Cytosolic NADPH may act as one of the signals that couple glucose metabolism to insulin secretion in the pancreatic ß-cell. NADPH levels in the cytoplasm are largely controlled by the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase (IDHc). Some studies have provided evidence for a role of malic enzyme in glucose-induced insulin secretion (GIIS) via pyruvate cycling, but the role of IDHc in ß-cell signaling is unsettled. IDHc is an established component of the isocitrate/α–ketoglutarate shuttle that transfers reducing equivalents (NADPH) from the mitochondrion to the cytosol. This shuttle is energy consuming since it is coupled to nicotinamide nucleotide transhydrogenase that uses the mitochondrial proton gradient to produce mitochondrial NADPH and NAD+ from NADP+ and NADH. To determine whether flux through IDHc is positively or negatively linked to GIIS, we performed RNAi knockdown experiments in ß-cells. Reduced IDHc expression in INS 832/13 cells and isolated rat islet ß-cells resulted in enhanced GIIS. This effect was mediated at least in part via the KATP-independent amplification arm of GIIS. IDHc knockdown in INS 832/13 cells did not alter glucose oxidation but it reduced fatty acid oxidation and increased lipogenesis from glucose. Metabolome profiling in INS 832/13 cells showed that IDHc knockdown increased isocitrate and NADP+ levels. It also increased the cellular contents of several metabolites linked to GIIS, in particular some Krebs cycle intermediates, acetyl-CoA, glutamate, cAMP and ATP. The results identify IDHc as a component of the emerging pathways that negatively regulate GIIS.

Breathlessness, also known as dyspnoea, is a debilitating and frequent symptom. Several reports have highlighted the lack of dyspnoea in a subgroup of patients suffering from COVID-19, sometimes referred to as “silent” or “happy hyp­oxaemia.” Reports have also mentioned the absence of a clear relationship between the clinical severity of the disease and levels of breathlessness reported by patients. The cerebral complications of COVID-19 have been largely demonstrated with a high prevalence of an acute encephalopathy that could possibly affect the processing of afferent signals or top-down modulation of breathlessness signals. In this review, we aim to highlight the mechanisms involved in breathlessness and summarize the pathophysiology of COVID-19 and its known effects on the brain-lung interaction. We then offer hypotheses for the alteration of breathlessness perception in COVID-19 patients and suggest ways of further researching this phenomenon.

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Temporary chronic pain reduction related to acute COVID-19 has been observed, providing new knowledge on the possible mechanisms of pain modulation and potential therapeutic options.

Hiccups are a rare but potentially debilitating side effect of opioid treatment, with only a handful of reported cases in the medical literature. the pathophysiological mechanism linking opioids and hiccups is unknown, and a lack of evidence exists concerning the optimal management of the condition. We report on a 64-year-old man diagnosed with advanced renal cancer and painful osteolytic metastases, presenting persistent hiccups while on opioid treatment. Hiccups recurred after multiple challenges with codeine, morphine and hydromorphone on separate occasions. Hiccups ceased only after opioid discontinuation, although various pharmacological treatments were tried to shorten the duration of hiccups. eventually, fentanyl was introduced and was well tolerated by the patient, without any recurrence of hiccups. the chronological correlation between opioid initiation and the onset of hiccups, as well as opioid discontinuation and the termination of hiccups leads to the conclusion that a causal role of codeine, morphine and hydromorphone in this occurrence is likely. Individual susceptibility probably plays a central role in the development of opioid-related hiccups. opioid rotation is a promising strategy in the management of opioid-related hiccups, particularly when the mere discontinuation of the opioid is not a viable option, such as in the oncology and palliative care field.