WJD 5~h Anniversary Special Issues(1):Insulin Insulin and bone:Recent developments

While insulin-like growth factorⅠis a well-known anabolic agent in bone evidence is beginning to accumulate that its homologue,insulin,also has some anabolic properties for bone.There is specific evidence that insulin may work to stimulate osteoblast differentiation,which in turn would enhance production of osteocalcin,the osteoblast-produced peptide that can stimulate pancreaticβcell proliferation and skeletal muscle insulin sensitivity.It is uncertain whether insulin stimulates bone directly or indirectly by increasing muscle work and therefore skeletal loading.We raise the question of the sequence of events that occurs with insulin resistance,such as type 2 diabetes.Evidence to date suggests that these patients have lower serum concentrations of osteocalcin,perhaps reduced skeletal loading,and reduced bone strength as evidenced by microindentation studies.

Short-Term Effects of Liraglutide versus Vildagliptin on Insulin Secretion and Sensitivity in Type 2 Diabetes: A Single Blinded Randomized Controlled Trial (LIRAVIS Study)

Background: We aimed to evaluate the short-term metabolic effects of a GLP-1a, (liraglutide) versus a DPP-4i, (vildagliptin) in a group of sub-Saharan type 2 diabetes patients. Methods: We conducted a randomized controlled single blinded clinical trial in 14 uncontrolled type 2 diabetes patients (HbA1c ≥ 53 mmol/mol) with mean duration of diabetes of 8 [1 - 12] years and median age of 57 [49 - 61] years. Baseline treatment consisted of metformin in monotherapy or metformin plus sulfonylureas. Participants were randomly allocated to 2 groups of add-on 1.2 mg/day subcutaneous liraglutide in group 1 or 100 mg/day of oral vildagliptin in group 2 for 2 weeks. In all participants, insulin secretion in response to mixed meal tolerance test, insulin sensitivity by 80 mU/m2/min hyperinsulinemic-euglycemic clamp, body composition, and lipid profile were measured before and after intervention. Results: At the end of intervention, insulin sensitivity remained unchanged both with liraglutide from 6.6 [4.2 - 7.9] to 6.9 [4.3 - 10.8] mg/kg/min;p = 0.61 and vildagliptin from 7.1 [5.3 - 9.0] to 6.5 [5.6 - 9.4] mg/kg/min (p = 0.86). The area under the C-peptide curve varied from 5.5 [1.0 - 10.9] to 14.9 [10.8 - 17.2] nmol/L/120min, p = 0.09 in group 1 and from 1.1 [0.5 - 14.1] to 13.0 [9.6 - 16.9] nmol/L/120min (p = 0.17) in group 2. LDL Cholesterol levels decreased significantly with liraglutide from 0.85 g/L [0.51 - 1.02] to 0.54 g/L [0.50 - 0.73] (p = 0.04) but not with Vildagliptin. Body weight tended to decrease in group 1 (−0.6 kg) versus modest increase in group 2 (+1.1 kg). Conclusion: Short-term metabolic effects of Liraglutide and Vildagliptin add-on therapy are comparable in sub-Saharan type 2 diabetes patients with a more favorable trend for Liraglutide on body weight, lipid profile, and insulin secretion.

The Principles of Insulin Management of Type 2 Diabetes Mellitus

Insulin therapy is an integral part of the pharmacological management of Type 2 diabetes mellitus. Guidelines recommended insulin therapy for those patients with suboptimal glycaemic control despite optimal medical treatments. Studies show that insulin therapy with the human and regular insulins improve glycaemic control, reduce the chronic complications, and inevitably improve patient’s quality of life. The new analogue insulin has a better safety profile and efficacies, and has been shown to achieve better outcomes and patient’s acceptability compared with the human and regular insulins. The diabetic guidelines also recommend the intensity of insulin therapy in a personalised glycaemic control strategy based on the patient’s profiles and their preferences. However, the guidelines do not recommend any standardised approach to the principles of insulin initiation, titration, and monitoring. This review summarises the essential principles of insulin initiation, titration, and monitoring in Type 2 diabetes mellitus.

Klotho生物学功能与Insulin/IGF-1通路关系的研究进展

Klotho基因是一个与衰老密切相关的基因,他参与维生素K和钙、磷的代谢,保护心血管系统,影响机体的免疫功能,对衰老及衰老相关性疾病进行调节.胰岛素/胰岛素样生长因子-1(insulin/insulin-like growth factor-1,Insulin/IGF-1)信号通路也参与衰老及衰老相关性疾病的调节,其发生改变可以增加寿命,延缓衰老.近年来大量研究发现Klotho发挥其生物学功能与其抑制Insulin/IGF-1信号通路的激活密切相关,本文就此予以综述.

无脊椎动物胰岛素样蛋白(Insulin-like/related peptides)研究进展——以昆虫为例

胰岛素样蛋白(Insulin-like/related peptides,ILPs)是无脊椎动物中胰岛素的同源基因。以昆虫为例,概述了ILPs的结构、表达以及相关通路特别是胰岛素信号通路(Insulin signaling pathway),并总结了其在调控机体生长、发育、新陈代谢、繁殖和免疫等生命过程中的作用。

Molecular mechanisms of insulin resistance in type 2 diabetes mellitus

Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade,which leads to defects in insu-lin signaling downstream to the insulin receptor.In addition,the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin.Among the many molecules involved in the intracellular processing of the signal provided by insulin,the insulin receptor substrate-2,the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest,as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo.Recently,studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression.Additionally,it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases,and weakens insulin signal transduction.Thus,in this review,the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized.In addition,this study provides potential new targets for the treatment and prevention of type 2 diabetes.

A paradox:Insulin inhibits expression and secretion of resistin which induces insulin resistance

AIM: To confirm whether insulin regulates resistinexpression and secretion during differentiation of 3T3-L1preadipocytes and the relationship of resistin with insulinresistance both in vivo and in vitro.METHODS: Supernatant resistin was measured duringdifferentiation of 3T3-L1 preadipocytes. L6 rat myoblastsand hepatoma cell line H4IIE were used to confirm thecellular function of resistin. Diet-induced obese ratswere used as an insulin resistance model to study therelationship of resistin with insulin resistance.RESULTS: Resistin expression and secretion wereenhanced during differentiation 3T3-L1 preadipocytes.This cellular differentiation stimulated resistin expressionand secretion, but was suppressed by insulin. Resistinalso induced insulin resistance in H4IIE hepatocytes andL6 myoblasts. In diet-induced obese rats, serum resistinlevels were negatively correlated with insulin sensitivity,but not with serum insulin.CONCLUSION: Insulin can inhibit resistin expressionand secretion in vitro, but insulin is not a major regulatorof resistin in vivo . Fat tissue mass affects insulinsensitivity by altering the expression and secretion ofresistin.

Targeting the insulin-like growth factor pathway in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor(IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed suchas monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor Ⅱ rather than insulin growth factor Ⅰ. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-Ⅰ signaling pathway for hepatocellular carcinoma treatment.

Involvement of insulin receptor substrates in cognitive impairment and Alzheimer’s disease

Type 2 diabetes一associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)一is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid p accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS 1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS 1 /1 RS2-mediated signaling in the central nervous system and cognitive decline.

Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats

AIM:To investigate the effects of mitofusin-2(MFN2) on insulin sensitivity and its potential targets in the liver of rats fed with a high-fat diet(HFD).METHODS:Rats were fed with a control or HFD for 4 or 8 wk,and were then infected with a control or an MFN2 expressing adenovirus once a week for 3wk starting from the 9th wk.Blood glucose(BG),plasma insulin and insulin sensitivity of rats were determined at end of the 4th and 8th wk,and after treatment with different amounts of MFN2 expressing adenovirus(108,109 or 1010 vp/kg body weight).BG levels were measured by Accu-chek Active Meter.Plasma insulin levels were analyzed by using a Rat insulin enzymelinked immunosorbent assay kit.Insulin resistance was evaluated by measuring the glucose infusion rate(GIR) using a hyperinsulinemic euglycemic clamp technique.The expression or phosphorylation levels of MFN2 and essential molecules in the insulin signaling pathway,such as insulin receptor(INSR),insulin receptor substrate 2(IRS2),phosphoinositide-3-kinase(PI3K),protein kinase beta(AKT2) and glucose transporter type 2(GLUT2) was assayed by quantitative real-time polymerase chain reaction and Western-blotting.RESULTS:After the end of 8wk,the body weight of rats receiving the normal control diet(ND) and the HFD was not significantly different(P>0.05).Compared with the ND group,GIR in the HFD group was significantly decreased(P<0.01),while the levels of BG,triglycerides(TG),total cholesterol(TC) and insulin in the HFD group were significantly higher than those in the ND group(P<0.05).Expression of MFN2 mRNA and protein in liver of rats was significantly downregulated in the HFD group(P<0.01) after 8 wk of HFD feeding.The expression of INSR,IRS2 and GLUT2 were down-regulated markedly(P<0.01).Although there were no changes in PI3K-P85 and AKT2 expression,their phosphorylation levels were decreased significantly(P<0.01).After intervention with MFN2 expressing adenovirus for 3wk,the expression of MFN2 mRNA and protein levels were up-regulated(P<0.01).There was no difference in body weight of rats between the groups.The levels of BG,TG,TC and insulin in rats were lower than those in the Ad group(P<0.05),but GIR in rats infected with Ad-MFN2 was significantly increased(P<0.01),compared with the Ad group.The expression of INSR,IRS2 and GLUT2 was increased,while phosphorylation levels of PI3K-P85 and AKT2 were increased(P<0.01),compared with the Ad group.CONCLUSION:HFDs induce insulin resistance,and this can be reversed by MFN2 over-expression targeting the insulin signaling pathway.

The Expression of Resistin in Adipose Tissues of Patients with Polycystic Ovary Syndrome and Insulin Resistance

The relationship between the expression of resistin in polycystic ovary syndrome （PCOS） and insulin resistance was investigated. The plasma resistin concentrations in 35 patients with PCOS and 40 controls were measured by ELISA. Luteinizing hormone （LH）, follicle-stimulating hormone （FSH）, and fasting insulin （FIN） were tested by radioimmunoassay. Insulin resistance index （HOMA-IR） was calculated. Fasting plasma glucose （FPG） was determined by oxidase test. Western blot and reverse transcriptase PCR （RT-PCR） methods were used to detect the expression of resistin in adipose tissues. The levels of plasma resistin, LH, LH/FSH and FIN and HOMA-IR in patients with PCOS were significantly higher than those in control group （all P〈0.05）. Plasma resistin was correlated positively with FPG, FIN, HOMA-IR, LH and LH/FSH （r=0.56, 0.60, 0.65, 0.48, and 0.42 respectively）. Resistin protein and mRNA expression levels in patients with PCOS were significantly higher than those in normal tissues （all P〈0.01）. It was concluded that resistin might be involved in the pathogenesis of insulin resistance of PCOS.

Possible roles of insulin, IGF-1 and IGFBPs in initiation and progression of colorectal cancer

AIM: To investigate the roles of serum insulin, insulinlike growth factor-1(IGF-1), and insulin-like growth factor binding proteins(IGFBPs) in the initiation and progression of colorectal cancer. METHODS: We determined serum insulin, IGF-1 and IGFBPs levels in 615 colorectal cancer patients and 650 control healthy donors by enzyme-linked immunosorbent assay(ELISA). In the meantime, their body mass index(BMI) and waist-to-hip ratio(WHR) were measured. RESULTS: Serum levels of insulin and IGF-1 as well as IGF-1/IGFBP-3 ratio in pre-operation patients were significantly elevated, but the level of IGFBP-3 was significantly decreased compared with normal controls and post-operation patients(P < 0.05 and P < 0.001,respectively). There is no significant difference(P > 0.05) in the levels of insulin, IGF-1, IGFBP-1, IGFBP-3 and IGF-1/IGFBP-3 between the patients with and without hepatic as well as distal abdominal metastases. WHR and BMI of colon cancer patients were positively and significantly correlated with the levels of insulin and IGF-1/IGFBP-3. In contrast, WHR and BMI were negatively correlated with IGFBP-3 level. CONCLUSION: The elevation of insulin, IGF-1 as well as IGF-1/IGFBP-3 ratio and the reduction of IGFBP-3 may be related to the initiation of colorectal cancer, but they are not related to the progression and outcome of the disease.

An overview on antidiabetic medicinal plants having insulin mimetic property

Diabetes mellitus is one of the common metabolic disorders acquiring around 2.8%of the world's population and is anticipated to cross 5.4%by the year 2025.Since long back herbal medicines have been the highly esteemed source of medicine therefore,they have become a growing part of modern,high-tech medicine.In view of the above aspects the present review provides profiles of plants(65 species) with hypoglycaemic properties,available through literature source from various database with proper categorization according to the parts used,mode of reduction in blood glucose(insulinomimetic or insulin secretagugues activity) and active phyloconsliluents having insulin mimetics activity.From the review it was suggested that,plant showing hypoglycemic potential mainly belongs to the family Leguminoseae,Lamiaceae,Liliaceae,Cucurbitaceae, Asteraceae,Moraceae,Rosaceae and Araliaceae.The most active plants are Allium sativum. Gymnema sylvestre,Citrullus colocynthis,Trigonella foenum greacum,Momordica charantia and Ficuts bengalensis.The review describes some new bioactive drugs and isolated compounds from plants such as roseoside,epigallocatechin gallate,beta-pyrazol-1-ylalanine,cinchonain Ib,leucocyandin 3-O-beta-d-galactosyl cellobioside,leucopelargonidin-3- O-alpha-L rhamuoside,glycyrrhetinic acid,dehydrotrametenolic acid,strictinin,isostrictinin,pedunculagin, epicatechin and christinin-A showing significant insulinomimetic and antidiabetic activity with more efficacy than conventional hypoglycaemic agents.Thus,from the review majorly,the antidiabetic activity of medicinal plants is attributed to the presence of polyphenols,flavonoida, terpenoids,coumarins and other constituents which show reduction in blood glucose levels.The review also discusses the management aspect of diabetes mellitus using these plants and their active principles.

Surrogate markers of insulin resistance:A review

Insulin resistance is a hallmark of obesity,diabetes,and cardiovascular diseases,and leads to many of the abnormalities associated with metabolic syndrome. Our understanding of insulin resistance has improved tremendously over the years,but certain aspects of its estimation still remain elusive to researchers and clinicians.The quantitative assessment of insulin sensitivity is not routinely used during biochemical investigations for diagnostic purposes,but the emerging importance of insulin resistance has led to its wider application research studies.Evaluation of a number of clinical states where insulin sensitivity is compromised calls for assessment of insulin resistance. Insulin resistance is increasingly being assessed in various disease conditions where it aids in examining their pathogenesis,etiology and consequences. The hyperinsulinemic euglycemic glucose clamp is the gold standard method for the determination of insulin sensitivity,but is impractical as it is labor-and time-intensive.A number of surrogate indices have therefore been employed to simplify and improve the determination of insulin resistance.The object of this review is to highlight various aspects and methodologies for current and upcoming measures ofinsulin sensitivity/resistance.In-depth knowledge of these markers will help in better understanding and exploitation of the condition.

Role of insulin/insulin-like growth factor 1 signaling pathway in longevity

The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is evolutionary conserved in diverse speciesincluding C.elegans, saccharomyces cerevisiae, Drosophila melanogaster, rodents and humans, which is involved in many interrelated functions that are necessary for metabolism, growth and reproduction. Interestingly, more and more research has revealed that insulin/IGF-1 signaling pathway plays a pivotal role in the regulation of longevity. Generally, disruption of the power of this pathway will extend longevity in species ranging from C.elegansto humans. The role of insulin/IGF-1 in longevit yis probably related to stress resistance. Although the underlying mechanisms of longevity are not fully understood, the Insulin/IGF-1 signaling pathway has attracted substantial attention and it will be a novel target to prevent or postpone age-related diseases and extend life span. In this review, we mainly focus on the similar constitution and role of insulin/IGF-1 signaling pathway in C.elegans, saccharomyces cerevisiae, rodents and humans.

Albiflorin Granule significantly decreased the cholesterol gallstone formation by the regulation of insulin transduction signal

Objective:To study the mechanism of insulin resistance in the cholesterol gallstone formation from insulin signal transduction pathway so as to reveal the possible mechanism and the effective role of Albiflorin Granule on preventing the cholesterol gallstones.Methods:Serum triglycerides(TG),free fatty acid(FFA),and total cholesterol(TC) from different groups were measured and liver cells Ins R,PKB,IKK-β protein expression levels were detected by western blotting.Results:Albiflorin significantly decreased the cholesterol gallstone formation rate,increased glucose infusion rate in gallstone guinea pigs and improved insulin resistance.Compared with the normal group,insulin receptor and PKB protein expression in GS group were significantly reduced.IKK-β protein in the GS group increased significantly and Albiflorin could reduce IKK-β protein expression in guinea pig liver cells.Conclusions:The model of insulin resistance in cholesterol gallstone guinea pig was successfully established,which plays an important role in the cholesterol gallstone formation.All aspects of insulin signaling pathway are involved in gallstone formation.Albiflorin can regulate various aspects of insulin signal transduction pathway to prevent the formation of gallbladder.

Insulin therapies: Current and future trends at dawn

Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closedloop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future.

Chronic Hyperinsulinism Induced Down-regulation of Insulin Post-Receptor Signaling Transduction in Hep G2 Cells

To study the regulatory effect of acute and chronic insulin treatmenton insulin post- re- ceptor signaling transduction pathway in a human hepatom a cell line (Hep G2 ) ,Hep G2 cells were incubated in the presence or absence of insulin with different concentrations in serum free m edia for16 h and then stim ulated with10 0 nmol/ L insulin for1m in.Protein levels of insulin receptor β- subunit(IRβ) ,insulin receptor substrate- 1(IRS- 1) and p85 subunit of phosphatidylinositol3- kinase(PI3- kinase) were determined in total cell lysates by Western- im munoblot.Phosphorylat- ed proteins IRβ,IRS- 1and interaction of PI3- kinase with IRS- 1were determ ined by im munopre- cipitation.Results showed that 1- min insulin stimulation rapidly induced tyrosine phosphorylation of IRβ and IRS- 1,which in turn,resulting in association of PI 3- kinase with IRS- 1.1- 10 0 nm ol/ L chronic insulin treatment induced a dose- dependent decrease in the protein level of IRβ and a slight decrease in the protein level of IRS- 1.There was a m ore marked reduction in the phospho- rylation of IRβ,IRS- 1,reaching a nadir of2 2 % (P<0 .0 1) and15 % (P<0 .0 1) of control lev- els,respectively,after16 h treatment with 10 0 nm ol/ L insulin.The association between IRS- 1 and PI3- kinase was decreased by6 6 % (P<0 .0 1) .There was no significant change in PI3- ki- nase protein levels. These data suggest that chronic insulin treatm ent can induce alterations of IRβ,IRS- 1and PI 3- kinase three early steps in insulin action,which contributes significantly to insulin resistance,and may account for desensitization of insulin action.

Reactivation of the insulin-like growth factor-Ⅱsignaling pathway in human hepatocellular carcinoma

Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma(HCC).Especially the over- expression of the fetal growth factor IGF-Ⅱ,IGF-Ⅰ receptor(IGF-IR),and cytoplasmic downstream effectors such as insulin-receptor substrates(IRS)contribute to proliferation,anti-apoptosis,and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱsignaling during HCC development and progression.Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies,various experimental strategies have been developed,including neutralizing antibodies and selective receptor kinase inhibitors,with respect to the specific and efficient reduction of oncogenic IGF-Ⅱ/IGF-IR-signaling.