Aims The aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase‐4 inhibitors (DPP‐4i), glucagon‐like peptide‐1 receptor agonists (GLP‐1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add‐on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model‐based meta‐analysis (MBMA). Methods A systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)‐ and haemoglobin A1c (HbA1c)‐lowering effects of three antidiabetic classes using NONMEM 7.3.0. Results Seventy‐six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add‐on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (−22.5 and −16.6%), liraglutide (−22.1 and −16.3%), and dulaglutide (−19.3 and −14.3%). The hypoglycaemic effects of DPP‐4i and SGLT2i were similar. Conclusions Once weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long‐acting GLP‐1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy.

The effects of hypoxia (10% O2) on the thermosensitivities of preoptic neurons were studied in urethanized rats and compared to the effects of hypercapnia (10% CO2). This was examined by regression of neuronal activity on preoptic temperature. During hypoxia, the slope of the regression line increased significantly in 8 (23%) of 35 warm-sensitive neurons and decreased in eight other neurons (P less than 0.05). During hypercapnia, the slope of the regression line decreased significantly in 7 (30%) of the 23 warm-sensitive neurons (P less than 0.05). No neuron was found that significantly increased the slope of the regression line. The effects of hypoxia on thermosensitivities (i.e. the slope of the regression line) of PO neurons differed from those of hypercapnia in chi-square analysis (P less than 0.05). Responses of the cold-sensitive neurons to hypoxia or hypercapnia did not generally differ from those of the warm-sensitive neurons. During hypoxia and hypercapnia, arterial blood pressure, respiratory frequency, heart rate, and EEG were recorded to examine their relations to neuronal activity. The present results indicate that the thermosensitivities of preoptic neurons are modified by both hypoxia and hypercapnia, but that hypoxic differ from hypercapnic effects.

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The effects of inspired CO2 on preoptic thermosensitive neurons were studied in urethanized rats. Most of the neurons changed their activities diversely while the rat breathed 4%, 7%, and 10% CO2 gas mixtures. Half of the neurons increased activity during CO2 inhalation, but activity was not necessarily intensified by elevating CO2 concentration. Thermosensitive neurons tended to increase activity more than thermally insensitive neurons. The effect of CO2 on sensitivity of thermosensitive neurons was also examined by regression of neuronal activity on preoptic temperature. The slopes of the regression lines during CO2 inhalation did not differ significantly from those during air inhalation in either warm-sensitive or cold-sensitive neurons, but CO2 did elevate the intercepts in most instances (P less than 0.01). However, if P less than 0.05 is accepted as a significance level, the slopes of the regression lines for warm-sensitive neurons tended to decrease during CO2 inhalation (9/39 pairs). The present results indicate that preoptic thermosensitive neurons generally increase their activities and modify their thermosensitivities during CO2 inhalation.

The purpose of this study was to see if the responses of thermosensitive neurons in the preoptic (PO) area to inspired CO2 seen in spontaneously ventilated rats were indirectly driven by reflexive changes in respiration and circulation. In urethanized, paralyzed, and artificially ventilated (AV) rats, the effects of 10% CO2 inhalation on PO thermosensitive neurons were examined by regression of neuronal activity on PO temperature. The experiments were made in intact rats and in rats whose peripheral chemo- and baro-receptors were denervated (AVD). In both AV and AVD rats, the slope of the regression line decreased significantly (P less than 0.05) during CO2 inhalation in half of the warm-sensitive neurons studied (64.3% in AV rats, 41.7% in AVD rats). Peripheral chemo- and baro-receptors thus do not appear to be responsible for decreased thermosensitivities of warm-sensitive neurons during CO2 inhalation. The tendency for activities of warm-sensitive neurons to increase progressively at lower Tpo was seen during CO2 inhalation in both AV and AVD rats. However, the average differences in mean firing rate between 10% CO2 and air inhalations were 2-3 imp/s greater at any Tpo in AV rats than in AVD rats. In AVD rats, warm-sensitive neurons were rather inhibited by CO2 at higher Tpo. Excitation of warm-sensitive neurons during CO2 inhalation in AV rats, which was independent of Tpo, was considered to be caused by the signals from peripheral receptors.