Mediating effect of acarbose on neurotransmitters in mental disorders: a review

Acarbose is used to control postpran-dial blood glucose in patients with type 2 diabetes and impaired glucose tolerance,since it improves insulin re-sistance and reduces blood lipids and cardiovascular com-plications.However,in recent years,many studies have found that acarbose can mediate and regulate a variety of neurotransmitter-related diseases,although the mech-anisms are not clear.Therefore,this paper analyzes the clinical effect of acarbose and its mediating effect on neu-rotransmitters of mental disorders through insulin,brain-gut axis,and calorie restriction,to provide a reference for the new clinical applications of acarbose.

Acarbose治疗非胰岛素依赖型糖尿病的降糖效果观察

Ａｃａｒｂｏｓｅ治疗非胰岛素依赖型糖尿病的降糖效果观察孙侃，俞茂华，史虹莉，杨秀芳，谢洁怡，朱禧星（上海医科大学华山医院糖尿病研究室２０００４０）关键词Ａｃａｒｂｏｓｅ；糖尿病；疗效用德国Ｂａｙｅｒ药厂研制的α－葡荡糖耷酶抑制剂Ａｃａｒｂｏｓｅ治疗１...

Factors associated with improvement in waist-to-height ratio among newly diagnosed type 2 diabetes patients treated with acarbose or metformin:A randomized clinical trial study

BACKGROUND The waist-to-height ratio(WHtR)is a promising anthropometric measure used to evaluate cardiovascular risk in diabetes and metabolic syndrome patients.The metformin and acarbose in Chinese as the initial hypoglycaemic treatment trial demonstrated that acarbose and metformin reduced the WHtR after 24 wk of treatment.AIM To investigate the factors associated with a decrease in the WHtR in newly diagnosed Chinese type 2 diabetes patients receiving acarbose or metformin monotherapy.METHODS At 24 wk,343 patients in the acarbose treatment and 333 patients in the metformin treatment were included in this analysis.On the basis of the reduction in the WHtR,these participants were divided into the following two groups:LowΔWHtR group and highΔWHtR group.Metabolic and related parameters associated with a highΔWHtR were investigated using univariate and multivariate logistic regression analyses.RESULTS A significant decrease in the WHtR was observed in both treatment groups(acarbose:-0.015,95%confidence interval[CI]:-0.018 to-0.012,P<0.001;metformin:-0.013,95%CI:-0.016 to-0.010,P<0.001).In both the acarbose and metformin groups,the WHtR of the women was more likely to be reduced than that of the men.In the acarbose group,a lower baseline area under the curve of glucagon-like peptide 1(AUCGLP-1)was associated with a highΔWHtR(odds ratio[OR]=0.796,P<0.001),while a higher baseline AUCGLP-1 was associated with a highΔWHtR in the patients treated with metformin(OR=1.133,P=0.025).Regarding the changes from baseline,an increase in AUCGLP-1 was associated with a highΔWHtR in the acarbose(OR=1.121,P=0.016)but not metformin group.A higher reduction in high-density lipoprotein cholesterol/non-highdensity lipoprotein cholesterol was also associated with a highΔWHtR in the acarbose arm(OR=20.735,P=0.001).In the metformin arm,a higher reduction in fasting plasma glucose(OR=0.843,P=0.039)and total cholesterol was associated with a highΔWHtR(OR=0.743,P=0.013).CONCLUSION A lower glucagon-like peptide 1 level and higher increase in glucagon-like peptide 1 are associated with a high reduction in the WHtR in newly diagnosed Chinese diabetes patients receiving treatment with acarbose.

Acarbose is again on the stage

Acarbose is an agent that has been used to treat type 2 diabetes for about 30 years;it prevents postprandial hyperglycemia by inhibiting carbohydrate digestion in the small intestine.Since incretin-based treatments have been preferred over the last 10 to 15 years,the use of acarbose is not as common in treating type 2 diabetes as before.Some studies have shown that acarbose also produces a weight-loss effect by increasing glucagon-like peptide 1(GLP-1).The positive effect of acarbose on GLP-1,and increasing evidence that it provides cardiovascular protection,suggests that acarbose may again be considered among the first-choice antidiabetic agents,as it was in the 1990s.

Effect on T cell subsets and function of isletβ cells of levemir combined with acarbose in elder patients with early-onset type 2 Diabetes Mellitus

Objective:To discuss the effect of the combined therapy of levemir and acarbose on T cell subsets and function of isletβ cells in elder patients with early-onset type 2 Diabetes Mellitus. Methods:According to the number parity of entry sequence, 100 cases of elder patients with early-onset type 2 Diabetes Mellitus are divided into the control group and the observation group of 50 cases. The control group was treated with novolin and acarbose, the observation group was given subcutaneous injection of levemir and acarbose treatment. Compare the T cell subsets and function of isletβ cells in two group of patients before the treatment (T0), treatment for 4 weeks (T1) ,treatment for 8 weeks (T2).Results:(1) The levels of T0, T1, T2CD3+, CD4+, CD4+/CD8+ were increased in both groups, and CD8+ decreased. Among them, the levels of T1, T2CD3+, CD4+, CD4+/CD8+ of the observation group were obviously higher than the control group, the level of CD8+ was lowly than the control group, the difference was statistically significant;(2) In the stage of T0, T1, T2, the levels of FPG, HbA1c, HOMA-IR were showed a downward trend, the levels of FIns, HOMA-B were increased. In these two groups, the levels of T1, T2FPG, HbA1c, HOMA-IR of the observation group were lower than the control group, and the levels of FIns, HOMA-B were higher than the control group, the difference was statistically significant;(3) In the control group occurred 3 cases of hypoglycemia, and the incidence of adverse reactions was 6%. However, in the observation group no occurred adverse reactions, the difference was statistically significant.Conclusions:The combined therapy of levemir and acarbose in elder patients with early-onset type 2 Diabetes Mellitus, It helps to improve immune function, protect the isletβ-cell function.

An investigation of acarbose effects in PCOS women with postprandial hyperglycemia

Objectives: To investigate the effects of insulin resistance on serum androgen level and ovulation of women with polycystic ovary syndrome (PCOS) and observe clinic role of acarbose in the treatment of hyperinsulinemia, postprandial hyperglycemia and anovulation. Methods: 14 women accompanied by postprandial hyperglycemia with PCOS were administrated by acarbose for 12 weeks.14 age-matched individuals who had similar body mass index and normal menstruation were served as controls. Results: Serum T levels declined significantly from 4.09±1.04 nmol/L to 1.71±0.54 nmol/L (P<0.001), after acarbose treatment for 12 weeks. 12 out of 14 cases restored ovulation and menstrual cycles after acarbose treatment, among which 4 got pregnant. Conclusion: Acarbose may play a role on reducing postprandial hyperglycemia and HbAic levels, increase ISI and FSG/FI, indirectly reduce serum androgen levels through reducing plasma insulin level and recover ovarian ovulation in PCOS women with postprandial hyperglycemia.

静脉注射Acarbose对大鼠胰岛素和胰升糖素分泌的影响

阿卡波糖（Ａｃａｒｂｏｓｅ）用于临床治疗糖尿病已多年，多认为该药在降低血糖的同时，也降低血中胰岛素（ＩＮＳ）水平。以往考虑这是由于Ａｃａｒｂｏｓｅ降低了血糖，从而减少了高血糖对β细胞分泌ＩＮＳ的刺激。近来有报告非肠道输入Ａｃａｒｂｏｓｅ可直接抑制大鼠...

Glycemic variability in insulin treated type 2 diabetes with well-controlled hemoglobin Alc and its response to further treatment with acarbose

Background Glycemic variability, an HbAlc-independent risk factor, has more deleterious effects than sustained hyperglycemia in the development of diabetic complications. This study analyzed the characteristics of glycemic variability in type 2 diabetes mellitus （T2DM） with HbAlc 〈6.5% in duration of twice daily premixed insulin treatment and the effect of further treatment with acarbose. Methods Eighty-six T2DM patients who used premixed insulin analogue （insulin aspart 30） twice daily and had HbAlc 〈6.5% and 20 controlled subjects with normal glucose regulation （NGR） were monitored using the continuous glucose monitoring （CGM） system. The mean amplitude of glycemic excursions （MAGE）, mean of daily differences （MODD） were used for assessing intra-day, inter-day glycemic variability. Hypoglycemia was defined as glucose level 〈3.9 mmol/L for at least 15 minutes in CGM. According to reference values of MAGE, T2DM patients were classified into two groups： Iow-MAGE group with MAGE 〈3.4 mmol/L （L-MAGE） and high-MAGE group with MAGE 〉3.4 mmol/L （H-MAGE）. H-MAGE group received further treatment with acarbose for 2 weeks and was monitored a second time with CGM system. Results After first CGM, L-MAGE group had 41 cases, and H-MAGE group had 45 cases. The MAGE and MODD of T2DM group were all higher than those of subjects with NGR （P 〈0.01）. Twenty-four percent （n=11） in H-MAGE group had a total of 13 hypoglycemic events, 10 of the 13 events occurred at night, meanwhile 5% （n=-2） in L-MAGE group had a total of 2 hypoglycemic events, which also occurred at night （hypoglycemic events： 24% vs. 5%, X2=6.40, P 〈0.01）. MAGE value was correlated with hypoglycemia value and 2-hour postprandial plasma glucose value （r=-0.32 and 0.26, respectively, P 〈0.05）. After further acarbose therapy and secondly CGM, MAGE and MODD values in H-MAGE group were all significantly decreased （40%, P 〈0.01, and 15%, P 〈0.05, respectively）, but remained higher than in the subjects with NGR （P 〈0.05）; 2% （n=-l） had a total of 1 hypoglycemic event, incidence significantly decreased （2% vs. 24%, X2=9.61, P 〈0.01）. Conclusions CGM system can detect the glycemic variability and asymptomatic hypoglycemic events of T2DM with well-controlled HbAlc in duration of insulin treatment. Combination therapy of premixed insulin twice daily with acarbose can flat glycemic variability and decrease hypoglycemic events.

Efficacy and safety of acarbose in the treatment of elderly patients with postprandial hypotension

Background Postprandial hypotension （PPH） occurs frequently in elderly people and may lead to syncope, falls, dizziness, weakness, angina pectoris, and stroke. Some studies suggest that the magnitude of the postprandial fall in blood pressure （BP） is influenced by the rate at which glucose enters the small intestine. We hypothesized that acarbose （α-glucosidase inhibitor）, a hypoglycemic agent that decreases the rate of glucose absorption in the small intestine, would attenuate PPH in the elderly, and would be safe in the treatment. Methods Forty-three elderly in-patients with PPH were recruited. All of them were in relatively stable conditions. They had semi-liquid standard meals without and with acarbose for the two following days： screening day and intervention day. Blood pressure and heart rate （HR） were recorded at baseline and every 15 minutes for 120 minutes using a non-invasive ambulatory blood pressure monitoring system during the study, and ejection fraction （EF） and fractional shortening （FS） were measured by two dimensional echocardiography. Results Compared with the screening day, the falls in systolic, diastolic and mean arterial blood pressure （SBP, DBP, MAP） （all P 〈0.05） were significantly attenuated after taking acarbose during breakfast, so were MAP （P 〈0.05） during lunch, DBP （P 〈0.05） and MAP （P 〈0.05） during supper. The change of HR was not statistically significant after taking acarbose in three meals. EF and FS were positively correlated with the relief rate. The effective power was 63%, and the incidence of adverse drug reaction （ADR） was 9%. Conclusion Acarbose is effective and safe in the treatment of elderly patients with PPH.

Improving acarbose production and eliminating the by-product component C with an efficient genetic manipulation system of Actinoplanes sp.SE50/110

Theα-glucosidase inhibitor acarbose is commercially produced by Actinoplanes sp.and used as a potent drug in the treatment of type-2 diabetes.In order to improve the yield of acarbose,an efficient genetic manipulation system for Actinoplanes sp.was established.The conjugation system between E.coli carryingØC31-derived integrative plasmids and the mycelia of Actinoplanes sp.SE50/110 was optimized by adjusting the parameters of incubation time of mixed culture(mycelia and E.coli),quantity of recipient cells,donor-to-recipient ratio and the concentration of MgCl2,which resulted in a high conjugation efficiency of 29.4%.Using this integrative system,a cloned acarbose biosynthetic gene cluster was introduced into SE50/110,resulting in a 35%increase of acarbose titer from 2.35 to 3.18 g/L.Alternatively,a pIJ101-derived replicating plasmid combined with the counter-selection system CodA(sm)was constructed for gene inactivation,which has a conjugation frequency as high as 0.52%.Meanwhile,almost all 5-flucytosine-resistant colonies were sensitive to apramycin,among which 75%harbored the successful deletion of targeted genes.Using this replicating vector,the maltooligosyltrehalose synthase gene treY responsible for the accumulation of component C was inactivated,and component C was eliminated as detected by LC-MS.Based on an efficient genetic manipulation system,improved acarbose production and the elimination of component C in our work paved a way for future rational engineering of the acarbose-producing strains.

Comparative functional genomics of the acarbose producers reveals potential targets for metabolic engineering

Theα-glucosidase inhibitor acarbose is produced in large-scale by strains derived from Actinoplanes sp.SE50 and used widely for the treatment of type-2 diabetes.Compared with the wild-type SE50,a high-yield derivative Actinoplanes sp.SE50/110 shows 2-fold and 3–7-fold improvement of acarbose yield and acb cluster transcription,respectively.The genome of SE50 was fully sequenced and compared with that of SE50/110,and 11 SNVs and 4 InDels,affecting 8 CDSs,were identified in SE50/110.The 8 CDSs were individually inactivated in SE50.Deletions of ACWT_4325(encoding alcohol dehydrogenase)resulted in increases of acarbose yield by 25%from 1.87 to 2.34 g/L,acetyl-CoA concentration by 52.7%,and PEP concentration by 22.7%.Meanwhile,deletion of ACWT_7629(encoding elongation factor G)caused improvements of acarbose yield by 36%from 1.87 to 2.54 g/L,transcription of acb cluster,and ppGpp concentration to 2.2 folds.Combined deletions of ACWT_4325 and ACWT_7629 resulted in further improvement of acarbose to 2.83 g/L(i.e.76%of SE50/110),suggesting that the metabolic perturbation and improved transcription of acb cluster caused by these two mutations contribute substantially to the acarbose overproduction.Enforced application of similar strategies was performed to manipulate SE50/110,resulting in a further increase of acarbose titer from 3.73 to 4.21 g/L.Therefore,the comparative genomics approach combined with functional verification not only revealed the acarbose overproduction mechanisms,but also guided further engineering of its high-yield producers.

Effects of Acarbose on incretins in newly diagnosed type 2 diabetic patients in different carbohydrate tolerance test

Objective To evaluate the effects of Acarbose on incretin level(glucagon-like peptide 1(GLP-1)and gastric inhibitory polypeptide(GIP)of type 2 diabetes mellitus(T2DM)patients after different kinds of glucose load.Methods A total of 32 newly diagnosed T2DM patients were enrolled in this study and randomly divided into

α-葡萄糖苷酶抑制剂TD-01抗糖尿病作用研究

目的TD-01是一化学合成的化合物，离体研究结果表明，TD-01具有α-葡萄糖苷酶抑制活性，为了证实TD-01具有α-葡萄糖苷酶抑制剂的作用和观察其作用特点，进行了相关抗糖尿病作用研究。方法在体外实验比较了TD-01和α-葡萄糖苷酶抑制剂拜唐苹（Acarbose）、倍欣（Voglibose）对α-葡萄糖苷酶（蔗糖酶、麦芽糖酶）和α-淀粉酶的抑制作用？体内实验选用正常ICR小鼠及四氧嘧啶高血糖小鼠，并以Acarbose作为阳性对照药，比较TD-01对蔗糖、淀粉和葡萄糖负荷后血糖升高的影响。还选用了链脲霉素（STZ）糖尿病大鼠模型，

Role of ezetimibe in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to steatohepatitis,advanced fibrosis and inflammatory changes.Ezetimibe inhibits cholesterol absorption from the intestinal lumen into enterocytes.The molecular target of ezetimibe is the sterol transporter Niemann-Pick C1-like 1 protein (NPC1L1).Human NPC1L1 is abundantly expressed in the liver and may facilitate the hepatic accumulation of cholesterol.Ezetimibe ex-erts beneficial effects on several metabolic variables.Ezetimibe treatment attenuates hepatic steatosis and is beneficial in terms of NAFLD biochemical markers.The combination of ezetimibe with other interventions may also be beneficial in NAFLD patients.Our group inves-tigated the ezetimibe-orlistat combination treatment in overweight and obese patients with hypercholeste-rolemia,with beneficial effects on NAFLD biochemical markers.These results are promising for patients with NAFLD,who usually have increased cardiovascular disease risk and need a multifactorial treatment.How-ever,it should be mentioned that most results are from animal studies and,although modest elevation of liver function tests may raise the suspicion of NAFLD,none of these tests are sensitive to establish the diagnosis of NAFLD with great accuracy.

Diabetes patients with comorbidities had unfavorable outcomes following COVID-19:A retrospective study

BACKGROUND Previous studies have shown that diabetes mellitus is a common comorbidity of coronavirus disease 2019(COVID-19),but the effects of diabetes or anti-diabetic medication on the mortality of COVID-19 have not been well described.AIM To investigate the outcome of different statuses(with or without comorbidity)and anti-diabetic medication use before admission of diabetic after COVID-19.METHODS In this multicenter and retrospective study,we enrolled 1422 consecutive hospitalized patients from January 21,2020,to March 25,2020,at six hospitals in Hubei Province,China.The primary endpoint was in-hospital mortality.Epidemiological material,demographic information,clinical data,laboratory parameters,radiographic characteristics,treatment and outcome were extracted from electronic medical records using a standardized data collection form.Most of the laboratory data except fasting plasma glucose(FPG)were obtained in first hospitalization,and FPG was collected in the next day morning.Major clinical symptoms,vital signs at admission and comorbidities were collected.The treatment data included not only COVID-19 but also diabetes mellitus.The duration from the onset of symptoms to admission,illness severity,intensive care unit(ICU)admission,and length of hospital stay were also recorded.All data were checked by a team of sophisticated physicians.RESULTS Patients with diabetes were 10 years older than non-diabetic patients[(39-64)vs(56-70),P<0.001]and had a higher prevalence of comorbidities such as hypertension(55.5%vs 21.4%,P<0.001),coronary heart disease(CHD)(9.9%vs 3.5%,P<0.001),cerebrovascular disease(CVD)(3%vs 2.2%,P<0.001),and chronic kidney disease(CKD)(4.7%vs 1.5%,P=0.007).Mortality(13.6%vs 7.2%,P=0.003)was more prevalent among the diabetes group.Further analysis revealed that patients with diabetes who took acarbose had a lower mortality rate(2.2%vs 26.1,P<0.01).Multivariable Cox regression showed that male sex[hazard ratio(HR)2.59(1.68-3.99),P<0.001],hypertension[HR 1.75(1.18-2.60),P=0.006),CKD[HR 4.55(2.52-8.20),P<0.001],CVD[HR 2.35(1.27-4.33),P=0.006],and age were risk factors for the COVID-19 mortality.Higher HRs were noted in those aged≥65(HR 11.8[4.6-30.2],P<0.001)vs 50-64 years(HR 5.86[2.27-15.12],P<0.001).The survival curve revealed that,compared with the diabetes only group,the mortality was increased in the diabetes with comorbidities group(P=0.009)but was not significantly different from the noncomorbidity group(P=0.59).CONCLUSION Patients with diabetes had worse outcomes when suffering from COVID-19;however,the outcome was not associated with diabetes itself but with comorbidities.Furthermore,acarbose could reduce the mortality in diabetic.

Computational Study on the Comparative Differences in the Activity of Inhibitors of Human versus Rat Alpha-Glucosidase

Differences between the inhibitory activities of specific compounds on analogous enzymes isolated from different animal species are one of the critical issues to evaluate when exploring structure-activity relationships. The activity of acarbose is about ten times stronger in rat than in human, and that of neosalacinol is similar in both species. Binding affinities of acarbose and neosalacinol to four catalytic domains of alpha-glucosidases in human and rat were compared to investigate the cause of activity differences among species. Species difference was brought about complicatedly by the balance of interaction with four domains, and the result was indicated that larger ligand would show larger species difference in activity.

New polychlorinated bibenzyls from Rhododendron minutiflorum

Five new polychlorinated bibenzyls(1-5)along with 3 known compounds(6-8)were isolated from the stems and leaves of Rhododendron minutiflorum.The chemical structures of all the isolates were determined by spectroscopic methods,and compounds 1 and 2 were further verified by single-crystal X-ray diffraction analyses.Compounds 1-5 were halogenated compounds which bear three to five chlorine atoms in their chemical structures.Biologi-cally,compounds 2,5 and 6 showed varying degrees of toxicity toward the Asian citrus psyllid(Diaphorina citri)with LD_(50) values 27.15,17.02 and 16.20 mg/L,respectively.These values were comparable to the positive control matrine(LD_(50)=11.86 mg/L),which were calculated using observations on day 6.Meanwhile,compound 4 hadα-glucosidase inhibitory activity with IC_(50) value of 17.87±0.74μM.

Post-Translational Derepression of Invertase Activity in Source Leaves via Down-Regulation of Invertase Inhibitor Expression Is Part of the Plant Defense Response

There is increasing evidence that pathogens do not only elicit direct defense responses, but also cause pronounced changes in primary carbohydrate metabolism. Cell-wall-bound invertases belong to the key regulators of carbohydrate partitioning and source-sink relations. Whereas studies have focused so far only on the transcriptional induction of invertase genes in response to pathogen infection, the role of post-translational regulation of invertase activity has been neglected and was the focus of the present study. Expression analyses revealed that the high mRNA level of one out of three proteinaceous invertase inhibitors in source leaves of Arabidopsis thaliana is strongly repressed upon infection by a virulent strain of Pseudomonas syringae pv. tomato DC3000. This repression is paralleled by a decrease in invertase inhibitor activity. The physiological role of this regulatory mechanism is revealed by the finding that in situ invertase activity was detectable only upon infection by P. syringae. In contrast, a high invertase activity could be measured in vitro in crude and cell wall extracts prepared from both infected and non-infected leaves. The discrepancy between the in situ and in vitro invertase activity of control leaves and the high in situ invertase activity in infected leaves can be explained by the pathogen-dependent repression of invertase inhibitor expression and a concomitant reduction in invertase inhibitor activity. The functional importance of the release of invertase from post-translational inhibition for the defense response was substantiated by the application of the competitive chemical invertase inhibitor acarbose. Posttranslational inhibition of extracellular invertase activity by infiltration of acarbose in leaves was shown to increase the susceptibility to P. syringae. The impact of invertase inhibition on spatial and temporal dynamics of the repression of photosynthesis and promotion of bacterial growth during pathogen infection supports a role for extracellular invertase in plant defense. The acarbose-mediated increase in susceptibility was also detectable in sid2 and cpr6 mutants and resulted in slightly elevated levels of salicylic acid, demonstrating that the effect is independent of the salicylic acid-regulated defense pathway. These findings provide an explanation for high extractable invertase activity found in source leaves that is kept inhibited in situ by post-translational interaction between invertase and the invertase inhibitor proteins. Upon pathogen infection, the invertase activity is released by repression of invertase inhibitor expression, thus linking the local induction of sink strength to the plant defense response.

Structural insight into substrate specificity of human intestinal maltase-glucoamylase

Human maltase-glucoamylase(MGAM)hydrolyzes linear alpha-1,4-linked oligosaccharide substrates,playing a crucial role in the production of glucose in the human lumen and acting as an efficient drug target for type 2 diabetes and obesity.The amino-and carboxyl-terminal portions of MGAM(MGAM-N and MGAM-C)carry out the same catalytic reaction but have different substrate specificities.In this study,we report crystal structures of MGAM-C alone at a resolution of 3.1Å,and in complex with its inhibitor acarbose at a resolution of 2.9Å.Structural studies,combined with biochemical analysis,revealed that a segment of 21 amino acids in the active site of MGAM-C forms additional sugar subsites(+2 and+3 subsites),accounting for the preference for longer substrates of MAGM-C compared with that of MGAM-N.Moreover,we discovered that a single mutation of Trp1251 to tyrosine in MGAM-C imparts a novel catalytic ability to digest branched alpha-1,6-linked oligosaccharides.These results provide important information for understanding the substrate specificity of alphaglucosidases during the process of terminal starch digestion,and for designing more efficient drugs to control type 2 diabetes or obesity.