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Journal Club

Journal Club. Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, Hattersley AT, McDonald TJ. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells . Diabetologia . 2013 Oct 12. [ Epub ahead of print]

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Journal Club

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  1. Journal Club Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, Hattersley AT, McDonald TJ. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia. 2013 Oct 12. [Epub ahead of print] de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM; the BEACON Trial Investigators. BardoxoloneMethyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease. N Engl J Med. 2013 Nov 9. [Epub ahead of print] 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文　 Matsuda, Masafumi 2013年11月21日8:30-8:55 ８階　医局

  2. C-pep 3617g=1mol ng/ml 3.617ng=1pmol, 1ng=0.276pmol ng/ml

  3. R. A. Oram : A. G. Jones : R. E. J. Besser : B. A. Knight : B. M. Shields : A. T. Hattersley (*) : T. J. McDonald (*) NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Barrack Road, Exeter, UK e-mail: A.T.Hattersley@ex.ac.uk e-mail: Timothy.mcdonald@nhs.net R. J. Brown : T. J. McDonald Department of Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK DiabetologiaDOI 10.1007/s00125-013-3067-x

  4. Aims/hypothesis Classically, type 1 diabetes is thought to proceed to absolute insulin deficiency. Recently developed ultrasensitive assays capable of detecting C-peptide under 5 pmol/l (18pg/ml) now allow very low levels of C-peptide to be detected in patients with long-standing type 1 diabetes. It is not known whether this low-level endogenous insulin secretion responds to physiological stimuli. We aimed to assess how commonly low-level detectable C-peptide occurs in long-duration type 1 diabetes and whether it responds to a meal stimulus.

  5. Methods We performed a mixed-meal tolerance test in 74 volunteers with long-duration (>5 years) type 1 diabetes, i.e. with age at diagnosis 16 (9–23)years (median [interquartile range]) and diabetes duration of 30 (19–41) years. We assessed fasting and stimulated serum C-peptide levels using an electrochemiluminescence assay (detection limit 3.3 pmol/l), and also the urinary C-peptide:creatinine ratio (UCPCR).

  6. We recruited 74 participants who had had type 1 diabetes for longer than 5 years. Participants had either been diagnosed at less than 30 years of age (n =68) or when older than 30 years and with islet autoantibodies present (n =6). All patients had been on insulin since diagnosis. Of the 74 participants, 38 (51%) were male. Age at diagnosis was 16 (9–23)years, median (interquartile range [IQR]), and duration of diabetes was 30(19–41)years, with BMI of 25 (23–28)kg/m2, HbA1c 7.9 (7.2–9.0)% (63 [55–75] mmol/mol), insulin dose 0.55 (0.44–0.69)units per kg of body weight per day and an estimated GFR of 89 (82–102)ml min−1 1.73m−2.

  7. Mixed-meal tolerance test Participants attended the Exeter National Institute for Health Research (NIHR) Clinical Research, having fasted from midnight, not taken their usual morning insulin and fully emptied their bladder upon waking. Fasting blood was taken for measurement of C-peptide, creatinine, glucose, HbA1c, and GAD and islet antigen 2 autoantibodies, and a second void urine sample was collected for UCPCR determination. Participants were given a standard mixed meal (Ensure Plus HP; Abbott Nutrition, Columbus, OH, USA) consisting of 6 ml/kg (maximum 360 ml) water and containing per 100 ml: 15.9 g carbohydrate, 7.9 g protein, 3.3 g fat and 125 kJ energy. Blood was taken for C-peptide and glucose analysis at 90 min post-completion of the mixed meal, with urine being collected for UCPCR determination at 120 min. All participants were asked to provide a home urine sample in a boric acid container, taken 2 h after an evening meal (and having voided the bladder before the meal). Serum and urine samples were stored at −80°C for subsequent analysis.

  8. C-peptide analysis We analysed serum C-peptide with a direct electro-chemiluminescenceimmunoassay using mouse monoclonal anti-C-peptide antibody (Roche Diagnostics, Mannheim, Germany) on an E170 analyser (Roche). The reported limit of detection is 3.3 pmol/l with a CV of 0.6% at 33 pmol/l. We compared our Roche assay with another assay, Ultrasensitive C-peptide ELISA (Mercodia, Sylveniusgatanm, Sweden), which is a solid-phase two-site enzyme immunoassay that uses a peroxidase-TMB (3,3′,5,5′-tetramethybenzidine) label on an automated ELISA system (Dynex DSX; Launch Diagnostics, Longfield, UK). The comparison involved dual analysis of 67 samples selected for having low levels of serum C-peptide. The reported limit of detection is 1.5 pmol/l with a CV of 5.5% at 37 pmol/l. Urinary C-peptide was analysed on the E170 analyser (Roche) as previously described.

  9. C-pep 3617g=1mol ng/ml 3.617ng=1pmol, 1ng=0.276pmol 3.617ng/ml 1ng/ml 18pg/ml The effect of a meal stimulus on serum C-peptide levels in participants with detectable insulin (n = 54). (a) Paired fasting and mixed meal results for all patients with detectable C-peptide. Each line represents an individual patient. (b) Results for all patients with fasting C-peptide below 30 pmol/l (n = 36). Of 54 patients, (80%) had a serum C-peptide value that rose after the mixed meal. None had a fall in the C-peptide value after the meal

  10. Results Post-stimulation serum C-peptide was detectable at very low levels (>3.3 pmol/l) in 54 of 74 (73%) patients. In all patients with detectable serum C-peptide, C-peptide either increased (n =43, 80%) or stayed the same (n =11) in response to a meal, with no indication of levels falling (p <0.0001). With increasing disease duration, absolute C-peptide levels fell although the numbers with detectable C-peptide remained high (68%, i.e. 25 of 37 patients with >30 years duration). Similar results were obtained for UCPCR.

  11. Conclusions/interpretation Most patients with long-duration type 1 diabetes continue to secrete very low levels of endogenous insulin, which increase after meals. This is consistent with the presence of a small number of still functional beta cells and implies that beta cells are either escaping immune attack or undergoing regeneration.

  12. Message インスリン分泌が平均30年の病歴の１型糖尿病患者でも若干残っているということだが。 インスリン分泌が足らないのは勿論だが「残っている」というのが大切らしい。

  13. Reactive oxygen species (ROS) The dimericKelch-like ECH-associated protein-1 (KEAP1) receptor contacts one NRF2 (nuclear factor (erythroid-derived-2)-like-2) molecule at two distinct N-terminal sites. The KEAP1–cullin-3 (CUL3) complex constantly targets NRF2 for proteosomal degradation through ubiquitylation of NRF2 Lys residues that are located at its N terminus, between the two KEAP1 interaction sites. Electrophiles and signals from reactive oxygen species (ROS) modify KEAP1 Cys residues, leading to zinc release and a conformation that is non-permissible for ubiquitylation. An alternative speculative model proposes that two NRF2 molecules are each contacted by the Kelch domain of dimericKEAP1. Phosphorylation of Ser40 by phosphatidylinositol 3-kinase (PI3K), protein kinase RNA (PKR)-like endoplasmic reticulum (ER) kinase (PERK) or protein kinase C (PKC) might also lead to ubiquitylation arrest. KEAP1 dimerizes through the broad complex–tramtrack–bric-a-brac (BTB) domain and interacts with NRF2 through the Kelch domain. The KEAP1 intervening region (IVR) that carries reactive Cys residues is located between the BTB and Kelch domains. ARE, antioxidant response element; CNC-bZIP, cap 'n' collar-basic leucine zipper; DGR, double glycine repeat; GSH, glutathione.

  14. The Keap1–Nrf2 system. Under normal conditions, Nrf2 is constantly ubiquitinated through Keap1 and degraded in the proteasome. Following exposure to electrophiles or oxidative stress, Keap1 is inactivated. Stabilized Nrf2 accumulates in the nucleus and activates many cytoprotective genes. Ub, ubiquitin. http://www.frontiersin.org/Journal/10.3389/fonc.2012.00200/full

  15. Bardoxolone methyl (also known as “RTA 402” and “CDDO-methyl ester”) is an orally-available first-in-class synthetic triterpenoid. It is an inducer of the Nrf2 pathway, which can suppress oxidative stress and inflammation Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene. The Nrf2 antioxidant response pathway is "the primary cellular defense against the cytotoxic effects of oxidative stress." Among other effects, NFE2L2 increases the expression of several antioxidant enzymes.

  16. N Engl J Med 2011; 365:327-336 BEAM Study

  17. the University of Groningen, Groningen, the Netherlands (D.Z., H.J.L.H.); Showa University School of Medicine, Tokyo (T.A.); Reata Pharmaceuticals, Irving, TX (P.A., M.C., A.G., M.K., C.J.M.); University of Chicago (G.L.B.) and AbbVie Pharmaceuticals (M.H.) — both in Chicago; Statistics Collaborative, Washington, DC (H.C.-S., J.W., D.W.); University of Glasgow, Glasgow, United Kingdom (J.J.M.); Rigshospitalet, University of Copenhagen, Copenhagen (H.-H.P.); Istituto di Ricovero e Cura a CarattereScientifico–Istituto di RicercheFarmacologiche Mario Negri, Bergamo, Italy (G.R.); University of Texas Southwestern Medical Center, Dallas (R.D.T.); University of California, Irvine (N.D.V.); University of Würzburg, Würzburg, Germany (C.W.); and Stanford University, Palo Alto, CA (G.M.C.). N Engl J Med 2013. DOI: 10.1056/NEJMoa1306033

  18. Background Although inhibitors of the renin–angiotensin–aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)–related factor 2 activators further reduce this risk is unknown.

  19. Oxidative stress and impaired antioxidant capacity intensify with the progression of chronic kidney disease. In animals with chronic kidney disease, oxidative stress and inflammation are associated with impaired activity of the nuclear 1 factor (erythroid-derived 2)–related factor 2 (Nrf2) transcription factor. The synthetic triterpenoidbardoxolone methyl and its analogues are the most potent known activators of the Nrf2 pathway. Studies involving humans, including persons with type 2 diabetes mellitus and stage 3b or 4 chronic kidney disease, have shown that bardoxolone methyl can reduce the serum creatinine concentration for up to 52 weeks.

  20. Methods We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m2 of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes.

  21. The trial was terminated early because of safety concerns, driven primarily by an increase in cardiovascular events in the bardoxolone methyl group.

  22. Figure 2. Kaplan–Meier Plots of the Time to the First Event of the Discrete Secondary Outcomes. Panel A shows the time to the first event of heart failure, defined as death due to heart failure or hospitalization for heart failure, among patients in the bardoxolone methyl group and those in the placebo group. Panel B shows the time to the first event of the secondary composite outcome (nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death from cardiovascular causes) in the two study groups. The first event was nonfatal myocardial infarction in 17 patients in the bardoxolone methyl group and 11 in the placebo group, nonfatal stroke in 12 patients in the bardoxolone methyl group and 8 in the placebo group, hospitalization for heart failure in 91 patients in the bardoxolone methyl group and 54 in the placebo group, and death from cardiovascular causes in 19 patients in the bardoxolone methyl group and 13 in the placebo group.

  23. Table S6. Physiological parameters during the trial *0.05<p-value<0.01, **0.01<p-value<0.001, ***p-value<0.001. †137 (placebo: 71, bardoxolone methyl: 66) patients have both valid baseline and Week 4 ABPM measurements.

  24. Why were these adverse effects identified in the current trial and not in the BEAM trial? First, the number of patient-months of drug exposure in the current trial was roughly 10 times that in the BEAM trial. Second, the population in the present trial had more severe chronic kidney disease than did the population in the BEAM trial. Observational studies have shown significantly higher rates of death and cardiovascular events, including heart failure, among patients with stage 4 chronic kidney disease than among patients with stage 3 chronic kidney disease. Finally, our trial used an amorphous spray-dried dispersion formulation of bardoxolone methyl at a fixed dose rather than at an adjusted dose.

  25. Results The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group.

  26. Conclusions Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.)

  27. Message 糖尿病でステージ4の慢性腎臓病（CKD）患者2185人を対象に、転写因子Nrf2活性化剤bardoxolone methylによる治療の効果を検討（BEACON試験）。主要評価項目の末期腎臓病または心血管死発生率は治療群、プラセボ群とも6％だった。プラセボ群に比べ、治療群で心血管イベント発生率が高く、本試験は中止された。

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