OBJECTIVE Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium–glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.
The green fluorescent protein (GFP)-homologous red fluorescent protein (RFP) from Discosoma (drFP583) which emits bright red fluorescence peaking at 583 nm is an interesting novel genetic marker. We show here that RFP maturation involves a GFP-like fluorophore which can be stabilized by point mutations selected from a randomly mutated expression library. By homology modeling, these point mutations cluster near the imidazolidinone ring of the chromophore. Exciting the GFP-like absorption band in the mutant proteins produces both green and red fluorescence. Upon unfolding and heating, the absorption spectrum of the RFP chromophore slowly becomes similar to that of the GFP chromophore. This can be interpreted as a covalent modification of the GFP chromophore in RFP that appears to occur in the final maturation step. ß
Ultrafast, intra‐oligomer fluorescence resonance energy transfer (FRET) between an immature green‐emitting GFP‐like chromophore to the mature red‐emitting chromophore is found in the novel red fluorescent protein wt‐DsRed (the picture shows the steady‐state absorption (solid line) and emission (dotted) spectra). Since FRET is by its very nature a short range process, it represents a highly suitable method to probe oligomerization. This work describes a method preferentially applicable to the efficient screening of protein variants with mutagenetically altered surface docking sites.
Ultrafast, intra‐oligomer fluorescence resonance energy transfer (FRET) between an immature green‐emitting GFP‐like chromophore to the mature red‐emitting chromophore is found in the novel red fluorescent protein wt‐DsRed (the picture shows the steady‐state absorption (solid line) and emission (dotted) spectra). Since FRET is by its very nature a short range process, it represents a highly suitable method to probe oligomerization. This work describes a method preferentially applicable to the efficient screening of protein variants with mutagenetically altered surface docking sites.
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