Early-stage Diabetic Patients Research Articles

Long-term effects of lowering postprandial glucose level on cardiovascular outcomes in early-stage diabetic patients with coronary artery disease: 10-year post-trial follow-up analysis of the DIANA study

AimsTo elucidate the long-term cardiovascular benefit of lowering postprandial hyperglycemia (PPG) in early-stage T2DM patients. MethodsThis 10-year post-trial follow-up study included 243 patients from the DIANA (DIAbetes and diffuse coronary Narrowing) study, a multi-center randomized controlled trial which compared the efficacy of one-year life-style and pharmacological (voglibose/nateglinide) intervention lowering PPG on coronary atherosclerosis in 302 early-stage T2DM subjects [impaired glucose tolerance (IGT) or newly-diagnosed T2DM] (UMIN-CTRID#0000107). MACE (all-cause death, non-fatal MI or unplanned coronary revascularization) were compared in (1) three assigned therapies (life-style intervention/vogliose/nateglinide) and (2) patients with and without improvement of PPG (reversion from IGT to NGT or from DM to IGT/NGT on 75 g oral glucose tolerance test). ResultsDuring the 10-year post-trial observational period, voglibose (HR = 1.07, 95%CI: 0.69–1.66, p = 0.74) or nateglinide (HR = 0.99, 95%CI: 0.64–1.55, p = 0.99) did not reduce MACE. Similarly, achieving the improvement of PPG was not associated with a reduction of MACE (HR = 0.78, 95%CI: 0.51–1.18, p = 0.25). However, in IGT subjects (n = 143), this glycemic management significantly reduced the occurrence of MACE (HR = 0.44, 95%CI: 0.23–0.86, p = 0.01), especially unplanned coronary revascularization (HR = 0.46, 95%CI: 0.22–0.94, p = 0.03). ConclusionsThe early improvement of PPG significantly reduced MACE and unplanned coronary revascularization in IGT subjects during the post-trial 10-year period.

Use of intravoxel incoherent motion diffusion-weighted imaging to detect early changes in diabetic kidneys

The purpose of the study was to examine differences in kidney intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters in early-stage diabetic patients versus healthy controls. Nineteen type 2 diabetic patients (group A) with a urinary albumin-to-creatinine ratio (ACR)<30mg/g and an estimated glomerular filtration rate (eGFR) of 80-120mL/(min1.73m2) and twelve healthy volunteers (group B) were recruited. Kidneys were scanned with 1.5-Tesla IVIM-DWI. Nine b values (0, 50, 100, 150, 200, 300, 400, 600, and 800s/mm2) were used. The parameters derived from IVIM-DWI were calculated for each kidney by two radiologists and included the perfusion fraction (f), diffusion coefficient (D), and pseudo-diffusion coefficient (D*). The mean values of f, D, and D* were calculated by selecting multiple regions of interest in the kidney. The diagnostic performance of the f, D, and D* values for the diagnosis of early diabetic kidney changes was determined by receiver operating characteristic analysis. Three radiologists independently measured the parameters derived from IVIM-DWI in the two groups by free-hand placing regions of interest, and the interclass coefficients (ICCs) were analyzed by SPSS.16.0 software. The f values of the kidneys were significantly higher in diabetic patients than in healthy volunteers. The D value of the kidneys was significantly lower in diabetic patients than in healthy volunteers. No significant differences in the D* values of the kidneys were observed between diabetic patients and healthy volunteers. The D values of the right kidneys were significantly higher than those of the left kidneys in both groups. The results of the receiver operating characteristic analysis were as follows: left kidney-f value AUC=0.650 (cutoff point≥27.49%) and D value AUC=0.752 (cutoff point≤1.68×10-3mm2/s); and right kidney-f value AUC=0.650 (cutoff point≥28.24%) and D value AUC=0.752 (cutoff point≤1.81×10-3 mm2/s). The diagnostic performance of the D* value was very low (AUC<0.6). No significant differences were present between the areas under the curves of the f and D values (P>0.05). The ICCs of the f value and D value were between 0.637 and 0.827. The ICC of the D* value was less than 0.3. The results of our study suggest that changes in kidneys detected by IVIM-DWI may serve as indicators of early diabetic kidney disease.

Differential Effects of Linagliptin on the Function of Human Islets Isolated from Non-diabetic and Diabetic Donors

Linagliptin is a dipeptidyl Peptidase-4 (DPP-4) inhibitor that inhibits the degradation of glucagon-like peptide 1 (GLP-1), and has been approved for the treatment of type 2 diabetes (T2D) in clinic. Previous studies have shown linagliptin improves β cell function using animal models and isolated islets from normal subjects. Since β cell dysfunction occurs during diabetes development, it was not clear how human islets of T2D patients would respond to linagliptin treatment. Therefore, in this study we employed human islets isolated from donors with and without T2D and evaluated how they responded to linagliptin treatment. Our data showed that linagliptin significantly improved glucose-stimulated insulin secretion for both non-diabetic and diabetic human islets, but its effectiveness on T2D islets was lower than on normal islets. The differential effects were attributed to reduced GLP-1 receptor expression in diabetic islets. In addition, linagliptin treatment increased the relative GLP-1 vs glucagon production in both non-diabetic and diabetic islets, suggesting a positive role of linagliptin in modulating α cell function to restore normoglycemia. Our study indicated that, from the standpoint of islet cell function, linagliptin would be more effective in treating early-stage diabetic patients before they develop severe β cell dysfunction.

Assessment of left ventricular function by three-dimensional speckle-tracking echocardiography in well-treated type 2 diabetes patients with or without hypertension.

The aims of this study were to investigate the myocardial deformation in well-treated type 2 diabetes patients with or without hypertension using three-dimensional speckle-tracking echocardiography and to explore variables that could affect myocardial deformation. We studied 82 patients with type 2 diabetes and controlled blood glucose, including 46 subjects with diabetes alone and 36 subjects with diabetes and well-controlled hypertension, and 40 age- and gender-matched controls. Left ventricular real-time three-dimensional (3D) full-volume images were recorded and analyzed using online software. The left ventricular ejection fraction, global longitudinal strain (GLS), global circumferential strain, global area strain, and global radial strain were measured and compared. Despite a similar three-dimensional left ventricular ejection fraction, GLS was significantly lower in patients with diabetes only than in controls (p < 0.001). Patients with diabetes and hypertension showed significantly lower systolic strains in all directions than controls and patients with diabetes only (p < 0.001 and p < 0.05, respectively). Multiple regression analysis revealed that fasting plasma glucose and left ventricular end-diastolic volume were significant factors influencing GLS in both diabetic groups. Early-stage diabetic patients showed an impaired left ventricular strain that was worsened by coexistent hypertension, although blood glucose and blood pressure were well controlled. Three-dimensional speckle-tracking echocardiography was able to detect these subclinical changes.

Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes, but currently no protein biomarkers have been introduced into clinical diagnosis, especially among early-stage diabetic patients. Our previous study in animal model showed Toll-like receptor (TLR) 4 and its downstream signaling molecules were associated with DPN. To assess the diagnostic values of TLR4, TNF-α, and IL-6 as biomarkers, here we detected their expressions in peripheral blood from normal controls, type 2 diabetic and DPN subjects. Both TLR4 mRNA and protein expressions increased significantly in DPN compare with both diabetic and control subjects. The protein levels of TNF-α and IL-6 were also raised significantly and correlated with TLR4 expression. Receiver operating characteristics (ROC) analysis suggested TLR4 and TNF-α had great potential advantages to predict the progression of neuropathy, the risks of DPN were increased in subjects with higher TLR4 (odds ratio: 5.27; 95% CI: 1.02–26.40) and TNF-α (odds ratio: 12.67; 95% CI: 2.35–68.22). These findings demonstrated TLR4 and TNF-α could be potential sensitive diagnostic biomarkers for DPN in both general population and type 2 diabetic subjects.

Clinical Predictors of Atheroma Progression Despite Optimal Glycemic Control in Early-Stage Diabetic Patients with Coronary Artery Disease: Insight from the DIANA Study

In the DIANA(DIAbetes and diffuse coronary NArrowing) study, which evaluated the impact of glucose-lowering therapy in early-stage diabetics with coronary artery disease(CAD), optimal glycemic control resulted in reduced disease progression on angiography. However, despite having a favorable glycemic status, some patients continued to exhibit disease progression. Factors associated with disease progression despite optimal glucose control remain to be elucidated. We sought to investigate clinical characteristics associated with substantial atheroma progression in early-stage diabetic patients with CAD who achieve favorable glycemic control. The DIANA study is a prospective randomized trial comparing the effects of lifestyle intervention and treatment with voglibose or nateglinide on disease progression on angiography in 302 CAD patients with impaired glucose tolerance/newly diagnosed diabetes. Of these patients, 137 CAD subjects who achieved optimal glycemic control were stratified according to the presence of disease progression on angiography: progressors(n=64) and non-progressors(n=73). Serial coronary angiography studies and quantitative coronary angiography analyses were conducted to evaluate disease progression. A multivariate analysis was performed to elucidate factors associated with disease progression. Despite the achievement of optimal glycemic control, atheroma progression was observed in 46% of the study subjects. The progressors exhibited lower decreases in systolic blood pressure(SBP: p=0.007) and reduced baseline total lesion lengths(TLL: p=0.01). The multivariate analysis demonstrated that a greater increase in SBP(p=0.006), treatment without statins(p=0.03) and the baseline TLL(p=0.007) were independently associated with disease progression. Residual risk factors contribute to the progression of coronary atherosclerosis in early-stage diabetics who exhibit improvements in their glycemic status. The present findings underscore the need to intensively modify multiple risk factors during the early diabetic phase in order to prevent atheroma progression.

The safety and effectiveness of TM81, a Chinese herbal medicine, in the treatment of type 2 diabetes: a randomized double‐blind placebo‐controlled trial

TM81 (or Tang-Min-Ling-Wan) is a Chinese medicine. Previous studies suggested that this medicine is effective for treating type 2 diabetes. This controlled trial evaluated the safety and effectiveness of TM81 in the treatment of type 2 diabetic patients. This study was a large-scale controlled clinical trial to evaluate the safety and effectiveness of TM81 on type 2 diabetes. After a 2-week run-in period, 480 overweight type 2 early-stage diabetic patients [35-65 years old, HbA1c ≥ 7.0%, fasting plasma glucose (FPG) 7.0-13.9 mM or 2 h plasma glucose (PG) > 11.1 mM, body mass index (BMI) ≥ 24 kg/m(2)] were enrolled. These patients were divided into a TM81 group and placebo group in a 3 : 1 ratio. The subjects received 6 g TM81 or placebo, three times daily for 12 weeks. After treatment, the HbA1c decrease was 1.02% in the TM81 group versus 0.47% in the placebo group. The FPG decreased 0.8 ± 0.1 mM in the TM81 group versus an increase of 0.2 ± 0.2 mM in the placebo group. The PG decreased 2.7 ± 0.3 mM in the TM81 group versus a decrease of 0.9 ± 0.4 mM in the placebo group (all p < 0.05). The TM81 was more effective for patients with higher baseline HbA1c levels. The TM81 group also showed improved β-cell function and increased homeostatic model assessment (HOMA)-β. In addition, body weight, BMI and waist circumference of subjects in the TM81 group were reduced, and the symptoms related to diabetes were improved. There were no significant differences in the types and frequency of adverse reactions between the two groups. The data showed that TM81 is effective in controlling blood glucose level and is safe to use in patients with early-stage type 2 diabetes.

Characteristics of color discrimination changes in diabetic patients without diabetic retinopathy

To detect the color discrimination changes in early-stage diabetic patients. Retrospective series case study. A total of 78 type 2 diabetic patients (126 eyes) without diabetic retinopathy were enrolled. Another 64 healthy individuals were selected as the normal control. Total error scores (TES) and each error score (ES) in distinguishing the red, green and blue colors were measured via the Farnsworth-Munsell 100 hue tester. The TES origin scores and their square roots were used for statistical analysis. The results of the two groups were compared. The influence of gender, age, duration of diabetic mellitus and application time of insulin on TES and each color's ES values was investigated. The t, t' or u-test was adopted to compare the mean of TES and ES values between these two groups; the Spearman rank correlation analysis was used to analyze the relationship between TES and ES values and age, duration and duration of insulin usage; the t test was employed to analyze the relationship between TES and ES values vs. gender; the number of superior, average, low discrimination eyes were analyzed via the χ(2) test. Wilcoxon rank sum analysis was adopted in determining the color discrimination ability between these three groups. The TES and its square root values in the diabetic and normal groups were 63.80 ± 34.19, 30.39 ± 4.57 and 7.69 ± 2.17, 5.50 ± 0.42, respectively. There were differences in both values between these two groups (t = 4.87, 4.91; P < 0.05). The error scores and its square root values in distinguishing the red, green, blue colors in the diabetic group were 9.39 ± 8.61, 12.67 ± 9.71, 12.39 ± 8.05 and 2.62 ± 1.60, 3.23 ± 1.51, 3.28 ± 1.27, respectively, and the values were 5.13 ± 3.59, 7.00 ± 1.84, 6.81 ± 2.70 and 1.95 ± 1.17, 2.62 ± 0.36, 2.52 ± 0.68, respectively, in the normal group. There were differences between these two groups (u = 3.62, 4.94, 5.40 and 2.40, 3.32, 4.03; P < 0.05). Differences existed in discriminating the three colors between two groups (u = 4.071, P < 0.05). Except for age (r = 0.38, P < 0.05), there was no relationship between color vision defects and age, duration (r = -0.02 ∼ 0.23, P > 0.05), gender (r = 0.32 ∼ 0.39, P > 0.05) or duration of insulin usage (r = -0.03 ∼ 0.11, P > 0.05). Color vision defects appear in early-stage diabetic patients. Color discrimination can play an important role in the evaluation of color perception damage and visual function in diabetic patients.

Transgenic zebrafish model of the C43G human insulin gene mutation

The human insulin gene/preproinsulin protein mutation C43G disrupts disulfide bond formation and causes diabetes in humans. Previous in vitro studies showed that these mutant proteins are retained in the endoplasmic reticulum (ER), are not secreted and are associated with decreased secretion of wild-type insulin. The current study extends this work to an in vivo zebrafish model. We hypothesized that C43G-green fluorescent protein (GFP) would be retained in the ER, disrupt β-cell function and lead to impaired glucose homeostasis. Islets from adult transgenic zebrafish expressing GFP-tagged human proinsulin mutant C43G (C43G-GFP) or wild-type human proinsulin (Cpep-GFP) were analyzed histologically across a range of ages. Blood glucose concentration was determined under fasting conditions and in response to glucose injection. Insulin secretion was assessed by measuring circulating GFP and endogenous C-peptide levels after glucose injection. The majority of β-cells expressing C43G proinsulin showed excessive accumulation of C43G-GFP in the ER. Western blotting showed that C43G-GFP was present only as proinsulin, indicating defective processing. GFP was poorly secreted in C43G mutants compared with controls. Despite these defects, blood glucose homeostasis was normal. Mutant fish maintained β-cell mass well into maturity and secreted endogenous C-peptide. In this model, the C43G proinsulin mutation does not impair glucose homeostasis or cause significant loss of β-cell mass. This model might be useful for identifying potential therapeutic targets for proper trafficking of intracellular insulin or for maintenance of β-cell mass in early-stage diabetic patients.

Effects of Voglibose and Nateglinide on Glycemic Status and Coronary Atherosclerosis in Early-Stage Diabetic Patients

Postprandial hyperglycemia and hyperinsulinemia have been considered as important determinants for the development of atherosclerosis. However, it remains to be elucidated whether correction of the postprandial glycemic status prevents atherosclerotic changes. The DIANA (DIAbetes and diffuse coronary NArrowing) study is a prospective randomized open-label multicenter trial. The 302 patients with coronary artery disease (CAD), impaired glucose tolerance/diabetes mellitus (DM) pattern according to 75-g oral glucose tolerance test and HbA(1c) <6.9% were randomly assigned to life-style intervention (n=101), voglibose (0.9 mg/day, n=100) or nateglinide treatment (180 mg/day, n=101). We compared 1-year coronary atherosclerotic changes evaluated by quantitative coronary arteriography. Although voglibose significantly increased the number of patients with normal glucose tolerance at 1 year, there were no significant differences in coronary atherosclerotic changes at 1 year. However, overall, less atheroma progression was observed in patients in whom glycemic status was improved at 1 year (%change in total lesion length: 3.5% vs. 26.2%, P<0.01, %change in averaged lesion length: 0.7% vs. 18.6%, P=0.02). Although coronary atherosclerotic changes were similar for voglibose and nateglinide, an improvement in glycemic status at 1 year was associated with less atheroma progression regardless of the treatment. Our findings underscore the management of glycemic abnormality to prevent coronary atherosclerotic changes in Japanese early-stage DM patients with CAD.

Characters of contrast sensitivity in diabetic patients without diabetic retinopathy

To explore the change of contrast sensitivity (CS) in diabetic patients without diabetic retinopathy. It was a case-control study. We screened and tested 52 type 2 diabetic patients (89 eyes) and 47 healthy persons (68 eyes). OPTEC 6500 contrast sensitivity tester was used to examine near and distance CS values on 1.5, 3.0, 6.0, 12.0, 18.0 cycles/degree (c/d) respectively. We kept strict inclusion criteria on subjects, no retinopathy was found and best corrected vision acuity was above 1.0. The difference of CS values between these two groups was investigated, and the influence of gender, age, duration of diabetic mellitus and application time of insulin on CS values, respectively. T-test or u-test was used to compare the means of CS values between these two groups, near and distance CS values in each group. Simple linear correlation and multiple regression analysis were used to analyze the single factor and multiple factors correlation between CS values and age, duration, gender, and application time of insulin, respectively. The maximum CS values in both distance and near were 112.67 ± 43.97, 85.85 ± 41.83 and 83.68 ± 35.91, 55.20 ± 24.14, both appeared in 6.0 c/d. The minimum CS values in both distance and near were 26.19 ± 17.69, 12.69 ± 7.09 and 18.68 ± 11.81, 8.22 ± 5.68, respectively, both appeared in 18.0 c/d. Distance and near CS values in diabetic group and control group had very significant differences at these five spatial frequencies (From 1.5 to 18.0 c/d, the test values on distance, t = 3.11, 3.38, 2.77, 3.48, 3.86; P < 0.05; the test values on near, u = 3.70, 3.22; t' = 3.69, 3.88, 4.25; P < 0.05). Abnormal rate in diabetic group on high, medium, low and all frequencies were higher than control group, regardless of distance or near CS values (in near χ(2) = 11.86, 8.17, 9.14, 5.81; P < 0.05; on 4 combinations in distance χ(2) = 13.27, 6.70, 4.01, 4.50; P < 0.05). In diabetic group, gender related with 3.0 and 6.0 c/d CS values on near-distance (r = 0.26, 0.28; P < 0.05); age related with high-frequencies on near (r = -0.45, -0.28; P < 0.05); duration of diabetic mellitus related with high-frequencies on near (r = -0.25, -0.39; P < 0.05), and related with medium, high frequencies on distance (r = -0.26, -0.28, -0.30, -0.34; P < 0.05); application time of insulin related with high-frequencies on distance (r = -0.30, -0.31; P < 0.05). There exists important sense of CS value on showing visual function changes accurately in early-stage of diabetes mellitus. The high frequencies on distance is the sensitive index in vision impairment. Duration of diabetes closely relates with changes of retinal function ultimately, can be classified as the most important risk factor of CS values decline in early-stage diabetic patients.

Length-Tension Relationship of Urinary Bladder Strips from Streptozotocin-Diabetic Rats

Streptozotocin-induced diabetes mellitus or the consumption of 5% sucrose in place of drinking water cause an increase in rat urinary bladder capacity and mass. Length-tension curves were generated using bladder body strips isolated from control, diabetic, or sucrose-drinking rats to determine whether the length-tension relationship was altered by the bladder hypertrophy associated with diabetic and nondiabetic diuresis. In addition, we compared the data using three different methods of expression: (1) absolute grams tension developed; (2) grams tension/100 mg tissue, and (3) grams tension/mm2. The cross-sectional area of strips from diabetic rats was increased compared to the other two groups. The length-passive tension curves for all three groups increased with increasing tissue length to a plateau. No optimal resting length for generation of active tension was found. Strips from diabetic and sucrose-drinking rats reached the plateau at a slightly larger passive tension than did strips from control rats. In addition, strips from diabetic and sucrose-drinking rats generally developed a greater active tension than did strips from control rats depending on the method of data presentation used. The data suggest that the complex nonlinear arrangement of smooth muscle fibers in the bladder wall results in the unusual length-tension curves generated by urinary bladder strips (as compared to skeletal or vascular smooth muscle). This relationship would be of benefit in the urinary bladders of early-stage diabetic patients before neuropathy development, where the stretching of the bladder wall would allow accommodation without any compromise of bladder function. The data indicate that comparisons of bladder strip function from control and diabetic rats should be done at passive tensions of greater than or equal to 2 g to ensure that maximal active tension is generated.