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  • 1.
    Almby, Kristina E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hammar, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Thombare, Ketan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Panagiotou, Amalia
    Uppsala Univ Hosp, Dept Internal Med, Uppsala, Sweden.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wiklund, Urban
    Umea Univ, Dept Radiat Sci, Biomed Engn, Umea, Sweden.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery2019In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 181, no 2, p. 161-171Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).

    Design: Experimental hyperinsulinemic-hypoglycemic clamp study.

    Methods: Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.

    Results: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.

    Conclusions/interpretation: Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

  • 2.
    Sarsenbayeva, Assel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Marques-Santos, Cátia M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Thombare, Ketan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Di Nunzio, Giada
    Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal.
    Almby, Kristina E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism2019In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 110, article id 104445Article in journal (Refereed)
    Abstract [en]

    Objective: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism.

    Methods: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m(2)). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 mu M - 20 mu M) and aripiprazole (0.002 mu M - 100 mu M). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis.

    Results: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term preincubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondria] functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG.

    Conclusion: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.

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