Abstract
BackgroundRegulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM).MethodsTwelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation.ResultsWe found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded.ConclusionsThese results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation.Trial registrationClinicalTrials.gov NCT02727790
Highlights
Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic hyperglycemia
We found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02)
These results indicate that repeated peripheral electrical stimulation (PES) treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production
Summary
Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic hyperglycemia. Gene expression of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), is hormonally upregulated by glucagon and by glucocorticoids, and is downregulated by insulin under fed conditions [6]. In addition to this direct hepatic action, central-mediated, neuroendocrine, mechanisms are involved in the regulation of gluconeogenesis. (i) Hypothalamic-hepatic axis–Gluconeogenesis is being affected through direct hepatic innervation by both the sympathetic system, through the splanchnic nerve, and the parasympathetic system, through the vagal nerve [7, 8] These pathways are stimulated by the ventromedial and the lateral hypothalamic areas respectively. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM)
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