Clozapine Induced Disturbances in Hepatic Glucose Metabolism: The Potential Role of PGRMC1 Signaling

Newly emerging evidence has implicated that progesterone receptor component 1 (PGRMC1) plays a novel role not only in the lipid disturbance induced by atypical antipsychotic drugs (AAPD) but also in the deterioration of glucose homoeostasis induced by clozapine (CLZ) treatment. The present study aimed to investigate the role of PGRMC1 signaling on hepatic gluconeogenesis and glycogenesis in male rats following CLZ treatment (20 mg/kg daily for 4 weeks). Recombinant adeno-associated viruses (AAV) were constructed for the knockdown or overexpression of hepatic PGRMC1. Meanwhile, AG205, the specific inhibitor of PGRMC1 was also used for functional validation of PGRMC1. Hepatic protein expressions were measured by western blotting. Meanwhile, plasma glucose, insulin and glucagon, HbA1c and hepatic glycogen were also determined by assay kits. Additionally, concentrations of progesterone (PROG) in plasma, liver and adrenal gland were measured by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Our study demonstrated that CLZ promoted the process of gluconeogenesis and repressed glycogenesis, respectively mediated by PI3K-Akt-FOXO1 and GSK3β signaling via inhibition of PGRMC1-EGFR/GLP1R in rat liver, along with an increase in fasting blood glucose, HbA1c levels and a decrease in insulin and hepatic glycogen levels. Furthermore, through PGRMC1-EGFR/GLP1R-PI3K-Akt pathway, knockdown or inhibition (by AG205) of PGRMC1 mimics, whereas its overexpression moderately alleviates CLZ-induced glucose disturbances. Potentially, the PGRMC1 target may be regarded as a novel therapeutic strategy for AAPD-induced hepatic glucose metabolism disorder.

The Association of Fried Meat Consumption With the Gut Microbiota and Fecal Metabolites and Its Impact on Glucose Homoeostasis, Intestinal Endotoxin Levels, and Systemic Inflammation: A Randomized Controlled-Feeding Trial

<b>Objective</b> <div><p>This randomized controlled-feeding trial aimed to determine the impact of fried meat intake on the gut-microbiota and fecal cometabolites and whether such impacts influenced host glucose homoeostasis, intestinal endotoxin levels and systemic inflammation.</p> <p><b>Methods</b></p> <p>117 overweight adults were randomized into two groups. Fifty-nine participants were provided fried meat 4 times per-week, and fifty-eight participants were restricted from fried meat intake, while holding food group and nutrient compositions constant, for 4 weeks. The gut-microbiota was analyzed by 16S rRNA sequencing. Glucose and insulin concentrations at 0, 30, 60 and 120 min of an oral glucose tolerance test(OGTT), fecal microbiota-host cometabolite levels, and intestinal endotoxin and inflammation serum biomarker levels were measured. The area under the curve (AUC) for insulin, <a>insulinogenic</a>-index(IGI) and <a>muscle insulin resistance index</a>(MIRI) were calculated.</p> <p><b>Results</b></p> <p>The participants who consumed fried meat had lower IGI values than the controls, but they had higher MIRI and AUC values of insulin and lipopolysaccharide, TNF-α, IL-10 and IL-2 levels(<i>P</i><0.05). Fried meat intake lowered microbial community richness and decreased <i>Lachnospiraceae</i> and <i>Flavonifractor</i> abundances while increasing <i>Dialister</i>, <i>Dorea </i>and <i>Veillonella</i> abundances(<i>P</i>-FDR<0.05), provoking a significant shift in the fecal cometabolite profile, with lower 3-indolepropionic acid, valeric acid and butyric acid concentrations and higher carnitine and methylglutaric acid concentrations(<i>P</i>-FDR<0.05). Changes in these cometabolite levels were significantly associated with changes in IGI and MIRI values and lipopolysaccharide, FGF21, TNF-α, IL-2 and IL-10 levels(<i>P</i><0.05).</p> <p><b>Conclusions</b></p> <p>Fried meat intake impaired glucose homoeostasis and increased intestinal endotoxin and systemic inflammation levels by influencing the gut-microbiota and microbial-host cometabolites. </p></div>

The Association of Fried Meat Consumption With the Gut Microbiota and Fecal Metabolites and Its Impact on Glucose Homoeostasis, Intestinal Endotoxin Levels, and Systemic Inflammation: A Randomized Controlled-Feeding Trial

<b>Objective</b> <div><p>This randomized controlled-feeding trial aimed to determine the impact of fried meat intake on the gut-microbiota and fecal cometabolites and whether such impacts influenced host glucose homoeostasis, intestinal endotoxin levels and systemic inflammation.</p> <p><b>Methods</b></p> <p>117 overweight adults were randomized into two groups. Fifty-nine participants were provided fried meat 4 times per-week, and fifty-eight participants were restricted from fried meat intake, while holding food group and nutrient compositions constant, for 4 weeks. The gut-microbiota was analyzed by 16S rRNA sequencing. Glucose and insulin concentrations at 0, 30, 60 and 120 min of an oral glucose tolerance test(OGTT), fecal microbiota-host cometabolite levels, and intestinal endotoxin and inflammation serum biomarker levels were measured. The area under the curve (AUC) for insulin, <a>insulinogenic</a>-index(IGI) and <a>muscle insulin resistance index</a>(MIRI) were calculated.</p> <p><b>Results</b></p> <p>The participants who consumed fried meat had lower IGI values than the controls, but they had higher MIRI and AUC values of insulin and lipopolysaccharide, TNF-α, IL-10 and IL-2 levels(<i>P</i><0.05). Fried meat intake lowered microbial community richness and decreased <i>Lachnospiraceae</i> and <i>Flavonifractor</i> abundances while increasing <i>Dialister</i>, <i>Dorea </i>and <i>Veillonella</i> abundances(<i>P</i>-FDR<0.05), provoking a significant shift in the fecal cometabolite profile, with lower 3-indolepropionic acid, valeric acid and butyric acid concentrations and higher carnitine and methylglutaric acid concentrations(<i>P</i>-FDR<0.05). Changes in these cometabolite levels were significantly associated with changes in IGI and MIRI values and lipopolysaccharide, FGF21, TNF-α, IL-2 and IL-10 levels(<i>P</i><0.05).</p> <p><b>Conclusions</b></p> <p>Fried meat intake impaired glucose homoeostasis and increased intestinal endotoxin and systemic inflammation levels by influencing the gut-microbiota and microbial-host cometabolites. </p></div>

Folate and vitamin B12 status: associations with maternal glucose and neonatal DNA methylation sites related to dysglycaemia, in pregnant women with obesity

Recent studies implicate maternal gestational diabetes mellitus (GDM) in differential methylation of infant DNA. Folate and vitamin B12 play a role in DNA methylation, and these vitamins may also influence GDM risk. The aims of this study were to determine folate and vitamin B12 status in obese pregnant women and investigate associations between folate and vitamin B12 status, maternal dysglycaemia and neonatal DNA methylation at cytosine-phosphate-guanine sites previously observed to be associated with dysglycaemia. Obese pregnant women who participated in the UK Pregnancies Better Eating and Activity Trial were included. Serum folate and vitamin B12 were measured at the oral glucose tolerance test (OGTT) visit. Cord blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. Regression models with adjustment for confounders were used to examine associations. Of the 951 women included, 356 (37.4%) were vitamin B12 deficient, and 44 (4.6%) were folate deficient. Two-hundred and seventy-one women (28%) developed GDM. Folate and vitamin B12 concentrations were not associated with neonatal DNA methylation. Higher folate was positively associated with 1-h plasma glucose after OGTT (β = 0.031, 95% CI 0.001–0.061, p = 0.045). There was no relationship between vitamin B12 and glucose concentrations post OGTT or between folate or vitamin B12 and GDM. In summary, we found no evidence to link folate and vitamin B12 status with the differential methylation of neonatal DNA previously observed in association with dysglycaemia. We add to the evidence that folate status may be related to maternal glucose homoeostasis although replication in other maternal cohorts is required for validation.

Renal gluconeogenesis: an underestimated role of the kidney in systemic glucose metabolism

Glucose levels are tightly regulated at all times. Gluconeogenesis is the metabolic pathway dedicated to glucose synthesis from non-hexose precursors. Gluconeogenesis is critical for glucose homoeostasis, particularly during fasting or stress conditions. The renal contribution to systemic gluconeogenesis is increasingly recognized. During the post-absorptive phase, the kidney accounts for ∼40% of endogenous gluconeogenesis, occurring mainly in the kidney proximal tubule. The main substrate for renal gluconeogenesis is lactate and the process is regulated by insulin and cellular glucose levels, but also by acidosis and stress hormones. The kidney thus plays an important role in the maintenance of glucose and lactate homoeostasis during stress conditions. The impact of acute and chronic kidney disease and proximal tubular injury on gluconeogenesis is not well studied. Recent evidence shows that in both experimental and clinical acute kidney injury, impaired renal gluconeogenesis could significantly participate in systemic metabolic disturbance and thus alter the prognosis. This review summarizes the biochemistry of gluconeogenesis, the current knowledge of kidney gluconeogenesis, its modifications in kidney disease and the clinical relevance of this fundamental biological process in human biology.