Theasinensin A attenuated diabetic development by restoring glucose homeostasis, improving hepatic steatosis and modulating gut microbiota in high-fat-diet/streptozotocin-induced diabetic mice

Theasinensin A(TSA),a dimer of epigallocatechin gallate,has been preliminarily demonstrated to have hypoglycemia and anti-inflammatory effects.However,little information is available on its potential mechanisms of anti-diabetes.Therefore,the present study aimed to investigate the influence of TSA on glucose and lipid metabolism and gut microbiota in high-fat-diet/streptozotocin-induced diabetic mice.As result,TSA improved polydipsia,polyphagia and impaired glucose tolerance of diabetic mice,declined the fasting blood glucose and hepatic triglyceride level,and enhanced the expression at mRNA level of insulin receptor substrate,phosphoinositide 3-kinase,protein kinase B and glucagon-like peptide 1 receptor(GLP-1R)in the diabetic liver.Moreover,TSA could restore the disorder of gut microbiota of diabetic mice.High-dose(100 mg/kg)TSA showed better benefi cial effects from the blood biochemical parameters,hepatic function and gut microbiota.In general,high-dose TSA significantly modulated gut microbiota by increasing the relative abundance of Akkermansia and decreasing the relative abundances of Acetatifactor,Anaerotruncus,Pseudofl avonifactor,Oscillibacter and Clostridium clusters.The results indicated that TSA could exert an anti-diabetes effect in diabetic mice through restoring glucose homeostasis,declining hepatic steatosis,activating insulin and GLP-1 signaling pathways,and ameliorating gut microbiota dysbiosis.

Chlorogenic Acid Maintains Glucose Homeostasis through Modulating the Expression of SGLT-1,GLUT-2,and PLG in Different Intestinal Segments of Sprague-Dawley Rats Fed a High-Fat Diet

Objective To reveal the effects and related mechanisms of chlorogenic acid(CGA)on intestinal glucose homeostasis.Methods Forty male Sprague-Dawley rats were randomly and equally divided into four groups:normal chow(NC),high-fat diet(HFD),HFD with low-dose CGA(20 mg/kg,HFD-LC),and HFD with high-dose CGA(90 mg/kg,HFD-HC).The oral glucose tolerance test was performed,and fast serum insulin(FSI)was detected using an enzyme-linked immunosorbent assay.The m RNA expression levels of glucose transporters(Sglt-1 and Glut-2)and proglucagon(Plg)in different intestinal segments(the duodenum,jejunum,ileum,and colon)were analyzed using quantitative real-time polymerase chain reaction.SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.Results At both doses,CGA ameliorated the HFD-induced body weight gain,maintained FSI,and increased postprandial 30-min glucagon-like peptide 1 secretion.High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression.Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.Conclusion An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis.CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg,thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.

interrelationships between ghrelin, insulin and glucose homeostasis: physiological relevance

Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated(AG) and unacylated(UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesityrelated disorders. However, due to the complexity ofits biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis.

Host Factors Alter Effects of Angiopoietin-Like Protein 8 on Glucose Homeostasis in Diabetic Mice

Recovery of functional beta cell mass offers a biological cure for type 1 diabetes. However, beta cell mass is difficult to regain once lost since the proliferation rate of beta cells after youth is very low. Angiopoietin like-protein 8 (ANGPTL8), a peptide that has a role in the regulation of lipoprotein lipase activity, was reported to increase beta cell proliferation in mice in 2013. Subsequent studies of human ANGPTL8 for short term (3 to 8 days) in non-diabetic mice showed little or no increase in beta cell proliferation. Here, we examined the effect of ANGPTL8 on glucose homeostasis in models that have not been examined previously. We expressed mouse ANGPTL8 using adenovirus in 2 mouse models of diabetes (streptozotocin and Non-Obese Diabetic (NOD) mice) over 2 weeks. Also, we tested ANGPTL8 in NOD mice deficient in leukocyte 12-lipoxygenase (12LO), an enzyme that contributes to insulitis and loss of beta cell function in NOD, in an effort to determine whether 12LO deficiency alters the response to ANGPTL8. Adenovirus-mediated expression of ANGPTL8 lowered blood glucose levels in streptozotocin treated mice without an increase in beta cell proliferation or serum insulin concentration. While ANGPTL8 did not reverse hyperglycemia in overtly hyperglycemic NOD mice or alter glucose homeostasis of non-diabetic NOD mice, ANGPTL8 reduced blood glucose levels in 12LOKO NOD mice. However, the lower glucose levels in 12LOKO NOD were not associated with higher serum insulin levels or beta cell proliferation. In summary, while mouse ANGPTL8 does not increase beta cell proliferation in NOD mice or streptozotocin treated mice in agreement with studies in non-diabetic mice, it lowers blood glucose levels in multiple low-dose streptozotocin induced diabetes and 12LO deficiency indicating that host factors influence the impact of ANGPTL8 on glucose homeostasis.

Sub-nanosized vanadate hybrid clusters maintain glucose homeostasis and restore treatment response in inflammatory disease in obese mice

Obesity is closely related with insulin resistance and chronic inflammation.Here,we report that unsaturated lipid-modified polyoxovanadates(ULPOVs)can restrict weight gain of diet-induced obese mice and improve their glycemic control and obesity-associated inflammation.Oral administration of the sub-nanosized ULPOVs at a low dosage for 7 weeks reduces the body weight and almost normalizes the blood glucose levels of obese mice fed on a high-fat diet.ULPOV treatment increases the activity of the nuclear receptor peroxisome proliferator-activated receptorγ(PPARγ)and reduces intestinal caloric intake,which may be the main reason for blood sugar and body weight control.In addition to insulin-sensitizing,PPARγactivation induced by ULPOV treatment in obese mice with atopic dermatitis(AD)promotes the type 2 T helper(TH_(2))cell selective responses and therapeutic effects on immune dysregulation caused by obesity.These data suggest sub-nanosized polyoxovanadate clusters as a class of potential candidates to relieve symptoms accompanied by diet-induced obesity.

Serum monoterpene levels, glucose homeostasis, lipid profiles, and metabolic syndrome in adults: NHANES, 2013–2014

Monoterpenes are organic compounds which have been studied for their medicinal benefits.However,the association between monoterpene exposure and metabolic parameters in humans is unknown.We investigated the connection between three specific monoterpenes(α-pinene,β-pinene,and limonene),glucose homeostasis biomarkers,lipid profiles,and metabolic syndrome(MS)in 1627 adults from the National Health and Nutrition Examination Survey(NHANES)2013–2014.We found serum levels ofα-pinene andβ-pinene were positively associated with fasting glucose,total cholesterol,triglyceride,and apolipoprotein B.In addition,increased levels of limonene andΣmonoterpene(sum of three monoterpene chemicals)were linked to higher insulin,β-cell function,total cholesterol,low density lipoprotein cholesterol(LDL-C),triglycerides,and apolipoprotein B.Participants with all three monoterpenes above the 50th percentile had notably higher values for total cholesterol and triglycerides compared to those with all three monoterpenes below the 50th percentile(P for trend<0.001).Regarding MS,higher serum concentrations ofα-pinene were linked to an increased risk of high-density lipoprotein cholesterol(HDL-C)insufficiency and hypertriglyceridemia.Elevated concentrations ofβ-pinene were associated with a higher prevalence of hypertriglyceridemia.Moreover,increased levels of limonene andΣmonoterpene were connected to a higher risk of MS,larger waist circumference,low HDL-C,hypertriglyceridemia,and higher blood pressure according to MS criteria.In conclusion,serum monoterpenes levels were linked to glucose regulation,lipid profiles,and indicators of MS.Further studies are necessary to clarify the potential causal relationships.

Impacts of different pancreatic resection ranges on endocrine function in Suncus murinus

BACKGROUND Surgical intervention involving the pancreas can lead to impaired glucose tolerance and other types of endocrine dysfunction.The scope of pancreatectomy and whether it includes the ventral pancreas are the key factors in the development of postoperative diabetes.The ventral and dorsal pancreases are almost separated in Suncus murinus(S.murinus).AIM To investigate the effects of different extents of pancreatic resection on endocrine function in S.murinus.METHODS Eight-week-old male S.murinus shrews were randomly divided into three experimental groups according to different pancreatic resection ranges as follows:ventral pancreatectomy(VPx)group;partial pancreatectomy(PPx)group;subtotal pancreatectomy(SPx)group;and a sham-operated group.Postprandial serum insulin,glucagon-like peptide-1(GLP-1),pancreatic polypeptide(PP),and somatostatin(SST)levels,as well as food intake,weight,blood glucose,and glucose tolerance were regularly measured for each animal.RESULTS S.murinus treated with PPx and SPx suffered from varying degrees of impaired glucose tolerance,but only a small proportion of the SPx group developed diabetes.Only S.murinus in the SPx group showed a significant decrease in food intake accompanied by severe weight loss,as well as a significant increase in postprandial serum GLP-1 levels.Postprandial serum PP levels decreased in both the VPx and PPx groups,but not in the SPx group.Postprandial serum SST levels decreased in both VPx and PPx groups,but the decrease was marginal.CONCLUSION Severe weight loss after pancreatectomy may be related to loss of appetite caused by compensatory elevation of GLP-1.PP and GLP-1 may play a role in resisting blood glucose imbalance.

Sapium ellipticum(Hochst) Pax ethanol leaf extract modulates glucokinase and glucose-6-phosphatase activities in streptozotocin induced diabetic rats

Objective:To examine the effects of Sapium ellipticum(SE) leaf extract on the hepatic activities of glucokinase and glucose-6-phosphatase in streptozotocin-induced diabetic Wistar rats.Methods:STZ-induced diabetic Wistar rats(four groups,n = 8) were used in this study.SE was assessed at two different doses,400 and 800 mg/kg BW,in comparison with metformin(METF)(12 mg/kg BW) as a reference antidiabetic drug.All treatments were done orally(p.o),twice daily at 8 h interval for a period of 21 days.Glucokinase and glucose-6-phosphatase activities were respectively determined using standard protocols.Hepatic and muscle glycogen contents were estimated as well.Results:STZ caused significant decrease in glucose-6-phosphatase activity and concomitant increase in glucokinase activity.SE extract especially at 400 mg dosage significantly reversed the alterations by increasing glucokinase activity by 40.31% and inhibiting glucose-6-phosphatase activity by 37.29% compared to diabetic control animals.However,the effects were significantly lower than that of METF which enhanced glucokinase activity by94.76% and simultaneously inhibited glucose-6-phosphatase activity by 49.15%.The extract also improved hepatic glycogen level by 32.37 and 27.06% at 400 and 800 mg dosage respectively.HPLC-MS analysis of some SE fractions in dynamic MRM mode(using the optimized compound-specific parameters) revealed among other active compounds,the presence of amentoflavone,which has been associated with antidiabetic function.Conclusions:The ability of SE extract to concurrently inhibit glucose-6-phosphatase and activate glucokinase in this study suggests that it may be a treatment option for type 2 diabetes patients,and the presence of amentoflavone in the plant extract may account for its anti-diabetic potential.

A review on mechanisms of action of bioactive peptides against glucose intolerance and insulin resistance

Insulin resistance leads to impaired glucose metabolism by disrupting both insulin secretion and sensitivity.Insulin resistance plays a key role in the pathophysiology of type 2 diabetes and metabolic syndrome.Reviews on the mechanisms of action of bioactive peptides on glucose homeostasis and insulin resistance are scarce.The recent discoveries of pathways and target cells in the management of glucose and energy metabolism have opened up new opportunities for identification of novel bioactive peptides on enhancing adipocyte differentiation and insulin signaling,glucose uptake,cholecystokinin receptor expression and activation,as well as insulin mimetics and incretin stimulants.Examples of food-derived bioactive peptides with glucoregulatory properties include Trp-Glu-Lys-Ala-Phe-Lys-Asp-Glu-Asp(WEKAFKDED),Gln-Ala-MetPro-Phe-Arg-Val-Thr-Glu-Gln-Glu(QAMPFRVTEQE),Glu-Arg-Tyr-Pro-Ile-Leu(ERKPIL),Val-Phe-LysGly-Leu(VFKGL),Phe-Leu-Val(FLV),Val-Pro-Pro(VPP),Ile-Arg-Trp(IRW),Ala-Lys-Ser-Pro-Leu-Phe(AKSPLF),Ala-Thr-Gln-Pro-Leu-Phe(ATNPLF),Phe-Glu-Glu-Leu-Gln(FEELN),Leu-Ser-Val-Ser-Val-Leu(LSVSVL),Val-Arg-Ileu-Arg-Leu-Leu-Gln-Arg-Phe-Asn-Lys-Arg-Ser(VRIRLLQRFNKRS),and Ala-GlyPhe-Ala-Gly-Asp-Asp-Ala-Pro-Arg(AGFAGDDAPR).However,as yet,clinical evidence on the effi cacy of such bioactive peptides is rare but is inevitable to establish their applications against glucose intolerance and insulin resistance.

Responses of the Adult Rat Glucose Metabolism to Early Life Feeding, Caloric Restriction and Refeeding

Early life overfeeding in the rat can be experimentally induced by reducing litter size. This investigation assessed the consequences of this manipulation on glucose metabolism in vivo and in isolated hepatocytes in 150-day old rats. Additionally, after body growth, the effects of caloric restriction and refeeding were tested. Adult rats from control （G9） and reduced litters （G3L） did not differ in body and fat weights, glucose tolerance or insulin resistance （insulin-induced hypoglycemia）, or hepatocyte glucose release under basal or gluconeogenic conditions. Caloric restriction （G3R） reduced body and fat weights, decreased glucose decay after insulin injection and decreased hepatocyte gluconeogenic glucose release. Refeeding after caloric restriction reversed these parameters to those of the freely-fed groups （G9 and G3L）. Taken together, these results suggest that the liver glucose metabolism is not programmed by lactational overfeeding, but rather is responsive to the current nutritional condition of the animal.

Probiotics supplementation for management of type Ⅱ diabetes risk factors in adults with polycystic ovarian syndrome: a meta-analysis of randomized clinical trial

This meta-analysis of randomized controlled trials aimed to evaluate the effects of probiotic supplementation on glucose homeostasis in patients with polycystic ovary syndrome(PCOS).The meta-analysis was performed in accordance with the Cochrane Handbook guidelines and relevant the preferred reporting items for systematic reviews and meta-analyses(PRISMA)statement criteria.Of 825 identified reports,11 randomized clinical trials were included in the meta-analysis.An analysis of pooled extracted data revealed that supplementation with probiotics significantly decreased fasting blood glucose(FBG,n=7;standardized mean difference(SMD)=−0.40;95%confidence interval(CI):−2.02,−0.02;P=0.04)and insulin levels(n=6;SMD=−0.57;95%CI:−0.89,−0.25;P=0.0004)and the homeostatic model assessment of insulin resistance(n=7;SMD=−0.64;95%CI:−0.96,−0.31;P=0.0001)while increasing the quantitative insulin sensitivity check index(QUICKI,n=5;SMD=0.58;95%CI:0.08,1.09;P=0.02)in patients with PCOS.The FBG-reducing effect decreased as the baseline body mass index(BMI)and mean age of the participants increased.Indeed,a greater number of bacterial species and a higher bacterial dose were shown to reduce QUICKI effectively.The systematic review indicated that probiotic supplementation may help to control glucose homeostasis in adults with polycystic ovarian syndrome.

Metabolic consequences of Helicobacter pylori infection and eradication

Helicobacter pylori(H.pylori)is still the most prevalent infection of the world.Colonization of the stomach by this agent will invariably induce chronic gastritis which is a low-grade inflammatory state leading to local complications(peptic ulcer,gastric cancer,lymphoma)and remote manifestations.While H.pylori does not enter circulation,these extragastric manifestations are probably mediated by the cytokines and acute phase proteins produced by the inflammed mucosa.The epidemiologic link between the H.pylori infection and metabolic changes is inconstant and controversial.Growth delay was described mainly in low-income regions with high prevalence of the infection,where probably other nutritional and social factors contribute to it.The timely eradication of the infection will lead to a more healthy development of the young population,along with preventing peptic ulcers and gastric cancer An increase of total,low density lipoprotein and high density liporotein cholesterol levels in some infected people creates an atherogenic lipid profile which could promote atherosclerosis with its complications,myocardial infarction,stroke and peripheral vascular disease.Well designed and adequately powered long-term studies are required to see whether eradication of the infection will prevent these conditions.In case of glucose metabolism,the most consistent association was found between H.pylori and insulin resistance:again,proof that eradication prevents this common metabolic disturbance is expected.The results of eradication with standard regimens in diabetics are significantly worse than in non-diabetic patients,thus,more active regimens must be found to obtain better results.Successful eradication itself led to an increase of body mass index and cholesterol levels in some populations,while in others no such changes were encountered.Uncertainities of the metabolic consequences of H.pylori infection must be clarified in the future.

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus

Solute carriers(SLCs) constitute the largest superfamily of membrane transporter proteins.These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions.They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake(e.g., SLC2A4/GLUT4), glucose reabsorption(e.g., SLC5A2/SGLT2), thermogenesis(e.g., SLC25A7/UCP-1), and ATP production(e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus(T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone(SLCO1B1/OATP1B1) and metformin(SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.

Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2

Adiponectin has been demonstrated to be a mediator of insulin sensitivity;however,the underlined mechanisms remain unclear.SESN2 is a stress-inducible protein that phosphorylates AMPK in different tissues.In this study,we aimed to validate the amelioration of insulin resistance by globular adiponectin(gAd)and to reveal the role of SESN2 in the improvement of glucose metabolism by gAd.We used a high-fat diet-induced wild-type and SESN2/C57BL/6J insulin resistance mice model to study the effects of six-week aerobic exercise or gAd administration on insulin resistance.In vitro study,C2C12 myotubes were used to determine the potential mechanism by overexpressing or inhibiting SESN2.Similar to exercise,six-week gAd administration decreased fasting glucose,triglyceride and insulin levels,reduced lipid deposition in skeletal muscle and reversed whole-body insulin resistance in mice fed on a high-fat diet.Moreover,gAd enhanced skeletal muscle glucose uptake by activating insulin signaling.However,these effects were diminished in SESN2/mice.We found that gAd administration increased the expression of SESN2 and Liver kinase B1(LKB1)and increased AMPK-T172 phosphorylation in skeletal muscle of wild-type mice,while in SESN2/mice,LKB1 expression was also increased but the pAMPKT172 was unchanged.At the cellular level,gAd increased cellular SESN2 and pAMPK-T172 expression.Immunoprecipitation experiment suggested that SESN2 promoted the formation of complexes of AMPK and LKB1 and hence phosphorylated AMPK.In conclusion,our results revealed that SESN2 played a critical role in gAd-induced AMPK phosphorylation,activation of insulin signaling and skeletal muscle insulin sensitization in mice with insulin resistance.

Glucokinase and glucokinase activator

Glucokinase (GK) plays a pivotal role in glucose homeostasis as the glucose sensor in the pancreas and liver. Loss of function of GK results in hyperglycemia, and gain of function causes congenital hyperinsulinemic hypoglycemia. We speculate that the progressive loss of GK at both messenger RNA (mRNA) and protein levels in the islets and liver would be the key mechanism for Type 2 diabetes (T2D) pathogenesis. The development of GK activator (GKA) as an anti-diabetic drug has been endeavored for several decades. The failure of the early development of GKAs is due to the limitation of understanding the mode of GKA action. The success of dorzagliatin in the treatment of T2D has brought new hope for GK in setting a good model for repairing the underlying defects in the pancreatic islets and liver of T2D patients.

AMPK in myocardial infarction and diabetes:the yin/yang effect

There has been considerable progress in our understanding of cardiac cell metabolism in health and disease,yet important gaps remain in basic knowledge and its translation to clinical care.AMP-activated protein kinase(AMPK)functions either to conserve ATP or to promote.alternative methods of ATP generation.Since the discovery of AMPK more than three decades ago and demonstration of its expression in the heart,interest has grown exponentially in this major fuel gauge as a modulator of the cellular response to ischemia.Such pathway may potentially explain the strong association between metabolic syndrome and ischemic heart disease.Still missing from our most recent cardiology textbooks,this article aims to summarize our understanding so far of the role of AMPK in coordinating the cellular response to ischemic stress and reperfusion injury in the heart.We aim to provide a focused update on the pharmacological agents activating AMPK for treatment of diabetes that show potential cardioprotective effects.Our hope is to stimulate future researchers to the potential benefits of harnessing the A MPK signaling pathway,or better one of its novel downstream targets for the treatment of myocardial ischemia.

Activating transcription factor 3 in immune response and metabolic regulation

Activating transcription factor 3(ATF3)is a member of the ATF/cyclic adenosine monophosphate(cAMP)-response element binding protein(CREB)family of transcription factors.In response to stress stimuli,ATF3 forms dimers to activate or repress gene expression.Further,ATF3 modulates the immune response,atherogenesis,cell cycle,apoptosis,and glucose homeostasis.Recent studies have shown that ATF3 may also be involved in pathogenesis of other diseases.However,more studies are needed to determine the role of ATF3 in metabolic regulation.