Rat Model Of Type-2 Diabetes Research Articles

Relationship between Urinary Liver-Type Fatty Acid-Binding Protein (L-FABP) and Sarcopenia in Spontaneously Diabetic Torii Fatty Rats.

Background Type 2 diabetes (T2D) is a known risk factor for diabetic kidney disease (DKD) and sarcopenia in older patients. Because there may be an interaction between DKD and sarcopenia, the aim of the present study is to investigate the relationship between urinary levels of liver-type fatty acid-binding protein (L-FABP) and sarcopenia using a novel rat model of T2D. Methods Male spontaneously diabetic Torii (SDT) fatty rats (n = 5) at 16 weeks of age were used as an animal model of T2D. Age- and sex-matched Sprague-Dawley (SD) rats (n = 7) were used as controls. Urine samples were obtained from the rats, and muscle strength was evaluated with the use of the forelimb grip test at 16, 20, and 24 weeks of age. Serum, kidney, soleus, and extensor digitorum longus (EDL) muscle samples were collected at 24 weeks of age. Urinary L-FABP levels were measured using dedicated enzyme-linked immunosorbent assays. Results Increased urinary L-FABP levels, focal glomerular sclerosis, moderate interstitial inflammation and fibrosis, and accumulation of renal oxidative proteins were significantly observed in the SDT fatty rats, compared to the SD rats. Muscle weight, muscle strength, cross-sectional areas of both type I and type IIb muscle fibers, and increasing rate of muscle strength were significantly decreased in the SDT fatty rats compared to the SD rats at 24 weeks. Urinary L-FABP levels at 20 and 24 weeks were significantly negatively correlated with muscle strength. Urinary L-FABP levels at 16 weeks were significantly negatively correlated with the increasing rate of muscle strength. Conclusions Urinary L-FABP reflects the degree of muscle strength and weight, as well as cross-sectional areas of muscle fibers. Although further clinical study is needed, urinary L-FABP may be useful to monitor the progression of sarcopenia and DKD in T2D patients.

Rotundic Acid Protects against Metabolic Disturbance and Improves Gut Microbiota in Type 2 Diabetes Rats.

Rotundic acid (RA) is a major triterpene constituent in the barks of Ilex rotunda Thunb, which have been widely used to make herbal tea for health care in southern China. RA has a variety of bioactivities such as anti-inflammation and lipid-lowering effect. However, little is known about the effects and mechanisms of RA on metabolic disturbance in type 2 diabetes (T2D) and its effect on gut microbiota. A T2D rat model induced by high fat diet (HFD) feeding and low-dose streptozotocin (STZ) injection was employed and RA showed multipronged effects on T2D and its complications, including improving glucolipid metabolism, lowering blood pressure, protecting against cardiovascular and hepatorenal injuries, and alleviating oxidative stress and inflammation. Furthermore, 16s rRNA gene sequencing was carried out on an Illumina HiSeq 2500 platform and RA treatment could restore the gut microbial dysbiosis in T2D rats to a certain extent. RA treatment significantly enhanced the richness and diversity of gut microbiota. At the genus level, beneficial or commensal bacteria Prevotella, Ruminococcus, Leuconostoc and Streptococcus were significantly increased by RA treatment, while RA-treated rats had a lower abundance of opportunistic pathogen Klebsiella and Proteus. Spearman’s correlation analysis showed that the abundances of these bacteria were strongly correlated with various biochemical parameters, suggesting that the improvement of gut microbiota might help to prevent or attenuate T2D and its complication. In conclusion, our findings support RA as a nutraceutical agent or plant foods rich in this compound might be helpful for the alleviation of T2D and its complications through improving gut microbiota.

Fabrication of Second Generation Smarter PLGA Based Nanocrystal Carriers for Improvement of Drug Delivery and Therapeutic Efficacy of Gliclazide in Type-2 Diabetes Rat Model

Drug delivery and therapeutic challenges of gliclazide, a BCS class II drug used in type 2 diabetes mellitus (T2DM) can be overcome by exploring smarter carriers of second-generation nanocrystals (SGNCs). A combined method of emulsion diffusion, high-pressure homogenization and solvent evaporation method were employed in the preparation of gliclazide loaded poly (D, L-lactide-co-glycolide) (PLGA) SGNCs. Taguchi experimental design was adopted in fabrication of Gliclazide SGNc using Gliclazide -PLGA ratio at 1:0.5, 1:0.75, 1:1 with stabilizer (Poloxamer-188, PEG 4000, HPMC E15 at 0.5, 0.75, 1% w/v). The formulated gliclazide of SGNCs were investigated for physicochemical properties, in vitro drug release, and in vivo performance studies using type-2 diabetes rat model. The formulation (SGNCF1) with Drug: PLGA 1: 0.5 ratio with 0.5% w/v Poloxamer-188 produced optimized gliclazide SGNCs. SGNCF1 showed spherical shape, small particle size (106.3 ± 2.69 nm), good zeta potential (−18.2 ± 1.30 mV), small PDI (0.222 ± 0.104) and high entrapment efficiency (86.27 ± 0.222%). The solubility, dissolution rate and bioavailability of gliclazide SGNCs were significantly improved compared to pure gliclazide. The findings emphasize gliclazide SGNCs produce faster release initially, followed by delayed release with improved bioavailability, facilitate efficient delivery of gliclazide in T2DM with better therapeutic effect.

Efficacy of Arabica Versus Robusta Coffee in Improving Weight, Insulin Resistance, and Liver Steatosis in a Rat Model of Type-2 Diabetes.

The effects of chronic coffee exposure in models of type 2 diabetes mellitus (T2D) is scarcely studied, and the efficacy of the main coffee species has never been compared. We tested the hypothesis that long-term consumption of arabica and robusta coffee may differentially delay and affect T2D development in Zucker diabetic fatty rats. Three study groups received either chow mixed with arabica or robusta instant coffee (1.8% w/w) or unsupplemented chow food for 10 weeks. Both coffee species reduced liver triglyceride content and area under the curve of fasting and postprandial insulin. At study end, plasma adiponectin, total cholesterol and high density lipoprotein levels were higher in the robust group compared with both arabica and control groups. The liver gene expression of Glucose-6-phosphatase, catalytic subunit (G6pc) and Mechanistic target of rapamycin (mTOR) in robusta and Cpt1a in both coffee groups was downregulated. In conclusion, long-term consumption of both coffee species reduced weight gain and liver steatosis and improved insulin sensitivity in a rat model of T2D. Robusta coffee was seemingly superior to arabica coffee with respect to effects on lipid profile, adiponectin level and hepatic gene expression.

Skeletal muscle energetics are compromised only during high-intensity contractions in the Goto-Kakizaki rat model of type 2 diabetes.

Type 2 diabetes (T2D) presents with hyperglycemia and insulin resistance, affecting over 30 million people in the United States alone. Previous work has hypothesized that mitochondria are dysfunctional in T2D and results in both reduced ATP production and glucose disposal. However, a direct link between mitochondrial function and T2D has not been determined. In the current study, the Goto-Kakizaki (GK) rat model of T2D was used to quantify mitochondrial function in vitro and in vivo over a broad range of contraction-induced metabolic workloads. During high-frequency sciatic nerve stimulation, hindlimb muscle contractions at 2- and 4-Hz intensities, the GK rat failed to maintain similar bioenergetic steady states to Wistar control (WC) rats measured by phosphorus magnetic resonance spectroscopy, despite similar force production. Differences were not due to changes in mitochondrial content in red (RG) or white gastrocnemius (WG) muscles (cytochrome c oxidase, RG: 22.2 ± 1.6 vs. 23.3 ± 1.7 U/g wet wt; WG: 10.8 ± 1.1 vs. 12.1 ± 0.9 U/g wet wt; GK vs. WC, respectively). Mitochondria isolated from muscles of GK and WC rats also showed no difference in mitochondrial ATP production capacity in vitro, measured by high-resolution respirometry. At lower intensities (0.25-1 Hz) there were no detectable differences between GK and WC rats in sustained energy balance. There were similar phosphocreatine concentrations during steady-state contraction and postcontractile recovery (τ = 72 ± 6 s GK versus 71 ± 2 s WC). Taken together, these results suggest that deficiencies in skeletal muscle energetics seen at higher intensities are not due to mitochondrial dysfunction in the GK rat.

Skeletal Muscle Mitochondrial Function in Goto‐Kakizaki Rat Model of Type 2 Diabetes

Type 2 diabetes (T2D) presents with significant comorbidities and reported exercise intolerance affecting over 30 million people in the US alone. Aerobic metabolism is the predominant pathway for fueling exercise and utilizing glucose, therefore mitochondrial oxidative phosphorylation (MOP) is important in diabetes and the future of diabetic interventions. However, studies in T2D have conflicting reports regarding the functional status of the mitochondrial pool suggesting deficits are an inherent cause of the disease but a comprehensive study has yet to be done. The Goto‐Kakizaki (GK) rat model of T2D was used to measure both mitochondrial function and density in vitro and in vivo over a broad range of metabolic challenges. Mitochondrial densities were similar in red (RG) and white gastrocnemius (WG) muscles of the GK rat (Cyt c oxidase, RG: 22.2 ± 1.6 versus 23.3 ± 1.7 μmol/min/g, WG: 10.8 ± 1.1 versus 12.1 ± 0.9 μmol/min/g; n=7–8). Mitochondria isolated from the muscles of GK rats and their Wistar controls showed no difference in mitochondrial respiration in vitro as measured by high resolution respirometry. Mitochondrial function in vivo, measured by 31Phosphorus magnetic resonance spectroscopy, was similar between GK and Wistar controls determined from phosphocreatine dynamics reaching similar exercise steady states at submaximal workloads with no difference in recovery time constant (72 ± 6 s GK vs. 71 ± 2 s Wistar). However, at exercise intensities beyond what can be sustained aerobically, the GK rat exhibited bioenergetic deficits suggesting something other than mitochondrial function is responsible at these workloads. The current work demonstrates normal mitochondrial function in a non‐obese non‐sedentary rat model of T2D in vitro and in vivo and no change in mitochondrial content. Taken together these results show when considering both density and function of mitochondria no deficit in MOP is present in the GK T2D rat model and may not be in T2D patients but these studies remain to be done.Support or Funding InformationNIH DK 095210, NIH R00HL121160, CIHR R5521A02This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Corosolic acid isolated from Eriobotrya japonica leaves reduces glucose level in human hepatocellular carcinoma cells, zebrafish and rats

Type 2 diabetes (T2D) with high morbidity and mortality is characterized by abnormal glucose and lipid metabolism due in part to insulin resistance in liver, which lead to elevated hyperglycemia and hyperlipidemia. This study sough to explore the effects of corosolic acid (CA) in different T2D models and explored the underlying mechanism. Separated from Eriobotrya japonica leaves, CA purity was above 95% measured by a HPLC method. Compared with cAMP and DEX induced T2D HepG2 model, CA significantly stimulated glucose consumption and improved glycogen accumulation by inhibiting PEPCK mRNA expression. And in cAMP and DEX induced T2D zebrafish model, CA reduced glycogen degradation and increased glucose consumption by regulating some key enzymes in carbon metabolism including GLUT1, GLUT2, GLUT3, LDHA, LDHB, GP, G6Pase, GYS1, and PFKFB3. In addition, insulin receptor signals were also involved in CA-regulated hypoglycemic action. Furthermore, in STZ-induced T2D rat model, compared with diabetic control groups, CA remarkably downregulated the levels of serum lipid, blood glucose, ICAM-1, malonaldehyde and insulin resistance index, while upregulated SOD activity and impaired glucose tolerance. In a conclusion, CA can regulate glucose and lipid metabolic adaptation in T2D like HepG2, zebrafish and rat models partly through reducing inflammation and oxidative stress and suppressing PEPCK.

Peripheral Mechanisms Mediating the Sustained Antidiabetic Action of FGF1 in the Brain.

We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic β-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of β-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of β-cell function and stimulation of HGU through increased hepatic glucokinase activity.

Effect of hydroalcohol extract of lemon (<i>Citrus limon</i>) peel on a rat model of type 2 diabetes

Purpose : To determine the effect of the hydroalcohol extract of lemon peel (LP) on a rat model of type 2 diabetes (T2D). Method : The rat model of T2D by injection of streptozotocin was established. The effects of a hydroalcoholic extract of LP was characterised on a rat model of type 2 diabetes based on body weight, food intake, fasting blood glucose (FBG), glucose tolerance test, and insulin tolerance test. Antioxidant activity and oxidative stress were analysed by superoxide dismutase (SOD) and malonaldehyde (MDA) assays. Results : In acute toxicity studies, administration of LP extract at 2000 mg/kg orally did not cause any symptoms of poisoning or death after 14 days. The body weight of rats increased after treatment with LP extracts. Food intake in diabetic rats decreased with LP extract treatment. Continual treatment with LP extracts for 35 days significantly reduced blood glucose levels in diabetic rats. Glucose tolerance improved, and insulin resistance was reduced after treatment with LP extracts. SOD and MDA data indicate that treatment with LP extract alleviated the oxidative stress in diabetic rats as well as enhanced the antioxidant activity of liver in a dosage-dependent manner. Conclusion : LP extract decreased food intake and FBG, but increased body weight in rats. The effect of LP on T2D is likely related to improved antioxidant activity and reduced oxidative stress. Thus, LP extract has potentials for the treatment of T2D. Keywords : Lemon peel, Type 2 diabetes, Antioxidant activity, Glucose tolerance, Insulin tolerance

Anti-diabetic activity of aqueous extract of Fructus Ligustri Lucidi in a rat model of type 2 diabetes

Purpose : To determine the anti-diabetic activity of an aqueous extract of Fructus Ligustri Lucidi (FLL) in a rat model of type 2 diabetes (T2D). Method : Body weight (BW), food intake (FI), fasting blood glucose (FBG), glucose tolerance testing and insulin tolerance testing were used to determine the anti-diabetic activity of an aqueous extract of Fructus Ligustri Lucidi (FLL) in a rat model of streptozotocin-induced T2D. Anti-oxidant activity and oxidative stress were assessed by superoxide dismutase (SOD) and malondialdehyde (MDA) analyses, respectively. Results : Following FLL extract treatment, diabetic rat BW increased, while FI and FBG levels decreased. FLL extract increased glucose tolerance and decreased insulin tolerance. Following treatment with 300 and 600 mg/kg FLL extract, MDA levels reached 13.5 ± 0.9 nmol/ml and 13.8 ± 1.1 nmol/ml, respectively. Compared to MDA levels of 19.5 ± 1.1 nmol/ml in diabetic control group, MDA levels was decreased by 30.8 % and 29.0 % after the treatment with 300 and 600 mg/kg FLL extract, respectively, indicating alleviated oxidative stress. Conclusion : The results show that aqueous FLL extract has the potential to alleviate T2D, resulting in reduced FI and FBG, and increased BW. The anti-diabetic activity of FLL extract on T2D may be relevant to reduced oxidative stress burden. Keywords : Fructus Ligustri Lucidi, Type 2 diabetes, Anti-oxidant activity, Glucose tolerance, Insulin tolerance, Anxiety-like behaviour

Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes

BackgroundCurcumin, a naturally occurring anti-inflammatory compound, has shown promise in pre-clinical studies to treat erectile dysfunction (ED) associated with type-1 diabetes. However, poor bioavailability following oral administration limits its efficacy. The present study evaluated the potential of topical application of curcumin-loaded nanoparticles (curc-np) to treat ED in a rat model of type-2 diabetes (T2D). AimDetermine if topical application of curc-np treats ED in a T2D rat model and modulates expression of inflammatory markers. MethodsCurc-np (4 mg curcumin) or blank nanoparticles were applied every 2 days for 2 weeks to the shaved abdomen of 20-week-old Zucker diabetic fatty male rats (N = 5 per group). Lean Zucker diabetic fatty male rat controls were treated with blank nanoparticles (N = 5). Penetration of nanoparticles and curcumin release were confirmed by 2-photon fluorescence microscopy and histology. Erectile function was determined by measuring intracorporal pressure (ICP) normalized to systemic blood pressure (ICP/BP) following cavernous nerve stimulation. Corporal tissue was excised and reverse transcription and quantitative polymerase chain reaction used to determine expression of the following markers: nuclear factor (NF)-κβ, NF-κβ-activating protein (Nkap), NF erythroid 2-related factor-2, Kelch-like enoyl-CoA hydratase-associated protein-1, heme oxygenase-1 (HO-1), variable coding sequence-A1, phosphodiesterase-5, endothelial and neuronal nitric oxide synthase, Ras homolog gene family member A, and Rho-associated coiled-coil containing protein kinases-1 and -2. OutcomesErectile function by determination of ICP/BP and expression of molecular markers in corporal tissue by RT-qPCR. ResultsNanoparticles penetrated the abdominal epidermis and persisted in hair follicles for 24 hours. Curc-np-treated animals exhibited higher average ICP/BP than animals treated with blank nanoparticles at all levels of stimulation and this was statistically significant (P < .05) at 0.75 mA. In corporal tissue, Nkap expression decreased 60% and heme oxygenase-1 expression increased 60% in curc-np- compared to blank nanoparticle–treated animals. ICP/BP values inversely correlated with Nkap and directly correlated with HO-1 expression levels. Clinical TranslationThese studies demonstrate the potential for topical application of curc-np as a treatment for ED in T2D patients. ConclusionsThe T2D animal model of ED represents a more prevalent disease than the more commonly studied type-1 diabetes model. Although there is improved erectile response in curc-np-treated animals, only at the lower levels of stimulation (0.75 mA) was this significant compared to the blank nanoparticle–treated animals, suggesting more studies are needed to optimize protocols and evaluate toxicity. Topical application of curc-np to a rat model of T2D can systemically deliver curcumin, treat ED, and modulate corporal expression of inflammatory markers.Draganski A, Tar MT, Villegas G, et al. Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes. J Sex Med 2018;15:645–653.

Remote ischemic preconditioning fails to reduce infarct size in the Zucker fatty rat model of type-2 diabetes: role of defective humoral communication

Remote ischemic preconditioning (RIPC), the phenomenon whereby brief ischemic episodes in distant tissues or organs render the heart resistant to infarction, has been exhaustively demonstrated in preclinical models. Moreover, emerging evidence suggests that exosomes play a requisite role in conveying the cardioprotective signal from remote tissue to the myocardium. However, in cohorts displaying clinically common comorbidities-in particular, type-2 diabetes-the infarct-sparing effect of RIPC may be confounded for as-yet unknown reasons. To investigate this issue, we used an integrated in vivo and in vitro approach to establish whether: (1) the efficacy of RIPC is maintained in the Zucker fatty rat model of type-2 diabetes, (2) the humoral transfer of cardioprotective triggers initiated by RIPC are transported via exosomes, and (3) diabetes is associated with alterations in exosome-mediated communication. We report that a standard RIPC stimulus (four 5-min episodes of hindlimb ischemia) reduced infarct size in normoglycemic Zucker lean rats, but failed to confer protection in diabetic Zucker fatty animals. Moreover, we provide novel evidence, via transfer of serum and serum fractions obtained following RIPC and applied to HL-1 cardiomyocytes subjected to hypoxia-reoxygenation, that diabetes was accompanied by impaired humoral communication of cardioprotective signals. Specifically, our data revealed that serum and exosome-rich serum fractions collected from normoglycemic rats attenuated hypoxia-reoxygenation-induced HL-1 cell death, while, in contrast, exosome-rich samples from Zucker fatty rats did not evoke protection in the HL-1 cell model. Finally, and unexpectedly, we found that exosome-depleted serum from Zucker fatty rats was cytotoxic and exacerbated hypoxia-reoxygenation-induced cardiomyocyte death.

Adipose depot-specific effects of ileal interposition surgery in UCD-T2D rats: unexpected implications for obesity and diabetes.

Ileal interposition (IT) surgery delays the onset of diabetes in a rat model of type-2 diabetes (UCD-T2DM). Here, to gain a deeper understanding of the molecular events underlying the effects of IT surgery, we examined the changes in the proteome of four white adipose depots (retroperitoneal, mesenteric, inguinal, and epididymal) and plasma-free fatty acid profile in pre-diabetic rats 1.5 months following IT or sham surgery. The IT-mediated changes were exerted mainly in mesenteric fat and spanned from delayed adipocyte maturation to a neuroendocrine remodeling. Conversely, inguinal, retroperitoneal, and epididymal depots showed opposite trends consistent with increased adipocyte maturation and adipogenesis development prior to overt signs of diabetes, probably orchestrated by peroxisome proliferator-activated receptor gamma signaling and higher plasma n-6/n-3 free fatty acid ratios. The resulting scenario suggests a targeted use of surgical strategies that seek to delay or improve diabetes in order to manipulate adipose depot-specific responses to maximize the duration and beneficial effects of the surgery.

Improvement of antihyperglycemic activity of nano-thymoquinone in rat model of type-2 diabetes

Thymoquinone is a bioactive constituent of Nigella sativa seeds. It has been reported to possess antihyperglycemic effect in rats. However, the effect of nanoformulation (NF) of thymoquinone has not been reported in literature. So, the present study was designed with the aim to investigate the effect of nanoformulation of thymoquinone in streptozotocin-nicotinamide induced type-2 diabetic rats and compare its effect with pure bioactive compound as well as metformin, a standard antidiabetic drug. It is the first study reporting the use of thymoquinone NF against diabetes.Polymeric nanocapsules (NCs) of thymoquinone and metformin were prepared by nanoprecipitation method using gum rosin, a biocompatible polymer. Box-Behnken statistical analysis tool was used for the optimization of polymer and other excipients. The NCs were then characterized with respect to particle size, stability, morphology, and in vitro drug dissolution profiles. Furthermore, thymoquinone (20, 40 & 80 mg/kg), metformin (150 mg/kg) and their nanoformulations (20, 40 & 80 mg/kg for thymoquinone and 80 mg/kg for metformin) per se were administered for 21 successive days to type-2 diabetic rats. Body weight and blood glucose levels were measured every week for 3 weeks. Serum lipid profile and glycosylated hemoglobin were estimated on 22nd day.The nanocapsules were stable, spherical in shape and size was less than 100 nm. Thymoquinone-and metformin-loaded NCs showed sustained release profile as compared to their pure forms. Oral administration of thymoquinone, metformin and their nanoformulations significantly decreased blood glucose level and glycated haemoglobin; and improved the lipid profile of diabetic rats as compared to diabetic control rats. Thymoquinone-loaded NCs (containing 10, 20 and 40 mg of thymoquinone) produced dose-dependent antihyperglycemic effect and this effect was comparable to thymoquinone and metformin. In conclusion, thymoquinone nanocapsules (actually containing half of the doses of thymoquinone) produced better antihyperglycemic effect in type-2 diabetic rats as compared to thymoquinone alone.

006 Topical Abdominal Application of Curcumin-containing Nanoparticles Protects Erectile Function and Correlates with Corporal Expression of Inflammatory Markers (HO-1 and Nf- kB) in a Rat Model of Type-2-diabetes

Although PDE5 inhibitors are the first line of therapy for men with erectile dysfunction (ED), patients with type 2 diabetes (T2D) are often refractory to this treatment. Chronic inflammation resulting from T2D contributes to the development of ED and curcumin, a natural anti-inflammatory compound, has recently been shown to have an effect on erectile function; however it is a molecule that exhibits poor oral bioavailability. To overcome this obstacle we designed a transdermal drug delivery system using nanoparticles to release curcumin (curc-NP) into the systemic blood circulation. The objective of this study is to investigate if curc-NP applied topically penetrate the skin and protect erectile function in a T2D rat model. Furthermore, we sought to study whether curcumin modulated the expression of erectile, inflammation and calcium sensitization markers in the corporal tissue. Zucker Diabetic Fat rats at 20 weeks of age were used as a model of T2D-related ED (3 groups; n=5). Treatment consisted of 6 applications over a 2 week period of curc-NP dispersed in coconut oil to the shaved rat abdomen (4 mg curcumin per application). Penetration of NP and curcumin release was confirmed by histology and in vivo multiphoton microscopy. Erectile function was determined by ICP/BP following cavernous nerve stimulation. Corporal tissue was removed after the surgery and total RNA was isolated using Trizol. Expression of markers of inflammation, erectile function, and smooth muscle calcium sensitization was assessed by Quantitative RT-PCR.

Contributions of Material Properties and Structure to Increased Bone Fragility for a Given Bone Mass in the UCD-T2DM Rat Model of Type 2 Diabetes.

Adults with type 2 diabetes (T2D) have a higher fracture risk for a given bone quantity, but the mechanisms remain unclear. Using a rat model of polygenic obese T2D, we demonstrate that diabetes significantly reduces whole-bone strength for a given bone mass (μCT-derived BMC), and we quantify the roles of T2D-induced deficits in material properties versus bone structure; ie, geometry and microarchitecture. Lumbar vertebrae and ulnae were harvested from 6-month-old lean Sprague-Dawley rats, obese Sprague-Dawley rats, and diabetic obese UCD-T2DM rats (diabetic for 69 ± 7 days; blood glucose >200 mg/dL). Both obese rats and those with diabetes had reduced whole-bone strength for a given BMC. In obese rats, this was attributable to structural deficits, whereas in UCD-T2DM rats, this was attributable to structural deficits and to deficits in tissue material properties. For the vertebra, deficits in bone structure included thinner and more rod-like trabeculae; for the ulnae, these deficits included inefficient distribution of bone mass to resist bending. Deficits in ulnar material properties in UCD-T2DM rats were associated with increased non-enzymatic crosslinking and impaired collagen fibril deformation. Specifically, small-angle X-ray scattering revealed that diabetes reduced collagen fibril ultimate strain by 40%, and those changes coincided with significant reductions in the elastic, yield, and ultimate tensile properties of the bone tissue. Importantly, the biomechanical effects of these material property deficits were substantial. Prescribing diabetes-specific tissue yield strains in high-resolution finite element models reduced whole-bone strength by a similar amount (and in some cases a 3.4-fold greater amount) as the structural deficits. These findings provide insight into factors that increase bone fragility for a given bone mass in T2D; not only does diabetes associate with less biomechanically efficient bone structure, but diabetes also reduces tissue ductility by limiting collagen fibril deformation, and in doing so, reduces the maximum load capacity of the bone. © 2018 American Society for Bone and Mineral Research.

Whitening and Impaired Glucose Utilization of Brown Adipose Tissue in a Rat Model of Type 2 Diabetes Mellitus

Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by 18F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic 18F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. 18F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased 18F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.

Antioxidant potential of Xylopia aethiopica fruit acetone fraction in a type 2 diabetes model of rats

The fruit decoction of Xylopia aethiopica (Dunal) A. Rich. is widely used for the treatment of diseases associated with oxidative stress such as diabetes, particularly in Africa. The present study was aimed to investigate the effects of X. aethiopica fruit acetone (XAFA) fraction in ameliorating oxidative stress in a type 2 diabetes (T2D) model of rats. The crude X. aethiopica fruit ethanolic extract was fractionated using solvents with increasing polarity and acetone fraction showed significantly (p<0.05) higher in vitro antioxidant potentials which were measured by (1,1-diphenyl-2-picrylhydrazyl radical (DPPH), hydroxyl radical (HRS) and nitric oxide (NO) assays compared to other fractions. It was then subjected to in vivo antioxidant study in a T2D rat model. Acetone fraction depicted potent in vitro antioxidant actions (IC50: DPPH: 19.82±0.73μg/mL; HRS: 25.34±6.19μg/mL; NO: 14.45±2.44μg/mL) compared to other fractions. Additionally, a significant (p<0.05) and dose-dependent improvement on the in vivo antioxidant status was observed in the animals in diabetic treated groups (DXAL, DXAH) compared to the diabetic control (DBC) group. The results of our study suggest that XAFA possesses potent antioxidant potential and could be used to ameliorate oxidative stress associated metabolic complications such as T2D.

Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes

Caloric restriction rapidly reverses type 2 diabetes (T2D), but the mechanism(s) of this reversal are poorly understood. Here we show that 3days of a very-low-calorie diet (VLCD, one-quarter their typical intake) lowered plasma glucose and insulin concentrations in a rat model of T2D without altering body weight. The lower plasma glucose was associated with a 30% reduction in hepatic glucose production resulting from suppression of both gluconeogenesis from pyruvate carboxylase (VPC), explained by a reduction in hepatic acetyl-CoA content, and net hepatic glycogenolysis. In addition, VLCD resulted in reductions in hepatic triglyceride and diacylglycerol content and PKCɛ translocation, associated with improved hepatic insulin sensitivity. Taken together, these data show that there are pleotropic mechanisms by which VLCD reverses hyperglycemia in a rat model of T2D, including reduced DAG-PKCɛ-induced hepatic insulin resistance, reduced hepatic glycogenolysis, and reduced hepatic acetyl-CoA content, PC flux, and gluconeogenesis.

Anti-Diabetic Potential of Ocimum gratissimum Leaf Fractions in Fortified Diet-Fed Streptozotocin Treated Rat Model of Type-2 Diabetes

Background: Ocimum gratissimum (OG) is used in the traditional management of diabetes in Nigeria. This study investigated the anti-diabetic potential of OG leaf fractions (OGLF) in a rat model of Type-2 diabetes (T2D). Methods: Methanol crude extract of OG leaf was fractionated with solvents of increasing order of polarity (n-hexane, chloroform, ethyl-acetate, n-butanol and water). The anti-diabetic potential of the fractions was evaluated in vivo. T2D was induced in Albino Wistar rats and treated with OGLF. Results: The T2D rats showed significant elevation in serum levels of fasting blood glucose (FBG), liver and kidney function biomarkers. At 4-week of intervention with OGLF, the untreated diabetic control group maintained severe hyperglycaemia in the presence of 61.7% serum insulin, 17.3% pancreatic β-cell function (HOMA-β) and 51.5% Insulin sensitivity. The glucose tolerance ability was enhanced in the n-butanol-fraction (OGb) treated group. With 74.8% available serum insulin and 38.6% improvement in insulin sensitivity, the OGb treated group had a 63.5% reduction in FBG and it was found to be most effective as it ameliorates a majority of the changes caused in the studied parameters in diabetic rats. Conclusions: The data from this study suggest that OGb fraction is a potential candidate for the development of an effective drug for the management of T2D.