Decreased Plasma Insulin Levels Research Articles

Quercetin prevents kidney against diabetes mellitus (type 1) in rats by inhibiting TGF-β/apelin gene expression.

One of the main causes of diabetic nephropathy is oxidative stress induced by hyperglycemia. Apelin inhibits insulin secretion. Besides, renal expression of TGF-β is increased in diabetes mellitus (DM). The preventive effect of quercetin (Q) against renal functional disorders and tissue damage developed by DM in rats was assessed. Forty male Wistar rats were grouped into normal control (NC), normal + quercetin (NQ: quercetin, 50mg/kg/day by gavage), diabetic control (DC: streptozotocin, 65mg/kg, i.p.), diabetic + quercetin pretreatment (D + Qpre), and diabetic + quercetin post-treatment (D + Qpost). All samples (24-hour urine, plasma, pancreatic, and renal tissues) were obtained at the terminal of the experiment. Compared to NC and NQ groups, DM ended in elevated plasma and glucose levels, decreased plasma insulin level, kidney dysfunction, augmented levels of malondialdehyde, decreased level of reduced glutathione, reduced enzymatic activities of superoxide dismutase and catalase, elevated gene expression levels of apelin and TGF-β, also renal and pancreatic histological damages. Quercetin administration diminished entire the changes. However, the measure of improvement in the D + Qpre group was higher than that of the D + Qpost group. Quercetin prevents renal dysfunction induced by DM, which might be related to the diminution of lipid peroxidation, strengthening of antioxidant systems, and prevention of the apelin/ TGF-β signaling pathway.

Quercetin prevents rats from type 1 diabetic liver damage by inhibiting TGF-ꞵ/apelin gene expression

BackgroundHyperglycemia-induced oxidative stress is a significant contributor to diabetic complications, including hepatopathy. The current survey aimed to evaluate the ameliorative effect of quercetin (Q) on liver functional disorders and tissue damage developed by diabetes mellitus in rats. MethodsGrouping of 35 male Wistar rats was performed as follows: sham; sham + quercetin (sham + Q: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage); diabetic control (Diabetes: streptozotocin (STZ), 65 mg/kg, i.p.); diabetic + quercetin 1 (D + Q1: quercetin, 25 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection); and diabetic + quercetin 2 (D + Q2: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection). Body weight, food intake, and water intake were measured. Ultimately, the samples of plasma and urine, as well as tissue samples of the liver and pancreas were gathered for later assays. ResultsSTZ injection ended in elevated plasma blood glucose levels, decreased plasma insulin levels, liver dysfunction (increased activity levels of AST, ALT, and ALP, increased plasma levels of total bilirubin, cholesterol, LDL, triglyceride, decreased plasma levels of total protein, albumin and HDL), enhanced levels of malondialdehyde, diminished activities of antioxidant enzymes (superoxide dismutase, and catalase), reduced level of glutathione (GSH) increased gene expression levels of apelin and TGF-ꞵ, plus liver histological destruction. All these changes were diminished by quercetin. However, the measure of improvement in the D + Q2 group was higher than that of the D + Q1 group. ConclusionsQuercetin improved liver function after diabetes mellitus type 1, possibly due to reduced lipid peroxidation, increased antioxidant systems, and inhibiting the apelin/TGF-ꞵ signaling pathway.

The role of fenugreek seed extract in alleviating pancreatic toxic effects and altering glucose homeostasis induced by acetamiprid via modulation of oxidative stress, apoptosis, and autophagy

Acetamiprid (ACMP) is a second-generation neonicotinoid that has been extensively used in the last few years. The present study examined the toxic effects of ACMP on the pancreas and glucose homeostasis through the evaluation of histological and biochemical changes and the possible ameliorative role of fenugreek seed extract (FG). Fifty adult albino rats were divided into 5 groups: negative control, positive control, FG-treated, ACMP-treated, and ACMP + FG-treated groups by oral gavage for 12 weeks. The ACMP-treated group highlighted significant elevations in plasma glucose, glycosylated haemoglobin levels (HbA1c), serum amylase, and serum lipase, along with a decrease in plasma insulin levels. In addition, significant increases in tumour necrosis factor- alpha (TNF-α) and malondialdehyde (MDA) were associated with reductions in the levels of interleukin 10 (IL-10), glutathione peroxidase, and catalase. Moreover, glucose-6-phosphatase and glycogen phosphorylase were significantly increased, with a significant reduction in hexokinase and liver glycogen stores. These biochemical changes were associated with histological changes in pancreatic sections stained by haematoxylin and eosin, Masson stain, and Orcein stain. ACMP-treated cells showed a marked reduction in β- cell immune reactivity to insulin, with pronounced p53, and beclin 1 immune expression. The use of FG with ACMP induced partial protection except for hexokinase and glycogen phosphorylase.

SAT072 Choline Deprivation Aggravates Hyperglycemia And Fatty Liver In Non-obese Streptozocin-induced Diabetic Rats

Abstract Disclosure: C. Liapi: None. A. Kyriakaki: None. H. Al Humadi: None. R. Al-Saigh1: None. A. Al Humadi: None. A. Lazaris: None. Background: Choline deprivation (CD) is an established model of steatohepatitis. There is a strong association between non-alcoholic fatty liver disease and diabetes mellitus that has a significant impact on the global health system. The combined state of CD and diabetes can resemble common cases in clinical practice including parenteral nutrition, pregnancy, chronic liver disease malnutrition and/ or alcoholism in diabetic individuals. The aim of this study was to investigate the effects of choline deprivation on glycemic control, insulin signaling pathway and lipid metabolism in non-obese streptozocin-induced diabetic rats. Methods: Thirty-two male adult Wistar rats were divided into four groups; control, diabetes (DM), choline-deprived diet (CDD), and combined group (DM+CDD); DM was induced by intraperitoneal streptozotocin administration. Body weight, fasting blood glucose and plasma insulin levels, lipid profile, liver biochemistry, liver histopathology and gene expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), glucose transporters 2 & 4 (GLUT-2 & -4) in hepatic tissue, were assessed. Results: The combination group (CDD+DM) showed a significant increase in blood glucose associated with a significant decrease in plasma insulin level and evidence of dyslipidemia with a significant increase in liver enzymes, histopathology showed extensive micro- and macrovesicular steatosis and a significant decrease in weight gain versus the control, CDD and DM group. A significant increase was observed in gene expression of IR, IRS-1, GLUT-2, and GLUT-4 in all the experimental groups versus the control. Conclusion: The combination of choline deficiency and diabetes has drawn some new scenarios on insulin and some hepatic metabolic pathways: (i) plasma insulin resistance with progressive hyperglycemia and hyperlipidemia.(ii) attenuation of hepatic insulin resistance or sensitization of insulin signaling pathways in the liver, due to the hepatotoxic effects of choline deficiency that could ultimately simulate features of the metabolic syndrome, and (iii) experimentally simulation of metabolic conditions seem to act synergistically, leading to poor glycemic control along with aggravation of hepatic steatosis. Presentation: Saturday, June 17, 2023

Effects of Kudzu Root on Oxidative Stress and Inflammation in Streptozotocin-induced Diabetic Rats

Background: Oxidative stress and inflammation are strictly connected, and both perform an important role in the pathogenesis of diabetes mellitus (DM). Objectives: This research aimed to investigate the potential protective effect of kudzu root against oxidative stress and inflammation in a streptozotocin (STZ)-induced DM animal model. Methods: DM was induced in male Wistar rats by intraperitoneal injection of STZ (50 mg/kg body weight). The kudzu root (100 mg/kg BW) was administered orally after 1 week of STZ administration in diabetic animals (for 6 weeks). Results: The diabetic animals exhibited a significant increase in fasting blood glucose, tumor necrosis factor-alpha, and malondialdehyde levels. However, they exhibited a significant decrease in plasma insulin level, superoxide dismutase, and glutathione peroxidase activity. Administration of kudzu root to diabetic animals reversed these effects. Conclusion: The current study indicated that kudzu root has potent antidiabetic properties, likely through its anti-inflammatory and anti-oxidative properties in the STZ-diabetic rat model.

895-P: Effect of Long-Term Empagliflozin Therapy on Plasma Beta-Hydroxy Butyrate (ß-OHB)—Lack of Effect of Concomitant Insulin, GLP-1 Agonist, or Pioglitazone Therapy

Sodium-glucose transporter 2 (SGLT2) inhibitors are associated with increased risk of euglycemic diabetic ketoacidosis in T2DM. Possible mechanisms include increased lipolysis, elevated glucagon, and decreased plasma insulin levels. Therefore, concomitant high dose insulin as well as thiazolidinediones could potentially attenuate the rise in β-OHB because of anti-lipolytic effects. However, this has not been examined in the real-world clinical studies. We examined the effect of long-term Empagliflozin therapy on plasma β-OHB in veterans with T2DM. A retrospective chart review was performed in 43 subjects who had fasting β-OHB, C-peptide and detailed anthropometric measurements and were followed for 23 ± 2.5 months. Subjects were categorized into two groups based on fasting β-OHB concentrations (< or ≥2.8mg/dl). Eleven patients (24.4%) had high (6.03 ±1.22mg/dl) while 32 (74.6%) had normal β-OHB (1.42±0.09 mg/dL). There was no difference in age (59 ± 4 vs 62 ±2 yrs), BMI (35±1 vs 32 ±1 kg/m2), or the duration of diabetes (15 ± 3 vs 18±2 yrs) between the two groups. Subjects with higher β-OHB had higher HbA1c (8.9 ±0.7 vs 7.9 ± 0.3%, p<0.05). There was no difference in fasting C-peptide (3.2 ± 0.9 vs 3.5 ± 0.5ng/ml), total daily insulin dose (184± 43 vs 214±19 units/day), number of subjects on Pioglitazone (54 vs 35%) or GLP-1 agonist therapy (36 vs 52%) between the two groups. In conclusion, long-term therapy with Empagliflozin leads to elevated β-OHB in 25% of T2DM and it was associated with poor glycemic control. Concomitant insulin or pioglitazone therapy did not alter plasma β-OHB concentration. Disclosure L.C.Ortiz: None. J.Wortham: None. S.Pinkson: None. J.Trejo: None. A.S.Mendoza: None. X.Chen: None. D.Tripathy: None.

Insulin ameliorates dim blue light at night-induced apoptosis in hippocampal neurons via the IR/IRS1/AKT/GSK3β/β-catenin signaling pathway

In recent years, the damaging effects of night light pollution, one of the environmental pollutions, on memory has been attracting attention. However, the underlying molecular mechanisms by which light at night, especially blue light at night, impairs memory remains unclear. Here, a total of 42 C57BL6/J mice that exposed to no light at night, dim white light at night (dLAN-WL), or dim blue light at night (dLAN-BL) for 28 days. Behavioral data indicated that exposure to dLAN-BL resulted in severe recognition memory impairment, as evidenced by the reduced recognition index and discrimination index in the novel object recognition test. At the same time, we observed a decrease in plasma insulin levels. Consistent with these changes, we also observed that dLAN-BL reduced the number of neurons in the CA1, CA3 and DG regions of the hippocampus, up-regulated the mRNA expression levels of Bax, down-regulated the mRNA expression levels of Bcl-2, Bcl-xl and the protein expression level of pIRS1, pAKT, pGSK3β, β-catenin in the hippocampus. In vitro experiments, we found that insulin (10 nM) inhibited apoptosis and up-regulated the protein expression levels of pAKT, pGSK3β, β-catenin of HT22 cells induced by H2O2 (200 μM). However, these changes disappeared when the insulin receptors (IR) in HT22 cells were silenced. Taken together, our findings suggested that the impairment of memory in mice induced by dLAN-BL was mediated by insulin via the IR/IRS1/AKT/GSK3β/β-catenin pathway. Data AvailabilityAll data generated or analyzed during this study are included in this published article.

145-OR: Selenite Treatment Impacts Adipocyte Metabolism and Counteracts Detrimental Effects of Diet-Induced Insulin Resistance

The loss of insulin receptor (IR) in white adipose tissue (WAT) is a feature of type 2 diabetes. Previously, we have demonstrated that feeding mice a preventive selenium rich HFD (SRHFD) , while not influencing obesity development, counteracted diet-induced downregulation of IR and insulin resistance. This was caused by selenite-induced Glutathione peroxidase 3 (GPx3) , which enhanced IR expression and concomitant whole-body insulin sensitivity. The positive correlation between GPX3 and IR levels was also present in humans. In the current study, we investigate A) which selenite (Se) transporter is responsible for the beneficial Se-induced metabolism of WAT using of 3T3-L1 cells, and B) the potential therapeutic effect of selenite supplementation in diet-induced obese mice. We find that LDL Receptor Related Protein (LRP) 8 is necessary for Se-induced upregulation of GPx3 and IR expression to modulate insulin action, as siRNA mediated LRP8 knockdown in 3T3-L1 cells abrogates Se-induced insulin-sensitizing effects with e.g. reduced GPx3 and IR expression. To assess the metabolic effect of selenite supplementation in diet-induced obese mice, C57BL/6N mice received a HFD for 6 weeks, which was followed by a SRHFD for further 12 weeks. Unexpectedly, feeding obese mice a SRHFD resulted in a 10% increase in body weight gain compared to the HFD-fed control group. Nevertheless, these mice exhibited signs of improved metabolism with a shift towards smaller adipocytes, as indicator of improved adipocyte metabolism, and decreased plasma insulin levels. Yet, this was accompanied by unaltered inflammation, GPx3 and IR expression. In conclusion, our data suggest that LRP8 represents a novel Se-transporter in adipocytes controlling insulin sensitivity and that established obesity precludes the beneficial increase of Se-induced GPx3 and IR regulation in WAT, highlighting the potential importance of GPx3 as a mediator of adipose tissue insulin sensitivity. Disclosure R.Hauffe: None. M.Rath: None. A.Kleinridders: Other Relationship; Novozymes. Funding Deutsche Forschungsgemeinschaft (KL 2399/4-1) German Ministry of Education and Research BMBF (82DZD00302)

Urotensin II receptor knockout alleviates streptozotocin‐induced hyperglucagonemia and diabetic kidney disease

Plasma and urinary levels of UII, a potent vasoactive peptide, are elevated in diabetes mellitus (DM) patients. UII receptor (UT) expression levels are also increased in the kidneys of humans and animals with DM. Palosuran, an orally active UT antagonist, increased insulin levels and improved renal function in uninephrectomized streptozotocin (STZ)‐treated rats. However, human studies on the potential use of palosuran for kidney protection in diabetes were inconclusive. In addition to UT antagonism, palosuran can activate somatostatin receptors. Also, the reduced affinity of palosuran for UT in intact cells and tissues suggests that it may not be an optimal UT antagonist. Thus, using non‐selective and less potent UT antagonists constitutes a weakness in the scientific rigor of the prior attempts to dissect UT as a potential therapeutic target in DKD. Hence, studies using genetic animal models and highly selective and potent pharmacological antagonists are needed to fill the gaps of understanding on the pathophysiological significance of the UII system in DM. In the present study, we examine the development of hyperglycemia and DKD in the wild‐type (WT) and UT knockout (KO) mouse model of type 1 DM.STZ‐treated mice showed increased blood glucose levels, glucosuria, decreased plasma insulin levels, and diabetic kidney disease (DKD), which UT KO attenuated. However, UT KO failed to reverse STZ‐induced insulin deficiency. To understand the underlying mechanism for alleviating hyperglycemia and DKD in UT KO despite the uncorrected insulin deficiency, we tested the role of the primary insulin counterregulatory hormone, glucagon. We found that STZ treatment increased plasma glucagon levels in WT mice but not in UT KO mice. This finding was supported by double immunohistochemistry of pancreatic islet sections, where STZ treatment reduced insulin and increased glucagon staining. UT KO reversed only the effect of STZ on glucagon staining. These findings suggest that UT KO protects the glucagon‐producing alpha cells but not the insulin‐producing beta cells.UII increased glucagon secretion in a cultured pancreatic alpha cell line, which UT inhibition reversed. Next, to determine how UII triggers glucagon secretion, we performed membrane potential recordings in alpha cells using the perforated‐patch clamp technique. UII produced depolarization of alpha cells. This effect was abolished by UT inhibition. Calcium (Ca2+) imaging demonstrated that UII stimulates intracellular Ca2+ ([Ca2+]i) elevation in alpha cells, which T‐ and L‐type Ca2+ channel blockers attenuated.Taken together, the results of this study suggest that: (1) STZ‐treatment causes insulin deficiency, hyperglycemia, glucosuria, DKD, and hyperglucagonemia. (2) UT KO reverses STZ effects, except insulin deficiency. (3) UII increases glucagon secretion by alpha cells, mediated by UII‐induced membrane depolarization and Ca2+ influx via T‐ and L‐type Ca2+ channels. Therefore, the reversal of hyperglycemia, glucosuria, and DKD in UT KO might be linked to the reversal of hyperglucagonemia.

Loss of urotensin II receptor diminishes hyperglycemia and kidney injury in streptozotocin-treated mice.

Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The expression levels of UII and UT in the kidney and circulating UII levels are increased in diabetes. UII also promotes mesangial proliferation and matrix accumulation in vitro. Here, we evaluate the effect of UT deletion on the development of hyperglycemia and diabetic kidney disease (DKD) in streptozotocin (STZ)-treated mice. Ten-week-old WT and UT knockout (KO) mice were injected with STZ for 5 days to induce diabetes. Blood glucose levels were measured weekly, and necropsy was performed 12 weeks after STZ injection. UT ablation slowed hyperglycemia and glucosuria in STZ-treated mice. UT KO also ameliorated STZ-induced increase in HbA1c, but not STZ-induced decrease in plasma insulin levels. However, STZ-induced increases in plasma glucagon concentration and immunohistochemical staining for glucagon in pancreatic islets were lessened in UT KO mice. UT ablation also protected against STZ-induced kidney derangements, including albuminuria, mesangial expansion, glomerular lesions, and glomerular endoplasmic reticulum stress. UT is expressed in a cultured pancreatic alpha cell line, and its activation by UII triggered membrane depolarization, T- and L-type voltage-gated Ca2+channel-dependent Ca2+influx, and glucagon secretion. These findings suggest that apart from direct action on the kidneys to cause injury, UT activation by UII may result in DKD by promoting hyperglycemia via induction of glucagon secretion by pancreatic alpha cells.

Beneficial effects of voluntary wheel running on activity rhythms, metabolic state, and affect in a diurnal model of circadian disruption

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the “circadian syndrome” and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.

D-Allulose Improves Endurance and Recovery from Exhaustion in Male C57BL/6J Mice.

d-Allulose, a rare sugar, improves glucose metabolism and has been proposed as a candidate calorie restriction mimetic. This study aimed to investigate the effects of d-allulose on aerobic performance and recovery from exhaustion and compared them with the effects of exercise training. Male C57BL/6J mice were subjected to exercise and allowed to run freely on a wheel. Aerobic performance was evaluated using a treadmill. Glucose metabolism was analyzed by an intraperitoneal glucose tolerance test (ipGTT). Skeletal muscle intracellular signaling was analyzed by Western blotting. Four weeks of daily oral administration of 3% d-allulose increased running distance and shortened recovery time as assessed by an endurance test. d-Allulose administration also increased the maximal aerobic speed (MAS), which was observed following treatment for >3 or 7 days. The improved performance was associated with lower blood lactate levels and increased liver glycogen levels. Although d-allulose did not change the overall glucose levels as determined by ipGTT, it decreased plasma insulin levels, indicating enhanced insulin sensitivity. Finally, d-allulose enhanced the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase and the expression of peroxisome proliferator-activated receptor γ coactivator 1α. Our results indicate that d-allulose administration enhances endurance ability, reduces fatigue, and improves insulin sensitivity similarly to exercise training. d-Allulose administration may be a potential treatment option to alleviate obesity and enhance aerobic exercise performance.

Hyperinsulinemia Associated Depression.

Hyperinsulinemia promotes fat accumulation, causing obesity. Being an inflammatory state, obesity can induce further inflammation and is a risk factor for HPA (hypothalamic pituitary axis) dysregulation through hypercortisolism-related hyperglycemia. In another hypothesis, the sympathetic nervous system (SNS) plays a significant role in the regulation of hormone secretion from the pancreas such as an increase in catecholamines and glucagon as well as a decrease in plasma insulin levels, a disruption on SNS activity increases insulin levels, and induces glycogenolysis in the liver and lipolysis in adipose tissue during hypoglycemia. Hyperglycemia-hyperinsulinemia exacerbates inflammation and increases the oxidative stress along with regulating the levels of norepinephrine in the brain sympathetic system. Increased inflammatory cytokines have also been shown to disrupt neurotransmitter metabolism and synaptic plasticity which play a role in the development of depression via inhibiting serotonin, dopamine, melatonin, and glutamate signaling. An increased level of plasma insulin over time in the absence of exercising causes accumulation of lipid droplets in hepatocytes and striated muscles thus preventing the movement of glucose transporters shown to result in an increase in insulin resistance due to obesity and further culminates into depression. Further hyperinsulinemia-hyperglycemia condition arising due to exogenous insulin supplementation for diabetes management may also lead to physiological hyperinsulinemia associated depression. Triple therapy with SSRI, bupropion, and cognitive behavioral therapy aids in improving glycemic control, lowering fasting blood glucose, decreasing the chances of relapse, as well as decreasing cortisol levels to improve cognition and the underlying depression. Restoring the gut microbiota has also been shown to restore insulin sensitivity and reduce anxiety and depression symptoms in patients.

Glycyrrhiza glabra alcoholic root extract ameliorates hyperglycemia, hyperlipidemia, and glycation-induced free iron-mediated oxidative reactions.

Hyperglycemia-associated oxidative stress leads to various pathophysiological complications in diabetes mellitus. Here, the effects of Glycyrrhiza glabra (G. glabra) root extract of streptozotocin (STZ)-induced diabetic changes and the associated free iron-mediated oxidative reactions were investigated. The animals were divided into five group, Group 1: Control (NC received buffer); Group 2: STZ-induced (DC); Group 3: Control treated withG. glabraroot extract (NT, 60mg/Kg b.w daily for 1month); Group 4: Diabetic treated withthe extract(60mg/Kg b.w daily for 1month); Group 5: Diabetic treated with glibenclamide (DTG, 8.6mg/Kg b.w for 1month). STZ (i) induced hyperglycemia, abnormal intraperitoneal glucose tolerance test (IPGTT), increased HbA1c and decreased plasma insulin levels (ii) hyperlipidemia (iii) lowered antioxidant enzyme activities (iv) diminished RBC membrane fluidity (v) enhanced hemoglobin glycation-induced iron release and associated free radical reactions. Treatment with the extract resulted in significant reversal of hyperglycemia (DC: 205.0±7.0mg/dl vs. DT: 87.5±4.5mg/dl, p<.05); HbA1c (DC: 11.5±2.0 vs. DT: 7.5±0.8 vs. DT: 7.5 ± 0.8, p<.05); insulin (DC: 0.3±0.06 vs. DT: 1.25±0.15 μgm/L, p<.05); free iron (DC: 150.4±7.07 vs. DT: 98.8±7.7 μgm/gm of Hb, p<.05); TBARS (DC + H2 O2 : 24.62±11.30 vs. DC + H2 O2 : 9.82±2.56 mmoles/h, p<.05); carbonyl (DC: 40.40±1.57 vs. DT: 25.50±1.12 mmoles/g of Hb, p<.05) levels and β-cell count/pancreatic islet (DC: 85±15 vs. DT: 125±20, p < .05). Thus, G. glabra extract is quite effective against hyperglycemia and the associated free iron-mediated oxidative stress. PRACTICAL APPLICATIONS: Chronic use of oral hypoglycemic synthetic drugs may produce side effects and drug resistance. Recently, various plant extracts are being researched to explore their antihyperglycemic potential. Here, the effects of this alcoholic powdered root extract on STZ-induced diabetic changes and associated oxidative stress, including hemoglobin-induced free iron-mediated oxidative reactions were examined. The STZ-induced diabetic changes and hemoglobin-glycation-induced free iron-mediated oxidative reactions were alleviated in the Wistar rats after 1-month of treatment with the extract. We have also reported previously that glycyrrhizin, a bioactive constituent of Glycyrrhiza glabra root inhibits peroxidase, esterase activities of hemoglobin and hemoglobin-mediated oxidative damage without affecting oxygen-binding capacity of the protein. This preclinical work further substantiates the potential therapeutic use of the G. glabra whole root extract in the treatment of diabetes mellitus.

Prolonged Low-Dose Dioxin Exposure Impairs Metabolic Adaptability to High-Fat Diet Feeding in Female but Not Male Mice.

ContextHuman studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk. We previously showed that a single high-dose TCDD exposure (20 µg/kg) decreased plasma insulin levels in male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. ObjectiveThe current study assessed whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in chow-fed or high-fat diet (HFD)-fed mice.MethodsMale and female mice were exposed to 20 ng/kg/d TCDD 2×/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females for TempO-Seq transcriptomic analysis.ResultsLow-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in females. TCDD caused a modest increase in islet area in males but reduced the percent beta cell area within islets in females. TempO-Seq analysis suggested abnormal changes to endocrine and metabolic pathways in female TCDDHFD islets.ConclusionOur data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice but promotes maladaptive metabolic responses in HFD-fed females.

Ameliorative Efficacy of the Cassia auriculata Root Against High-Fat-Diet + STZ-Induced Type-2 Diabetes in C57BL/6 Mice.

Diabetes mellitus is a major metabolic disorder worldwide. Several herbs are being tested for the management of diabetes. Cassia auriculata is one of those herbs known for its nutritional value and health benefits. However, limited scientific evidence has been shown on the elucidation of its root bioactives as well as biological activity. This study attempted to identify and characterize phenolic compounds from the potent root extract and to evaluate its antioxidant as well as antidiabetic properties in both in vitro and in vivo models. The results revealed that the total polyphenol and flavonoid contents were highest in the methanolic extract. The methanolic extract of the C. auriculata root showed the highest antioxidant and antidiabetic activities in vitro than other extracts. These biological activities may be because the extract is rich in coumaric acid and −OH groups as revealed by high-performance liquid chromatography and Fourier-transform infrared spectroscopy analyses, respectively. Further, the antidiabetic activity of the methanolic extract was studied in a diet-induced type-2 diabetes mellitus (T2DM) C57BL/6 mouse model. A significant increase in fasting blood glucose and decreased plasma insulin levels in T2DM mice confirmed the development of the diabetic condition. In addition, the T2DM mice showed oxidative stress in the plasma as well as muscle tissue and significant alterations in the plasma biochemistry, viz., lipid profile, liver, and renal function tests. However, the administration of the ethanolic extract of the C. auriculata root (150 mg/kg body weight) to T2DM mice normalized the condition comparable to that of control mice. Thus, the extract can be used as a potent antioxidant and antidiabetic agent in pharmaceutical companies.

Effect of Diabetes Mellitus on Uterine contractility in Pregnant Rat Model: Possible Role of L ̵ carnitine

Objective: to detect the changes induced by STZ induced diabetes on uterine contractility and expression of connexin 43 in pregnant rat and the possible role of L carnitine to detect the role of L Carnitine in a model of diabetic pregnant rat. Method:40 female Sprague Dawley rats were subdivided into four groups; G I (NC): normal pregnant rats, G II (DI): in which rats received single i.p injection of 40 mg/kg b.wt STZ at day 1 of pregnancy, G III (DI+CAR): in which rats received STZ as above, and then at day 3 of pregnancy, diabetic pregnant rats received daily i.p L carnitine injection at a dose of 100 mg/kg b.wt till end of pregnancy, and G IV (DI+INS): in which rats received STZ as above, and then at day 3 of pregnancy, diabetic pregnant rats received daily i.p insulin injection at a dose of 1 IU/100 g b.wt (till end of pregnancy. Plasma glucose and insulin level, uterine contractility, pathological changes were assessed at the end of the experiment and scarifying of rats. Results: STZ induced DM caused significant increase in plasma glucose level, decreased plasma insulin level, impaired uterine contractility, pathological changes in diabetic group compared to normal control group. L Carnitine caused significant improvement in the studied parameters.

1900-P: HNF1A Deficiency Leads to Perturbed Glucagon Secretion in Humans

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). Carriers are normoglycemic in childhood, but with age, they develop hyperglycemia associated with insulin secretory defects and beta cell dysfunction. Although endogenous glucose production has been reported, glucagon in HNF1A-MODY has been less explored. Patients respond well to low dose sulfonylureas such as gliclazide, which increases insulin secretion independent of glucose but may predispose to hypoglycemia. We aimed to investigate whether low dose gliclazide had an effect on glucagon secretion in HNF1A-MODY. Additionally, we explored the potential of GLP-1 to normalize hormone secretion using in vivo and in vitro models of HNF1A deficiency. A 75g oral glucose tolerance test was performed in 7 MODY patients before and 72h after stopping gliclazide. Glucose rise was greater off gliclazide (p=0.003), while c-peptide and glucagon levels were similar between the groups. When adjusting for glucose levels during the OGTT, the change from baseline glucagon levels (Δ glucagon/glucose ratio) showed a significant decrease in those taking gliclazide (p=0.048), while there was no difference in Δ c-peptide/glucose ratio. Hnf1a-/- mice compared to WT mice are hyperglycemic, have decreased plasma insulin levels and hyperglucagonemia that was not suppressed after a glucose challenge (p=0.008). Furthermore, induction of the HNF1A variant Pro291fsInsC in rat INS1 cells reduced insulin and increased glucagon secretion, both of which were improved by GLP-1 treatment. Using the TIGER database we found HNF1A to be heterogeneously expressed in human islets, and siHNF1A reduced insulin secretion at high glucose. Collectively, these findings indicate that HNF1A is also essential for the regulation of glucagon secretion and glucose homeostasis. The mechanism by which GLP-1 normalizes insulin and glucagon secretion needs further investigation but could contribute to a better understanding of treatment response in HNF1A-MODY. Disclosure C. Saponaro: None. A. Acosta-Montalvo: None. L. Anguelova: None. J. Thevenet: None. M. Chiral: None. G. Pasquetti: None. A. Piron: None. M. Cnop: None. V. Gmyr: None. J. Prehn: None. J.A. Kerr-Conte: None. F. Pattou: None. M. Pontoglio: None. K.R. Owen: None. I. Spiliotis: None. C. Bonner: None. Funding European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme; Oxford Health Sciences Research Committee (1233)

Metformin and l-glutamine ameliorate pancreatic damage induced by chronic nicotine exposure in adult male albino rats

Nicotine is a major addictive component of tobacco and cigarettes. It is believed to play a major role in the development of many diseases of pancreas including induction of pancreatitis and pancreatic cancer. This study was designed to assess the ameliorative effect of metformin &amp; L-glutamine administered either individually or in combination on pancreatic damage induced by chronic exposure to nicotine. Fifty-six adult male albino rats were divided into 7 weight matched groups of 8 animals per each group and treated once daily for a period of 10 weeks according to the following protocol; group I (normal control): left without intervention ; they were allowed to free access to balanced diet &amp; distilled water for the end of the experiment, group II (metformin treated group; Met): metformin was administrated to normal rats at a dose of (150 mg/kg /day /orally); group III (glutamine group ; LG): in which L-glutamine was given to normal rats at a dose of 500 mg/kg by oral gavage); group IV (diseased non-treated group ;Nicotine) were injected subcutaneously with nicotine (1.5 mg/kg/day after day) to induce pancreatitis; group V (Nicotine +Met), VI (Nicotine +LG) &amp;VII (Nicotine +Met + LG) were treated by (Nicotine +Met, Nicotine +LG &amp; Nicotine +Met + LG respectively) by the same doses and routs described above. At the end of the experiment the following biochemical parameters were measured (fasting blood glucose, plasma insulin level, serum amylase and lipase level, tumor necrosis factor alpha (TNF-α), heat shock protein 70 (HSP70) &amp; reduced glutathione; GSH) to investigate the protective effect of either or both drugs on pancreas. Additionally, histopathological evaluations of pancreatic tissues were assessed. The current study documented the damaging effect of nicotine on pancreas evidenced by significant increase of (blood glucose level due to decrease in plasma insulin level, serum lipase and amylase &amp; TNF-α levels along with significant reduction of GSH in pancreatic tissue &amp; heat shock protein -70. This was accompanied by histopathological alteration in pancreatic tissue. The previously mentioned parameters illustrate partial significant improvement in concomitant administration of individual or both metformin &amp; L glutamine along with nicotine. In conclusion, co- supplementation of metformin and L glutamine documented to be anti-hyperglycemic, antioxidant and anti-inflammatory which can ameliorate the damaging effect of nicotine on pancreas. The combination use of both drugs produces more protective effect than each other alone.  Â

Platelet-rich plasma improves impaired glucose hemostasis, disrupted insulin secretion, and pancreatic oxidative stress in streptozotocin-induced diabetic rat

Our study aimed to investigate the effects of platelet-rich plasma (PRP) on impaired glucose homeostasis, disrupted islet insulin secretion, and pancreatic oxidative status in streptozotocin (STZ)-diabetic rats. A total of 64 Sprague-Dawley male were randomized to four groups including controls, diabetes, control-PRP, and diabetes-PRP. The rats received the PRP (0.5 ml/kg, SC injection) twice weekly for 4 weeks. Plasma glucose and insulin levels, pancreatic oxidative stress markers and islet insulin secretion and content were measured. Compared with the control group, in the diabetic group, increased plasma glucose and malondialdehyde (MDA) levels and decreased plasma insulin level, islet insulin secretion, pancreatic superoxide dismutase (SOD), and catalase activities were observed. PRP treatment significantly reduced plasma glucose and MDA levels and enhanced plasma insulin, antioxidant enzyme activity, islet insulin secretion, and content in the diabetic rats. These findings showed that PRP can improve pancreatic islet insulin secretion, pancreatic oxidative stress and regulate plasma insulin and glucose levels in diabetic rats.