Constitutive Modeling of Annealed OFHC with Wide Strain-Rate and Temperature Effects: Incorporating Dislocation Dynamics and Normalized Microstructural Size Evolution.

The flow stress of face-centered cubic (FCC) metals exhibits a rapid increase near a strain rate of 104 s-1 under fixed-strain conditions. However, many existing constitutive models either fail to capture the mechanical characteristics of this plastic deformation or use piecewise strain-rate hardening models to describe this phenomenon. Unfortunately, these piecewise models may suffer from issues such as discontinuity of physical quantities and difficulties in determining segment markers, and struggle to reflect the underlying physical mechanisms that give rise to this mutation phenomenon. In light of this, this paper proposes that the abrupt change in flow stress sensitivity to strain rate in FCC metals can be attributed to microstructural evolution characteristics. To address this, a continuous semiempirical physical constitutive model for FCC metals is established based on the microstructural size evolution proposed by Molinari and Ravichandran and the dislocation motion slip mechanism. This model effectively describes the mutation behavior of strain-rate sensitivity under fixed strain, particularly evident in an annealed OFHC. The predicted results of the model across a wide range of strain rates (10-4-106 s-1) and temperatures (77-1096 K) demonstrate relative errors generally within ±10% of the experimental values. Furthermore, the model is compared with five other models, including the mechanical threshold stress (MTS), Nemat-Nasser-Li (NNL), Preston-Tonks-Wallace (PTW), Johnson-Cook (JC), and Molinari-Ravichandran (MR) models. A comprehensive illustration of errors reveals that the proposed model outperforms the other five models in describing the plastic deformation behavior of OFHC. The error results offer valuable insights for selecting appropriate models for engineering applications and provide significant contributions to the field.

Effects of treatment with Glucagon-like peptide-1 receptor agonist on prediabetes with overweight/obesity: A systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the effects of Glucagon-like peptide-1 receptor agonist (GLP-1RA) on prediabetes with overweight/obesity. METHODS: A search of PubMed, Embase, Cochrane Library, and Web of Science databases was performed to identify randomised controlled trials (up to 4 July 2022) which evaluated the effect of GLP-1RA on prediabetes with overweight/obesity. RESULTS: Eight hundred and nine articles were retrieved (80 from PubMed, 481 from Embase, 137 from Cochrane library, and 111 from Web of Science) and a total of 5 articles were included in this meta-analysis. More individuals in GLP-1RAs group regressed from prediabetes to normoglycemia than individuals in the placebo group (OR = 4.56, 95% CI:3.58, 5.80, P = 0.004); fewer individuals in GLP-1RAs group were diagnosed with diabetes than those in the placebo group (OR = 0.31, 95% CI:0.12,0.81, P = 0.017). Results from five studies showed that GLP-1RAs significantly reduced fasting glucose (mean difference = -0.41 mmol/L, 95% CI: -0.58, -0.25, P < 0.00001), with an acceptable heterogeneity (I2  = 42%). CONCLUSIONS: The present meta-analysis suggested that GLP-1RA significantly improves glucose metabolism, reduces systolic blood pressure and body weight in prediabetes with overweight/obesity. It could also prevent the development of diabetes and reverse abnormal glucose metabolism.

Research on non-cohesive jet formed by Zr-based amorphous alloys.

The shaped charge jet formation of a Zr-based amorphous alloy and the applicability of different numerical algorithms to describe the jet formed were experimentally and numerically investigated. X-ray experiments were performed to study jet characteristics. The numerical results for the Zr-based amorphous alloy jet formed via the Euler and smooth particle hydrodynamics (SPH) algorithms were compared and analyzed using the Autodyn hydrocode. Particle motion was examined based on material properties. The Zr-based amorphous alloy formed a noncohesive jet driven by an 8701 explosive. Both the Euler and SPH algorithms achieved high accuracy for the determination of jet velocity. When the improved Johnson-Holmquist constitutive model (JH-2) was used, numerical results confirmed the model's suitability for the Zr-based amorphous alloy. The Euler algorithm effectively reflected jet shape within a short computing time, whereas the SPH algorithm was highly suitable for showing the shape of the jet tail within a long computing time. In the 3D Euler model, the flared jet mouth indicated radial particle dispersion; however, in the 2D model, particle dispersion in the head was directly observed by using the JH-2 material model. The brittle fracture of the material reduced the proportion of particles near the liner apex forming a jet. Furthermore, a new method in which stagnation pressure was used to predict jet formation and its coherence was proposed since the collapse angle was difficult to obtain.

Research on the Formation Characteristics of the Shaped Charge Jet from the Shaped Charge with a Trapezoid Cross-Section.

The formation characteristics of the shaped charge jet (SCJ) from the shaped charge with a trapezoid cross-section is analyzed in this work. A theoretical model was developed to analyze the collapsing mechanism of the liner driven by the charge with a trapezoid cross-section. Based on the theoretical model, the axial and radial velocities of the SCJ from different trapezoid cross-section charges. The pressure model was employed to calculate the velocity for the subcaliber shaped charge, which was verified through numerical simulation. The results show that the influence of the angle of the trapezoidal charge (acute angle) on the axial velocity of the SCJ is not distinct, whereas the variation of the radial velocity of the shaped charge jet is obvious as the change in the angle of the trapezoidal charge. In addition, the related X-ray experiments were conducted to verify the theory. The theoretical results correlate with the experimental results reasonably well.

Current Advances in 3D Dynamic Cell Culture Systems.

The traditional two-dimensional (2D) cell culture methods have a long history of mimicking in vivo cell growth. However, these methods cannot fully represent physiological conditions, which lack two major indexes of the in vivo environment; one is a three-dimensional 3D cell environment, and the other is mechanical stimulation; therefore, they are incapable of replicating the essential cellular communications between cell to cell, cell to the extracellular matrix, and cellular responses to dynamic mechanical stimulation in a physiological condition of body movement and blood flow. To solve these problems and challenges, 3D cell carriers have been gradually developed to provide a 3D matrix-like structure for cell attachment, proliferation, differentiation, and communication in static and dynamic culture conditions. 3D cell carriers in dynamic culture systems could primarily provide different mechanical stimulations which further mimic the real in vivo microenvironment. In this review, the current advances in 3D dynamic cell culture approaches have been introduced, with their advantages and disadvantages being discussed in comparison to traditional 2D cell culture in static conditions.

Formation and Penetration Properties of a Shaped Charge with Zr41.2Ti13.8Cu12.5Ni10Be22.5 Liner.

In the military field, determining how to increase the hole-expanding ability of shaped charge warheads is a key and difficult issue with respect to warhead development. Amorphous alloys have grains or grain boundaries, with unique mechanical properties. Zr41.2Ti13.8Cu12.5Ni10Be22.5 can be used as the liner material of shaped charges, resulting in high-speed particle flows that differ from those of traditionally shaped charges. In this paper, based on the analysis of the mechanical response characteristics of Zr41.2Ti13.8Cu12.5Ni10Be22.5 and its fracture morphology under impact, combined with the formation theory of shaped charge jets, a semi-empirical formula is derived to calculate the velocity of non-cohesive high-speed particle flow considering the elastic strain energy loss. Additionally, the reliability of the proposed theoretical model is verified through experiments. The penetration process of Zr-based amorphous alloy high-speed particle flow into a concrete target is theoretically analyzed, and the penetration stages of the high-speed particle flow into the target are clearly distinguished. Combined with the penetration theory of shaped charge particle jets, a high-speed particle flow penetration model is proposed, and a pore expansion model is established through an energy method. The experimentally obtained data on depth of penetration are in agreement with the theoretical calculation results.

Influence Mechanism of Foamed Concrete Coating Thickness on the Blast Resistance of RC Walls.

How to effectively reduce the damage of frequent accidental explosions and explosion attacks to existing walls is an important concern of the blast resistance field. In the present study, the influence of the foamed concrete (density 820 kg/m3, water-cement ratio 0.4) coating thickness on the blast resistance of a 120 mm RC (reinforced concrete) wall was studied through blast experiments, numerical simulations, and shock wave theory. Results show that the influences of foamed concrete on the blast resistance of RC walls are jointly decided by the stress drop caused by impedance effect and exponential attenuation and the stress rise caused by high-speed impact compression. The coating thickness mainly affects the foam concrete's fragmentation degree and stress attenuation. A lower critical coating thickness exists in foamed concrete-coated RC walls. The blast resistance of the RC wall will decrease when the coating thickness is less than that value. The lower critical coating thickness is related to the intensity of blast load and the energy absorption capacity of foamed concrete, and it can be predicted by monitoring the explosive stress and energy incident to the RC wall.

The Modulatory Role of Growth Hormone in Inflammation and Macrophage Activation.

Inflammation is a body's response to remove harmful stimuli and heal tissue damage, which is involved in various physiology and pathophysiology conditions. If dysregulated, inflammation may lead to significant negative impacts. Growth hormone (GH) has been shown responsible for not only body growth but also critical in the modulation of inflammation. In this review, we summarize the current clinical and animal studies about the complex and critical role of GH in inflammation. Briefly, GH excess or deficiency may lead to pathological inflammatory status. In inflammatory diseases, GH may serve as an inflammatory modulator to control the disease progression and promote disease resolution. The detailed mechanisms and signaling pathways of GH on inflammation, with a focus on the modulation of macrophage polarization, are carefully discussed with potential direction for future investigations.

Dapagliflozin partially restores reproductive function in MC4R KO obese female mice.

Obese women often have certain degree of reproductive dysfunction with infertility. Although the clinical impact of obesity on female infertility has been extensively studied, the effective and targeted treatment is still lacking. Melanocortin-4-receptor knock-out (MC4R KO) mouse is an over-eating obese model with hyperphagia, hyperinsulinemia, reduced growth hormone (GH), and insulin resistance. Dapagliflozin improved the metabolic and hormonal parameters in MC4R KO mice. MC4R KO female mice were treated with dapagliflozin for 14 weeks from 14-week age. Age-matched WT littermates and non-treated MC4R KO mice were used as control groups. Food intake was measured daily. Body weight was measured twice a week. Estrous cycles, GH, and luteinizing hormone (LH) profiles were measured. Selected tissues were collected at the end of experiments for gene expression profiles and hematoxylin-eosin staining. Regularity and mode of hormonal profiles were restored by the dapagliflozin treatment. Estrous cycle was partially normalized, number of CL was significantly increased, and the expression of Kiss1 and Gnrh1 in the hypothalamus and LH in the pituitary was markedly increased by the dapagliflozin treatment. It is conclsuded that dapagliflozin may recover LH and GH profiles partially through modification of relevant gene expression in the hypothalamus and pituitary, and result in an improved ovulation rate in obese mouse model. Dapagliflozin may therefore improve fertility in obese patients.

Time-Restricted Feeding Restored Insulin-Growth Hormone Balance and Improved Substrate and Energy Metabolism in MC4RKO Obese Mice.

BACKGROUND: Dysregulation of metabolic regulatory hormones often occurs during the progress of obesity. Key regulatory hormone insulin-growth hormone (GH) balance has recently been proposed to maintain metabolism profiles. Time-restricted feeding (TRF) is an effective strategy against obesity without detailed research on pulsatile GH releasing patterns. METHODS: TRF was performed in an over-eating melanocortin 4 receptor-knockout (MC4RKO) obese mouse model using normal food. Body weight and food intake were measured. Series of blood samples were collected for 6-h pulsatile GH profile, glucose tolerance test, and insulin tolerance test at 5, 8, and 9 weeks of TRF, respectively. Indirect calorimetric recordings were performed by the Phenomaster system at 6 weeks for 1 week, and body composition was measured by nuclear magnetic resonance spectroscopy (NMR). Substrate- and energy metabolism-related gene expressions were measured in terminal liver and subcutaneous white adipose tissues. RESULTS: TRF increased pulsatile GH secretion in dark phase and suppressed hyperinsulinemia in MC4RKO obese mice to reach a reduced insulin/GH ratio. This was accompanied by the improvement in insulin sensitivity, metabolic flexibility, glucose tolerance, and decreased glucose fluctuation, together with appropriate modification of gene expression involved in substrate metabolism and adipose tissue browning. NMR measurement showed that TRF decreased fat mass but increased lean mass. Indirect calorimeter recording indicated that TRF decreased the respiratory exchange ratio (RER) reflecting consumption of more fatty acid in energy production in light phase and increased the oxygen consumption during activities in dark phase. CONCLUSIONS: TRF effectively decreases hyperinsulinemia and restores pulsatile GH secretion in the overeating obese mice with significant improvement in substrate and energy metabolism and body composition without reducing total caloric intake.

Rotating Day and Night Disturb Growth Hormone Secretion Profiles, Body Energy Metabolism, and Insulin Levels in Mice.

BACKGROUND: Insulin and growth hormone (GH) - 2 vital metabolic regulatory hormones - regulate glucose, lipid, and energy metabolism. These 2 hormones determine substrate and energy metabolism under different living conditions. Shift of day and night affects the clock system and metabolism probably through altered insulin and GH secretion. METHODS: Five-week-old male mice were randomly assigned to a rotating light (RL) group (3-day normal light/dark cycle followed by 4-day reversed light/dark cycle per week) and normal light (NL) group. Body weight and food intake were recorded every week. Series of blood samples were collected for pulsatile GH analysis, glucose tolerance test, and insulin tolerance test at 9, 10, and 11 weeks from the start of intervention, respectively. Indirect calorimetric measurement was performed, and body composition was tested at 12 weeks. Expressions of energy and substrate metabolism-related genes were evaluated in pituitary and liver tissues at the end of 12-week intervention. RESULTS: The RL group had an increased number of GH pulsatile bursts and reduced GH mass/burst. RL also disturbed the GH secretion regularity and mode. It suppressed insulin secretion, which led to a disturbed insulin/GH balance. It was accompanied by the reduced metabolic flexibility and modified gene expression involved in energy balance and substrate metabolism. Indirect calorimeter recording revealed that RL decreased the respiratory exchange ratio (RER) and oxygen consumption at the dark phase, which resulted in an increase in fat mass and free fatty acid levels in circulation. CONCLUSION: RL disturbed pulsatile GH secretion and decreased insulin secretion in male mice with significant impairment in energy, substrate metabolism, and body composition.

The GH-IGF-1 Axis in Circadian Rhythm.

Organisms have developed common behavioral and physiological adaptations to the influence of the day/night cycle. The CLOCK system forms an internal circadian rhythm in the suprachiasmatic nucleus (SCN) during light/dark input. The SCN may synchronize the growth hormone (GH) secretion rhythm with the dimming cycle through somatostatin neurons, and the change of the clock system may be related to the pulsatile release of GH. The GH-insulin-like growth factor 1 (IGF-1) axis and clock system may interact further on the metabolism through regulatory pathways in peripheral organs. We have summarized the current clinical and animal evidence on the interaction of clock systems with the GH-IGF-1 axis and discussed their effects on metabolism.

LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity.

Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin's effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin's activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2's anti-obesity potential. In this review, we will analyze LEAP-2's effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2's potential as a promising therapeutic target for obesity.

Suppression of hyperinsulinemia restores growth hormone secretion and metabolism in obese mice.

The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High insulin and low GH levels are often observed in obesity, contributing to reduced energy expenditure and further fat accumulation. Although suppression of hyperinsulinemia is proposed as a treatment for obesity, changes in GH secretion and energy metabolism following this treatment are not thoroughly studied. This leaves unexplained observations, such as unchanged lean mass following insulin reduction. In this study, high-fat diet-induced obese (DIO) and normal chow-fed lean mice on a C57BL/6J background were treated for 7 weeks with diazoxide (1250 mg/kg in food), a KATP channel opener that suppressed insulin secretion. Diazoxide treatment for 10 days was sufficient to increase pulsatile GH secretion in DIO mice before any significant body weight change. The restored insulin-GH balance in DIO mice was followed by improvement in substrate and energy metabolism in a prolonged treatment period (4-6 weeks), including reduced fat mass, increased lipid oxidation and energy expenditure, as well as improved insulin sensitivity and metabolic flexibility. These metabolic benefits occurred along with the changes in the expression level of genes regulated by the insulin-GH balance. When applying diazoxide to normal chow-fed normoinsulinemic lean mice, none of the above metabolic effects was observed, suggesting that the metabolic changes following diazoxide treatment were mediated through the suppression of hyperinsulinemia. These results suggest that suppression of hyperinsulinemia by diazoxide restores GH secretion and improves substrate and energy metabolism in DIO mice.

Knockdown of microRNA-203 reduces cisplatin chemo-sensitivity to osteosarcoma cell lines MG63 and U2OS in vitro by targeting RUNX2.

Clinical studies have reported that miRNAs abnormal expression are associated with the generation of cisplatin-resistant to osteosarcoma. Our previous research found that miR-203 is downregulated in osteosarcoma cells and overexpressed miR-203 exerts antitumor properties on osteosarcoma cells. However, the role and mechanism of miR-203 in regulating the sensitivity of cisplatin in osteosarcoma cells remains unclear. This study aimed to investigate the effects of miR-203 in cisplatin therapy for osteosarcoma cells in vitro and determined the underlying mechanism. In this study, we found that miR-203 was significantly upregulated in osteosarcoma cells after exposure to cisplatin. miR-203 knockdown reduced the sensitivity of osteosarcoma cells to cisplatin by suppressing cell apoptosis, cell cycle arrest, and inducing invasion. Meanwhile, we found that miR-203 knockdown reduces the therapeutic sensitivity of osteosarcoma cells by upregulating RUNX2. Moreover, we found that RUNX2 silencing sensitizes osteosarcoma cells to chemotherapy treatment of cisplatin. In summary, our findings demonstrated that miR-203 knockdown reduces cisplatin chemo-sensitivity to osteosarcoma cells in vitro by targeting RUNX2, and speculated that miR-203 may be a target for drug resistance of osteosarcoma to cisplatin.

Stimulation of endogenous pulsatile growth hormone secretion by activation of growth hormone secretagogue receptor reduces the fat accumulation and improves the insulin sensitivity in obese mice.

Obese individuals often show low growth hormone (GH) secretion, which leads to reduced lipid mobilization and further fat accumulation. Pharmacological approaches to increase GH levels in obese individuals by GH injection or GH-releasing hormone receptor agonist showed promising effects on fat reduction. However, side effects on glucose metabolism and the heavy costs on making large peptides hindered their clinical application. Here, we tested whether stimulation of endogenous GH secretion by a synthetic GH secretagogue receptor (GHSR) agonist, hexarelin, improved the metabolism in a hyperphagic obese mouse model. Male melanocortin 4 receptor knockout mice (MC4RKO) were pair-fed and received continuous hexarelin (10.56 µg/day) or vehicle infusion by an osmotic pump for 3-4 weeks. Hexarelin treatment significantly increased the pulsatile GH secretion without detectable alteration on basal GH secretion in MC4RKO mice. The treated mice showed increased lipolysis and lipid oxidation in the adipose tissue, and reduced de novo lipogenesis in the liver, leading to reduced visceral fat mass, reduced triglyceride content in liver, and unchanged circulating free fatty acid levels. Importantly, hexarelin treatment improved the whole-body insulin sensitivity but did not alter glucose tolerance, insulin levels, or insulin-like growth factor 1 (IGF-1) levels. The metabolic effects of hexarelin were likely through the direct action of GH, as indicated by the increased expression level of genes involved in GH signaling pathways in visceral adipose tissues and liver. In conclusion, hexarelin treatment stimulated the pulsatile GH secretion and reduced the fat accumulation in visceral depots and liver in obese MC4RKO mice with improved insulin sensitivity without altered levels of insulin or IGF-1. It provides evidence for managing obesity by enhancing pulsatile GH secretion through activation of GHSR in the pituitary gland.

Compressive Behavior of (Cu0.47Zr0.45Al0.08)98Dy2 Bulk Metallic Glass at Different Strain Rates.

The mechanical properties of (Cu0.47Zr0.45Al0.08)98Dy2 bulk metallic glass (BMG) were characterized under various strain rates by quasi-static and dynamic compressive tests. In the quasi-static compressive tests, the yield stress of (Cu0.47Zr0.45Al0.08)98Dy2 BMG increased from 1234 MPa to 1844 MPa when the strain rate was increased from 0.001 s-1 to 0.01 s-1, and the yield stress decreased to 1430 MPa at the strain rate of 0.1 s-1. In the dynamic compressive tests, when the strain rate increased from 1550 s-1 to 2990 s-1, the yield stress of (Cu0.47Zr0.45Al0.08)98Dy2 BMG first decreased from 1508 MPa to 1404 MPa, and then increased to 1593 MPa. The fracture behaviors of (Cu0.47Zr0.45Al0.08)98Dy2 BMG were studied by using scanning electron microscopy to examine the fracture surface. Fracture occurred in the pure shear mode with strain rates below 2100 s-1, whereas shear fracture and normal fracture occurred simultaneously under strain rates of 2650 s-1 and 2990 s-1.

Suppression of Insulin Secretion in the Treatment of Obesity: A Systematic Review and Meta-Analysis.

OBJECTIVE: This proof-of-concept study aimed to evaluate the efficacy and safety of suppression of insulin secretion in the treatment of obesity. METHODS: A search of PubMed, Embase, and Cochrane databases was performed to identify randomized controlled trials (up to January 1, 2020) that used drugs that directly suppress insulin secretion (diazoxide or octreotide) in the treatment of obesity. The extracted data were analyzed using random-effects meta-analysis. RESULTS: A total of seven randomized controlled trials were included, with four using diazoxide and three using octreotide to suppress insulin secretion. Suppression of insulin secretion significantly reduced fasting insulin level (mean difference: -3.94 mIU/L; 95% CI: -7.40 to -0.47) but slightly increased fasting blood glucose level (mean difference: 0.48 mmol/L; 95% CI: 0.24 to 0.72). Following the suppression of insulin secretion, significant reductions in body weight (mean difference: -3.19 kg; 95% CI: -5.71 to -0.66), BMI (mean difference: -1.65 kg/m2 ; 95% CI: -2.41 to -0.90), and fat mass (mean difference: -5.92 kg; 95% CI: -8.28 to -3.56) were observed compared with placebo in the pooled data. No significant difference in fat-free mass was observed (mean difference: 0.56 kg; 95% CI: -0.40 to 1.52). CONCLUSIONS: Results suggest that suppression of insulin secretion may lead to reduced body weight and fat mass with slightly increased blood glucose in individuals with obesity.

Insulin and Growth Hormone Balance: Implications for Obesity.

Disruption of endocrine hormonal balance (i.e., increased levels of insulin, and reduced levels of growth hormone, GH) often occurs in pre-obesity and obesity. Using distinct intracellular signaling pathways to control cell and body metabolism, GH and insulin also regulate each other's secretion to maintain overall metabolic homeostasis. Therefore, a comprehensive understanding of insulin and GH balance is essential for understanding endocrine hormonal contributions to energy storage and utilization. In this review we summarize the actions of, and interactions between, insulin and GH at the cellular level, and highlight the association between the insulin/GH ratio and energy metabolism, as well as fat accumulation. Use of the [insulin]:[GH] ratio as a biomarker for predicting the development of obesity is proposed.

Dapagliflozin restores insulin and growth hormone secretion in obese mice.

The well-documented hormonal disturbance in a general obese population is characterised by an increase in insulin secretion and a decrease in growth hormone (GH) secretion. Such hormonal disturbance promotes an increase in fat mass, which deteriorates obesity and accelerates the development of insulin resistance and type 2 diabetes. While the pathological consequence is alarming, the pharmaceutical approach attempting to correct such hormonal disturbance remains limited. By applying an emerging anti-diabetic drug, the sodium-glucose cotransporter 2 inhibitor, dapagliflozin (1 mg/kg/day for 10 weeks), to a hyperphagic obese mouse model, we observed a significant improvement in insulin and GH secretion as early as 4 weeks after the initiation of the treatment. Restoration of pathological disturbance of insulin and GH secretion reduced fat accumulation and preserved lean body mass in the obese animal model. Such phenotypic improvement followed with concurrent improvements in glucose and lipid metabolism, insulin sensitivity, as well as the expression of metabolic genes that were regulated by insulin and GH. In conclusion, 10 weeks of treatment with dapagliflozin effectively reduces hyperinsulinemia and restores pulsatile GH secretion in the hyperphagic obese mice with considerable improvement in lipid and glucose metabolism. Promising outcomes from this study may provide insights into drug intervention to correct hormonal disturbance in obesity to delay the diabetes progression.