Decreased Plasma Insulin Research Articles

The Effect of GLP-1 and GIP on the Microvascular Blood Flow after Consuming a Mixed Nutrient Meal: A Research Protocol

Introduction: Nutrient and gas exchange via microvascular blood flow is a key process of circulatory function. There is a significant decrease in the microvascular blood flow to skeletal muscle after orally ingesting glucose. Incretins like glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), are released in response to glucose in the gut, stimulating insulin release. Incretins roles in promoting glucose uptake is thought to impact vascular blood flow. Our protocol plans to investigate if incretins and the subsequent insulin release contribute to the decrease in microvascular blood flow. Methods: 20 healthy young adults will consume a high glucose mixed nutrient meal. Using contrast-enhanced ultrasound (CEU) and a blood glucose meter, microvascular blood flow and blood glucose will be measured. Blood GLP-1 and GIP will be measured using a sandwich enzyme immunoassay, while an electrochemiluminescence technique using an autoanalyzer will measure insulin. Measurements will be recorded at 0, 1, and 2 hours post-prandial. In a randomized order, the protocol will be repeated with infusion of GIP and GLP-1 inhibitors, GIP(3-30)NH2 and exendin(9-39)NH2 or saline. Results: With normal incretin secretion, we anticipate a significant decrease in microvascular blood flow, along with an increase in blood insulin, GIP/GLP-1 levels. We postulate that supressing incretins will increase the microvascular blood flow along with decreased plasma insulin and no change in GLP-1/GIP levels. Discussion: Through our methods, we propose a study design which evaluates the relationship of incretins and insulin on post-prandial microvascular blood flow. Our expected results aim to provide data that can be applied to the progressive treatment of type II diabetes with incretins like GLP-1. Understanding the impact of incretin treatment on the microvascular blood flow could be beneficial to the discovery of an adverse effect or how glucose uptake in peripheral tissues is altered. These are vital aspects of developing a clinical treatment to diabetes and our results will provide a basis to work off. Conclusion: The goal of this protocol was to investigate and provide insight to fully understand incretins and their effects. It will propel research on the biochemical pathways involving incretin and microvascular blood flow, which then helps progress treatment of complications like diabetes.

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.

Development of a novel feeding method for Japanese black calves with thermophile probiotics at postweaning.

Probiotic effects of compost containing thermophiles on productivity have been reported in domestic animals, although not cattle. We evaluated the effects of administering Caldibacillus hisashii, a thermophile contained in compost, on growth, blood components, faecal organic acid concentrations and microbiota population in Japanese black calves. Calves were administered C. hisashii from 3 to 5 months of age. Administering C. hisashii decreased feed intake without affecting body weight, indicating that feed efficiency is improved by administration. Administering C. hisashii decreased plasma insulin concentration without affecting glucose and non-esterified fatty acid concentrations. Chao1 was decreased by exposure at 5 months of age. Similarly, weighted and unweighted UniFrac distances were affected by treatment at 5 months of age. Faecal abundance of the phylum Bacteroidetes tended to be increased by exposure. Faecal propionic acid concentration was correlated positively with faecal abundance of phylum Bacteroidetes but negatively with that of Firmicutes. Interestingly, the population of the genus Methanobrevibacter, representing the majority of methanogens, was lowered by exposure and was negatively correlated with faecal propionic acid concentration. Administration of C. hisashii has the potential to improve growth performance of Japanese black calves and to contribute to reducing environmental load, which may be associated with altered endocrine kinetics and gut microbial populations. This study revealed that isolated thermophiles included in compost may exert probiotic effects on calves.

MemAID: Memory advancement with intranasal insulin vs. placebo in type 2 diabetes and control participants: a randomized clinical trial.

BackgroundThis study aimed at assessing the long-term effects of intranasal insulin (INI) on cognition and gait in older people with and without type 2 diabetes mellitus (T2DM).MethodsPhase 2 randomized, double-blinded trial consisted of 24 week treatment with 40 IU of INI (Novolin® R, off-label use) or placebo (sterile saline) once daily and 24 week follow-up. Primary outcomes were cognition, normal (NW), and dual-task (DTW) walking speeds. Of 244 randomized, 223 completed baseline (51 DM-INI, 55 DM-Placebo, 58 Control-INI, 59 Control-Placebo; 109 female, 65.8 ± 9.1; 50–85 years old); 174 completed treatment (84 DM, 90 Controls); 156 completed follow-up (69 DM).ResultsDM-INI had faster NW (~ 7 cm/s; p = 0.025) and DTW on-treatment (p = 0.007; p = 0.812 adjusted for baseline difference) than DM-Placebo. Control-INI had better executive functioning on-treatment (p = 0.008) and post-treatment (p = 0.007) and verbal memory post-treatment (p = 0.004) than Control-Placebo. DM-INI increased cerebral blood flow in medio-prefrontal cortex (p < 0.001) on MRI. Better vasoreactivity was associated with faster DTW (p < 0.008). In DM-INI, plasma insulin (p = 0.006) and HOMA-IR (p < 0.013) decreased post-treatment. Overall INI effect demonstrated faster walking (p = 0.002) and better executive function (p = 0.002) and verbal memory (p = 0.02) (combined DM-INI and Control-INI cohort, hemoglobin A1c-adjusted). INI was not associated with serious adverse events, hypoglycemic episodes, or weight gain.ConclusionThere is evidence for positive INI effects on cognition and gait. INI-treated T2DM participants walked faster, showed increased cerebral blood flow and decreased plasma insulin, while controls improved executive functioning and verbal memory. The MemAID trial provides proof-of-concept for preliminary safety and efficacy and supports future evaluation of INI role to treat T2DM and age-related functional decline.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-022-11119-6.

Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion.

Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic β-cells. Whether mitofusin gene expression, and hence, mitochondrial network integrity, is important for glucose or incretin signaling has not previously been explored. Here, we generated mice with β-cell–selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2-dKO mice displayed elevated fed and fasted glycemia and a more than fivefold decrease in plasma insulin. Mitochondrial length, glucose-induced polarization, ATP synthesis, and cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2-dKO mice, and glucagon-like peptide 1 or glucose-dependent insulinotropic peptide receptor agonists largely corrected defective glucose-stimulated insulin secretion through enhanced EPAC-dependent signaling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps–based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the β-cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in β-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.

Genetic Reduction of Glucose Metabolism Preserves Functional β-Cell Mass in KATP-Induced Neonatal Diabetes.

β-Cell failure and loss of β-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in β-cell exhaustion/failure, loss of β-cell mass still occurs in KATP gain-of-function (GOF) mouse models of human neonatal diabetes in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased β-cell metabolism is responsible for β-cell failure and that reducing glucose metabolism will prevent loss of β-cell mass. To test this, KATP-GOF mice were crossed with mice carrying β-cell–specific glucokinase haploinsufficiency (GCK+/−), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/− mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/− mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin, and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/− mice. Strikingly, KATP-GOF/GCK+/− mice demonstrated preserved β-cell mass and identity compared with the marked decrease in β-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/− mice demonstrated restoration of body weight and liver and brown/white adipose tissue mass and function and normalization of physical activity and metabolic efficiency compared with KATP-GOF mice. These results demonstrate that decreasing β-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and β-cell failure independently of compensatory insulin hypersecretion and β-cell exhaustion.

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.

Diets Containing Egg or Whey Protein and Inulin Fiber Improve Energy Balance and Modulate Gut Microbiota in Exercising Obese Rats.

Dietary protein, prebiotic fiber, and exercise individually have been shown to aid in weight loss; however less is known of their combined effects on energy balance. The effects of diets high in protein and fiber, with exercise, on energy balance, hormones, and gut microbiota, were determined. Obese male rats were fed high-fat diets with high protein and fiber contents from egg protein and cellulose, egg protein and inulin, whey protein and cellulose, or whey protein and inulin, together with treadmill exercise. We found that inulin enriched diets decreased energy intake and respiratory quotient (RQ), increased energy expenditure (EE), and upregulated transcripts for cholecystokinin (CCK), peptide YY, and proglucagon in distal gut. Notably, CCK1-receptor blockade attenuated the hypophagic effects of diets and in particular whey-inulin diet, and β-adrenergic blockade reduced EE across all diets. Egg-cellulose, egg-inulin, and whey-inulin diets decreased weight gain, adiposity, and hepatic lipidosis; decreased lipogenic transcripts, improved glycemic control, and upregulated hepatic glucose metabolism transcripts; and decreased plasma insulin and leptin. Importantly, diet was linked to altered gut microbial composition and plasma metabolomics, and a subset of predicted metagenome pathways and plasma metabolites significantly correlated, with plasma butyric acid the most strongly associated to metagenome function. Combination of dietary egg or whey protein with inulin and exercise improved energy balance, glucose metabolism, upregulated anorectic hormones, and selectively modulated gut microbiota and plasma metabolites.

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.

Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets.

Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients’ appetite and improve insulin sensitivity and hyperinsulinemia mainly through activating 5-HT2CR in the hypothalamus. It is known that the mCPP, a kind of 5-HT2CR agonist, decreases plasma insulin concentration in mice and previous research in our laboratory found that mCPP inhibited glucose-stimulated insulin secretion (GSIS) by activating 5-HT2CR on the β cells. However, the effect of lorcaserin on GSIS of pancreatic β cell has not been studied so far. The present study found that 5-HT2CR was expressed in both mouse pancreatic β cells and β-cell–derived MIN6 cells. Dose-dependent activation of 5-HT2CR by lorcaserin suppressed GSIS and SB242084 or knockdown of 5-HT2CR abolished lorcaserin’s effect in vitro. Additionally, lorcaserin also suppressed GSIS in high-fat diet (HFD)-fed mice in dose-dependent manner. Lorcaserin did not change insulin synthesis ATP content, but lorcaserin decrease cytosolic free calcium level [(Ca2+)i] in MIN6 cells stimulated with glucose and also inhibit insulin secretion and (Ca2+)i in MIN6 treated with potassium chloride. Furthermore, stimulation with the L-type channel agonist, Bay K8644 did not restore GSIS in MIN6 exposed to lorcaserin. Lorcaserin inhibits the cAMP generation of MIN6 cells and pretreatment with the Gα i/o inhibitor pertussis toxin (PTX), abolished lorcaserin-induced suppression of GSIS in β cells, while membrane-permeable cAMP analogue db-cAMP had same effect as PTX. These date indicated lorcaserin coupled to PTX-sensitive Gα i/o proteins in β cells reduced intracellular cAMP level and Ca2+ influx, thereby causing GSIS dysfunction of β cell. These results highlight a novel signaling mechanism of lorcaserin and provide valuable insights into the further investigation of 5-HT2CR functions in β-cell biology and it also provides guidance for the clinical application of lorcaserin.

Evaluation of Gamma Amino Butyric Acid (GABA) and Glibenclamide Combination Therapy in Streptozotocin Induced Diabetes.

Type 1-diabetes (T1D) is characterized by autoimmune destruction of β-cells and loss of endogenous insulin. A lifelong dependency on exogenous supply of insulin presents a great challenge in the pharmacotherapy of T1D that elicits a quest for alternative therapies, which can protect β-cells and revive their insulinogenic functions. GABA (γ-aminobutyric acid) has immunoprotective and β-cell regenerative capabilities. Co-administration of an insulin secretagogue, such as glibenclamide (Glib), along with GABA may enhance the pancreatic insulin output in T1D. The present study evaluated the possible mechanism of GABA in the improvement of glucose tolerance and its effects in streptozotocin (STZ) induced T1D along with Glib. Wistar rats (180-220 g) were administered a single dose of STZ (55 mg/kg, i.p.). GABA (100 mg/kg, i.p.) and Glib (5 or 10 mg/kg, i.p.) alone or in combination were administered for 28 days. Body weight (b.w.), water consumption, fasting blood glucose (FBG), oral glucose tolerance, plasma lipids, insulin, and muscle GLUT-4 (glucose transporters) protein level were assessed. T1D significantly decreased b.w. and increased water-intake in rats. An increase in FBG and a decrease in plasma insulin and muscle GLUT-4 indicated STZ-triggered destruction of β-cells in diabetic rats accompanied with dyslipidemia. GABA or Glib (10 mg/kg) significantly improved b.w., plasma insulin and GLUT-4 levels, and ameliorated FBG and blood lipid profile in diabetic rats. GABA and Glib (5 mg/kg) combination therapy achieved far better control over hyperglycemia and related pathogenic conditions (b.w., water-intake, insulin, GLUT-4, lipids). The anti-diabetic effect of combination therapy was significantly more pronounced in comparison to individual drug treatments. Histopathological analysis revealed an increase in the number of functional pancreatic-islets by combination therapy. GABA revitalized β-cells against STZ-toxicity. GABA and Glib synergistically augmented insulin secretion that can be used to manage T1D and its complications. GABA has the potential to remarkably enhance the therapeutic outcome in diabetic patients and reduce the dose of existing anti-diabetic drugs such as Glib.

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.

Xanthohumol Requires the Intestinal Microbiota to Improve Glucose Metabolism in Diet-Induced Obese Mice.

The polyphenol xanthohumol (XN) improves dysfunctional glucose and lipid metabolism in diet-induced obesity animal models. Because XN changes intestinal microbiota composition, the study hypothesizes that XN requires the microbiota to mediate its benefits. To test the hypothesis, the study feeds conventional and germ-free male Swiss Webster mice either a low-fat diet (LFD, 10% fat derived calories), a high-fat diet (HFD, 60% fat derived calories), or a high-fat diet supplemented with XN at 60mg kg-1 body weight per day (HXN) for 10 weeks, and measure parameters of glucose and lipid metabolism. In conventional mice, the study discovers XN supplementation decreases plasma insulin concentrations and improves Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). In germ-free mice, XN supplementation fails to improve these outcomes. Fecal sample 16S rRNA gene sequencing analysis suggests XN supplementation changes microbial composition and dramatically alters the predicted functional capacity of the intestinal microbiota. Furthermore, the intestinal microbiota metabolizes XN into bioactive compounds, including dihydroxanthohumol (DXN), an anti-obesogenic compound with improved bioavailability. XN requires the intestinal microbiota to mediate its benefits, whichinvolves complex diet-host-microbiota interactions with changes in both microbial composition and functional capacity. The study results warrant future metagenomic studies which will provide insight into complex microbe-microbe interactionsand diet-host-microbiota interactions.

Inhibition of dipeptidyl peptidase-4 averts free fatty acids deposition in the hearts of oral estrogen-progestin contraceptive-induced hyperinsulinemic female rats.

Free fatty acid (FFA) deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which feature hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen-progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue, and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac FFA deposition in estrogen-progestin-treated female rats. From our data, estrogen-progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, TG/high-density lipoprotein cholesterol (TG/HDL-C) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway (ADA/XO/UA), lipid peroxidation, glycogen synthase activity, and alanine phosphatase; whereas cardiac glucose-6-phosphate dehydrogenase, Na+/K+-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG, TG/HDL-C ratio, and alkaline phosphatase. These were accompanied by reduced ADA/XO/UA pathway, lipid peroxidation, and augmented NO and Na+/K+-ATPase in estrogen-progestin OC-treated rats. DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen-progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders.

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.

Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.

The chemical chaperon 4-phenyl butyric acid restored high-fat diet- induced hippocampal insulin content and insulin receptor level reduction along with spatial learning and memory deficits in male rats

This study assessed the effect of a chronic high-fat diet (HFD) on plasma and hippocampal insulin and corticosterone levels, the hippocampus insulin receptor amount, and spatial learning and memory with or without receiving 4-phenyl butyric acid (4-PBA) in male rats. Rats were divided into high-fat and normal diet groups, then each group was subdivided into dimethyl sulfoxide (DMSO) and 4-PBA groups. After weaning, the rats were fed with HFD for 20 weeks. Then, 4-PBA or DMSO were injected for 3 days. Subsequently, oral glucose tolerance test was done. On the following day, spatial memory tests were performed. Then the hippocampus Bip, Chop, insulin, corticosterone, and insulin receptor levels were determined. HFD increased plasma glucose, leptin and corticosterone concentrations, hippocampus Bip, Chop and corticosterone levels, food intake, abdominal fat weight and body weight along with impaired glucose tolerance. It decreased plasma insulin, and insulin content, and its receptor amount in hippocampus. HFD lengthened escape latency and shortened the duration spent in target zone. 4-PBA administration improved the HFD- induced adverse changes. Chronic HFD possibly through the induction of endoplasmic reticulum (ER) stress and subsequent changes in the levels of hippocampal corticosterone, insulin and insulin receptor along with possible leptin resistance caused spatial learning and memory deficits.

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.

Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue

ObjectiveStudies in mice have shown that the decrease in lipoprotein lipase (LPL) activity in adipose tissue upon fasting is mediated by induction of the inhibitor ANGPTL4. Here, we aimed to validate this concept in humans by determining the effect of a prolonged fast on ANGPTL4 and LPL gene and protein expression in human subcutaneous adipose tissue. MethodsTwenty-three volunteers ate a standardized meal at 18.00 h and fasted until 20.00 h the next day. Blood was drawn and periumbilical adipose tissue biopsies were collected 2 h and 26 h after the meal. ResultsConsistent with previous mouse data, LPL activity in human adipose tissue was significantly decreased by fasting (−60%), concurrent with increased ANGPTL4 mRNA (+90%) and decreased ANGPTL8 mRNA (−94%). ANGPTL4 protein levels in adipose tissue were also significantly increased by fasting (+46%), whereas LPL mRNA and protein levels remained unchanged. In agreement with the adipose tissue data, plasma ANGPTL4 levels increased upon fasting (+100%), whereas plasma ANGPTL8 decreased (−79%). Insulin, levels of which significantly decreased upon fasting, downregulated ANGPTL4 mRNA and protein in primary human adipocytes. By contrast, cortisol, levels of which significantly increased upon fasting, upregulated ANGPTL4 mRNA and protein in primary human adipocytes as did fatty acids. ConclusionANGPTL4 levels in human adipose tissue are increased by fasting, likely via increased plasma cortisol and free fatty acids and decreased plasma insulin, resulting in decreased LPL activity.This clinical trial was registered with identifier NCT03757767.