Clearance Rate Of Glucose Research Articles

DNAJB3 Deficiency Exacerbates Diet-Induced Obesity and Insulin Resistance

ObjectivesThe prevalence of obesity and Type 2 Diabetes (T2D) continues to rise worldwide, leading to many other chronic diseases and imposing a large economic burden. DNAJ, also known as HSP40 (Heat Shock Protein-40), subfamily B, member 3 (DNAJB3), is a chaperone protein that can be induced under various stressors. Recent reports implicated DNAJB3 in protection against obesity and T2D. Specifically, DNAJB3 was downregulated in some patients with obesity and T2D; however, precise underlying mechanisms remained unclear. We hypothesized that lack of DNAJB3 will increase body weight and body fat, inflammation, glucose intolerance and insulin resistance in diet-induced obese mice, compared to B6 wild type (WT) littermates fed the same diets. MethodsThree DNAJB3 knockout (KO) mutant lines were generated at the Pennington Biomedical Research Center (KO 30, 44 and 47). Male and female KO and wild type (WT) littermates were fed a high fat diet (45% kcal fat) for 12 weeks. Body weight and composition were measured weekly, and a glucose tolerance test (GTT) was conducted. Following euthanasia, blood, adipose and muscle tissues were harvested and used for serum analyses and tissue gene/protein expression, respectively. ResultsCompared to WT, only DNAJB3 KO male and female mice of line 47 demonstrated significantly higher body weight and fat mass (P < 0.05). Similarly, line 47 also showed a lower rate of glucose clearance as measured by GTT. Consistent with increased body weight and fat mass, male mice in line 47 also exhibited significantly higher mRNA levels of inflammatory markers including TNFα and IL-1β, in gonadal fat, compared to WT and lines 30 and 44. Moreover, similar trends towards increased TNF-α and MCP-1 expression was observed in muscle tissues of KO males of line 47, when compared to WT (P < 0.47), and line 30 (P < 0.15) respectively. ConclusionsAbsence of DNAJB3, increases adiposity, glucose intolerance and inflammation in diet-induced obese mice in both males and females. these findings suggest that DNAJB3 plays an important role in metabolic functions and glucose homeostasis, which warrants further research as a potential therapeutic target for obesity and T2D. Funding SourcesFunded by Qatar National Research Funds, Hamad Bin Khalifa University & Qatar Biomedical Research Institute, Qatar.

Cost-effective low-dose streptozotocin and high-fat diet improve the type 2 diabetes mellitus rat analysis

Objective: The induction of type II diabetes mellitus (T2DM) rat model using the Sprague Dawley (SD) species is commonly performed for further laboratory experimental purposes. Various laboratory conditions or even other environments provide different outcomes in achieving the model utilising the previous protocol. Materials and Methods: We performed an experimental animal study. Researchers administered a revamped induction regimen involving a variation of a high-fat diet (HFD) with several low-dose streptozotocin injections and a glucose drink immediately after injection. Results: HFD-fed rats have demonstrated severe hyperglycaemic status, though they were further evaluated to assess their insulin sensitivity. Analysing subgroups, HFD with glucose drink indicated poor insulin sensitivity after 2 h of intraperitoneal insulin injection. Poor glucose clearance revealed insulin resistance in the rat model (P = 0.026). Different dietary courses and fasting blood glucose were found not significant, P < 0.05. Complementary glucose in HFD was much more likely to cause hyperglycaemic characteristic, although HFD alone did not indicate many discrepancies in hyperglycaemic condition χ2 (2, N = 216) =181.385, P < 0.01. The extra glucose in HFD greatly decreased glucose clearance efficiency, although HFD alone did not demonstrate a clear correlation with the glucose clearance rate, χ2 (2, N = 1003) =700.638, P < 0.01. In addition, the hyperglycaemic state was conversely correlated with insulin sensitivity (r = −0.727, P < 0.001). Conclusion: This approach provides an alternative T2DM induction technique in SD rats. The key features of T2DM, including hyperglycaemic state and insulin insensitivity, were successfully developed in the animal model.

High-fat diet activates liver iPLA2γ generating eicosanoids that mediate metabolic stress

High-fat (HF) diet–induced obesity precipitates multiple metabolic disorders including insulin resistance, glucose intolerance, oxidative stress, and inflammation, resulting in the initiation of cell death programs. Previously, we demonstrated murine germline knockout of calcium-independent phospholipase A2γ (iPLA2γ) prevented HF diet–induced weight gain, attenuated insulin resistance, and decreased mitochondrial permeability transition pore (mPTP) opening leading to alterations in bioenergetics. To gain insight into the specific roles of hepatic iPLA2γ in mitochondrial function and cell death under metabolic stress, we generated a hepatocyte-specific iPLA2γ-knockout (HEPiPLA2γKO). Using this model, we compared the effects of an HF diet on wild-type versus HEPiPLA2γKO mice in eicosanoid production and mitochondrial bioenergetics. HEPiPLA2γKO mice exhibited higher glucose clearance rates than WT controls. Importantly, HF-diet induced the accumulation of 12-hydroxyeicosatetraenoic acid (12-HETE) in WT liver which was decreased in HEPiPLA2γKO. Furthermore, HF-feeding markedly increased Ca2+ sensitivity and resistance to ADP-mediated inhibition of mPTP opening in WT mice. In contrast, ablation of iPLA2γ prevented the HF-induced hypersensitivity of mPTP opening to calcium and maintained ADP-mediated resistance to mPTP opening. Respirometry revealed that ADP-stimulated mitochondrial respiration was significantly reduced by exogenous 12-HETE. Finally, HEPiPLA2γKO hepatocytes were resistant to calcium ionophore-induced lipoxygenase-mediated lactate dehydrogenase release. Collectively, these results demonstrate that an HF diet increases iPLA2γ-mediated hepatic 12-HETE production leading to mitochondrial dysfunction and hepatic cell death.

Polylysine-bilirubin conjugates maintain functional islets and promote M2 macrophage polarization

Macrophage polarization is one of the main factors contributing to the proinflammatory milieu of transplanted islets. It causes significant islet loss. Bilirubin exhibits protective effects during the islet transplantation process, but the mode of delivering drugs along with the islet graft has not yet been developed. In addition, it remains unclear whether bilirubin or its derivatives can modulate macrophage polarization during islet transplantation. Therefore, this study aimed to develop an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets for protection and to explore its macrophage modulation activities. In in vitro studies, the PLL-BR was shown to tightly adhere to the islet surface. It also exhibited enhanced cytoprotective effects against oxidative and inflammatory conditions by promoting M2-type macrophage polarization. In in vivo studies, the PLL-BR-protected islets successfully prolonged the euglycemia period in diabetic mice and accelerated the blood glucose clearance rate by maintaining the insulin secretion function. Compared to the untreated islets, the PLL-BR-encapsulated islets induced anti-inflammatory responses that were characterized by elevated levels of M2 macrophage markers and local vascularization. In conclusion, PLL-BR can be used as a tool for reprograming macrophage polarization while providing a more efficient immune protection for transplanted islets. Statement of significanceMacrophage polarization is one main factor that caused significant loss of transplanted islets. Bilirubin possesses protective effects toward pancreatic islet, but how to deliver the drug along with the islet graft has not yet been harnessed. More importantly, whether bilirubin or its derivatives could modulate macrophage polarization during the host rejections has also not been answered. In this study, we developed an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets and explore its role in macrophage modulation activities. PLL-BR could attach to the surface of islets and exerted high oxidation resistance and anti-inflammatory effect. For the first time, we demonstrate that bilirubin and its derivatives effectively promoted the M2-type macrophage polarization, and optimize the immune microenvironment for islets survival and function.

PSI-12 Effects of supplementing propionate in a finishing diet on dry matter intake, glucose clearance, and blood metabolites

Abstract The objective of this experiment was to determine if supplementing propionate alters DMI, glucose clearance rate, and blood metabolite concentrations in steers fed a finishing diet. Holstein (n = 15) steers were individually fed a finishing diet ad-libitum. Steers were allocated by BW to receive: no Ca propionate (CON), 100 g/d (LOW), or 300 g/d (HIGH) in the diet. Orts were collected and weighed daily to determine DMI. Blood samples were collected on d 0, 7, and 21, and BW recorded on d 0, 14, and 28. A glucose tolerance test was conducted on d 14 and 28 of the trial. Samples were analyzed for whole blood glucose and lactate, and plasma NEFA. Data were analyzed using a mixed model with treatment, day and their interaction included, with day as a repeated measure. The CON treatment had greater (P &amp;lt; 0.01) DMI than LOW and HIGH. BW was greater for CON throughout the experiment and all treatments had an increased BW on day 28 (P = 0.03 for the interaction). Whole blood glucose concentrations tended (P = 0.09) to be higher on d 21 than d 0 and 7, but was not affected by treatment (P = 0.58). Plasma NEFA concentrations were lower (P = 0.05) for CON than other treatments, and greater (P = 0.002) on d 0 than d 7 and 21. Whole blood lactate concentrations were greater (P = 0.05) on d 7, than d 0 and 21, but was not effected by treatment (P = 0.13). There was no treatment (P ≥ 0.16) or day effect (P ≥ 0.36) on glucose peak, plateau, or clearance rate. These data indicate that supplemental propionate may decrease dry matter intake but might not alter glucose clearance rate.

Response to a glucose tolerance test in early-lactation Holstein cows receiving a supplementation of biotin, folic acid, and vitamin B12

The aim of the study was to evaluate glucose and insulin metabolism of cows receiving a supplementation of biotin (B8), folic acid (B9), and vitamin B12 (B12) during the transition period. According to a 2 × 2 factorial arrangement, 32 cows were randomly assigned to 9 incomplete blocks according to their previous 305-d milk yield. Within each block, cows were randomly assigned to 1 of the following levels of biotin from -27 to 28 d relative to the parturition: (1) no biotin supplement (B8-) or (2) 20 mg/d of dietary biotin (B8+). Within each level of biotin, the cows received either (1) 2-mL weekly intramuscular injections of saline 0.9% NaCl (B9B12-) or (2) 2.6 g/d of dietary folic acid and 2-mL weekly intramuscular injections of 10 mg of vitamin B12 (B9B12+). An intravenous glucose tolerance test was performed at 25 d in milk. Baseline plasma glucagon, glucose, and nonesterified fatty acid concentrations did not differ among treatments. For B9B12+ cows, baseline plasma insulin concentration and maximal glucose concentration after glucose administration were greater when also combined with biotin compared with no biotin combination, whereas there was no effect in B9B12- cows. There was no treatment effect on time to reach half-maximal glucose and insulin concentrations, glucose positive incremental area under the curve, and glucose and insulin clearance rates. Regarding insulin results, maximal plasma concentration and positive incremental area under the curve were respectively 51 and 74% greater for cows receiving the B8 supplement than for cows who did not. Moreover, plasma nonesterified fatty acid concentration nadir tended to be reached later for B8 cows. Insulin peak was reached earlier for cows in the group B9B12+ than cows in B9B12-, regardless of B8 supplementation. Under the current conditions, our results suggested that cows receiving a B8 supplement had a reduced insulin sensitivity in early lactation. Insulin response was faster for B9B12+ cows, but this was not translated into further improvements following the glucose administration challenge.

Diabetogenic diet-induced insulin resistance associates with lipid droplet proteins and adipose tissue secretome, but not with sexual dimorphic adipose tissue fat accumulation in Wistar rats

The role of sexual dimorphic adipose tissue fat accumulation in the development of insulin resistance is well known. However, whether vitamin A status and/or its metabolic pathway display any sex- or depot (visceral/subcutaneous)-specific pattern and have a role in sexual dimorphic adipose tissue development and insulin resistance are not completely understood. Therefore, to assess this, 5 weeks old Wistar male and female rats of eight from each sex were provided either control or diabetogenic (high fat, high sucrose) diet for 26 weeks. At the end, consumption of diabetogenic diet increased the visceral fat depots (p < 0.001) in the males and subcutaneous depot (p < 0.05) in the female rats, compared to their sex-matched controls. On the other hand, it caused adipocyte hypertrophy (p < 0.05) of visceral depot (retroperitoneal) in the females and subcutaneous depot of the male rats. Although vitamin A levels displayed sex- and depot-specific increase due to the consumption of diabetogenic diet, the expression of most of its metabolic pathway genes in adipose depots remained unaltered. However, the mRNA levels of some of lipid droplet proteins (perilipins) and adipose tissue secretory proteins (interleukins, lipocalin-2) did display sexual dimorphism. Nonetheless, the long-term feeding of diabetogenic diet impaired the insulin sensitivity, thus affected glucose clearance rate and muscle glucose-uptake in both the sexes of rats. In conclusion, the chronic consumption of diabetogenic diet caused insulin resistance in the male and female rats, but did not corroborate with sexual dimorphic adipose tissue fat accumulation or its vitamin A status.

FAT DEPOSITION IN THE NUCHAL REGION IS ASSOCIATED WITH INSULIN RESISTANCE AND LOW METABOLIC CLEARANCE RATE OF GLUCOSE IN ADULT MALES

Background: The role of classical proxies for obesity such as the body mass index (BMI) and waist circumference (WC) in the development of insulin resistance (IR) is well reported. However, there is the dearth of information on the association between subcutaneous fat deposition in the nuchal region and the development of IR.Objective: This study determined the interplay between thickness of cervical fat fold (CFF) and development of IR.Methods: Fifty adult males with CFF and 50 males without CFF were enrolled into this study. Standard Oral Glucose Tolerance Testing (OGTT) was performed and fasting plasma glucose (FPG), 2 hours post prandial glucose (2hrPPG), lipids, fasting insulin (FI), 2 hours postprandial insulin (2hrPPI) levels were determined. Thereafter, indices of IR and estimated metabolic clearance rate of glucose (eMCR) were calculated using standard formula.Results: Levels of FI, 2hrPPI and the median values of indices of IR were significantly higher while median values of indices of insulin sensitivity and eMCR were significantly lower in CFF compared with the controls. Predicting the diagnostic property of CFF for insulin sensitivity with reference to Quantitative Insulin Sensitivity Check Index (QUICKI) cut-off values, the Area Under the Receiver Operating Characteristic Curve (AUROC) was 0.695 (P-value = 0.043) and a CFF cut-off value of 12.5 cm had 75% sensitivity and 55.3% specificity.Conclusion: Adult males with CFF have IR and low eMCR and are thus, prone to developing cardiovascular and metabolic diseases. Also, CFF thickness appears to be a good anthropometric index of insulin resistance.

Computational Fluid Dynamics (CFD) Modeling and Simulation of Flow Regulatory Mechanism in Artificial Kidney Using Finite Element Method.

There is an enormous need in the health welfare sector to manufacture inexpensive dialyzer membranes with minimum dialysis duration. In order to optimize the dialysis cost and time, an in-depth analysis of the effect of dialyzer design and process parameters on toxins (ranging from tiny to large size molecules) clearance rate is required. Mathematical analysis and enhanced computational power of computers can translate the transport phenomena occurring inside the dialyzer while minimizing the development cost. In this paper, the steady-state mass transport in blood and dialysate compartment and across the membrane is investigated with convection-diffusion equations and tortuous pore diffusion model (TPDM), respectively. The two-dimensional, axisymmetric CFD model was simulated by using a solver based on the finite element method (COMSOL Multiphysics 5.4). The effect of design and process parameters is analyzed by solving model equations for varying values of design and process parameters. It is found that by introducing tortuosity in the pore diffusion model, the clearance rate of small size molecules increases, but the clearance rate of large size molecules is reduced. When the fiber aspect ratio (db/L) varies from 900 to 2300, the clearance rate increases 37.71% of its initial value. The results also show that when the pore diameter increases from 10 nm to 20 nm, the clearance rate of urea and glucose also increases by 2.09% and 7.93%, respectively, with tolerated transport of albumin molecules.

Divergent Changes in Serum Branched-Chain Amino Acid Concentrations and Estimates of Insulin Resistance throughout Gestation in Healthy Women

Branched-chain amino acid (BCAA) concentrations in the blood have been correlated with insulin resistance, but this relation throughout gestation (period in which insulin resistance typically increases) is unclear. The objective of this study was to determine the associations between changes in BCAA concentrations and estimates of insulin resistance throughout gestation. Serum BCAA (Leu, Ile, Val) concentrations and insulin resistance/sensitivity [i.e., homeostatic model assessment-2 of insulin resistance (HOMA2-IR), estimated metabolic clearance rate (MCR) of glucose, and estimated first- and second-phase insulin responses] were assessed at early (EP; 8.5±0.2 wk) and/or late (LP; 29.2±0.8 wk) pregnancy in 53 healthy women from the Glowing cohort. Adjusted Spearman correlations were used to evaluate the association between BCAA and insulin resistance/sensitivity measures at EP and LP, adjusted for body fat percentage and gestational weight gain (GWG). A multiple linear regression analysis was used to assess the association between changes in HOMA2-IR and BCAAs throughout gestation. Groups were made post hoc based on the mean percentage change (10% decrease) in Leu throughout gestation, creating a group with a ≥10% decrease in LeuLP-EP (BELOW) and a <10% decrease in LeuLP-EP (ABOVE), and Student's t tests were performed to assess differences between groups. Leu and Ile concentrations positively correlated with HOMA2-IR at both time points, but these relations at EP disappeared/weakened when adjusted for body fat percentage. From EP to LP, the change in Leu (LeuLP-EP) was negatively associated with the change in HOMA2-IR (HOMA2-IRLP-EP) (β = -0.037, P=0.006). MCR was lower in the BELOW group compared with the ABOVE group, whereas there was no difference in HOMA2-IR between groups. In this pregnancy cohort, BCAA concentrations decreased throughout gestation, whereas the mean insulin resistance did not change. These data do not support a connection between changes in blood BCAA concentrations and estimates of insulin resistance in pregnant women. This trial is registered at clinicaltrials.gov as NCT01131117.

Utilization of raw and gelatinized starch by blunt snout bream Megalobrama amblycephala as evidenced by the glycolipid metabolism, glucose tolerance and mitochondrial function

This study aimed to evaluate the influences of dietary raw and gelatinized wheat starch and their ratios on the glycolipid metabolism, glucose tolerance and mitochondrial function of blunt snout bream Megalobrama amblycephala. Three diets incorporating 100% raw starch (R100), 100% gelatinized starch (G100) and 75% raw starch +25% gelatinized starch (R75/G25) were randomly assigned to 15 cages of fish for 10 weeks, after which fish were sampled. Then the remaining fish within each treatment were combined and later split into 6 tanks for a time series sampling in a glucose tolerance test. Daily gain index, relative feed intake and plasma levels of glucose, triglyceride, pyruvate and lactate all showed little difference among all the treatments. The R75/G25 group obtained the highest feed efficiency and tissue (namely liver and the abdominal fat tissue) glycogen contents. However, the highest tissue (namely muscle, liver and the abdominal fat tissue) lipid contents and plasma total cholesterol levels were both observed in the G100 group. In addition, the G100 group obtained significantly higher transcriptions of glucose transporter 2, glucokinase, peroxisome proliferator activated receptor γ and acetyl-CoA carboxylase α, but relatively low transcripts of the genes involved in gluconeogenesis and fatty acid β-oxidation, compared with the R100 group. The R100 group showed the highest glucose clearance rate, while the area under the glucose curve showed no statistical difference. Furthermore, the R100 group had relatively low activities of mitochondrial complex I, II, III and V as well as the transcriptions of cytochrome c oxidase 2, cytochrome b and NADH dehydrogenase 1 and ATP synthase 6 compared with other groups. Overall, our results suggested that high dietary inclusions of gelatinized starch could enhance the glucose transportation, glycolysis, lipogenesis, lipid deposition, glucose tolerance and mitochondrial function of blunt snout bream, while depress the gluconeogenesis and fatty acid oxidation.

Insulin sensitivity depends on the route of glucose administration

Aims/hypothesisThe small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels.MethodsIn this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment.ResultsGlucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min−1 kg−1 per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min−1 kg−1 (nmol/l)−1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration.Conclusions/interpretationOur study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance.Trial registrationClinicalTrials.gov NCT03223129.Graphical abstract

Polylysine-Bilirubin Conjugates Maintain Functional Islets and Promote M2 Macrophage Polarization

Macrophage polarization has been considered as one main factor that contributes to the pro-inflammatory milieu of the transplanted islets and caused significant islet loss. Bilirubin possesses protective effects in islet transplantation, but how to deliver the drug along with the islet graft has not yet been harnessed. More importantly, whether bilirubin or its derivates could modulate macrophage polarization during the host rejections has also not been answered. To this end, we aimed to develop an e-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets for protection and explore its macrophage modulation activities. In vitro studies indicated that PLL-BR tightly adheres to the islet surface, and achieved enhanced cytoprotective effects against oxidative and inflammatory conditions by promoting M2 type macrophage polarization. In vivo data demonstrated that PLL-BR protected islets successfully prolonged the period of euglycemia in diabetic mice and accelerated the clearance rate of blood glucose by maximumly maintain the insulin secretion function. The PLL-BR encapsulated islets elicited anti-inflammatory response characterized by the elevated proportion of M2 macrophage markers and local vascularization compared to untreated islets. Hence PLL-BR might serve as a useful tool for reprograming the macrophage polarization and providing a more efficient immune protection for transplanted islets and improve the outcomes.

The characteristics of glucose homoeostasis in grass carp and Chinese longsnout catfish after oral starch administration: a comparative study between herbivorous and carnivorous species of fish.

An oral starch administration trial was used to evaluate glucose homoeostasis in grass carp (Ctenopharyngodon idella) and Chinese longsnout catfish (Leiocassis longirostris Günther). Fish were administered with 3 g of a water and starch mixture (with 3:2 ratio) per 100 g body weight after fasting for 48 h. Fish were sampled at 0, 1, 3, 6, 12, 24 and 48 h after oral starch administration. In grass carp, plasma levels of glucose peaked at 3 h but returned to baseline at 6 h. However, in Chinese longsnout catfish, plasma glucose levels peaked at 6 h and returned to baseline at 48 h. The activity of intestinal amylase was increased in grass carp at 1 and 3 h, but no significant change in Chinese longsnout catfish was observed. The activity of hepatic glucose-6-phosphatase fell significantly in grass carp but change was not evident in Chinese longsnout catfish. The expression levels and enzymic activity of hepatic pyruvate kinase increased in grass carp, but no significant changes were observed in the Chinese longsnout catfish. Glycogen synthase (gys) and glycogen phosphorylase (gp) were induced in grass carp. However, there was no significant change in gys and a clear down-regulation of gp in Chinese longsnout catfish. In brief, compared with Chinese longsnout catfish, grass carp exhibited a rapid increase and faster clearance rate of plasma glucose. This effect was closely related to significantly enhanced levels of digestion, glycolysis, glycogen metabolism and glucose-induced lipogenesis in grass carp, as well as the inhibition of gluconeogenesis.

MiR-133 inhibits kidney injury in rats with diabetic nephropathy via MAPK/ERK pathway.

The aim of this study was to explore the effect of micro ribonucleic acid (miR)-133 on kidney injury in rats with diabetic nephropathy (DN) through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. The model of DN was first established in rats. Blood glucose, renal index, urinary micro-albumin (UMA), and creatinine clearance rate (CCr) were detected. Meanwhile, the protein expression levels of miR-133, kidney injury molecule-1 (KIM-1) and anti-inflammatory cytokine interleukin-8 (IL-8) were measured using Western blotting. Human renal proximal tubular epithelial cell line human kidney-2 (HK-2) was treated with high glucose to simulate DN cells in vivo. Subsequently, Western blotting was performed to detect the protein expression of KIM-1. After HK-2 cells were treated with high glucose and silenced miR-133 for 24 h, the expression changes in KIM-1 was evaluated. In DN group, blood glucose, renal index, UMA, and CCr were all markedly higher than those of control group. This indicated the successful establishment of DN model in rats. The expression level of miR-133 was significantly up-regulated in DN model rats. Meanwhile, the downstream protein phosphorylated-EPK (p-EPK) showed a significantly increasing trend as well. Additionally, the protein expressions of KIM-1 and IL-8 were notably elevated. High-glucose-treated HK-2 cells showed significantly up-regulated expression levels of miR-133, KIM-1, and IL-8. After 24 h of combined treatment with high glucose and miR-133 silence, the expressions of KIM-1 and IL-8 were markedly down-regulated. MiR-133 may be related to the occurrence and development of DN. The silence of miR-133 inhibits kidney injury in DN via the MAPK/ERK signaling pathway. Our findings suggest that miR-133 may be an effective target for the treatment of DN.

Muscle Insulin Resistance in Youth with Obesity and Normoglycemia is Associated with Altered Fat Metabolism.

This study aimed to phenotype and compare adipose, hepatic, and muscle insulin sensitivity (IS) in a diet- and physical activity-controlled cohort of normoglycemic youth with obesity with that of participants without obesity (controls) to distinguish early metabolic abnormalities in pediatric obesity. Thirty-eight participants (17 in the control group [BMI < 85th percentile] and 21 youth with obesity [BMI ≥ 95th percentile]; age: 12-21 years; 76% female; Tanner stage 4-5; sedentary) were enrolled. Tissue-specific IS was measured using a four-phase hyperinsulinemic-euglycemic clamp with glucose and glycerol isotope tracers to assess suppression of endogenous glucose release and lipolysis by insulin. Intramyocellular lipid content was assessed by 1 H-magnetic resonance spectroscopy, and hepatic fat fraction (HFF) and visceral fat were assessed by magnetic resonance imaging. Calf-muscle mitochondrial activity was measured with exercise-stimulated 31 P-magnetic resonance spectroscopy. Youth with obesity had higher HFF (P < 0.001), visceral fat (P = 0.024), and intramyocellular lipid content (P = 0.017) and lower muscle (glucose clearance rate [P < 0.001]), adipose (P < 0.0001), and hepatic IS (P < 0.003). Mitochondria postexercise response was not different. In participants with obesity, muscle IS inversely correlated with HFF (r = 0.700, P = 0.002) and suppressed free fatty acid concentrations (r = -0.65, P = 0.003). Inactive normoglycemic youth with obesity had decreased muscle, adipose, and hepatic IS. Free fatty acids and liver fat were inversely associated with muscle IS, which argues for lipid-targeted interventions.

High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet.

Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor vitamin. The scarce reports on the adverse effects on metabolic health of supplementation with high-dose NR warrant substantiation. Here, we aimed to examine the physiological responses to high-dose NR supplementation in the context of a mildly obesogenic diet and to substantiate this with molecular data. An 18-week dietary intervention was conducted in male C57BL/6JRccHsd mice, in which a diet with 9000 mg NR per kg diet (high NR) was compared to a diet with NR at the recommended vitamin B3 level (control NR). Both diets were mildly obesogenic (40 en% fat). Metabolic flexibility and glucose tolerance were analyzed and immunoblotting, qRT-PCR and histology of epididymal white adipose tissue (eWAT) were performed. Mice fed with high NR showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT, including sirtuin 1 (SIRT1)-mediated PPARγ (proliferator-activated receptor γ) repression, downregulated AKT/glucose transporter type 4 (GLUT4) signaling, an increased number of crown-like structures and macrophages, and an upregulation of pro-inflammatory gene markers. In conclusion, high-dose NR induces the onset of WAT dysfunction, which may in part explain the deterioration of metabolic health.

Over-expression of miR-34c leads to early-life visceral fat accumulation and insulin resistance

Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis. Male and female cU2 mice exhibit significant weight gain, accompanied by marked increase in abdominal fat mass and metabolic abnormalities, including reduction of both glucose clearance rate and insulin sensitivity, as early as two months of age. Adipogenesis derailment at this early age is suggested by decreased expression of adiponectin, the fat mass and obesity-associated gene, and the adiponectin receptor R1, coupled with a reduction of the brown fat biomarker PAT2 and the adipogenesis inhibitor SIRT1. Notably, adiponectin is an important adipokine and an essential regulator of glucose and fatty acid homeostasis. cU2 mice may provide a crucial animal model for investigating the role of miR-34c in early onset insulin resistance and visceral fat mass increase, contributing to accelerated body weight gain and metabolic disorders. Intervention in this dysregulation may open a new preventive strategy to control early-life weight gain and abnormal insulin resistance, and thus prevalent adult and late life obesity.

Obesity Status Affects the Relationship Between Protein Intake and Insulin Sensitivity in Late Pregnancy

The purpose of this study was to determine the associations between amount and type of dietary protein intake and insulin sensitivity in late pregnancy, in normal weight and overweight women (29.8 ± 0.2 weeks gestation, n = 173). A 100-g oral glucose tolerance test (OGTT) was administered following an overnight fast to estimate the metabolic clearance rate of glucose (MCR, mg·kg−1·min−1) using four different equations accounting for the availability of blood samples. Total (TP), animal (AP), and plant (PP) protein intakes were assessed using a 3-day food record. Two linear models with MCR as the response variable were fitted to the data to estimate the relationship of protein intake to insulin sensitivity either unadjusted or adjusted for early pregnancy body mass index (BMI) because of the potential of BMI to influence this relationship. There was a positive association between TP (β = 1.37, p = 0.002) and PP (β = 4.44, p < 0.001) intake in the last trimester of pregnancy and insulin sensitivity that weakened when accounting for early pregnancy BMI. However, there was no relationship between AP intake and insulin sensitivity (β = 0.95, p = 0.08). Therefore, early pregnancy BMI may be a better predictor of insulin sensitivity than dietary protein intake in late pregnancy.

Effects of feeding a high- or moderate-starch prepartum diet to cows on newborn dairy heifer calf responses to intravenous glucose tolerance tests early in life

The objective of this study was to evaluate the effect of feeding a prepartum diet with a high or moderate starch content on growth and insulin sensitivity of female offspring early in life. Thirty-eight Holstein heifer calves were born to dams fed either a high-starch (26% starch on a DM basis, HI; n = 20) or moderate-starch (14% starch on a DM basis, MOD; n = 18) prepartum diet commencing at 28 ± 3 d before expected parturition date. Following birth, all calves were housed individually and fed three 2-L meals of colostrum within the first 24 h of life and offered 10 L/d of milk replacer (26% CP, 18% fat, mixed to 130 g/L). Body weight of calves was measured at birth and on d 2 (after colostrum feeding but before milk feeding), 10 ± 2, and 20 ± 2. A glucose tolerance test was performed at a minimum of 6 h after their last colostrum or milk meal to evaluate insulin sensitivity on d 2, 10 ± 2 and 20 ± 2. Body weight did not differ throughout between HI and MOD calves; however, calves born to primiparous dams were smaller compared with those born to multiparous dams. Glucose or insulin concentrations were not different before the glucose tolerance test. Following the glucose tolerance test, maximum glucose concentrations were not different between treatments at any time point. However, HI calves had greater insulin area under the curve, and HI calves had greater maximum insulin concentrations on d 2. Glucose or insulin clearance rates were not different nor was the calculated insulin sensitivity index between treatments. These findings suggest that feeding a HI prepartum diet may reduce some insulin sensitivity indicators of female offspring early in life.