On admission she was found to be in significant metabolic acidosis pH 7. Inflammatory markers were raised WCC She was treated for urinary sepsis with IV antibiotics, IV fluids and insulin sliding scale. There was no family history of diabetes. She was discharged home on insulin Mixtard 30 34 units morning, and 16 units evening. Conclusion: Patients on atypical antipsychotics should be monitored for any signs and symptoms of hyperglycaemia and the complications associated with diabetes.
Physicians must be made aware of the growing association between atypical antipyschotic agents and hyperglycaemia. Browse other volumes. Clozapine-associated diabetes.
Am J Med ; : — Lindenmayer JP, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus. Am J Psychiatry ; : New onset diabetes and atypical antipsychotics. Eur Neuropsychopharmacol ; 11 : 25 — Diabetes as a result of atypical anti-psychotic drugs—a report of three cases.
Diabet Med ; 17 : —6. Diabetes mellitus associated with clozapine therapy. Pharmacotherapy ; 20 : —7. Novel antipsychotics and new onset diabetes. Biol Psychiatry ; 44 : — Hyperglycemia associated with the use of atypical antipsychotics.
J Clin Psychiatry ; 62 : 30 —8. Mir S, Taylor D. Atypical antipsychotics and hyperglycaemia. Int Clin Psychopharmacol ; 16 : 63 — Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy ; 21 : —7. Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature.
J Am Board Fam Pract ; 14 : — Olanzapine-induced diabetes mellitus. Ann Pharmacother ; 35 : —5. Roefaro J, Mukherjee SM. Olanzapine-induced hyperglycemic nonketonic coma. Ann Pharmacother ; 35 : —2. Olanzapine-induced glucose dysregulation. Ann Pharmacother ; 34 : —7. Hyperglycemia and olanzapine. Hyperglycemia associated with olanzapine.
J Clin Psychiatry ; 59 : —9. New-onset diabetes mellitus associated with quetiapine. Can J Psychiatry ; 45 : —9. New-onset diabetes mellitus associated with the initiation of quetiapine treatment. J Clin Psychiatry ; 60 : —7.
Risperidone-associated new-onset diabetes. Biol Psychiatry ; 50 : —9. Risperidone-associated diabetic ketoacidosis. Psychosomatics ; 42 : — Diabetic ketoacidosis associated with risperidone treatment? Psychosomatics ; 41 : — Resolution of hyperglycemia on risperidone discontinuation: a case report.
J Clin Psychiatry ; 63 : —4. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study.
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Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry ; 58 : —6. Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol ; : — US Department of Veterans Affairs medical care system as a resource to epidemiologists.
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Davies's textbook of adverse drug reactions. London, United Kingdom: Arnold Publishers, Rothman KJ. Modern epidemiology. Categorical data analysis using the SAS system. Rosack J. New studies raise questions about antipsychotic efficacy. Psychiatr News ; 38 : Tardive dyskinesia. Schizophr Bull ; 19 : — A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry ; 60 : — Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis.
BMJ ; : —6. Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia: a randomized controlled trial. JAMA ; : — Geddes J. Schizophr Bull ; 29 : — Dickson RA, Hogg L.
Pregnancy of a patient treated with clozapine. Psychiatr Serv ; 49 : —3. Antipsychotic-induced weight gain: a comprehensive research synthesis. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology ; 28 : — Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year.
J Clin Psychiatry ; 63 : — Time-dependent covariates in the Cox proportional-hazards regression model. Annu Rev Public Health ; 20 : — An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry ; 59 : —6. Cross-system service use among VA mental health patients living in Philadelphia. Adm Policy Ment Health ; 28 : — Cross-system service use among psychiatric patients: data from the Department of Veterans Affairs.
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Pharmacoeconomics ; 18 : — Determinants of medication compliance in schizophrenia: empirical and clinical findings.
Schizophr Bull ; 23 : — Avorn J. Balancing the cost and value of medications: the dilemma facing clinicians. Pharmacoeconomics ; 20 suppl 3 : 67 — Avorn J, Solomon DH. Cultural and economic factors that mis shape antibiotic use: the nonpharmacologic basis of therapeutics. Ann Intern Med ; : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Lambert , Bruce L. Correspondence to Dr. Oxford Academic. Google Scholar. Francesca E. Donald R. Gregory W. Kwan Hur. Cite Cite Bruce L.
Select Format Select format. Permissions Icon Permissions. Abstract To evaluate risk of new-onset type 2 diabetes associated with use of selected antipsychotic agents, the authors conducted a new-user cohort study in a national sample of US Veterans Health Administration patients with schizophrenia and no preexisting diabetes.
TABLE 1. They also claim that this may be negated by patients with "lower catabolism". Which cytPs are used to metabolize the drug, and is there any evidence that this varies in patients?
Overall, it is not clear whether the concentrations and conditions used in these experiments is physiologically relevant. Therefore, insulin secretion could be directly detected over time, which is essential to show. This would prevent the confounding variable of having to take secretion efficiency into account. More trivially, why are the data in Figure 5D presented first? In fact, this species is more prevalent than the HMI forms and may reflect aggregated species Figure 6C.
Indeed, these species may or may not also be targeted for ERAD molecular weight markers were not included in Figure 8B. Thank you for submitting your article "The antipsychotic olanzapine-induced misfolding and ERAD of proinsulin accounts for atypical development of diabetes" for consideration by eLife. Your article has been reviewed by three peer reviewers, including Elizabeth A Miller as the Reviewing Editor and Reviewer 1, and the evaluation has been overseen by Vivek Malhotra as the Senior Editor.
The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission. After discussion among the reviewers and senior editor, we agreed that your study provides some thought-provoking new insight into the molecular mechanisms by which diabetes may arise rapidly after onset of patient treatment with olanzapine.
That said, there was agreement among reviewers that some of the claims should be toned down, and you should state more clearly the limitations and caveats. Most importantly, the focus on ERAD including in the title was considered unwarranted. There was concern about the extent to which ERAD can account for the observed phenotypes, as well as the problem that MG treatment does not rescue secretion even if degradation is blocked.
Therefore, ERAD is unlikely to explain insulin secretion defect, although reduced insulin secretion could partially explain the ERAD this was the point of the BFA experiment suggested by Reviewer 3 in the original evaluation. ERAD should thus be appropriately de-emphasized as a driving mechanism.
The other over-riding concern was about the concentrations of olanzapine that might accrue in patient cells. Of course, such measures are difficult to make, but by our estimates the effective concentration in your in vitro proinsulin folding experiment is at more than an order of magnitude higher than could possibly be achieved in patient tissue.
Thus, the experiment shown in Figure 8C is particularly problematic, where a very high level of drug is required to see a quite subtle in vitro effect. The reviewers agreed that these data muddy the waters and should be removed. Thus, the ultimate conclusion is that although the mechanism of action remains unclear, your findings still provide insight into proinsulin misfolding as a potential side-effect of olanzapine treatment. You should be more careful in claiming a direct mechanism since that is not supported by the data shown.
Specifically, when editors judge that a submitted work as a whole belongs in eLife but that some conclusions require a modest amount of additional new data, as they do with your paper, we are asking that the manuscript be revised to either limit claims to those supported by data in hand, or to explicitly state that the relevant conclusions require additional supporting data.
Our expectation is that the authors will eventually carry out the additional experiments and report on how they affect the relevant conclusions either in a preprint on bioRxiv or medRxiv, or if appropriate, as a Research Advance in eLife , either of which would be linked to the original paper. In this revised version, the authors have added another antibody to establish the secretion of pro-insulin and insulin in their cell model, but many of the key experiments are all still only performed with the original antibody that doesn't recognise insulin.
Thus, the primary concern expressed by both other reviewers that the precursor-product relationship cannot be established, has not been fully resolved. My interpretation of the data is that OLA treatment prevents the production of the P' "processed proinsulin" form, but it was hard for me to know exactly what the P' protein corresponds to.
So, I suspect that most of the conclusions are correct but greater clarity is needed regarding the P' protein what it is and how it changes with OLA treatment. This should therefore be quantified in all of the pulse-chase experiments presented it is currently missing from many. The full precursor-product analysis requested in the original critique would go a long way to clarifying this. In the revised manuscript submitted to eLife , Mori and colleagues have added new data and models, and have addressed many of the comments that previously precluded publication.
A better characterization of the antibodies, the inclusion of data with islets and other unaffected substrates, an effect with lower doses of olanzapine, and improved fluorescence images further support the authors' earlier conclusions. However, there is still the question of whether the effect of the drug is direct or indirect. It is likely that the intracellular concentration in patients is even lower, given considerations regarding logP and the free vs bound population of the drug.
Two reviewers also expressed doubt that ERAD targeting was a major contributor to reduced levels of pro-insulin. With the exception of a modest effect of MG, there are no further supporting data. Therefore, the title and statements such as "indicating that a part of newly synthesized proinsulin is constitutively subjected to ERAD" are premature.
Moreover, a previous comment to determine whether enhanced ERAD targeting might be apparent when ER protein export is inhibited for, example, with BFA or dominant negative SAR1 was completely misinterpreted by the authors in the rebuttal, who replied "We have not used BFA in this manuscript".
The experiments using ITC are problematic. Does 1 mM risperidone also have the same, subtle effect? In the experiments using mice in which there is an increase in the amount of HMP-1, there is similarly no control for olanzapine. Does risperidone, or an inactive olanzapine derivative, have the same effect?
Another reviewer commented on the prolonged passage of these cells and whether they truly reflect islet biology. More mundane, the statement "Intracellular localization of A1PI was not affected…" is not clear.
Do the authors mean that secretion was unaffected? Finally, what is the significance of using the anti-KDEL antibody. This is mentioned in the absence of any context. In the Discussion section, the authors state, "olanzapine produced aberrantly disulfide-bonded proinsulin….
Are there any data to support this? The authors later state that the drug did not induce apoptosis, which appears to be in conflict with this earlier claim. The manuscript is much improved but Figure 8C and the conclusions associated with that panel are seriously flawed.
Were it not for this panel I believe the paper could be acceptable for publication. There is also a small matter of Figure 9D. No conclusion can be reached from this experiment, which puts the text of the manuscript in this part at risk of not being supported by real data. The interpretation that the drug acts directly on proinsulin is almost certainly wrong — so why imply such a thing when it is totally unnecessary to the paper? Don't the authors want to comment on the fact that the monomeric proinsulin in the nonreducing gel is also protected by MG?
It is clearly shown on the gel and the quantification in the graph below. Why would the authors not make this point? We have shown that olanzapine also did not significantly affect the maturation of hemagglutinin from high mannose-type to complex type Figure 5E , which requires correct disulfide bond formation for folding Segal et al. We did not observe any changes in disulfide-bonded status of PDI in mouse islets after treatment with olanzapine Figure 10B.
Although we could not detect direct interaction between olanzapine and oxidoreductases in the ER by ITC Figure 8A , we have found that olanzapine inhibited oxidative folding of purified proinsulin, leading to aberrant formation of intermolecular disulfide bonds Figure 8C.
We have shown that olanzapine-induced misfolding of proinsulin also occurred when mouse islets were treated with olanzapine Figure 10A-C. We have found that olanzapine inhibited oxidative folding of purified proinsulin, leading to aberrant formation of intermolecular disulfide bonds Figure 8C.
We have employed mouse monoclonal antibody I which immunoprecipitated mature proinsulin 2 and insulin 2 in addition to previously used, and have shown that MIN6 cells secrete both mature proinsulin and insulin non-reducing conditions, Figure 2E.
Most importantly, we have succeeded in showing the decrease in the amount of proinsulin in mouse islets after treatment with olanzapine Figure The precursor-product relationship for proinsulin 2 and insulin 2 was already and clearly shown by pulse 20 minutes -chase experiment using I Figure 3E and Figure 4B, lanes We have also shown that olanzapine did not alter the localization of insulin Figure 8A and 8B , allowing us to focus on the behavior of proinsulin in olanzapine-treated cells.
We have now shown the precursor-product relationship for proinsulin 2 and processed proinsulin 2 by conducting shorter pulse 3 min -chase experiments using Figure 3C. We believe that processed proinsulin is unlikely to be aggregation prone to yield the HMP products because it was secreted Figure 3B and that it is likely to be produced around the Golgi apparatus because the level of processed proinsulin was markedly decreased by treatment with brefeldin A Figure 3D.
Our explanation for why OLA treatment prevents the production of processed proinsulin is that OLA treatment induced misfolding of proinsulun and retention of misfolded proinsulin in the ER. In the revised manuscript submitted to eLife, Mori and colleagues have added new data and models, and have addressed many of the comments that previously precluded publication.
We would draw your attention to the finding that daily oral administration of olanzapine produced HMP-1 and even higher molecular weight forms of proinsulin in mouse islets Figure 10E-F , albeit that we could not determine the concentration of olanzapine in serum. We consider that the increase in the level of intracellular proinsulin in MIN6 cells treated with both olanzapine and MG over that in MIN6 cells treated with olanzapine alone is marked Figure 5D, right top panel.
We apologize for our insufficient explanation. To this end, we must treat MIN6 cells with 1 none, 2 olanzapine, 3 brefeldin A, 4 olanzapine and brefeldin, and 5 olanzapine, brefeldin A and MG During this experiment, we found that brefeldin A is quite toxic to MIN6 cells.
In most cases, when MIN6 cells were treated with brefeldin A for longer periods, a lower amount of radioisotope was incorporated into proteins, as shown below. We thought that it is difficult to obtain meaningful results with this experiment. This was modified with AMS to stop the reaction, as was described previously in the legend.
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The authors declare no competing financial interests. We thank Kaoru Miyagawa for her technical and secretarial assistance, Dr.
Akira Hattori Kyoto University and Ms. Masataka Kunii Osaka University for useful antibody information, and Ms. Nanae Fujimoto for her help in islet isolation. Animal experimentation: All mouse experiments were conducted under pathogen-free conditions and in line with Institutional Animal Care protocols approved by Kyoto University Q This article is distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use and redistribution provided that the original author and source are credited.
Article citation count generated by polling the highest count across the following sources: Crossref , PubMed Central , Scopus. Phagocytosis requires rapid actin reorganization and spatially controlled force generation to ingest targets ranging from pathogens to apoptotic cells.
How actomyosin activity directs membrane extensions to engulf such diverse targets remains unclear. Here, we combine lattice light-sheet microscopy LLSM with microparticle traction force microscopy MP-TFM to quantify actin dynamics and subcellular forces during macrophage phagocytosis. We show that spatially localized forces leading to target constriction are prominent during phagocytosis of antibody-opsonized targets.
Contractile myosin-II activity contributes to late-stage phagocytic force generation and progression, supporting a specific role in phagocytic cup closure. Observations of partial target eating attempts and sudden target release via a popping mechanism suggest that constriction may be critical for resolving complex in vivo target encounters.
Overall, our findings present a phagocytic cup shaping mechanism that is distinct from cytoskeletal remodeling in 2D cell motility and may contribute to mechanosensing and phagocytic plasticity. Recently it was reported that UCH37 activity is stimulated by branched ubiquitin chain architectures.
To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and NMR structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal ubiquitins that emanate from a branched ubiquitin. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear ubiquitin chains from having access to the UCH37 active site.
In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH Proteasomes containing UCH37 C88A , which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique ubiquitin chain architecture is aided by a DUB.
Key processes of biological condensates are diffusion and material exchange with their environment. Experimentally, diffusive dynamics are typically probed via fluorescent labels.
However, to date, a physics-based, quantitative framework for the dynamics of labeled condensate components is lacking. Here, we derive the corresponding dynamic equations, building on the physics of phase separation, and quantitatively validate the related framework via experiments.
We show that by using our framework, we can precisely determine diffusion coefficients inside liquid condensates via a spatio-temporal analysis of fluorescence recovery after photobleaching FRAP experiments. We showcase the accuracy and precision of our approach by considering space- and time-resolved data of protein condensates and two different polyelectrolyte-coacervate systems. Interestingly, our theory can also be used to determine a relationship between the diffusion coefficient in the dilute phase and the partition coefficient, without relying on fluorescence measurements in the dilute phase.
This enables us to investigate the effect of salt addition on partitioning and bypasses recently described quenching artifacts in the dense phase. Our approach opens new avenues for theoretically describing molecule dynamics in condensates, measuring concentrations based on the dynamics of fluorescence intensities, and quantifying rates of biochemical reactions in liquid condensates.
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