Role of G protein-coupled receptor kinases in glucose-dependent insulinotropic polypeptide receptor signaling

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a member of class II G protein-coupled receptors. Recent studies have suggested that desensitization of the GIPR might contribute to impaired insulin secretion in type II diabetic patients, but the molecular mechanisms of GIPR signal termination are unknown. Using HEK L293 cells stably transfected with GIPR complementary DNA (L293-GIPR), the mechanisms of GIPR desensitization were investigated. GIP dose dependently increased intracellular cAMP levels in L293-GIPR cells, but this response was abolished (65%) by cotransfection with G protein-coupled receptor kinase 2 (GRK2), but not with GRK5 or GRK6. Beta-arrestin-1 transfection also induced a significantly decrease in GIP-stimulated cAMP production, and this effect was greater with cotransfection of both GRK2 and beta-arrestin-1 than with either alone. In betaTC3 cells, expression of GRK2 or beta-arrestin-1 attenuated GIP-induced insulin release and cAMP production, whereas glucose-stimulated insulin secretion was not affected. GRK2 and beta-arrestin-1 messenger RNAs were identified by Northern blot analysis to be expressed endogenously in betaTC3 and L293 cells. Overexpression of GRK2 enhanced agonist-induced GIPR phosphorylation, but receptor endocytosis was not affected by cotransfection with GRKs or beta-arrestin-1. These results suggest a potential role for GRK2/beta-arrestin-1 system in modulating GIP-mediated insulin secretion in pancreatic islet cells. Furthermore, GRK-mediated receptor phosphorylation is not required for endocytosis of the GIPR.     

糖依赖性胰岛素释放肽在脂肪代谢中的作用

越来越多的研究表明,糖依赖性胰岛素释放肽(GIP)在脂代谢中具有重要的促合成作用,包括对葡萄糖摄取、脂肪酸合成、脂蛋白脂酶活性的刺激,造成脂肪酸在脂肪组织的沉积.同时,GIP可抑制胰高血糖素和异丙肾上腺素诱导的脂肪分解,进而增加脂肪的堆积.在肥胖的动物模型中,长期阻断GIP的信号转导可以明显改善血糖、减轻体重,此外,还可减少高脂饮食诱导的肥胖的发生.以上研究结果为肥胖、糖尿病的预防和治疗提供了一种新的思路.     

维吾尔族和汉族2型糖尿病合并冠心病患者冠状动脉病变的比较

目的 探讨维吾尔族与汉族T2DM合并冠心病(CHD)患者的冠状动脉病变特点.方法 分析648例患者资料.从病变血管支数、病变部位、病变狭窄程度加以分析研究.结果 各相同积分段比较,维吾尔族患者平均年龄均小于汉族患者(P＜0.05).Gensini积分随着年龄增长而增加,相同年龄段比较,维吾尔族患者Gensini积分均高于汉族患者(P＜0.05).两组患者3支血管病变发生率最高,随着年龄增长,单支血管病变发生率逐渐减少,3支血管病变发生率逐渐增加.结论 冠状动脉病变随着年龄增长而增加,维吾尔族患者的冠状动脉病变严重程度较相同年龄段汉族患者重,发病年龄或许比汉族患者早.     

The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.     

2型糖尿病患者血糖变异性与冠状动脉病变程度之间的关系

目的:探讨2型糖尿病患者血糖变异性与冠状动脉病变程度之间的关系。方法:连续入选因胸痛入我院准备行冠状动脉造影的2型糖尿病患者521例,入院采集一般资料后采用动态血糖监测系统(CGMS)进行连续3 d的血糖监测反映血糖波动情况,然后行冠状动脉造影并根据结果分为冠心病组381例、非冠心病组140例,用Gensini积分法评价冠状动脉病变程度。对两组间各项参数进行比较,并与Gensini积分进行相关性分析。结果:(1)冠心病组患者日内平均血糖波动幅度(MAGE)、餐后血糖波动幅度(PPGE)、超敏C反应蛋白(hs-CRP)和血肌酐(Cr)水平明显高于对照组[MAGE(3.9±1.2)vs.(3.3±1.0)mmol/L,PPGE(4.1±1.8)vs.(3.4±1.5)mmol/L,hs-CRP(10.1±11.1)vs.(5.9±6.0)mg/L,Cr(87±21)vs.(76±17)mmol/L,均P0.001]。(2)在整体研究患者中Pearson相关性分析显示Gensini积分和MAGE、年龄、PPGE、糖化血红蛋白(Hb A1c)水平密切正相关。(3)以Gensini积分作为因变量,各相关因素作为自变量进行多因素逐步回归分析表明年龄、MAGE、hs-CRP和Hb A1c是影响Gensini积分的独立危险因子。结论:在2型糖尿病患者中日内血糖波动幅度影响冠状动脉病变程度,日内血糖波动幅度越大冠状动脉病变程度越重,血糖波动性的风险应该得到广泛关注。     

Association between isolated hypercholesterolemia, isolated hypertriglyceridemia and coronary artery disease in south Indian type 2 diabetic patients

Very high prevalence rates of coronary artery disease have been reported among Indians. The aim of this study was to determine the relative importance of isolated hypercholesterolemia, isolated hypertriglyceridemia, isolated high low-density lipoprotein and isolated low high-density lipoprotein in coronary artery disease among South Indian type 2 diabetic subjects. The study group comprised of 17,885 type 2 diabetic patients attending our institute. A history of documented myocardial infarction was considered as the diagnostic criteria for coronary artery disease. Isolated hypercholesterolemia was defined as serum cholesterol over 200 mg/dL with normal serum triglyceride levels (< or = 200 mg/dL); isolated hypertriglyceridemia was defined as serum triglyceride level over 200 mg/dL with normal serum cholesterol levels (< or = 200 mg/dL). Isolated low high-density lipoprotein was defined as one below 35 mg/dL with normal serum triglyceride levels. Isolated high low-density lipoprotein cholesterol was defined as one over 150 mg/dL with normal serum triglyceride levels. Normolipidemia was defined as serum cholesterol and serum triglyceride both upto 200 mg/dL, high-density lipoprotein 35 mg/dL or above and low-density lipoprotein upto 150 mg/dL. The prevalence of coronary artery disease was significantly high among patients with isolated hypercholesterolemia (4.1%; p < 0.001), isolated high low-density lipoprotein (4.5%; p < 0.001) and isolated low high-density lipoprotein (3.9%; p = 0.005) compared to normolipidemic individuals (2.8%), but not in those with isolated hypertriglyceridemia (3.4%). The odds ratios for coronary artery disease increased with each quartiles of isolated cholesterol, isolated low-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein ratio and reached statistical significance in the last quartile (p < 0.05). There was no significant increase in the odds ratios for coronary artery disease in relation to quartiles of isolated triglycerides. For isolated low high-density lipoprotein, when the last quartile was taken as the reference, the odds ratio for coronary artery disease in the first quartile reached statistical significance (p = 0.03). Multivariate regression analysis revealed age (odds ratio 1.06; p < 0.001), male sex (odds ratio 1.7; p < 0.001), hypercholesterolemia (odds ratio 1.26; p = 0.07) and high low-density lipoprotein levels (odds ratio 1.22; p = 0.043) to be strongly associated with coronary artery disease. Among South Indian type 2 diabetic subjects, serum isolated hypercholesterolemia and high low-density lipoprotein cholesterol but not isolated hypertriglyceridemia appear to be associated with coronary artery disease.     

The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: A post hoc analysis

In a phase 2 trial of once-weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL-40 (also known as chitinase-3 like-protein-1), intercellular adhesion molecule 1 (ICAM-1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL-40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM-1 levels versus placebo and dulaglutide, and high-sensitivity C-reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N-terminal-pro hormone B-type natriuretic peptide levels were not significantly changed in any group. YKL-40, hsCRP, and ICAM-1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis-generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk.     

Independent association between triglycerides and coronary artery disease in Taiwanese type 2 diabetic patients

BACKGROUND: This study evaluated the association between triglycerides (TG) and coronary artery disease (CAD) in Taiwanese adults with type 2 diabetes mellitus (T2DM). METHODS: A total of 1150 patients (542 men and 608 women) aged 62.5+/-11.6 years were studied. CAD was diagnosed by history or an abnormal electrocardiogram (coronary probable or possible by Minnesota codes). Age, body mass index (BMI), smoking, use of insulin, anti-hypertensive agents and lipid-lowering agents, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) were considered as potential confounders. RESULTS: Patients with CAD were older, had higher prevalences of use of anti-hypertensive and lipid-lowering agents, and had higher BMI, SBP, DBP and TG. CAD increased significantly with increasing quartiles of TG (P-trend < 0.001). Ln(TG) was significantly correlated with BMI, FPG, HbA1c, DBP, TC, HDL-c (inversely) and LDL-c. Ln(TG) was associated with CAD with an unadjusted odds ratio of 1.411 (1.145-1.740). The odds ratio after adjustment for all confounders was slightly attenuated but still statistically significant: 1.380 (1.043-1.826). None of the other lipid parameters of TC, HDL-c and LDL-c were significantly associated with CAD in logistic models when they were entered for adjustment either separately or simultaneously. Sensitivity analyses by using history alone or history and coronary probable as diagnostic criteria for CAD did not change the association between TG and CAD. CONCLUSIONS: TG is an independent risk factor for CAD in Taiwanese T2DM, independent of TC, HDL-c, LDL-c or other confounders.     

2型糖尿病患者冠状动脉病变严重程度与血清胱抑素C相关性研究

目的 探讨2型糖尿病患者冠状动脉病变程度与血清胱抑素C（Cys C）的关系.方法 选取2011年10月至2013年10月2型糖尿病患者180例,经冠状动脉造影分为冠心病组与非冠心病组,比较两组血清Cys C的差异;同时按冠心病严重程度分为单支病变组、双支病变组及多支病变组,比较三组间血清Cys C水平的差异.应用多因素非条件Logstic逐步回归分析法分析2型糖尿病合并冠心病的危险因素.结果 血清Cys C水平糖尿病非冠心病组[（0.83±0.16）mg/L]低于糖尿病冠心病组[（1.06±0.14）mg/L].随着冠心病严重程度的加重,血清Cys C水平不断升高,甘油三酯、糖化血红蛋白、血清Cys C与冠心病存在相关性,血清Cys C为糖尿病合并冠心病的独立危险因素（OR=1.230）.结论 血清Cys C水平与2型糖尿病患者冠心病的发生、发展及预后密切相关,可能成为冠心病的一项重要预测指标.     

Association between beta2-adrenergic receptor genetic polymorphisms and nocturnal asthmatic patients of Chinese Han nationality

BACKGROUND: As a result of the finding that the mutation of Arg into Gly at beta(2)-adrenergic receptor (beta(2)-AR)16 loci could promote the downregulation effect triggered by the beta(2)-agonist, it was supposed that Gly16 might be associated with the downregulation of beta(2)-AR in patients with nocturnal asthma. OBJECTIVE: It was the aim of this study to analyze the association between beta(2)-AR genetic polymorphisms and nocturnal asthmatic patients of Chinese Han nationality. METHODS: A polymerase chain reaction allele-specific oligonucleotide hybridization assay was used to determine 16 and 27 loci alleles of beta(2)-AR genetic polymorphisms in 25 nocturnal asthmatic patients (nocturnal asthma group), 22 non-nocturnal asthmatic patients (non-nocturnal asthma group), and 72 healthy people (control group). All people investigated were of Chinese Han nationality. RESULTS: The distribution frequency of genotype Arg/Arg, Arg/Gly, and Gly/Gly at beta(2)-AR 16 loci was 12, 16 and 72% in the nocturnal asthma group; and 27, 41 and 32% in the non-nocturnal asthma group. There was a significant increase in the frequency of genotype Gly/Gly and allele Gly in the nocturnal asthma group compared with the non-nocturnal asthma group (p < 0.01). However, there was no significant difference in the frequency of genotype Gly/Gly and allele Gly in the non-nocturnal asthma group, compared with the control group. There was no significance in the frequency of the genotypes and alleles of beta(2)-AR 27 loci among the three groups (p > 0.05). CONCLUSION: The Gly16 polymorphism of beta(2)-AR was overrepresented in nocturnal asthmatic patients, correlated with nocturnal asthma, and therefore appeared to be an important genetic factor in the expression of this asthmatic phenotype.     

Body composition as a risk factor for coronary artery disease in Chinese type 2 diabetic patients in Taiwan.

This study aimed to clarify whether body mass index (BMI), waist/hip ratio (WHR) or percent body fat (%fat) is associated with coronary artery disease (CAD) in Chinese type 2 diabetic patients in Taiwan. A total of 463 patients were recruited. BMI and WHR were measured by standard methods and %fat by bioelectrical impedance. CAD was diagnosed as acute myocardial infarction, angina pectoris, or an electrocardiogram showing 'coronary probable or possible' according to the Minnesota codes. Age, sex, diabetes duration, hypertension, smoking, fasting plasma glucose, hemoglobin A(1c),and serum concentrations of total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol were treated as confounders. Results showed that 144 patients had CAD. Age, hypertension, HDL-C and %fat were independently associated with CAD. CAD prevalence was 25.5%, 26.8%, 31.9% and 43.0%, respectively, for the first to fourth quartile of %fat (p<0.05). Multivariate-adjusted odds ratio for CAD for every 1% increase in %fat was 1.02 (1.01-1.03); and 1.01 (0.73-1.88), 1.26 (0.69-2.32) and 2.11 (1.09-4.07) for the second to fourth quartile, respectively, compared with the first quartile. BMI and WHR were not associated with CAD in similar analyses. In conclusion, %fat was a better predictor for CAD than BMI and WHR in Chinese type 2 diabetic patients in Taiwan.     

2型糖尿病合并冠心病患者对氧磷酶1基因多态性分析

目的探讨对氧磷酶1(PON1)基因多态性与2型糖尿病合并冠心病的相关性。方法使用变性高效液相色谱分析方法检测了202例2型糖尿病合并冠心病患者、177例单纯2型糖尿病患者和206名健康对照者;共检测了PON1基因G-126C、L55M和Q192R 3个多态性的基因型,比较分析3组间各基因型和等位基因频率分布的差异。结果 2型糖尿病合并冠心病组的Q192R位点R等位基因频率明显高于对照组(67.1%比60.2%,P=0.024),其他位点在各组间差异无统计学意义。结论PON1基因Q192R位点R等位基因与2型糖尿病合并冠心病发病相关。     

Diagnosing coronary artery disease in diabetic patients

Although several diagnostic modalities are available to the clinician interested in diagnosing coronary artery disease, very few have been validated in diabetic populations. This review discusses the non-invasive diagnosis of coronary disease in diabetic patients. Evidence regarding the prevalence and prognostic significance of silent ischemia is reviewed and the potential impact of silent ischemia on the diagnostic characteristics of the exercise treadmill test discussed. Other diagnostic tools are considered, and recommendations are made with respect to screening asymptomatic diabetic patients for coronary artery disease.     

中国2型糖尿病人群内皮细胞一氧化氮合酶基因多态性与冠心病风险的相关性研究

目的 观察中国2型糖尿病人群中内皮细胞一氧化氮合酶（eNOS）基因多态性位点rs1799983与rs2070744是否与冠心病风险相关.方法 以2005年3月至2010年10月412例2型糖尿病胸痛患者为研究人群,其中266例患有冠心病[男性171例,女性95例,平均年龄（64±9岁）],146例为无冠心病对照[男性67例,女性79例,平均年龄（62±10）岁].选取eNOS的2个单核苷酸多态性（SNPs）：rs1799983（G＞T）和rs2070744（T＞C）.应用聚合酶链反应-限制性内切酶片段长度多态性（PCR-RFLP）技术对eNOS基因SNPs读取个体基因型,采用病例-对照研究的方法,研究eNOS基因多态性与冠心病风险的关系.结果 SNP rs1799983在冠心病组与无冠心病组中T等位基因频率分别为10.4％和9.3％,T等位基因携带者较非携带者冠心病风险有增高趋势（OR=1.214）,但差异无统计学意义（P＞0.05）.SNP rs2070744在冠心病组与无冠心病组中C等位基因频率分别为10.5％和9.4％,C等位基因携带者较非携带者冠心病风险有增加趋势（OR=1.117）,但差异亦无统计学意义（P＞0.05）.校正其他已知冠心病风险因素如性别、年龄、BMI、糖尿病病程、高血压病病史、脂代谢异常病史以及吸烟史后,仍未发现rs1799983和rs2070744与冠心病风险的相关性.结论 在中国2型糖尿病人群中,eNOS基因SNP rs1799983和rs2070744可能不是冠心病的主要风险因子.     

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Objective  The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods  Eight obese patients with type 2 diabetes with poor glycaemic control (HbA_1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results  Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)⁻¹ (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)⁻¹ (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]⁻¹). Conclusions  Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. ClinicalTrials.gov ID no.: NCT 00612950 Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.     

The effects of glucose-dependent insulinotropic polypeptide infused at physiological concentrations in normal subjects and Type 2 (non-insulin-dependent) diabetic patients on glucose tolerance and B-cell secretion

Summary The effects of porcine glucose-dependent insulinotropic polypeptide given by continuous intravenous infusion in normal subjects (n=6) and Type 2 (non-insulin-dependent) diabetic patients (n=6) have been investigated. The subjects were studied on 2 separate days after overnight fasts. On each day 25 g of glucose was infused from 0–30 min plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (0.75 pmol·kg^–1·min^–1) or control solution. During the glucose-dependent insulinotropic polypeptide infusion plasma glucose values were reduced in normal subjects from 30–60 min (p<0.01) and in Type 2 diabetic patients at 45 and 60 min (p<0.05). In the normal subjects insulin concentrations were greater from 10–35 min (p<0.01) following glucose-dependent insulinotropic polypeptide infusion and peak values were increased by 123%. In the Type 2 diabetic patients following glucose-dependent insulinotropic polypeptide infusion insulin levels were increased from 4–40 min (p<0.01) but peak values were only increased by 27%. In the normal subjects C-peptide values were greater from 25–45 min (p<0.01) following glucose-dependent insulinotropic polypeptide infusion and peak C-peptide levels were increased by 82%. In the Type 2 diabetic patients following the glucose-dependent insulinotropic polypeptide infusion C-peptide levels were increased from 6–55 min (p<0.01) and peak values were increased by 20%. Plasma glucose-dependent insulinotropic polypeptide levels were within the physiological post prandial range during the glucose-dependent insulinotropic polypeptide infusion. Glucose-dependent insulinotropic polypeptide is insulinotropic in normal subjects and Type 2 diabetic patients at physiological concentrations and results in improved glucose tolerance. This insulinotropic effect is less marked in the diabetic patients and may represent insensitivity of the B cell to glucose-dependent insulinotropic polypeptide.