2型糖尿病患者血清铁代谢相关指标检测意义

目的 探讨2型糖尿病患者血清铁调素(Hepcidin)、铁蛋白(SF)、转铁蛋白受体(sTfR)和血清铁(SI)的变化与临床意义。方法 130例2型糖尿病患者,分为两组,A组为微量蛋白尿组45例(mAlb30～300 mg/24 h),B组为正常蛋白尿组85例(mAlb＜30 mg/24 h),另选同期45例健康体检者为对照C组。各组均取空腹晨血5 ml离心取血清检测铁调素,SF,sTfR和SI含量。结果 A组患者血清铁调素和SF水平(42.27±32.12 ng/ml,211.6±107.2 ng/ml)均显著高于B组(26.12±18.36 ng/ml,179.1±109.7 ng/ml; P均＜0.05)和C组(9.47±1.65 ng/ml,84.41±47.10 ng/ml),(P均＜0.01); B组患者铁调素和SF水平显著高于C组(P均＜0.01)。各组之间SI水平(15.26 μmol/L,18.65 μmol/L,17.71 μmol/L)和sTfR水平(1.12 μg/L,1.05 μg/L,1.16 μg/L)差异均无统计学意义(t=0.469～1.176,P均＞0.05)。相关分析显示,2型糖尿病患者铁调素与SF呈显著正相关(r=0.329,P＜0.05),铁调素与sTfR,SI无显著相关性(r=0.169,P＞0.05; r=-0.149,P＞0.05)。结论 2型糖尿病患者体内存在以血清铁调素、SF增高为主的铁超负荷和铁代谢紊乱,并与尿微量清蛋白的排泄呈正相关。因此,检测血清铁调素和SF可作为糖尿病早期肾功能损伤的重要预测因子。     

Postprandial Dysmetabolism and Oxidative Stress in Type 2 Diabetes: Pathogenetic Mechanisms and Therapeutic Strategies

Postprandial dysmetabolism in type 2 diabetes (T2D) is known to impact the progression and evolution of this complex disease process. However, the underlying pathogenetic mechanisms still require full elucidation to provide guidance for disease prevention and treatment. This review focuses on the marked redox changes and inflammatory stimuli provoked by the spike in blood glucose and lipids in T2D individuals after meals. All the causes of exacerbated postprandial oxidative stress in T2D were analyzed, also considering the consequence of enhanced inflammation on vascular damage. Based on this in‐depth analysis, current strategies of prevention and pharmacologic management of T2D were critically reexamined with particular emphasis on their potential redox‐related rationale.     

Frequency and Severity of the Dawn Phenomenon in Type 2 Diabetes: Relationship to age

OBJECTIVE

To know whether age has an independent effect on the dawn phenomenon in noninsulin-using type 2 diabetes.

RESEARCH DESIGN AND METHODS

Eighty-one individuals with type 2 diabetes were matched for HbA_1c and divided by age into three subgroups of 27 individuals (1: ≥70 years; 2: 60–69 years; and 3: ≤59 years). All underwent ambulatory continuous glucose monitoring for quantifying the dawn phenomenon (i.e., the absolute [∂G, mg/dL] or relative [∂G%] increments from nocturnal nadirs to prebreakfast time points).

RESULTS

HbA_1c levels and 24-h glycemic profiles were similar across the three groups. Glucose increments (mean ± SEM) were identical in the three groups: ∂G (mg/dL), 22.0 ± 4.7 (1), 21.3 ± 3.6 (2), and 18.0 ± 3.6 (3) and δG (%), 19.9 ± 4.9 (1), 21.6 ± 4.4 (2), and 17.6 ± 4.2 (3). Using the most common definition (∂G >10 mg/dL), the prevalence of the dawn phenomenon was 52, 70, and 59% in groups 1, 2, and 3, respectively.

CONCLUSIONS

The dawn phenomenon is present in the elderly.The dawn phenomenon is a feature of dysglycemia likely to be common in most subjects with type 1 or type 2 diabetes (1–3). However, the definition of this condition remains somewhat unclear, and controversy still exists about its magnitude and frequency, especially in elderly individuals with type 2 diabetes (4,5). For that reason, we set out to explore whether the magnitude and frequency of the dawn phenomenon in type 2 diabetes varied across different age categories.     

Additive Postprandial Glucose-Lowering Effects of Mitiglinide and Sitagliptin in Patients with Type 2 Diabetes Mellitus

Introduction

The aim of this research was to compare the pharmacodynamics of the combination of mitiglinide and sitagliptin to that of each agent alone in Korean patients with type 2 diabetes mellitus (T2DM).

Methods

Patients with T2DM received mitiglinide alone, sitagliptin alone, or both drugs together in randomized sequence. A meal tolerance test (MTT) was conducted for each group, and plasma concentrations of glucose, insulin, C-peptide, glucagon, and intact glucagon-like peptide-1, and dipeptidyl peptidase-4 activity were measured from 2 h before breakfast through 4 h after breakfast on day 0 (pretreatment) and day 1 (posttreatment) of each treatment period. Integrated values of these pharmacodynamic variables were analyzed for changes from pretreatment to posttreatment and for differences between the three treatment groups.

Results

Twenty-six patients with glycated hemoglobin A_1c level of 7.4% ± 0.6%, fasting plasma glucose concentration of 141 ± 22 mg/dL, postprandial plasma glucose (PPG) concentration of 264 ± 48 mg/dL 1 h after the MTT, and diabetes duration of 3.0 ± 3.1 years (mean ± SD) were included in the study. Compared with mitiglinide or sitagliptin alone, the combination treatment lowered PPG additively (P < 0.001 vs. mitiglinide or sitagliptin alone) and the insulin secretory response (P = 0.03 vs. mitiglinide or sitagliptin alone). The integrated insulin concentrations changed significantly from before to after treatment (P < 0.01), but the change did not differ between the combination and mitiglinide groups. The insulinogenic index increased significantly after the combination treatment (P < 0.001 vs. mitiglinide or sitagliptin alone). The combination of mitiglinide and sitagliptin was generally well tolerated, with no hypoglycemic events.

Conclusions

The combination of mitiglinide and sitagliptin did not trigger hypoglycemia and controlled postprandial glucose excursion more effectively compared with either drug alone.     

Premeal Injection of Rapid-Acting Insulin Reduces Postprandial Glycemic Excursions in Type 1 Diabetes

OBJECTIVE

To assess the effect of three premeal timings of rapid-acting insulin on postprandial glucose excursions in type 1 diabetes.

RESEARCH DESIGN AND METHODS

Ten subjects participated in a three-way randomized crossover trial. Mean ± SD age was 45.5 ± 12.1 years, A1C was 8.55 ± 1.50%, duration of diabetes was 23.8 ± 7.8 years, and duration of continuous subcutaneous insulin infusion therapy was 8.5 ± 6.1 years. Insulin aspart was administered at 30, 15, or 0 min before mealtime.

RESULTS

Area under the curve was lower in the −15 stratum (0.41 ± 0.51 mmol/l/min) than that in the −30 stratum (1.89 ± 0.72 mmol/l/min, P = 0.029) and 0 stratum (2.11 ± 0.66 mmol/l/min, P = 0.030). Maximum glucose excursion was lower in the −15 stratum (4.77 ± 0.52 mmol/l) than that in the −30 (6.48 ± 0.76 mmol/l, P = 0.025) and 0 stratum (6.93 ± 0.76 mmol/l, P = 0.022). Peak glucose level was lower in the −15 stratum (9.26 ± 0.72 mmol/l) than that in the −30 stratum (11.74 ± 0.80 mmol/l, P = 0.007) and the 0 stratum (12.29 ± 0.93, P = 0.009). Time spent in the 3.5–10 mmol/l range was higher in the −15 stratum (224.5 ± 25.0 min) than that in the 0 stratum (90.5 ± 23.2 min, P = 0.001). There was no significant difference in occurrence of glucose levels <3.5 mmol/l between strata (P = 0.901).

CONCLUSIONS

Administration of rapid-acting insulin analogs 15 min before mealtime results in lower postprandial glucose excursions and more time spent in the 3.5–10.0 mmol/l range, without increased risk of hypoglycemia.One of the most challenging aspects of attaining adequate glycemic control is limiting the postprandial raise of glucose. Current American Diabetes Association guidelines recommend aiming for postprandial blood glucose levels <10 mmol/l (1,2). With the advent of rapid-acting insulin analogs (insulin lispro, aspart, and glulisine), individuals with diabetes can attain lower postprandial glucose excursions (3–5). Therefore, because of the possibility of giving the dose of insulin at mealtime rather than 15–30 min before the meal, as was recommended for human insulin (6), rapid-acting insulin analogs have become the preferred mealtime insulin for people with type 1 diabetes (7,8).After a meal, the postprandial glucose peak mostly occurs between 1 and 2 h with a mean peak time of 75 min (9). Rapid-acting insulin analogs display a maximum effect at ∼100 min after subcutaneous injection (10). Thus, the question arises whether perhaps it would be better to inject the mealtime insulin 15 or even 30 min before the start of a meal. In this way the insulin peak action is better synchronized with the glycemic excursions after a meal, thereby potentially minimizing the height of the postprandial glucose excursions. Limited data address this topic. The aim of this study was to measure the effect of different premeal timing of rapid-acting insulin on postprandial excursions.     

老年2型糖尿病骨代谢的研究

目的　了解老年人 2型糖尿病骨代谢的现状及影响骨代谢的有关因素 ,对 2型糖尿病并发骨质疏松作出早期诊断和治疗。方法　用QCT法分别测定男女糖尿病及非糖尿病患者的骨密度 (BMD) ,用放免法检测骨钙素 (BGP)及Ⅰ型胶原羧基端肽 (ICTP)、甲状旁腺激素 (PTH)等指标。结果　男女糖尿病患者BMD及BGP均低于非糖尿病者 ,而ICTP及PTH均高于非糖尿病者 ,BMD与糖尿病病程、ICTP、PTH、血糖呈显著负相关。结论　糖尿病患者存在BMD显著下降 ,其骨代谢特点是骨吸收增加 ,骨形成降低。血糖控制不良是糖尿病并发骨质疏松的危险因素之一。     

2型糖尿病患者血清脂肪特异性丝氨酸蛋白酶抑制剂与糖脂代谢的相关性研究

目的探讨2型糖尿病患者血清中脂肪特异性丝氨酸蛋白酶抑制剂(vaspin)与糖脂代谢的关系。方法用ELISA法测定80例2型糖尿病,69例空腹糖耐量受损患者,73例健康对照者血清中vaspin的水平,同时测定空腹血糖(FBG)、总胆固醇(TCHO)、甘油三酯(TG)、空腹胰岛素(FINS)、糖化血红蛋白(HBA1C)、超敏CRP(hsCRP),并做统计学处理。结果 2型糖尿病组vaspin水平显著高于健康对照组和空腹糖耐量受损组(P<0.05),空腹糖耐量受损组vaspin水平高于健康对照组(P<0.05)。同组患者中肥胖亚组vaspin水平高于非肥胖亚组(P<0.05),2型糖尿病组中血清vaspin与体质指数(body mas index,BMI)、FBG、FINS、HOMA-IR、TG、hsCRP呈正相关(r值分别为0.472、0.464、0.302、0.347、0.268、0.311,P<0.05)。结论 Vaspin是联系2型糖尿病糖脂代谢的重要脂肪因子,与BMI、FBG、FINS、HOMA-IR、TG、hsCRP呈正相关,可为2型糖尿病治疗提供新思路。     

GLP-1受体激动剂对肥胖2型糖尿病糖脂代谢的影响

目的评价艾塞那肽对肥胖2型糖尿病糖脂代谢的影响。方法选取收治的50例肥胖2型糖尿病患者作为研究对象,按照随机平行分组法随机分为治疗组与对照组各25例,对照组给予常规降糖、降脂、降压等药物治疗,治疗组联用艾塞那肽治疗,连续治疗3个月,比较两组血糖、血脂等指标变化情况。结果两组治疗前空腹血糖(FPG)、餐后血糖(PPG)、糖化血红蛋白(Hb Alc)水平比较均无明显差异(P>0.05),治疗后均较治疗前明显改善(P<0.05),但同期比较治疗组较对照组改善明显(P<0.05);两组治疗前甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)水平比较并无明显差异(P>0.05),治疗后对照组各项指标变化不明显(P>0.05),治疗组TG、TC、LDL水平较治疗前明显改善(P<0.05)。结论艾塞那肽配合常规降糖药物治疗对肥胖2型糖尿病患者糖脂代谢水平有改善作用,值得推广应用。     

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.

RESULTS

Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.

CONCLUSIONS

Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.Type 2 diabetes is closely related to atherosclerosis and the development of cardiovascular complications such as myocardial infarction or stroke. Recent studies on cardiovascular end points in patients with type 2 diabetes call into question the value of A1C-focused treatments in reducing macrovascular complications of diabetes (1–3). Other markers such as glucose excursions, hypoglycemia, or postprandial generation of oxidative stress may add important information for the judgment of cardiovascular risk in patients with type 2 diabetes (1,2). Postprandial microvascular blood flow is under dynamic regulation and is diversely affected by changes in postprandial glucose and insulin levels (4). Increasing postprandial insulin levels stimulate microvascular blood flow by inducing the endothelial release of nitric oxide via the activation of the phosphatidylinositol 3-kinase system (5,6). In contrast, increasing blood glucose levels were shown to oppose the insulin effects on endothelial cells and to impair postprandial microvascular blood flow (7). A reduced first-phase insulin release with an augmented increase in postprandial glucose levels followed by an impairment in endothelial function and postprandial microvascular blood flow is an early feature of type 2 diabetes (4,8). These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11).VIAject is a new, ultra–fast-acting insulin formulation shown to have more rapid insulin absorption than that for human regular insulin and insulin lispro. The aim of this study was to compare the effect of preprandial subcutaneous administration of insulin VIAject with preprandial application of human regular insulin and insulin lispro on several markers of endothelial and microvascular function after a standardized liquid meal test in patients with type 2 diabetes.     

Metabolism of Insulin Glargine After Repeated Daily Subcutaneous Injections in Subjects With Type 2 Diabetes

OBJECTIVE

To investigate concentration of plasma insulin glargine after its subcutaneous dosing compared with concentration of its metabolites 1 (M1) and 2 (M2) in subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Nine subjects underwent a 32-h euglycemic glucose clamp study (0.4 units/kg glargine after 1 week of daily glargine administration). Glargine, M1, and M2 were measured by a specific liquid chromatography-tandem mass spectrometry assay.

RESULTS

Glargine was detected in only five of the nine subjects, at few time points, and at negligible concentrations. M1 was detected in all subjects and exhibited the same pattern as traditional radioimmunoassay-measured plasma insulin. M2 was not detected at all.

CONCLUSIONS

After subcutaneous injection, glargine was minimally detectable in blood, whereas its metabolite M1 accounted for most (>90%) of the plasma insulin concentration and metabolic action of the injected glargine.After subcutaneous injection in vivo, the long-acting insulin analog glargine undergoes a sequential cleavage of the COOH terminus of the B-chain–forming metabolites M1 and M2 (1,2). M1 and M2 fully retain the same metabolic properties as human insulin (HI), but in contrast to glargine, they do not differ from HI in affinity for IGF-1 receptor (IGF-1R) and mitogenesis (3). In the companion article in this issue (Bolli et al. [4]), glargine metabolism has been studied in subjects with type 1 diabetes, but there are no data on type 2 diabetes. The aim of the current study was to shed light on this question.     

Effect of Oral Sebacic Acid on Postprandial Glycemia, Insulinemia, and Glucose Rate of Appearance in Type 2 Diabetes

OBJECTIVE

Dicarboxylic acids are natural products with the potential of being an alternate dietary source of energy. We aimed to evaluate the effect of sebacic acid (a 10-carbon dicarboxylic acid; C10) ingestion on postprandial glycemia and glucose rate of appearance (R_a) in healthy and type 2 diabetic subjects. Furthermore, the effect of C10 on insulin-mediated glucose uptake and on GLUT4 expression was assessed in L6 muscle cells in vitro.

RESEARCH DESIGN AND METHODS

Subjects ingested a mixed meal (50% carbohydrates, 15% proteins, and 35% lipids) containing 0 g (control) or 10 g C10 in addition to the meal or 23 g C10 as a substitute of fats.

RESULTS

In type 2 diabetic subjects, the incremental glucose area under the curve (AUC) decreased by 42% (P < 0.05) and 70% (P < 0.05) in the 10 g C10 and 23 g C10 groups, respectively. At the largest amounts used, C10 reduced the glucose AUC in healthy volunteers also. When fats were substituted with 23 g C10, AUC of R_a was significantly reduced on the order of 18% (P < 0.05) in both healthy and diabetic subjects. The insulin-dependent glucose uptake by L6 cells was increased in the presence of C10 (38.7 ± 10.3 vs. 11.4 ± 5.4%; P = 0.026). This increase was associated with a 1.7-fold raise of GLUT4.

CONCLUSIONS

Sebacic acid significantly reduced hyperglycemia after a meal in type 2 diabetic subjects. This beneficial effect was associated with a reduction in glucose R_a, probably due to lowered hepatic glucose output and increased peripheral glucose disposal.The World Health Report launched in 2002 by the World Health Organization advised that more than 1 billion adults worldwide are overweight and at least 300 million are clinically obese. Type 2 diabetes can be considered a threatening obesity-related disease because hyperglycemia causes relevant complications such as micro- and macroangiopathy. Patients with type 2 diabetes exhibit increased hepatic glucose output, which is identified as the main cause of fasting hyperglycemia and is associated with impaired plasma glucose clearance (1) and reduced hepatic synthesis of glycogen of ∼25–45% compared with that in nondiabetic subjects (2). Increased hepatic gluconeogenesis has been considered to be responsible for elevated hepatic glucose output in type 2 diabetes (3). When glycogen is available in adequate amounts, there is an autolimitation of hepatic glucose production. In diabetes, a breakdown of this autoregulation may occur if glycogenolysis is limited by glycogen depletion (4).Jenkins et al. (5) have shown that spreading the nutrient load over a longer period of time by increased meal frequency, the so-called nibbling diet, is beneficial in terms of reduction of circulating levels of glucose, insulin, and free fatty acids in type 2 diabetes. Thus, the availability of snacks poor in fat and that do not induce hyperglycemia and/or overstimulate insulin secretion would be a good tool in the diet of insulin-resistant, type 2 diabetic subjects.Dicarboxylic acids are naturally occurring substances produced by both higher plants and animals via ω-oxidation of fatty acids (6,7). In plants, long-chain dicarboxylic acids are components of natural protective polymers, cutin and suberin, which support biopolyesters involved in waterproofing the leaves and fruits, regulating the flow of nutrients among various plant cells and organs, and minimizing the deleterious impact of pathogens (7). In animals and humans, medium chain dicarboxylic acids, which include prevalently sebacic (C10) and dodecanedioic (C12) acids, derive from the β-oxidation of longer chain dicarboxylic acids (8). Long-chain dicarboxylic acids, in turn, are formed from the correspondent fatty acids by ω-oxidation in the microsomal membranes (9) or are taken in with a diet rich in vegetables (7).We have shown previously that medium-chain dicarboxylic acids represent a suitable alternate energy substrate to glucose in clinical conditions with marked insulin resistance and/or impaired aerobic glycolysis (10). Interestingly, in type 2 diabetes, medium-chain dicarboxylic acids are rapidly oxidized, do not stimulate insulin secretion, and reduce muscle fatigue (11). Nevertheless, the effect of C10 or C12, not as a substitute but in addition to available carbohydrates, on glucose homeostasis has never been studied.On this basis, our aim was to investigate the effect of oral administration of C10 on postprandial glycemia, insulinemia, and glucose rate of appearance (R_a) in type 2 diabetic subjects compared with that in healthy volunteers. To further elucidate the mechanism of action of sebacic acid in diabetes, insulin-mediated glucose uptake and GLUT4 protein expression were assessed in L6 cells in vitro.     

Time in Range in Relation to All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes: A Prospective Cohort Study

OBJECTIVEThere is growing evidence linking time in range (TIR), an emerging metric for assessing glycemic control, to diabetes-related outcomes. We aimed to investigate the association between TIR and mortality in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSA total of 6,225 adult patients with type 2 diabetes were included from January 2005 to December 2015 from a single center in Shanghai, China. TIR was measured with continuous glucose monitoring at baseline, and the participants were stratified into four groups by TIR: >85%, 71–85%, 51–70%, and ≤50%. Cox proportional hazards regression models were used to estimate the association between different levels of TIR and the risks of all-cause and cardiovascular disease (CVD) mortality.RESULTSThe mean age of the participants was 61.7 years at baseline. During a median follow-up of 6.9 years, 838 deaths were identified, 287 of which were due to CVD. The multivariable-adjusted hazard ratios associated with different levels of TIR (>85% [reference group], 71–85%, 51–70%, and ≤50%) were 1.00, 1.23 (95% CI 0.98–1.55), 1.30 (95% CI 1.04–1.63), and 1.83 (95% CI 1.48–2.28) for all-cause mortality (P for trend <0.001) and 1.00, 1.35 (95% CI 0.90–2.04), 1.47 (95% CI 0.99–2.19), and 1.85 (95% CI 1.25–2.72) for CVD mortality (P for trend = 0.015), respectively.CONCLUSIONSThe current study indicated an association of lower TIR with an increased risk of all-cause and CVD mortality among patients with type 2 diabetes, supporting the validity of TIR as a surrogate marker of long-term adverse clinical outcomes.