Severe Hyperglycemia Due to Protein Kinase Inhibitor Therapy in a Patient With Poorly Controlled Diabetes Mellitus.

The efficacy and safety of zanubrutinib, a highly selective next-generation Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia and lymphoplasmocytoides immunocytoma seems favorable. Adverse events comprise neutropenia, thrombocytopenia, infection, anemia, and atrial fibrillation. This report describes a 75-year-old man suffering from polydipsia, polyuria, and blurred vision for 10 days. He was diagnosed with lymphoplasmocytoides immunocytoma in 2003. After various therapies, he was started on zanubrutinib in October 2022. A diagnosis of diabetes mellitus had never been established before. On arrival in the emergency department, his plasma glucose was 37.2 mmol/L (671 mg/dL) and glycated hemoglobin (HbA1c) was 14.2%. Circulating antibodies showed positivity for glutamic acid decarboxylase (GAD-65), and his C-peptide level was 1.3 nmol/L (normal range, 0.37-1.47 nmol/L), equivalent to 3.9 ng/mL (normal range 1.1-5.0 ng/mL). From the patient's medical history, it became obvious that the metabolic situation had been problematic for many years, and that diabetes could have been taken into account at least in the summer of 2020 when HbA1c was 6.7%. In patients on tyrosine kinase inhibitors, careful assessment of glycemic control (monitoring HbA1c and blood glucose levels periodically even for nondiabetic patients) is recommended to prevent a major diabetic emergency.

[Exercise and diet in colorectal cancer prevention and therapy]. / Körperliche Aktivität und Ernährung in der Prävention und Therapie des Kolorektalen Karzinoms.

INTRODUCTION: Colorectal carcinoma is a leading cause of cancer diseases in Europe. Due to modern therapies survival rate is increasing. Nevertheless, cancer and its treatment is associated with significant morbidity. Physical activity appears as having a positive impact on cancer risk, as well as, reducing peri- and postoperative morbidity and mortality. METHODS: We searched pubmed and googlescholar for English- and German-language studies from inception to September 2022. The search terms physical activity, colon cancer, colorectal cancer, diet, survivors. prehabilitation, postoperative morbidity, quality of life and outcome were used. Guidelines of national advisory commmittees and Cochrane reviews were included. RESULTS: There is considerable evidence that physical activity is associated with reduced risk of colon cancer, epigenetic mechanisms play a central role in connection. Different studies showed a risk reduction of 12 to 27 percent. A prehabilitation programme consisting of exercise, nutritional intervention, and psychosocial rehabilitation can reduce peri- and postoperative complications. Aerobic exercise and strength training can improve survival rates and overall mortality. However, a causal relationship between nutritional treatment and cancer related symptoms (e.g. fatigue) is missing. CONCLUSION: There is a wide range of scientific papers on the influence of physical activity and nutrition; nevertheless, its influence on the various stages of colorectal disease are not addressed adequately. Recommendations concerning prehabilitation and tertiary prevention can only be given on the basis of heterogeneous trial data.

[Bowel preparation in patients with Diabetes mellitus: Development of a procedure model]. / Koloskopievorbereitung bei Patienten mit Diabetes mellitus: Entwicklung einer Handlungsempfehlung.

BACKGROUND: Adequate bowel preparation prior to colonoscopy is the key factor for high quality preparation for colonoscopy. Inadequate preparation can result in prolonged procedure time, incomplete colonoscopy and an increased risk of procedural adverse events. Diabetes mellitus has been identified as a predictor of inadequate colonoscopy bowel preparation. Currently, standard recommendations for diabetes patients before colonoscopy are missing. METHODS: This review is based on a selective literature search in PubMed and Google Scholar carried out in June 2021. Systematic reviews, guidelines, expert opinions, and recommendations from German and international societies were also considered. RESULTS: The currently available preparations comprise two different groups: High-, medium- and low- volume polyethylene glycol (PEG) preparations and hyperosmotic agents. So far, a couple of reviews tried to identify outcome related differencies. Results are heterogeneous. In practise, preparation agents and timing of preparation as well as a thorough patient information before the preparation process are considered the most relevant items. In diabetes patients, preinterventional dietary recommendations are of paramount importance. CONCLUSION: Split dosing of PEG preparations are recommended in diabetes patients with expected motility disorders. Extensive counseling about preparation intake and dietary recommendations should be offered.

Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner.

Astrocyte dysfunction is a primary factor in hepatic encephalopathy (HE) impairing neuronal activity under hyperammonemia. In particular, the early events causing ammonia-induced toxicity to astrocytes are not well understood. Using established cellular HE models, we show that mitochondria rapidly undergo fragmentation in a reversible manner upon hyperammonemia. Further, in our analyses, within a timescale of minutes, mitochondrial respiration and glycolysis were hampered, which occurred in a pH-independent manner. Using metabolomics, an accumulation of glucose and numerous amino acids, including branched chain amino acids, was observed. Metabolomic tracking of 15N-labeled ammonia showed rapid incorporation of 15N into glutamate and glutamate-derived amino acids. Downregulating human GLUD2 [encoding mitochondrial glutamate dehydrogenase 2 (GDH2)], inhibiting GDH2 activity by SIRT4 overexpression, and supplementing cells with glutamate or glutamine alleviated ammonia-induced inhibition of mitochondrial respiration. Metabolomic tracking of 13C-glutamine showed that hyperammonemia can inhibit anaplerosis of tricarboxylic acid (TCA) cycle intermediates. Contrary to its classical anaplerotic role, we show that, under hyperammonemia, GDH2 catalyzes the removal of ammonia by reductive amination of α-ketoglutarate, which efficiently and rapidly inhibits the TCA cycle. Overall, we propose a critical GDH2-dependent mechanism in HE models that helps to remove ammonia, but also impairs energy metabolism in mitochondria rapidly.

Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein.

The stress-inducible and senescence-associated tumor suppressor SIRT4, a member of the family of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5), regulates bioenergetics and metabolism via NAD+-dependent enzymatic activities. Next to the known mitochondrial location, we found that a fraction of endogenous or ectopically expressed SIRT4, but not SIRT3, is present in the cytosol and predominantly localizes to centrosomes. Confocal spinning disk microscopy revealed that SIRT4 is found during the cell cycle dynamically at centrosomes with an intensity peak in G2 and early mitosis. Moreover, SIRT4 precipitates with microtubules and interacts with structural (α,ß-tubulin, γ-tubulin, TUBGCP2, TUBGCP3) and regulatory (HDAC6) microtubule components as detected by co-immunoprecipitation and mass spectrometric analyses of the mitotic SIRT4 interactome. Overexpression of SIRT4 resulted in a pronounced decrease of acetylated α-tubulin (K40) associated with altered microtubule dynamics in mitotic cells. SIRT4 or the N-terminally truncated variant SIRT4(ΔN28), which is unable to translocate into mitochondria, delayed mitotic progression and reduced cell proliferation. This study extends the functional roles of SIRT4 beyond mitochondrial metabolism and provides the first evidence that SIRT4 acts as a novel centrosomal/microtubule-associated protein in the regulation of cell cycle progression. Thus, stress-induced SIRT4 may exert its role as tumor suppressor through mitochondrial as well as extramitochondrial functions, the latter associated with its localization at the mitotic spindle apparatus.