʻuwai aloha me ka pioglitazone therapy e ʻoi loa aku ke kiʻekiʻe o ka plasebo (11% vs 8%, p 7% ʻekolu mau wai ma hope o ka hoʻomaka ʻana o ka hoʻohiolo ʻana i ke kō. hānai.

ʻO ka hopena o ka pioglitazone, e like me TZD ʻē aʻe, loiloi ʻia e ka pae o HbA1c. ʻO ka lawaʻana o ke kūpaʻa a me ka hopena o nā lāʻau hoʻoleʻa haʻahaʻa e hana ana e kāohi i ka gluconeogenesis a i ʻole ko ka hoʻowalewale ʻana i ka huna ʻana o ka insulin e kā mākou iho pono i nā ʻāmiola i hoʻopaʻa ʻia ma o ka hoʻoikaika maikaʻi mai ka basal a i ʻole postprandial glycemia. ʻO ka TZD, e hōʻemi pono i ka pale ʻana i ka insulin, ʻaʻohe o ka hopena hypoglycemic wikiwiki, kahi mea maʻalahi e loiloi me ka mālama pono o ka home. Ma kēia mea, ʻike nui ka poʻe maʻi i ka pioglitazone e pono e kaohi o ka HbA1c ma ka liʻiliʻi i hoʻokahi manawa i kēlā me kēia ʻekolu mahina. I ka loaʻa ʻole o ka loaʻa ʻana o nā waiwai glycated i hoʻohālikelike ʻia (HbA1c