Ressecção parcial de pâncreas x regeneração x terapia incretínica humanos
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Ressecção parcial de pâncreas x regeneração x terapia incretínica humanos

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Em humanos a ressecção pancreática parcial não induz regeneração de massa de células beta.

Em humanos a ressecção pancreática parcial não induz regeneração de massa de células beta.

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Ressecção parcial de pâncreas x regeneração x terapia incretínica humanos Ressecção parcial de pâncreas x regeneração x terapia incretínica humanos Document Transcript

  • COMMENTARYTargeting b-cell functions in therapy for type 2diabetes function by early intervention is both with longer duration of diabetes than inRecently, Leahy et al. issued a necessary and important. those with shorter duration, suggesting a‘‘consensus statement’’ in regard to In a longitudinal study of obese Pima decrease in the capacity to compensatetargeting b-cell function in therapy Indians by Weyer et al.2, failure to aug- insulin secretion against insulin resistancefor type 2 diabetes that recommends ment b-cell function to compensate for by disease duration and that early inter-continued multidisciplinary efforts to increased insulin demand as a result of vention might be necessary, even in leanrealign treatment of type 2 diabetes decreased insulin sensitivity, due to type 2 diabetes.to preserve b-cell function by early weight gain for example, was found to be A previous study using streptozotocin-intervention. This might be applicable involved in deterioration of glucose treated mini-pigs showed that b-cell func- homeostasis in type 2 diabetes. It is tion in vivo is closely related to b-cellnot only for obese type 2 diabetes in important to determine whether or not mass, even when only slightly reduced5.Europe and America, but also for lean this pathogenesis is also applicable to lean A decrease in b-cell mass in type 2 diabe-type 2 diabetes in Asia. To establish type 2 diabetes in Asia. Sato et al.3 tes compared with that in normal subjectsevidence, development of non- showed, by a cross-sectional study using is shown by cross-sectional studies usinginvasive measurements of b-cell mass the oral glucose tolerance test, that b-cells specimens of autopsies or surgical opera-for longitudinal observation during begin to deteriorate during normoglyce- tions, but longitudinal studies are absent.long duration of diabetes is critical. mia with a minimal elevation of fasting In a cross-sectional study using specimensIn addition, studies that clarify the plasma glucose in Japanese subjects. In derived from autopsies, b-cell mass indevelopment of b-cell dysfunction our previous cross-sectional study, endo- individuals showed extreme variabilitywith regard to both mass reduction genous insulin secretion shown by indices and markedly overlapped in normal sub-and functional impairment are of serum C-peptide immunoreactivity jects and patients with type 2 diabetes,required for the development of novel (CPR) levels was negatively correlated despite the significant average decrease in with years from diagnosis, suggesting pro- b-cell mass in type 2 diabetes6. Thesestrategies to preserve b-cell function gressive deterioration of b-cell function results show that measurement of b-cellby treatment of type 2 diabetes. over several decades of diabetes exposure mass at one time point in an individual(J Diabetes Invest, doi: 10.1111/j.2040- in Japanese type 2 diabetes4. Interestingly, cannot predict progression to type 2 dia-1124.2011.00117.x, 2011) body mass index (BMI) was positively betes and that longitudinal observation is correlated with indices of CPR, suggesting necessary. Trials to find useful probes toLeahy et al.1 recently issued a consensus that increased insulin resistance positively visualize b-cell mass in vivo continue7.statement that recommends targeting affects endogenous insulin secretion, even Such non-invasive methods, if realized,b-cell function for therapy in type 2 dia- in lean type 2 diabetes. However, the will be valuable to clarify the relationshipbetes. The consensus is based on recent positive effect of BMI on endogenous between function and mass of b-cells dur-studies showing that declining b-cell insulin secretion is weaker in patients ing the natural course of type 2 diabetesfunction, a pathogenesis of type 2 diabe-tes, begins early in the disease’s natural Genetic factors, environmental factors, aging, etc.history, accelerates markedly after reach-ing a compensatory threshold, drives theprogression of the disease and is poten-tially reversible, particularly in the earlystages. They concluded that continued β cell mass reduction Functional impairment of individual cellsmultidisciplinary effort to realign treat-ment of type 2 diabetes to preserve b-cell*Corresponding author. Shimpei Fujimoto Insufficient insulin secretion in vivoTel.: +81-75-751-3560 Fax: +81-75-751-4244E-mail address: fujimoto@metab.kuhp.kyoto-u.ac.jpReceived 15 February 2011; accepted 20 February 2011 Figure 1 | Pathogenesis of type 2 diabetes mellitus.178 Journal of Diabetes Investigation Volume 2 Issue 3 June 2011 ª 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd
  • Targeting b-cell functionin longitudinal studies and to evaluate the protein and a nuclear factor11,12. Interest- 5. Larsen MO, Rolin B, Wilken M, et al.effects of early intervention. ingly, an increase in the intracellular Measurements of insulin secretory In the consensus statement, Leahy et al. cAMP level by GLP-1 receptor agonist capacity and glucose tolerancestressed the importance of basic research ameliorates impaired ATP production by to predict pancreatic b-cell massto elucidate the nature and mechanisms of suppressing endogenous ROS generation in vivo in the nicotinamide ⁄ streptozo-b-cell failure in type 2 diabetes. Under- in diabetic b-cells, which suggests that in- tocin Go ¨ttingen minipig, a modelstanding the molecular basis of b-cell pro- cretin therapy might have an important of moderate insulin deficiency andliferation and apoptosis is required to role in recovering impaired metabolism- diabetes. Diabetes 2003; 52: 118–123.realize clinical application of early inter- secretion coupling11. Studies to elucidate 6. Rahier J, Guiot Y, Goebbels RM, et al.vention to preserve b-cell mass. Unlike the mechanism of b-cell dysfunction, Pancreatic b-cell mass in Europeanin rodents, a 50% pancreatectomy does including mass reduction and functional subjects with type 2 diabetes.not prompt b-cell regeneration in adult impairment, will contribute to establishing Diabetes Obes Metab 2008; 10(Suppl 4):humans8; the difference between the novel strategies to preserve b-cell function 32–42.mechanisms of b-cell replication in in treatment of type 2 diabetes. 7. Mukai E, Toyoda K, Kimura H, et al.human and rodents has been shown9. GLP-1 receptor antagonist as a poten-Many beneficial effects of incretin on the Shimpei Fujimoto*, Nobuya Inagaki tial probe for pancreatic b-cell imag-preservation of rodent b-cells have been Department of Diabetes and Clinical ing. Biochem Biophys Res Communproposed, but thorough evaluation of the Nutrition, Graduate School of Medicine, 2009; 389: 523–526.effects in human b-cells is required. Fur- Kyoto University, Kyoto, Japan 8. Menge BA, Tannapfel A, Belyaev O,thermore, extreme variability of b-cell et al. Partial pancreatectomy in adultmass in humans shows that the pathogen- REFERENCES humans does not provoke b-cell reg-esis of type 2 diabetes is derived from 1. Leahy JL, Hirsch IB, Peterson KA, et al. eneration. Diabetes 2008; 57: 142–149.functional impairment of insulin secre- Targeting b-cell function early in the 9. Fiaschi-Taesch N, Bigatel TA, Sicari B,tion, as well as from reduction of b-cell course of therapy for type 2 diabetes et al. Survey of the human pancreaticmass (Figure 1). Indeed, glucose-specific mellitus. J Clin Endocrinol Metab 2010; b-cell G1 ⁄ S proteome reveals aimpairment of insulin secretion is charac- 95: 4206–4216. potential therapeutic role for cdk-6teristic in type 2 diabetes; the insulin 2. Weyer C, Bogardus C, Mott DM, et al. and cyclin D1 in enhancing humanresponse to intravenous administration of The natural history of insulin secretory b-cell replication and function in vivo.arginine is preserved, whereas the insulin dysfunction and insulin resistance in Diabetes 2009; 58: 882–893.response to intravenous administration of the pathogenesis of type 2 diabetes 10. Fujimoto S, Nabe K, Takehiro M, et al.glucose is severely impaired in patients mellitus. J Clin Invest 1999; 104: 787– Impaired metabolism-secretion cou-with type 2 diabetes10. Results from 794. pling in pancreatic b-cells: role ofdiabetic rodent and human islets show 3. Sato Y, Komatsu M, Katakura M, et al. determinants of mitochondrial ATPthat decreased glucose-stimulated insulin Diminution of early insulin response production. Diabetes Res Clin Practsecretion in diabetes is derived, at least in to glucose in subjects with normal 2007; 77(Suppl 1): S2–S10.part, from impaired metabolism–secretion but minimally elevated fasting plasma 11. Mukai E, Fujimoto S, Sato H, et al.coupling in b-cells; impaired glucose glucose. Evidence for early b-cell dys- Exendin-4 suppresses Src activationmetabolism and adenosine triphosphate function. Diabet Med 2002; 19: 566– and reactive oxygen species produc-(ATP) production in b-cells causes a 571. tion in diabetic GK rat islets in andecrease in glucose-stimulated insulin 4. Funakoshi S, Fujimoto S, Hamasaki A, Epac-dependent manner. Diabetessecretion. We propose that ATP produc- et al. Analysis of factors influencing 2011; 60: 218–226.tion in b-cells is impaired by endogenous pancreatic b-cell function in Japanese 12. Yoshihara E, Fujimoto S, Inagaki N,overproduction of reactive oxygen species patients with type 2 diabetes: associa- et al. Disruption of TBP-2 ameliorates(ROS) and by diminished hyperpolariza- tion with body mass index and dura- insulin sensitivity and secretion with-tion of mitochondrial membrane potential tion of diabetic exposure. Diabetes Res out affecting obesity. Nat Communas a result of overexpression of uncoupling Clin Pract 2008; 82: 353–358. 2010; 1: art. no. 127.ª 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd Journal of Diabetes Investigation Volume 2 Issue 3 June 2011 179