Abstract
Sodium–glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote urinary glucose excretion. Conversely, they cause behavioural changes, such as hyperphagia, that result in a positive energy balance. The relationship between energy homeostasis and SGLT2 inhibitors-induced behavioural changes remains unclear. Here we show that ipragliflozin, a SGLT2 inhibitor, time-dependently affects behaviour and enhances energy expenditure in normal and type 2 diabetic Goto–Kakizaki (GK) rats, using continuous glucose telemetry. Alongside increased urinary glucose excretion, ipragliflozin increased total food and water intakes in normal and GK rats. In normal rats, ipragliflozin treatment acutely disturbed the circadian rhythms of food and water intakes, activity, and body temperature. Subsequently, these rhythms gradually returned towards a normal state. However, activity and body temperature remained suppressed. In GK rats, ipragliflozin did not affect circadian rhythms. Blood glucose values assessed by glucose telemetry were significantly reduced in both ipragliflozin-treated groups. Despite these behavioural and glycaemic changes, ipragliflozin significantly increased oxygen consumption during dark and light periods in both groups. Ipragliflozin reduced body weight in normal rats only. Thus, ipragliflozin decreases blood glucose beyond compensatory hyperphagia in normal and GK rats, resulting in enhanced basal energy expenditure, despite acutely altering circadian rhythms in normoglycaemic individuals.
Highlights
IntroductionThis change is connected with the increasing prevalence of obesity, which can drive type 2 diabetes[1,2]
Type 2 diabetes is becoming an increasingly common disorder
We show that ipragliflozin, a SGLT inhibitor, time-dependently affects behaviour and enhances energy expenditure in normal Wistar and type 2 diabetic Goto–Kakizaki (GK) rats using continuous glucose telemetry, which is a newly-established technology for continuous glucose monitoring[12]
Summary
This change is connected with the increasing prevalence of obesity, which can drive type 2 diabetes[1,2] Lifestyle interventions such as the control of body weight and food intake are essential to delay disease progression and improve glycaemic control in type 2 diabetes[3]. Considering the technical methods for measuring the response of blood glucose to SLGT2 inhibitors, while the technique of continuous glucose monitoring is easy to use in humans, continuous glucose measurement in rodent models has been technically difficult Since any stress such as restraint or anaesthesia tends to increase blood glucose in rodent models[11], a method for measuring the long-term continuous glycaemic profile under unrestrained and conscious conditions was needed. We show that ipragliflozin, a SGLT inhibitor, time-dependently affects behaviour and enhances energy expenditure in normal Wistar and type 2 diabetic Goto–Kakizaki (GK) rats using continuous glucose telemetry, which is a newly-established technology for continuous glucose monitoring[12]
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