Effect of dapagliflozin SGLT-2 inhibitory on brain and hypothalamic functionality in humans and mice

Author(s)

Letícia da Silva Pires

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2017-03-23

Examining board members

Bruno Geloneze Neto; Marciane Milanski; Gabriel Forato Anhê

• Advisor: Licio Augusto Velloso; Bruno Geloneze Neto

Abstract

Type 2 diabetes mellitus is one of the diseases with the fastest increasing prevalence in the world. This is mostly due to the increased prevalence of obesity. Multiple pathophysiological abnormalities are involved in this problem and affect different organs, including the brain. The balance between eating behavior and energy expenditure is a biological process that is coordinate by the brain and the hypothalamus as the main structure involved, particularly the arcuate nucleus, where two subpopulations of neurons, NPY/AgRP and POMC/CART, respond to peripheral signals that inform about the availability of energy in the body. Variations in blood glucose levels are rapidly detected by hypothalamic neurons generating signals that play a role in the control of hunger and energy expenditure. The mechanisms involved in the hypothalamic response to glucose are still poorly understood, but it is believed that their membrane transporters, GLUT and SGLT play an important role in this process. The sodium-glucose co-transporter type 2 (SGLT-2) is expressed in the kidney and brain, including hypothalamic regions involved in food control. Inhibition of SGLT-2 leads to glycosuria and caloric loss concomitant with a decrease in body weight. However, it is currently unknown the mechanistic details involved in this phenomenon. In this work, in mice, we observed by immunofluorescence that SGLT-2 is present in the arcuate nucleus and colocalize with POMC and NPY neurons, suggesting that SGLT-2 is involved in feeding control. Also, mice treated with dapagliflozin showed glycosuria, which was accompanied by improved fasting glycemia, as well as a reduction in the area under glucose curve during a glucose tolerance test (GTT). We also observed a decrease in body weight and a slight but not significant reduction in epididymal adipose mass. In the clinical intervention in eutrophic and normoglycemic women volunteers treated with 10 mg per day of dapagliflozin for one week, we observed a numerical reduction, although not significant, in body mass index (BMI), waist circumference and sagittal abdominal diameter. In addition, there was a better efficiency in glycemic response and insulin sensitivity. The use of dapagliflozin can alter the connections of the hypothalamus with other regions of the brain and play a possible role in food control. The new actions of the drug described here may contribute to the advancement in understanding the hypothalamic mechanisms involved in food control and energy expenditure and create new therapeutic perspectives for obesity (AU)

• FAPESP's process: 14/26591-8 - Acute effect of dapagliflozin SGLT-2 inhibitory on brain and hypothalamic functionality in humans and mice C57BL/6
• Grantee: Letícia da Silva Pires
• Support Opportunities: Scholarships in Brazil - Master