Dexamethasone-induced Insulin Resistance Research Articles

Dexamethasone-Induced Insulin Resistance Attenuation by Oral Sulfur-Oxidovanadium(IV) Complex Treatment in Mice.

Vanadium compounds are known to exert insulin-enhancing activity, normalize elevated blood glucose levels in diabetic subjects, and show significant activity in models of insulin resistance (IR). Faced with insulin resistance, the present work investigates the antidiabetic performance of a known oxidovanadium(IV)-based coordination compound-[VIVO(octd)]-and effects associated with glucocorticoid-induced insulin resistance in mice. The effects of [VIVO(octd)] were evaluated in a female Swiss mice model of insulin resistance induced by seven days of dexamethasone treatment in comparison with groups receiving metformin treatment. Biological assays such as hematological, TyG index, hepatic lipids, glycogen, oxidative stress in the liver, and oral glucose tolerance tests were evaluated. [VIVO(octd)] was characterized with 51V NMR, infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy, and mass spectrometry (ESI-FT-MS). The [VIVO(octd)] oral treatment (50 mg/kg) had an antioxidant effect, reducing 50% of fast blood glucose (p < 0.05) and 25% of the TyG index, which is used to estimate insulin resistance (p < 0.05), compared with the non-treated group. The oxidovanadium-sulfur compound is a promising antihyperglycemic therapeutic, including in cases aggravated by insulin resistance induced by glucocorticoid treatment.

Role of Hentriacontane on dexamethasone-induced insulin resistance in rats

BackgroundThe worldwide incidence of morbidity and mortality linked to diabetes mellitus is on the ascent, with insulin resistance (IR) standing out as a key characteristic. Given the restricted safety and effectiveness observed in current therapeutic approaches, there exists a demand for novel anti-diabetic pharmaceuticals. This study aims to explore the impact of Hentriacontane, a naturally occurring long-chain alkane hydrocarbon, in an experimental model of IR induced by dexamethasone. The animals were administered dexamethasone (0.08 mg/kg b.w. s.c.) for six weeks to produce IR in the experimental animals. The animals distributed into five groups (n = 6) were: Normal group, IR group, IR + Hentriacontane low dose (2 mg/kg b.w./day p.o.), IR + Hentriacontane high dose (5 mg/kg b.w./day p.o.), and IR + Metformin (250 mg/kg b.w./day p.o.). Following the experimental period, blood/serum samples were taken for the assessment of various biochemical parameters, and a histopathological investigation of the pancreas was carried out. ResultsThe inhibitory concentration (IC50) value of Hentriacontane in various in-vitro assays targeting anti-diabetic and anti-oxidant effects indicates its efficacy in mitigating diabetes and scavenging free radicals. Findings from in-vivo studies demonstrate that this phytoconstituent notably lowers fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) levels in dexamethasone-induced diabetic rats. Administration of hentriacontane effectively counteracts dexamethasone-induced impairments in oral glucose tolerance tests. Further, Hentriacontane normalizes lipid profiles and restores beta-cell function in diabetic rats. ConclusionThis study has provided scientific support and evidence that Hentriacontane has a positive hypoglycemic impact on insulin-resistant rats induced by dexamethasone. Additional studies are required to ascertain the most effective dosage, duration of therapy and molecular mode of action.

Insulin-sensitizing and antioxidant effects of &lt;i&gt;Ethulia&lt;/i&gt; &lt;i&gt;conyzoïdes&lt;/i&gt; aqueous extract in dexamethasone-induced insulin resistant rats

Rising the prevalence of type 2 diabetes mellitus in sub-saharian Africa has necessitated surveys of antidiabetic medicinal plants. Ethulia conyzoïdes is a plant widely used in traditional medicine to treat diabetes. However, the different mechanisms by which it exerts its antidiabetic effects remain unknown. Thus, this study aimed to investigate the effect of Ethulia conyzoïdes aqueoux extract on dexamethasone-induced insulin resistance in Wistar rats. Insulin resistance was induced by intraperitoneal injection of dexamethasone (1mg/kg) for 8 days and the animals received simultaneously, orally, distilled water (insulin resistant control group) and, metformin (100 mg/kg) or Ethulia conyzoïdes aqueoux extract at doses of 133 and 266 mg/kg. Normal control rats received NaCl 0.9% (intraperitoneal by injection) and distilled water orally. Insulin sensitivity, total cholesterol, triglycerides, transaminases activity and redox status were evaluated. Results showed a significant reduction of insulin tolerance (p&lt;0.001), a drastic increased of transaminase activity (p&lt;0.05), hyperlipidemia, and a great potentiation of liver antioxidant enzymes (GSH, SOD and catalase) in insulin resistant control group. Ethulia conyzoïdes aqueoux extract markedly improved insulin sensitivity and reversed all the modified parameters. This study demonstrated the efficacy of Ethulia conyzoïdes aqueoux extract to improve insulin sensitivity and manage biochemical disorders induced by insulin resistance. Short term administration of dexamethasone appears to stimulate the first line antioxidant defense in order to counteract oxidative stress, meaning that Ethulia conyzoïdes aqueoux extract inhibited free radicals production.

Comparative Therapeutic Effect of Single/Combined Administration of Saxagliptin, Metformin and Intranasal Insulin on Dexamethasone Induced Insulin Resistance in Albino Wistar Rat Model.

Glucocorticoids have therapeutic benefits in the management of several inflammatory and immunological disorders. Despite these medicinal effects, they have the drawback of causing metabolic disorders such as hyperglycemia, insulin resistance etc., which is known to be a key indicator of metabolic syndrome. Metabolic syndrome is a major predisposing factor to type 2 diabetes mellitus and cardiomyopathy. This study was designed to compare and evaluate the effects of saxagliptin, metformin and intranasal insulin (when used singly or in combination) on dexamethasone induced insulin resistance. Fifty-six female rats were randomly assigned into eight groups. Group 1 represented the control; Group 2 was administered with dexamethasone (1mg/kg) (untreated); Group 3 received dexamethasone + intranasal insulin (2IU); Group 4 received dexamethasone + intranasal insulin + metformin (40mg/kg); Group 5; received dexamethasone + intranasal + saxagliptin (8mg/kg); Group 6 received dexamethasone + metformin (40mg/kg); Group 7 received dexamethasone + saxagliptin (8mg/kg); Group 8 received dexamethasone + saxagliptin(8mg/kg) + metformin(40mg/kg). Treatments were given for one week. At the end of the study, blood samples were collected for biochemical assays and pancreas excised for histological examination. Dexamethasone (1mg/kg) induced hyperglycemia, hyperinsulinemia, dyslipidemia, impaired glucose tolerance and disrupted the structural integrity of the pancreas. Treatment with saxagliptin, metformin and their combination significantly decreased blood glucose level, decreased LDL Level and improved glucose tolerance. The selected hypoglycemic agents used in present study ameliorate the dexamethasone induced hyperglycemia and insulin resistance of which the combination of metformin with saxagliptin showed greater efficacy.

Arctostaphylos uva-ursi L. leaves extract and its modified cysteine preparation for the management of insulin resistance: chemical analysis and bioactivity

Bearberry (Arctostaphylos uva-ursi L.) is a perennial plant of the heather family (Ericaceae). The leaves are dominated by arbutin, phenol carbonic acids flavonoids, saponins, etc. It was previously shown that the bearberry leaves extract reduced blood glucose level in healthy animals under glucose overload, so it need to be studied more detail. The aim of the study was to investigate the chemical composition and the effect of dry alcohol extract from bearberry leaves, which enriched with cysteine, on the rats pancreas under experimental dexamethasone-induced insulin resistance (IR). Arctostaphylos uva-ursi L. leaves extract and its modified cysteine preparation were obtained according to the developed method with 50% ethanol solution. Their phytochemical profile, hypoglycaemic and pancreatic protective effect were investigated. Phenologlycoside (arbutin), phenolic carboxylic acid (gallic acid), 5 flavonoids and 4 hydroxycinnamic acids were identified and quantified in the extracts by HPLC. Present data revealed that bearberry leaves alcoholic dry extract enriched with cysteine has a hypoglycaemic and pancreatic protective effect in treated animals under dexamethasone-induced IR model. Treatment improved hyperglycaemia, insulin resistance and beta cell reduction induced by dexamethasone injections.Graphical

Efficacy of Emilia coccinea aqueous extract on inhibition of α-amylase enzyme activity and insulin resistance in dexamethasone treated-rats

BackgroundDiabetes mellitus is one of the most common chronic metabolic diseases throughout the world, characterized by hyperglycemia and insulin resistance. The purpose of this study was to evaluate the effects of aqueous extract of Emilia coccinea (AEEC) leaves on dexamethasone-induced insulin resistance in rats and on in vitro α-amylase enzyme activity. MethodsInsulin resistance was induced by intraperitoneal injection of dexamethasone (1 mg/kg) for 8 days in rats. The animals were concomitant received extracts at doses of 107.5; 215; 430 mg/kg for this period. At the end of the treatment, blood glucose level, lipid profile, transaminases, triglyceride glucose (TyG) index, body mass and relative organ weight were evaluated. ResultsThe results showed that AEEC inhibits α-amylase enzyme with an IC50 of 34.10 μg/ml in vitro. AEEC significantly reduced blood glucose level, triglycerides, TyG index, total and LDL cholesterol, liver weight and increased HDL cholesterol. Moreover, it reduced ALAT and ASAT activity. These parameters were strongly modify by dexamethasone. ConclusionAEEC plays antidiabetic roles by ameliorating insulin resistance and reducing postprandial blood glucose level through α-amylase enzyme inhibition.

Evaluation of Toxicity and Antidiabetic Activity of Ethanolic Extract of Flowers of Moringa oleifera against Dexamethasone Induced Hyperglycemia in Albino Wistar Rats

Diabetes is a defect in the ability of the body to convert glucose (sugar) to energy. Glucose is the main source of energy in our body. When food is digested it is metabolized into fats, proteins, or carbohydrates. Glucose is then transferred to the blood and is used by the cells for energy production. To investigate the antidiabetic effect ethanolic extracts of flowers of Moringa oleifera against dexamethasone-induced insulin resistance in wistar albino rats. To study the antidiabetic effect, flowers of Moringa oleifera were collected and authenticated, extracted and investigated for acute toxicity and dexamethasone induced hyperglcemia. The animals treated with EEMOF at a dose of 100mg/kg and 200mg/kg prevented the development of hyperglycemia, hypercholesteremia and hypertriglyceridemia in dexamethasone induced insulin resistance models. Oral administration of Moringa oleifera 100mg/kg and 200mg/kg reduces serum glucose, triglyceride, total cholesterols and LDL concentration and improve the concentration of HDL in dexamethasone administered rats. The lignin Moringa oleifera showed significant anti-diabetic effect in rats after oral administration. The present study demonstrated that Moringa oleifera could be useful in Management of diabetes associated with abnormalities in lipid profiles. Further study need to isolate, identify the active compounds and find out the possible mechanism of actions.

Coriander Oil Reverses Dexamethasone-Induced Insulin Resistance in Rats.

In the present study, we aimed to investigate the effect of coriander oil on dexamethasone-induced insulin resistance in rats and characterize its chemical composition using gas chromatography-mass spectrometry (GC-MS). Rats were divided into five groups (n = 6): Normal control, insulin resistance (IR) control, IR + metformin (50 mg/kg/day, PO, Per Oral), IR + coriander oil low dose (0.5 mL/kg, PO), and IR + coriander oil high dose (1 mL/kg, PO). IR groups were injected with a dose of 10 mg/kg dexamethasone subcutaneously for four consecutive days. All groups received either vehicle or drugs daily for four days. Animal weights and pancreatic weights were measured, and oral glucose tolerance test was performed at the end of study. Fasting glucose, triglycerides (TG), total cholesterol (TC), HDL and insulin levels in serum, MDA, and GSH levels in pancreatic tissue were measured and HOMA-IR was calculated. Immunoexpression of apoptosis markers BAX, and BCL2 was measured in pancreatic tissues and BAX/BCL2 ratio was calculated. Histopathological examination of pancreatic tissues was also performed. Pancreatic weight, serum HDL, pancreatic GSH, and BCL2 were decreased while serum glucose, insulin, TG, TC levels, AUC of OGGT, HOMA-IR, pancreatic MDA, BAX, and BAX/BCL2 ratio were increased in IR rats. Histopathological examination showed congestion, vacuolation and hemorrhage in pancreatic islets. These changes were reversed by metformin and the high dose of coriander oil treatments. The obtained activities could be attributed to the presence of 21 volatile compounds, identified by GC-MS. Our study indicates that coriander oil can be used as an adjuvant antihyperglycemic agent in type 2 diabetes. Further experiments are needed to determine the therapeutic dose and the treatment time.

The effect of Madhumeha Kusumakar Rasa – an Ayurved medicine – in insulin resistance

Madhumeha Kusumakar Rasa (MKR) is an Ayurved formulation having a strong pharmacological base for diabetes management. This study aimed to validate MKR's efficacy in dexamethasone-induced insulin resistance (IR). Albino Wistar rats were divided into four groups. Group 1 served as the normal control, Group 2 received dexamethasone 1.5mg/kg (i.p.), Group 3 received dexamethasone and metformin 200mg/kg (p.o.), and Group 4 received dexamethasone and MKR 236mg/kg (p.o.). Animals were evaluated for serum glucose levels and glucose tolerance, serum insulin, Homeostatic model assessment of insulin resistance (HOMA-IR), Homeostatic model assessment of insulin sensitivity (HOMA-IS), fasting glucose to insulin ratio (FGIR), and lipid parameters. Pancreas, liver, and kidneys were evaluated for reduced Glutathione (GSH) and Malondialdehyde (MDA) levels. These tissues were also evaluated for histopathological changes. MKR showed significant improvement in serum glucose and glucose tolerance, serum insulin and HOMA-IR, HOMA-IS, and FGIR. It also showed a significant improvement in lipid parameters as compared to the dexamethasone-treated group. It prevented depletion of GSH levels and elevation in MDA levels. These effects were supported by histopathological analysis. MKR treatment significantly attenuated dexamethasone-induced IR. This study validates the mechanism of the anti-diabetic potential of MKR.

Ocimum gratissimum enhances insulin sensitivity in male Wistar rats with dexamethasone-induced insulin resistance.

The antidiabetic activities of Ocimum gratissimum (OG) leaf extract are well documented in experimental diabetes induced by beta cell destruction resulting in hypoinsulinemia. There is however paucity of data on its effect in conditions characterized by hyperinsulinemia. This study therefore investigated the effect of OG on insulin resistance induced by dexamethasone in male Wistar rats. Twenty male Wistar rats grouped as control, normal + OG, Dex and Dex + OG were used. Control and normal + OG received normal saline while Dex and Dex + OG received dexamethasone (1mg/kg, i.p) followed by distilled water or OG (400mg/kg) for 10days. Levels of fasting blood glucose (FBG), insulin, HOMA-IR, liver and muscle glycogen, hexokinase activities, hepatic HMG CoA reductase activity were obtained. Histopathology of pancreas and liver tissues was carried out using standard procedures. Body weight reduced significantly in the Dex and Dex + OG groups compared with the control. FBG (147.8 ± 9.93mg/dL), insulin (2.98 ± 0.49 µIU/ml) and HOMA-IR (1.11 ± 0.22) of Dex animals were higher than the control (FBG = 89.22 ± 6.53mg/dL; insulin = 1.70 ± 0.49 µIU/ml; HOMA-IR = 0.37 ± 0.04). These were significantly reduced in the Dex + OG (FBG = 115.31 ± 5.93mg/dL; insulin = 1.85 ± 0.11µIU/ml; HOMA-IR = 0.53 ± 0.08) compared with Dex. Glycogen content and hexokinase activities were increased in the Dex + OG. Increased pancreatic islet size, hepatic steatosis and HMG Co A reductase activity were observed in the Dex but reduced in Dex + OG. OG promotes cellular glucose utilization and reduces hepatic fat accumulation in Wistar rats with insulin resistance induced by dexamethasone. Further study to identify the involved signal transduction will throw more light on the observed effects.

Protective Effects of Garcinia kola Stem Barks Aqueous Extract on Metabolic Disorders and Oxidative Stress in Dexamethasone-Induced Insulin Resistance in Rat

Aim: To evaluate how the aqueous extract of Garcinia kola (GK) stem bark impacted dexamethasone-induced insulin resistance in male rats. Method: This work was completed in 2020. A phytochemical screening of the extract was first carried out. Using acute and subacute studies (11 days), the effect of the extract was evaluated at 100 mg/kg and 200 mg/kg, on dexamethasone-induced hyperglycemic rats. Glycemia was measured before and after treatment in both studies, while histological examination for isolated liver, kidneys and pancreas was performed, body weight and some internal organs determined, and biochemical assays. for blood samples were performed only for the subacute study. Results and Conclusion : An examination of the plant's chemistry showed the presence of alkaloids, phenolic compounds, flavonoids, saponins, coumarins, anthocyanins, and anthraquinones. GK extract decreased the Area Under Curve induced by dexamethasone (DEXA) injection both in the acute and in the subacute test. The extract and glibenclamide decrease the alanine amino transferase activity induced by DEXA. In both the glibenclamide and extract groups, total protein levels increased. The uric acid level in all dexamethasone-treated rats remains elevated when compared to the normal control group. Superoxide dismutase activity increased in both groups treated with the extract or glibenclamide. DEXA induced islet hypertrophy in the pancreas, vascular congestion, cytolysis, and vacuolation of hepatocytes. The kidney presented leucocyte infiltration and a decrease in glomerular cell density. All those abnormalities were improved by the administration of glibenclamide or the extract of Garcinia kola.

Pushpraj Mujalde, *Sourabh Jain, Neha Jain, Dr. Swapnil Sharma, Dr. Jaya Dwivedi

Abstract-Diabetes is a defect in the ability of the body to convert glucose (sugar) to energy. Glucose is the main source of energy in our body. When food is digested it is metabolized into fats, proteins, or carbohydrates. Glucose is then transferred to the blood and is used by the cells for energy production. To investigate the antidiabetic effect ethanolic extracts of flowers of Moringa oleifera against dexamethasone induced insulin resistance in wistar albino rats. To study the antidiabetic effect, flowers ofMoringaoleiferawerecollectedandauthenticated, extracted and investigated for acute toxicity and dexamethasone induced hyperglcemia. The animals treated with EEMOF at a dose of 100mg/kg and 200mg/kg prevented the development ofhyperglycemia,hypercholesteremiaandhypertriglyceridemia in dexamethasone induced insulin resistance models. Oral administration of Moringa Oleifera 100mg/kg and 200mg/kg reduces serum glucose, triglyceride, total cholesterols and LDLconcentration and improve the concentration of HDLin dexamethasone administered rats. The lignin Moringa Oleifera showed significant anti-diabetic effect in rats after oral administration. The present study demonstrated that Moringa Oleifera could be useful in Management of diabetes associated with abnormalities in lipid profiles. Further study need to isolate, identify the active compounds and find out thepossiblemechanismofactions.

Obesity Augments Glucocorticoid-Dependent Muscle Atrophy in Male C57BL/6J Mice.

Glucocorticoids promote muscle atrophy by inducing a class of proteins called atrogenes, resulting in reductions in muscle size and strength. In this work, we evaluated whether a mouse model with pre-existing diet-induced obesity had altered glucocorticoid responsiveness. We observed that all animals treated with the synthetic glucocorticoid dexamethasone had reduced strength, but that obesity exacerbated this effect. These changes were concordant with more pronounced reductions in muscle size, particularly in Type II muscle fibers, and potentiated induction of atrogene expression in the obese mice relative to lean mice. Furthermore, we show that the reductions in lean mass do not fully account for the dexamethasone-induced insulin resistance observed in these mice. Together, these data suggest that obesity potentiates glucocorticoid-induced muscle atrophy.

Rational Design, Synthesis and Evaluation of Novel Rodanine Derivatives for Antihyperglycemic Activity

A new series of rhodanines with phenyl substitution at the fifth position of rhodanine ring were designed targeting the PPAR-γ receptor for their possible antihyperglycemic activity. The rational design and molecular modeling studies were performed against PPAR-γ (PDB ID: 2PRG). The compounds were docked and thereafter subjected for the synthesis via dithiocarbamate formation followed by Knoevenagel condensation. Structures were confirmed by IR, NMR and Mass spectral analysis. All synthesized compounds were screened for in vitro glucose uptake assay using isolated hepatocytes. The Compounds A5 and B5 having N-(p-methoxy benzyl) at third position of rhodanine ring showed good glucose uptake activity. These two compounds were further studied for the in vivo antihyperglycemic study against dexamethasone induced insulin resistance. The compounds were tested at single dose level of 10 mg/kg, per oral. The compound B5 showed significant antihyperglycemic activity when compared with the standard drug, pioglitazone. The illustration, about the molecular design, synthesis, analysis, glucose uptake study and in vivo antihyperglycemic activity is reported here along with the structure activity relationships.

Protective Effects of Aqueous Extract of Baillonella toxisperma Stem Bark on Dexamethasone-Induced Insulin Resistance in Rats

The aim of this study was to evaluate the effects of the aqueous extract of Baillonella toxisperma stem bark on dexamethasone-induced insulin resistance in rats. A quantitative phytochemical study was done on the aqueous extract of Baillonella toxisperma for the total phenol, flavonoid, and flavonol determination. Insulin resistance was induced by intraperitoneal injection of dexamethasone (1 mg/kg) for 8 days, one hour before oral administration of different treatments (extract at doses of 60, 120, and 240 mg/kg and metformin at 40 mg/kg). During the test, body weight and blood glucose level were evaluated on days 1 and 8. At the last day of treatment, the glucose tolerance test was performed in rats; after that, blood samples were collected for triglycerides, total cholesterol, LDL and HDL cholesterols, transaminases (ALT and AST), and total protein level determination. Organs (heart, liver, pancreas, and kidneys) were also collected for the relative organ weight determination. The results showed that the aqueous extract of B. toxisperma is rich in total phenols, flavonoids, and flavonols. This extract significantly reversed the metabolic alterations (lipid profile, protein level, and transaminase activity) induced by dexamethasone in rats. At doses of 120 and 60 mg/kg, Baillonella toxisperma also significantly decreases (p < 0.05; p < 0.01) postprandial hyperglycemia in insulin resistance rats. The results suggest that Baillonella toxisperma can manage insulin resistance and may be useful for the treatment of type 2 diabetes mellitus.

Dexamethasone-Induced Mitochondrial Dysfunction and Insulin Resistance-Study in 3T3-L1 Adipocytes and Mitochondria Isolated from Mouse Liver.

Dexamethasone is a glucocorticoid analog, which is reported to induce insulin resistance and to exacerbate diabetic symptoms. In this study, we investigated the association between mitochondrial dysfunction and the pathophysiology of dexamethasone-induced insulin resistance. An insulin resistance model in 3T3-L1 adipocyte was established by 48-h treatment of 1 μM dexamethasone, followed with the detection of mitochondrial function. Results showed that dexamethasone impaired insulin-induced glucose uptake and caused mitochondrial dysfunction. Abnormality in mitochondrial function was supported by decreased intracellular ATP and mitochondrial membrane potential (MMP), increased intracellular and mitochondrial reactive oxygen species (ROS) and mtDNA damage. Mitochondrial dynamic changes and biogenesis were suggested by decreased Drp1, increased Mfn2, and decreased PGC-1, NRF1, and TFam, respectively. The mitochondrial DNA (mtDNA) copy number exhibited no change while the mitochondrial mass increased. In agreement, studies in isolated mitochondria from mouse liver also showed dexamethasone-induced reduction of mitochondrial respiratory function, as suggested by decreased mitochondrial respiration controlling rate (RCR), lower MMP, declined ATP synthesis, opening of the mitochondrial permeability transition pore (mPTP), damage of mtDNA, and the accumulation of ROS. In summary, our study suggests that mitochondrial dysfunction occurs along with dexamethasone-induced insulin resistance in 3T3 L1 adipocytes and might be a potential mechanism of dexamethasone-induced insulin resistance.

Effect of intranasal insulin on peripheral glucose profile in dexamethasone-induced insulin resistance in Wistar rats

This study evaluates the therapeutic potential of intranasal insulin (INI) in dexamethasone-induced insulin resistance in Wistar rats. In the first phase of the study, thirteen, healthy, untreated male Wistar rats were divided into 2 groups and administered either vehicle (0.9% Normal saline, 20 µl) or insulin (2 IU) intranasally to assess intranasal delivery of insulin in brain. In the second phase of experiments, to evaluate the acute effects of intranasal insulin on peripheral blood glucose, intranasal or intraperitoneal insulin was co-administered with or without dexamethasone 10 mg/kg to 26 male Wistar rats and blood glucose monitored. To evaluate effect of intranasal insulin in peripheral metabolic disease model, insulin or vehicle was administered via intranasal or intraperitoneal (IP) route to control or dexamethasone (Dex)-treated (0.5 mg/kg, IP) female Wistar rats for seven consecutive days. Twenty-four hours after last dose, trunk blood was collected via cardiac puncture. Biochemical assay of glucose, lipid and insulin was performed on serum while enzyme activity – glucokinase and glucose-6-phosphatase (G6Pase) or lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PDH) were assayed from liver and brain homogenates respectively. Acute intranasal but not intraperitoneal insulin elevated brain insulin after 30 min. In animals administered single dose of 10 mg/kg dexamethasone, intranasal and intraperitoneal insulin lowered blood glucose within one hour. However, only the former’s effect was maintained at the 3rd and fourth hour. Dex-induced hyperglycemia was associated with increased hepatic glucose-6-phosphatase activity and decreased high-density lipoprotein (HDL), these effect were attenuated by subchronic (INI) administration. Also INI did not induce oxidative stress in the brain which suggests no brain damage during the period of study. Subchronic administration of INI was able to reduce the effect of Dex-induced hyperglycemia that is associated with increased hepatic glucose-6-phosphatase activity and decreased high-density lipoprotein (HDL) without damage to the brain. We demonstrate the potential of brain targeting with intranasal insulin in a rat model of insulin resistance and peripheral metabolic disease.

Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance

Glucocorticoids (GCs) are potent therapeutic agents frequently used for treatment of number of conditions, including hematologic, inflammatory, and allergic diseases. Both their therapeutic and adverse effects display significant interindividual variation, partially attributable to genetic factors. We have previously isolated a seven-gene region of rat chromosome 8 sensitizing to dexamethasone (DEX)-induced dyslipidemia and insulin resistance (IR) of skeletal muscle. Using two newly derived congenic strains, we aimed to investigate the effect of one of the prime candidates for this pharmacogenetic interaction, the Zbtb16 gene. Adult male rats of SHR-Lx.PD5PD-Zbtb16 (n = 9) and SHR-Lx.PD5SHR-Zbtb16 (n = 8) were fed standard diet (STD) and subsequently treated with DEX in drinking water (2.6 µg/ml) for 3 days. The morphometric and metabolic profiles of both strains including oral glucose tolerance test, triacylglycerols (TGs), free fatty acids, insulin, and C-reactive protein levels were assessed before and after the DEX treatment. Insulin sensitivity of skeletal muscle and visceral adipose tissue was determined by incorporation of radioactively labeled glucose. The differential segment of SHR-Lx.PD5SHR-Zbtb16 rat strain spans 563 kb and contains six genes: Htr3a, Htr3b, Usp28, Zw10, Tmprss5, and part of Drd2. The SHR-Lx.PD5PD-Zbtb16 minimal congenic strain contains only Zbtb16 gene on SHR genomic background and its differential segment spans 254 kb. Total body weight was significantly increased in SHR-Lx.PD5PD-Zbtb16 strain compared with SHR-Lx.PD5SHR-Zbtb16 , however, no differences in the weights of adipose tissue depots were observed. While STD-fed rats of both strains did not show major differences in their metabolic profiles, after DEX treatment the SHR-Lx.PD5PD-Zbtb16 congenic strain showed increased levels of TGs, glucose, and blunted inhibition of lipolysis by insulin. Both basal and insulin-stimulated incorporation of radioactively labeled glucose into skeletal muscle glycogen were significantly reduced in SHR-Lx.PD5PD-Zbtb16 strain, but the insulin sensitivity of adipose tissue was comparable between the two strains. The metabolic disturbances including impaired glucose tolerance, dyslipidemia, and IR of skeletal muscle observed after DEX treatment in the congenic SHR-Lx.PD5PD-Zbtb16 reveal the Zbtb16 locus as a possible sensitizing factor for side effects of GC therapy.

Insulin resistance enhances the mitogen-activated protein kinase signaling pathway in ovarian granulosa cells.

The ovary is the main regulator of female fertility. Granulosa cell dysfunction may be involved in various reproductive endocrine disorders. Here we investigated the effect of insulin resistance on the metabolism and function of ovarian granulosa cells, and dissected the functional status of the mitogen-activated protein kinase signaling pathway in these cells. Our data showed that dexamethasone-induced insulin resistance in mouse granulosa cells reduced insulin sensitivity, accompanied with an increase in phosphorylation of p44/42 mitogen-activated protein kinase. Furthermore, up-regulation of cytochrome P450 subfamily 17 and testosterone and down-regulation of progesterone were observed in insulin-resistant mouse granulosa cells. Inhibition of p44/42 mitogen-activated protein kinase after induction of insulin resistance in mouse granulosa cells decreased phosphorylation of p44/42 mitogen-activated protein kinase, downregulated cytochrome P450 subfamily 17 and lowered progesterone production. This insulin resistance cell model can successfully demonstrate certain mechanisms such as hyperandrogenism, which may inspire a new strategy for treating reproductive endocrine disorders by regulating cell signaling pathways.

Hibiscus noldea (Malvaceae) Aqueous Extract Prevents Insulin Resistance and Protects Pancreatic Islets From Dexamethasone Damages in Rat.

&lt;p&gt;&lt;em&gt;Hibiscus noldea&lt;/em&gt; leaves-stems aqueous extract is used in Cameroonian traditional medecine to manage diabetes. To investigate the preventive effect of &lt;em&gt;Hibiscus noldea&lt;/em&gt; aqueous extract on dexamethasone-induced insulin resistance, the animals received one of the following treatments: distilled water (10 mL/kg), metformine (200 mg/kg), or &lt;em&gt;H. noldea&lt;/em&gt; (100 or 200 mg/kg) concomitantly with dexamethasone (0.5 mg/kg, ip) for ten days. Body weight was evaluated daily and blood glucose levels were measured. At the end of experiment, insulin sensitivity test was performed and lipid profile, transaminases Aspartate amino transferase, Alanin amino transferase, malondialdehyde, superoxide dismutase, catalase, and reduced glutathione were evaluated. Histological analysis of the liver was investigated to estimate glycogen content using Periodic Acid Schiff coloration and histomorphometry of pancreatic islets area was performed.&lt;/p&gt;&lt;p&gt;The administration of dexamethasone during ten days induced body weight loss, hyperglycaemia, insulinresistance, an imbalance in lipid profile, an increase in transaminases and oxidative stress. Dexamethasone treatment also induced an increase in the pancreatic islets area and depletion in the levels of hepatic glycogen. Concomitant administration of dexamethasone and the aqueous plant extract prevented the rise in blood glucose levels, reduced insulinresistance, improved lipid profile and oxidative status. The aqueous extract of &lt;em&gt;H. noldea&lt;/em&gt; prevented the use of glycogen storage and the increase in pancreatic islet area in dose dependent manner.&lt;/p&gt;&lt;p&gt;Conclusion: The stem leaves aqueous extract from &lt;em&gt;Hibiscus noldea&lt;/em&gt; have the ability to reduce insulinresistance via its antihyperglycaemic, hypolipidemic and antioxidant activities. These results justify the use of this extract in the management of diabetic state.&lt;/p&gt;