ABSTRACT
AIMS/HYPOTHESIS: Following on from the emerging importance of the pancreas circadian clock on islet function and the development of type 2 diabetes in rodent models, we aimed to examine circadian gene expression in human islets. The oscillator properties were assessed in intact islets as well as in beta cells. METHODS: We established a system for long-term bioluminescence recording in cultured human islets, employing lentivector gene delivery of the core clock gene Bmal1 (also known as Arntl)-luciferase reporter. Beta cells were stably labelled using a rat insulin2 promoter fluorescent construct. Single-islet/cell oscillation profiles were measured by combined bioluminescence-fluorescence time-lapse microscopy. RESULTS: Human islets synchronised in vitro exhibited self-sustained circadian oscillations of Bmal1-luciferase expression at both the population and single-islet levels, with period lengths of 23.6 and 23.9 h, respectively. Endogenous BMAL1 and CRY1 transcript expression was circadian in synchronised islets over 48 h, and antiphasic to REV-ERBα (also known as NR1D1), PER1, PER2, PER3 and DBP transcript circadian profiles. HNF1A and PDX1 exhibited weak circadian oscillations, in phase with the REV-ERBα transcript. Dispersed islet cells were strongly oscillating as well, at population and single-cell levels. Importantly, beta and non-beta cells revealed oscillatory profiles that were well synchronised with each other. CONCLUSIONS/INTERPRETATION: We provide for the first time compelling evidence for high-amplitude cell-autonomous circadian oscillators displayed in human pancreatic islets and in dispersed human islet cells. Moreover, these clocks are synchronised between beta and non-beta cells in primary human islet cell cultures.
Subject(s)
ARNTL Transcription Factors/metabolism , Islets of Langerhans/metabolism , Animals , Circadian Clocks/genetics , Circadian Clocks/physiology , Female , Humans , In Vitro Techniques , Islets of Langerhans/physiology , Male , Middle Aged , Rats , TemperatureSubject(s)
Drug Information Services , Drug Industry , Interprofessional Relations , Pharmacists , PhysiciansABSTRACT
Twelve patients (8 females, 4 males) with panhypopituitarism who had been thoroughly examined psychiatrically in 1957 and 1958 were reexamined in 1974 for psychopathologic alterations in the course of their endocrine disease. Eleven patients had been receiving an adequate hormonal treatment during the intervening years or (four patients) until the time of their death. Seven patients showed a good or excellent result of hormonal therapy, in respect of the psychic symptoms: the endocrine psychosyndrome which had been observed prior to treatment had improved considerably. Signs of organic brain syndrome were judged to be caused by age and not by the endocrinopathy. The factors influencing prognosis of psychic symptoms are: alteration in mental activity, in the sense of apathy and lack of drive, and the extent of social distegration caused by these alterations; the age of the patient at the onset of symptoms and the lapse of time prior to the beginning of adequate therapy; finally the personality structure and the social situation of the patient.
