RESUMO
The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
Assuntos
Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Medicina Baseada em Evidências , Modelos Biológicos , Terapia de Alvo Molecular , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacologia , Ensaios Clínicos como Assunto , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Síndrome Metabólica/complicações , Síndrome Metabólica/prevenção & controle , Terapia de Alvo Molecular/efeitos adversosRESUMO
ß-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, ß-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on ß-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ~2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased ß-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced ß-cell dysfunction in the BB rat, which suggests a link between ß-cell lipotoxicity and islet inflammation.
Assuntos
Ácidos Graxos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Estado Pré-Diabético/imunologia , Estado Pré-Diabético/metabolismo , Animais , Quimiocina CCL2/sangue , Emulsões/farmacologia , Feminino , Imuno-Histoquímica , Interleucina-10/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Fosfolipídeos/farmacologia , Ratos , Ratos Endogâmicos BB , Reação em Cadeia da Polimerase em Tempo Real , Óleo de Soja/farmacologiaRESUMO
A 23-year-old woman known to have methylmalonic acidemia (MMA) since birth suffered bilateral visual loss within 5 days. Multiple sclerosis, Leber hereditary optic neuropathy, vasculitis, infections (in particular treponema), and vitamin deficiency were ruled out. The optic nerve head changed from normal in appearance to atrophic. Treatment attempts with high-dose intravenous steroids and coenzyme Q10 combined with vitamin E were ineffective. The patient's underlying disease was metabolically well controlled by strict diet and carnitine supplementation. Toxic damage of both optic nerves due to MMA is the most likely mechanism. MRI showed moderate enhancement of both optic nerves. To our knowledge, this is the first report of a morphological correlate on MRI.