刺梨果酒通过胰岛素介导的PI3K途径改善1-型糖尿病大鼠机体糖代谢紊乱

为了探讨刺梨果酒对链脲佐菌素(STZ)诱导的1-型糖尿病大鼠糖代谢紊乱的影响及其作用机制。采用一次性腹腔注射STZ的方法建立1-型糖尿病大鼠模型,将造模成功后的大鼠分为刺梨果酒高、中、低剂量组和模型组,并设空白对照组。灌胃给药期间测定大鼠的饮食饮水量和体重,每2周测一次空腹血糖(FBG),实验期28 d。实验结束后测量血清胰岛素(Insulin,Ins)和果糖胺的含量;实时灾光定量PCR(real time polymerase chain reaction,RT-PCR)测定肝脏磷脂酞肌醇3-激酶(Phosphoinositide 3-kinase,PI3K)、蛋白激酶B(protein kinase B,Akt/PKB)和葡萄糖转运载体2(Glucose Transporter 2,GLUT2),以及骨骼肌葡萄糖转运载体4(Glucose Transporter 4,GLUT4)m RNA相对表达量。结果表明,与模型组相比,刺梨果酒高、中、低剂量组多饮多食的症状明显好转,体重下降受到抑制;刺梨果酒高、中、低剂量可显著(p<0.05)降低空腹血糖,分别下降了21.20%,36.14%和8.75%;果糖胺降低了11.32%,16.65%和8.33%;血清胰岛素水平分别上升了39.69%,45.87%和17.82%。与模型组相比,刺梨果酒高、中、低剂量组均可显著升高肝脏PI3K、PKB和GLUT2及骨骼肌GLUT4 mRNA相对表达量。本试验说明一定量的刺梨果酒具有改善STZ诱导的1-型糖尿病大鼠糖代谢紊乱,其中中剂量效果更明显。

T-S模糊模型H_∞控制应用于1-型糖尿病人的血糖调节（英文）

研究T-S模糊模型的H_∞控制问题,将其应用于1-型糖尿病人的血糖调节。基于构造模糊Lyapunov函数和应用Lyapunov稳定性理论,提出设计H_∞状态反馈模糊控制器的新方法,使得对应闭环系统是全局渐近稳定的,并满足预先指定的H_∞性能。将所设计的H_∞状态反馈模糊控制器应用到Bergman最小模型,达到调节1-型糖尿病人血糖的目的。实例说明了理论结果的有效性。

谷氨酸脱羧酶抗体的测定在1-型糖尿病中的临床意义

目的 :了解并分析GAD抗体与糖尿病分型的关系。方法 :应用酶联免疫法对 1 1 0例 1 -型糖尿病患者及 1 32例 2 -型糖尿病患者进行GAD抗体及ICA的测定。结果 :①GAD抗体的阳性率在 1 -型及 2 -型糖尿病患者中分别为 74.54%和 8.33% ,前者高于后者 ,有显著性差异 (P <0 .0 1 )。②ICA的阳性率在 1 -型及 2 -型糖尿病患者中分别为 38.1 8%和 4.55% ,前者高于后者 ,有显著性差异 (P <0 .0 1 )。③在 1 -型中GAD抗体与ICA的阳性率分别为 74.54%和 38.1 8% ,二者有显著性差异 (P <0 .0 1 )。结论 :GAD抗体可用于糖尿病的分型及指导治疗。

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer's disease?

Glucagon-like peptide- 1 （GLP- 1） has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus （T2DM）. Both Alzheimer＇s disease （AD） and T2DM share some common pathophysiologic hallmarks, such as amyloid β （Aβ）, phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Aβ and tau protein. Combine these findings, GLP- 1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP- 1, communities between T2DM and AD, new progresses of GLP - 1 in treating T2MD and improving some pathologic hanmarks of AD.

Expression of interferon inducible protein-10 in pancreas of mice

AIM: To investigate the expression of interferon inducible protein-10 (IP-10) in pancreas of mice and to discuss its possible role in the pathogenesis of type 1 diabetes.METHODS: Non-obese diabetic (NOD) mice were used as experiment group and BALB/c mice as non-diabetic prone model. Immunohistochemistry method was used to evaluate the expression of IP-10 in the pancreas of NOD mice and BALB/c mice. Immunoelectron microscope was used to show the location of IP-10 in pancreatic islet β cells.RESULTS: Pancreatic islets were positively stained in all the NOD mice. Insulitis could be found in mice at the age of 4 wk. The weakly positive results were found in control group with no insulitis. Immunoelectron microscopy further demonstrated that IP-10 was produced by pancreatic β cells and stored in cytoplasm of the cells.CONCLUSION: IP-10 can be largely produced in pancreatic islets of NOD mice at the age of 2 wk when there is no significant insulitis, and may play an important part in the pathogenesis of type 1 diabetes by attracting immune cells to infiltrate the pancreatic islets.

Adiponectin receptor 1 and small ubiquitin-like modifier 4 polymorphisms are associated with risk of coronary artery disease without diabetes

Background The genes encoding adiponectin receptor 1 （ADIPOR1） and small ubiquitin-like modifier 4 （SUM04） have been linked to anti-atherogenic effects, but little is known about whether polymorphisms in the two genes, acting separately or interacting, affect risk of coronary artery disease （CAD） without diabetes. Methods We genotyped 200 CAD patients without diabetes and 200 controls without CAD or diabetes at three single-nucleotide polymorphisms （SNPs） in ADIPOR1 and one SNP in SUM04, which were chosen based on previous studies. Potential associations were also explored between these SNPs and clinical characteristics of CAD without diabetes. Results Risk alleles at three SNPs inADIPOR1 （rs7539542-G, rs7514221-C and rs3737884-G） and the G allele at SNP rs237025 in SUM04 significantly increased risk of CAD without diabetes, with ORs ranging from 1.79 to 4.44. Carriers of any of these four risk alleles showed similar adverse clinical characteristics. Compared with individuals with a CC or GC genotype, those with a GG genotype at rs3737884 were at significantly higher risk of CAD that affected the left anterior descending coronary artery （OR： 6.77, P = 0.009）, the right coronary artery （OR： 4.81, P = 0.028） or a relatively large number of vessels （P = 0.04）. Individuals carrying a risk allele at one or more of the three SNPs in ADIPOR1 as well as a risk allele at the SNP in SUM04 were at significantly higher risk of CAD without diabetes than individuals not carrying any risk alleles （OR： 5.82, 95% CI： 1.23-27.7, P= 0.013）. Conelusions SNPs in ADIPORl and SUMO4 are associated with elevated risk of CAD without diabetes, and SNPs in the two genes may interact to jointly affect disease risk.

Advancements in glucagon-like peptide-1 receptor agonist therapy for type 2 diabetes

Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are novel hypoglycemic agents that have garnered widespread acceptance in the treatment of type 2 diabetes,largely attributed to their safety profile,potent hypoglycemic effects,and metabolic advantages.Their primary mechanisms of action encompass promoting insulin release,inhibiting glucagon secretion,bolstering pancreatic islet cell function,curbing appetite,and slowing gastric emptying.This article delves into the clinical evidence underscoring the efficacy of various GLP-1RAs.Notably,these agents have demonstrated marked improvements in glycemic control,significant weight reduction,and substantial cardiovascular and renal protection.Nonetheless,certain adverse effects of GLP-1RAs,such as pancreatitis and intestinal obstruction,have been reported,warranting vigilant monitoring by healthcare professionals.In sum,GLP-1RAs hold significant promise in the management of type 2 diabetes,offering notable cardiovascular and renal advantages.

Transplantation for the treatment of type 1 diabetes

Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin Alc levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events （even with only partial islet function evident）. Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pretransplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the longterm viability and function of the graft to maintain improved glucose control over time.

Gene therapy for type 1 diabetes mellitus in rats by gastrointestinal administration of chitosan nanoparticles containing human insulin gene

AIM:To study the expression of human insulin gene in gastrointestinal tracts of diabetic rats. METHODS: pCMV.Ins, an expression plasmid of the human insulin gene, wrapped with chitosan nanoparticles, was transfected to the diabetic rats through lavage and coloclysis, respectively. Fasting blood glucose and plasma insulin levels were measured for 7 d. Reverse transcription polymerase chain reaction (RT-PCR) analysis and Western blot analysis were performed to confirm the expression of human insulin gene. RESULTS: Compared with the control group, the fasting blood glucose levels in the lavage and coloclysis groups were decreased significantly in 4 d (5.63 ± 0.48 mmol/L and 5.07 ± 0.37 mmol/L vs 22.12 ± 1.31 mmol/L, respectively, P < 0.01), while the plasma insulin levels were much higher (32.26 ± 1.81 μIU/mL and 32.79 ± 1.84 μIU/mL vs 14.23 ± 1.38 μIU/mL, respectively, P < 0.01). The human insulin gene mRNA and human insulin were only detected in the lavage and coloclysis groups. CONCLUSION: Human insulin gene wrapped with chitosan nanoparticles can be successfully transfected to rats through gastrointestinal tract, indicating that chitosan is a promising non-viral vector.

Advances of N-terminal modifications of GLP-1 and their applications for the treatment of type 2 diabetes

Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity, by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine（Gly8） and α-aminoisobutyric acid（Aib8） have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.

Effect of Sancaijiangtang on plasma nitric oxide and endothelin-1 levels in patients with type 2 diabetes mellitus and vascular dementia:a single-blind randomized controlled trial

OBJECTIVE: To observe the effect of Sancaijiangtang powders on plasma nitric oxide and endothelin-1 levels. We sought to identify the common pathological link and mechanism of action for Traditional Chinese medicine in type 2 diabetes mellitus and vascular dementia,and to explicate the material basis for treating the different diseases with the same method in Traditional Chinese Medicine.METHODS: In total,168 patients with type 2 diabetes mellitus and vascular dementia were enrolled in the study,and randomly divided into two groups by simple randomization. Patients in the treatment group received oral Sancaijiangtang powders with pioglitazone hydrochloride three times daily,while patients in the control group received pioglitazone hydrochloride alone. The treatment course was for12 weeks. Mini-mental state examinations(Chinese version) and Montreal Cognitive Assessments(Beijing version) were performed,and fasting plasma glucose,fasting insulin,hemoglobin A1 c,homeostasis model assessment of insulin resistance,plasma nitric oxide and endothelin-1 levels were measured before and after the treatment.RESULTS: The post-treatment levels for all measurements in both groups were better than pre-treatment levels(P < 0.05). The post-treatment levels for all measurements in the treatment group were better than the levels measured in the control group(P < 0.05).CONCLUSION: Type 2 diabetes mellitus and vascular dementia have common pathological mechanisms for insulin resistance and endothelium dysfunction. Sancaijiangtang powders could improve the release of nitric oxide and inhibit the secretion of endothelin-1. Therefore,the material basis exists for treating the different diseases with the same method in Traditional Chinese Medicine.

The association between PPP1R3 gene polymorphisms and type 2 diabetes mellitus

Objective To detect the relationship between the polymorphism of the glycogen-targeting regulatory subunit of the skeletal muscle glycogen-associated protein phosphatase 1 (PPP1R3) gene and type 2 diabetes by case-control study. Methods We genotyped the PPP1R3 gene Asp905Tyr polymorphism and a common 3'-untranslated region AT (AU)-rich element (ARE) polymorphism in 101 type 2 diabetic patients and 101controls by oligonucleotide ligation assay (OLA) and polyacrylamide gel elecrophoresis, respectively. Results Subjects with Tyr/Tyr genotypes whose body mass index (BMI)<25 were used as the reference group. Those whose BMI25 with Asp905 had a 3.66-fold increase (95% CI: 1.48-9.06, P=0.005) in type 2 diabetes risk. No association was found between 3'UTR ARE polymorphism and type 2 diabetes mellitus (OR=1.15; 95% CI: 0.62-2.14, P=0.65). Conclusion A joint effect between the Asp905 and BMI increases the risk of type 2 diabetes, and Asp905Tyr and ARE polymorphism of PPP1R3 gene are not the major diabetogenic gene variants in Chinese population.

Relationship of large multifunctional proteasome 7 gene polymorphism with susceptibility to type 1 diabetes mellitus and DR3 gene

Objective To study the relationship of the large multifunctional proteasome 7 (LMP7) gene polymorphism with susceptibility to type 1 diabetes mellitus (DM-1) and the DR3 gene in south Chinese Han population.Methods LMP7 genotypes and the DR3 gene were identified in 71 DM-1 patients and 86 healthy persons (as controls) by polymerase chain reaction-restriction fragment length polymorphism. DM-1 patients and controls were divided into DR3-positive and DR3-negative subjects. The frequencies of LMP7 genotypes and alleles were compared between DM-1 patients and controls respectively in the random subjects and in the DR3-matched subjects. Furthermore, DM-1 patients were divided into 3 groups according to the age of diabetic onset: group A≤14 years, group B 15-30 years, group C≥31 years.Results In the random subjects, the frequency of LMP7-B/B was lower (39% vs 58%, P<0.05) and that of LMP7-B/A was higher (54% vs 31%, P<0.01) in DM-1 patients than that in controls. In DR3-positive subjects, the frequencies of LMP7 genotypes and alleles showed no differences between DM-1 patients and controls. In DR3-negative subjects, the frequency of LMP7-B/B was decreased (40% vs 61%) and that of LMP7-B/A was increased (55% vs 28%, P<0.01) in DM-1 patients. The frequencies of LMP7 genotypes and alleles showed no significant differences among different ages of diabetic onset.Conclusions LMP7-B/B may be the protective genotype, and LMP7-B/A may be the susceptible genotype of DM-1, and this may not be affected by the DR3 gene. Persons with LMP7-B/B may have a decreased risk, and those with LMP7-B/A have an increased risk suffering from DM-1. The LMP7 gene may not be associated with the age of diabetic onset.

CTLA-4 gene A/G polymorphism associated with diabetes mellitus in Han Chinese

OBJECTIVE: To investigate the association of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene A/G polymorphism with susceptibility to diabetes mellitus in Han Chinese. METHODS: An A/G transition at position 49 of exon 1 was analyzed in 31 patients with type 1 diabetes, 31 patients with type 2 diabetes, and 36 controls were analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: A highly significant increase in the frequency of the G allele was seen in patients with type 1 diabetes compared with controls (66.1 % vs. 34.7%, respectively; P

Incretin-based therapies for type 2 diabetes with nonalcoholic fatty liver disease: a systematic review and meta-analysis

We conducted a systematic review and meta-analysis of randomized controlled trials（RCTs） to determine the effectiveness and safety of incretin-based therapies（IBTs） for the treatment of type 2 diabetes（T2DM） with nonalcoholic fatty liver disease（NAFLD）. Electronic databases such as the Cochrane library, EMbase, Pub Med, and three Chinese databases were searched for RCTs that compared IBTs with other treatments or placebo for T2 DM with NAFLD. Two reviewers independently assessed the risk of bias, extracted, and analyzed the data. A meta-analysis was performed using Revman 5.2. Publication bias was evaluated. Seven RCTs involving 532 patients were ultimately included. The results of meta-analysis（random-effects model） revealed that IBTs had a significant reduction in serum ALT（WMD –12.30, 95% CI –17.53~–7.06） and BMI（WMD –2.64, 95% CI –4.35~–0.94）. However, there was no significant difference in other outcomes including Hb A1 c, AST, TC, TG and HOMA-RA. IBTs were well tolerated by patients but the evidence was limited. The significant decrease in hepatic biochemical markers following treatment with IBTs, as well as improvements in BMI, suggested that IBTs may be an effective option for T2 DM with NAFLD.

Mature insulin production by engineered non-βcells

To pursue insulin and islet transplantation replacement therapy for type 1 diab etes based on engineered human non β cells which secrete mature insulin Methods Human proinsulin cDNA was cloned from its genomic gene and mutated by overlap e xtension PCR, introducing furin consensus cleavage sequences (Arg Xaa Lys/Arg Arg) An expression vector encoding a genetically modified human proinsulin c DNA was generated and transduced to Hela, 293, and L02 cells by lipofectin medi ated DNA transfection Following G418 screening, the surviving L02 cells were s elected and enriched Insulin levels in the supernatant and cells were evaluate d using radioimmunoassay and immunofluorescence staining Results Three sites in the insulin gene were mutated simultaneously Insulin gene m odified cells were able to express insulin at different levels: 8 45-188 00? μIU/24 h/2 0×10 6 Hela cells and 159 88-242 14?μIU/24 h/2 0×10 6 293 cells for transient expression, and 2 56-61 95?μIU/24 h/2 0×10 6 from se veral L02 clones screened with G418 No insulin was released by control cells Furthermore, immunofluorescence staining confirmed that proinsulin was stored a s vacuoles in the cytoplasm of L02 cells Conclusion A correctly mutated human proinsulin cDNA was obtained successfully, transfected and expressed efficiently in non beta cells, lending support to the study of s omatic gene therapy in diabetes mellitus

Case Report:Fulminant type 1 diabetes in China:a case report and review of the literature

Fulminant type 1 diabetes is a recently discovered subtype of idiopathic type 1 diabetes, defined as diabetes with an extremely rapid process of β-cell destruction and progression to hyperglycemia and ketoacidosis. In this report, we present a case of fulminant type 1 diabetes in a 45-year-old Chinese woman, along with a review of the literature. The patient presented with sudden onset of polydipsia and polyuria after flu-like symptoms. Findings on admission included a high blood glucose level and ketoacidosis, but normal HbAlc level. The C-peptide stimulation test showed severe impairment of insulin secretion. Autoantibodies to glutamic acid decarboxylase （GAD） were negative. These results are compatible with the diagnosis of fulminant type 1 diabetes. Human leukocyte antigen-DR7 （HLA-DR7） was available in this case. It is concluded that this rapidly progressing type of diabetes exists, and we propose that HLA-DR7 might be predisposed to fulminant type 1 diabetes in Chinese patients.