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1.  Endothelial Dysfunction and Microvascular Complications in Type 1 Diabetes Mellitus 
We examined whether alterations in vascular endothelial function and early structural changes in atherosclerosis are associated with microvascular complications in patients with type 1 diabetes mellitus (DM). Flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (IMT) measurement were performed in 70 young adults (aged 19 to 35 yr), 48 with type 1 DM, and 22 normal controls. Patients with diabetes had a lower peak FMD response (7.8±3.9 vs. 11.1±1.9%, p<0.001) and increased IMT (0.51±0.10 vs. 0.42±0.07 mm, p<0.001) compared with controls. Twenty (41.7%) of the patients had microvascular complications including neuropathy, nephropathy, or retinopathy. In these complicated diabetic patients, we found a lower FMD response (6.1±2.5 vs. 9.9±3.5%, p=0.001) compared with diabetics without microvascular complications. The presence of microvascular complications was also associated with older age and longer duration of the disease. However, no differences were observed in IMT, body size, blood pressure, HbA1c, C-reactive protein, low-density lipoprotein or high-density lipoprotein cholesterol levels between complicated and non-complicated patients. Endothelial dysfunction and early structural atherosclerotic changes are common manifestations in type 1 DM, and endothelial dysfunction is thought to be an early event in the atherosclerotic process and important in the pathogenesis of microvascular complications.
PMCID: PMC2526502  PMID: 18303203
Vascular Endothelial; Atherosclerosis; Microangiopathy; Diabetes Mellitus
2.  Plasma adiponectin, IL-6, hsCRP, and TNF-α levels in subject with diabetic foot and their correlation with clinical variables in a North Indian tertiary care hospital 
Pro- and anti-inflammatory processes are crucial in different phases of wound healing and their disturbances interfere with tissue homeostasis after the manifestation of ulcers, leading to chronic non-healing wounds. However, data on the association between infl ammation and acute foot syndrome are scarce.
Materials and Methods:
Circulating levels of acute-phase reactants and cytokines were measured in diabetic patients with ulcer (n = 162) and without ulcer (n = 162) in a case control study.
Of the patients, 85.1% had type 2 diabetes. Subjects with diabetic foot ulcer showed lower median plasma level of adiponectin [8.4 (7.1–9.2) ng/ml vs. 13.4 (12.1–14.2) ng/ml], and higher median plasma levels of interleukin-6 (IL-6) [32.5 (9.4–44.8) ng/ml vs. 6.7 (4.6–14.6) ng/ml], high-sensitivity C-reactive protein (hsCRP) [12.6 (11.2–13.6) mg/ml vs. 8.4 (7.1–9.2) mg/ml], and tumor necrosis factor-alpha (TNF-α) [99.4 (79.9–121.5) ng/ml vs. 4.9 (4.5–5.6) ng/ml]. A positive correlation was found between body mass index (BMI) (r = −0.088, P < 0.264) and retinopathy (r = 0.249, P < 0.001) for adiponectin. For IL-6, it was between grade of ulcer (r = 0.250, P < 0.001), BMI (r = −0.161, P < 0.04), low density lipoprotein-cholesterol (LDL-C) (r = −0.155, P < 0.049), triglycerides (r = −0.165, P < 0.035), retinopathy (r = −0.166, P < 0.035), nephropathy (r = −0.199, P < 0.011), and smoking (r = −0.164, P < 0.036). For hsCRP: grade of ulcer (r = 0.236, P < 0.002), BMI (r = −0.155, P < 0.048), LDL-C (r = −0.174, P < 0.026), triglycerides (r = −0.216, P < 0.005), retinopathy (r = −0.165, P < 0.037), nephropathy (r = −0.028, P < 0.007), and smoking (r = −0.164, P < 0.036), while total cholesterol (r = −0.209, P < 0.007) and neuropathy (r = 0.141, P < 0.072) for TNF-α.
This study demonstrates that diabetic subjects with various grades of diabetic foot ulcer showed a higher IL-6, hsCRP, TNF-α, and lower adiponectin plasma levels in comparison with diabetes without foot ulcer, independent of the concomitant infections. It would be interesting to fi nd out whether an activation of immune system precedes the development of foot ulcer and whether anti-infl ammatory therapies might be effective in improving the outcome in such patients.
PMCID: PMC3475902  PMID: 23087862
Correlation; diabetic foot ulcer; India; inflammatory marker
3.  Oral manifestations in type-2 diabetes and related complications 
Knowledge of the wide spectrum of the oral markers of diabetes is imperative as one frequently encounters individuals with undetected, untreated or poorly controlled diabetes.
The objective was to study the oral manifestations in type 2 diabetes mellitus (DM) and to establish an association between oral manifestations and associated microvascular and macrovascular complications.
Materials and Methods:
50 cases of DM were selected who had oral complications. The control group comprised 50 age- and sex-matched diabetic patients without any oral complications.
Oral manifestations in DM included periodontal disease in 34%, oral candidiasis in 24%, tooth loss in 24%, oral mucosal ulcers in 22%, taste impairment in 20%, xerostomia and salivary gland hypofunction in 14%, dental caries in 24%, and burning mouth sensation in 10% cases. Fasting [(FBG) (P = 0.003)] and postprandial blood glucose [(PPBG) (P = 0.0003)] levels were significantly higher among cases. The P values for neuropathy, retinopathy, nephropathy, cardiovascular disease, dyslipidemia, and sepsis were 0.0156, 0.0241, 0.68, 0.4047, 0.0278, and 0.3149, respectively, which were significant for neuropathy, retinopathy, and dyslipidemia.
Several oral complications are seen among diabetics. Association of oral markers in DM and microvascular complications suggests that there is a significant association between the two.
PMCID: PMC3475903  PMID: 23087863
Diabetes mellitus; dyslipidemia; neuropathy; oral complications; retinopathy
4.  Nitrosylated Proteins in Monocytes as a new Marker of Oxidative-Nitrosative Stress in Diabetic Subjects with Macroangiopathy 
Peroxynitrite plays an important role in the pathogenesis of diabetic complications. Nitrosylated protein expression in peripheral blood monocytes reflects intracellular peroxynitrite injury, and thus could be a marker of higher diagnostic and prognostic value than plasma nitrotyrosine level. The purpose of this pilot study was to assess if peripheral blood monocytes of diabetic subjects accumulate nitrosylated proteins, and if nitrosylated protein expression correlates with blood glucose control, variables of lipid profile, C-reactive protein concentration (a marker of inflammation), and differs in patients with and without diabetic macrovascular and microvascular complications.
Nitrosylated protein expression in peripheral blood monocytes (Western blot analysis) was assessed in 31 subjects with diabetes mellitus (29 Type 2, 2 Type 1; 20 males, 11 females; mean age 66 years). The presence of microangiopathy was defined by retinopathy, albumin excretion, and/or neuropathy, and macroangiopathy by carotid plaques, a history of myocardial infarction, and/or stroke.
Diabetic subjects accumulated significant amounts of nitrosylated proteins in peripheral blood monocytes. Nitrosylated protein expression positively correlated with body weight, blood glucose, HbA1C, and plasma C-reactive protein concentrations in the whole cohort as well as in subjects with diabetic macroangiopathy.
Monocyte nitrosylated protein expression is a new biomarker of metabolic control and inflammation in diabetic subjects with macroangiopathy. A more detailed assessment of diabetic microvascular complications in a larger group of patients is needed to determine if this variable can be employed as a biomarker of the presence, severity, and progression of diabetic neuropathy, retinopathy, and nephropathy.
PMCID: PMC3057071  PMID: 18726872
nitrosylated proteins; diabetes mellitus; plasma glucose; HbA1C; lipids
5.  Prevalence of Metabolic Syndrome and its influence on microvascular complications in the Indian population with Type 2 Diabetes Mellitus. Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular Genetic Study (SN-DREAMS, report 14) 
The Metabolic syndrome (MS) consists of central obesity, glucose intolerance, hyperinsulinemia, low high density lipoproteins, high triglycerides and hypertension. Different studies have observed that MS causes microvascular complications in patients with type 2 diabetes. The aim of the study was to find out the prevalence of MS in the Indian population with type 2 diabetes mellitus in relation to gender, duration of diabetes, and to evaluate the influence of MS and its individual components on microvascular complications such as diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
A population-based cross sectional survey was conducted with 1414 patients having type 2 diabetes mellitus. The International Diabetes Federation (IDF) criteria were used to identify the metabolic syndrome. Diabetic retinopathy was graded using the stereoscopic digital fundus photography. Neuropathy was assessed by measuring the vibration perception threshold through a sensitometer. Nephropathy was diagnosed by the presence of microalbuminuria in the first morning urine sample.
The age and gender adjusted prevalence of MS, using the IDF criteria, in the South Indian population was 73.3%. The prevalence was higher in women (83.3%), compared to men (65.3%). In subjects with diabetes mellitus, without and with MS, the prevalence of retinopathy was 21.3% and 16.9% (p = 0.057); prevalence of nephropathy was 20.5% and 18.0% (p = 0.296), and prevalence of neuropathy was17.2% and 19.4% (p = 0.353) respectively. Overall and in women, the clustering of MS components led to an increase in the prevalence of diabetic nephropathy. The prevalence of retinopathy and neuropathy in MS subjects, who had diabetes for < 10 years, was more in both men and women; it was more in women but not in men when the duration of diabetes varied from 11-20 years.
The association of MS with microangiopathies decreased with an increase in the duration of diabetes. MS behaved differently in men and women. It may need to be managed differently in the two groups.
PMCID: PMC2993661  PMID: 21067623
6.  Lipoprotein(a) in type 2 diabetic subjects and its relationship to diabetic microvascular complications 
World Journal of Diabetes  2012;3(5):105-109.
AIM: To estimate the level of serum lipoprotein (a) [Lp (a)] in type 2 diabetes mellitus patients and to determine the relationship between Lp(a) in type 2 diabetes mellitus patients and micro-vascular complications.
METHODS: A cross sectional study was performed that enrolled 144 subjects with type 2 diabetes mellitus above the age of 25 years attending outpatient clinic of Government Medical College, Kozhikode. Lp(a) levels were measured quantitatively in venous samples using Turbidimetric Immunoassay in all subjects. Each patient was evaluated for micro vascular complications, namely diabetic retinopathy, nephropathy and neuropathy. The relationship between Lp(a) levels and the micro vascular complications was assessed by univariate analysis.
RESULTS: Mean age of cases was 53.93 ± 10.74 years with a male to female ratio of 1.3:1. Mean duration of diabetes was 9.53 ± 7.3 years. Abnormal Lp(a) levels (≥ 30 mg/dL) were observed in 38 (26.4%) diabetic subjects. Seventy-eight (54.16%) cases had diabetic nephropathy and significantly higher Lp(a) levels were found among these cases [Median 28.2 mg/dL (Interquartile range; IQR 24.4-33.5) vs 19.3 mg/dL (IQR 14.7-23.5); P < 0.05]. Retinopathy was present among 66 (45.13%) cases and peripheral neuropathy was detected among 54 (37.5%) cases. However, Lp(a) levels were not significantly different among those with or without retinopathy and neuropathy. Positive correlation was found between higher Lp(a) levels and duration of diabetes (r = 0.165, P < 0.05) but not with HbA1c values (r = – 0.083).
CONCLUSION: Abnormal Lp(a) levels were found among 26.4% of diabetic subjects. Patients with diabetic nephropathy had higher Lp(a) levels. No association was found between Lp(a) levels and diabetic retinopathy or neuropathy. Longer duration of diabetes correlated with higher Lp(a) levels.
PMCID: PMC3360222  PMID: 22645639
Diabetes mellitus; Lipoprotein(a); Micro vascular complications; Diabetic nephropathy; Diabetic retinopathy; Diabetic neuropathy
7.  The effect of autoimmunity on the development time of microvascular complications in patients with type 1 diabetes mellitus 
Type 1 diabetes mellitus (DM) is an autoimmune disease with chronic complications that is becoming more frequent as life expectancy of diabetics has increased owing to improved methods of detection and better management. In this study, we investigated whether the presence of autoimmunity can be used in predicting the development time of microvascular complications.
Our study included 52 patients with type 1 diabetes mellitus (DM). The subjects had developed microvascular complications and they had been tested for anti-GAD (glutamic acid decarboxylase) antibodies and/or islet-cell antibodies (ICA). In the assessment of microvascular complications, we used ocular fundus examination, electromyography (EMG), and 24-h urine microalbuminuria tests.
Of the patients included in the study, 30 were female and 22 were male. Of all patients characterized for the existence of diabetic complications, 36 of 52 had both diabetic retinopathy and diabetic nephropathy, 5 patients had diabetic neuropathy, and 11 patients had diabetic retinopathy only. At the diagnosis of diabetes, 20 in 52 patients tested negative for autoantibodies (anti-GAD and anti-ICA), while 32 of 52 tested positive for anti-GAD and/or anti-ICA. The mean HbA1C level of autoantibody-negative patients was 7.7%, while antibody-positive patients had slightly higher HbA1c levels (7.9%). However, this difference was not statistically significant (p>0.05). The mean development time of microvascular complications in autoantibody-positive patients was calculated as 11: 40±6.46 years, and in patients with negative autoimmunity results it was 10.91±6.70 years.
The presence of diabetes-related autoantibodies (DRAs) in patients with type 1 diabetes mellitus does not have a significant effect on the development time of diabetic microvascular complications.
PMCID: PMC4103811  PMID: 25007947
Autoantibodies; Diabetes Complications; Diabetes Mellitus; Type 1
8.  HbA1c for diagnosis of type 2 diabetes. Is there an optimal cut point to assess high risk of diabetes complications, and how well does the 6.5% cutoff perform? 
Glycated hemoglobin (HbA1c) has recently been recommended for the diagnosis of type 2 diabetes mellitus (T2DM) by leading diabetes organizations and by the World Health Organization. The most important reason to define T2DM is to identify subjects with high risk of diabetes complications who may benefit from treatment. This review addresses two questions: 1) to assess from existing studies whether there is an optimal HbA1c threshold to predict diabetes complications and 2) to assess how well the recommended 6.5% cutoff of HbA1c predicts diabetes complications. HbA1c cutoffs derived from predominantly cross-sectional studies on retinopathy differ widely from 5.2%–7.8%, and among other reasons, this is due to the heterogeneity of statistical methods and differences in the definition of retinopathy. From the few studies on other microvascular complications, HbA1c thresholds could not be identified. HbA1c cutoffs make less sense for the prediction of cardiovascular events (CVEs) because CVE risks depend on various strong risk factors (eg, hypertension, smoking); subjects with low HbA1c levels but high values of CVE risk factors were shown to be at higher CVE risk than subjects with high HbA1c levels and low values of CVE risk factors. However, the recommended 6.5% threshold distinguishes well between subjects with and subjects without retinopathy, and this distinction is particularly strong in severe retinopathy. Thus, in existing studies, the prevalence of any retinopathy was 2.5 to 4.5 times as high in persons with HbA1c-defined T2DM as in subjects with HbA1c <6.5%. To conclude, from existing studies, a consistent optimal HbA1c threshold for diabetes complications cannot be derived, and the recommended 6.5% threshold has mainly been brought about by convention rather than by having a consistent empirical basis. Nevertheless, the 6.5% threshold is suitable to detect subjects with prevalent retinopathy, which is the most diabetes specific complication. However, most of the studies on associations between HbA1c and microvascular diabetes complications are cross-sectional, and there is a need for longitudinal studies.
PMCID: PMC3848642  PMID: 24348061
diabetes mellitus; diagnostic criteria; diagnosis; HbA1c; retinopathy
9.  Dyslipidaemia Associated with Type 2 Diabetics with Micro and Macrovascular Complications among Ghanaians 
In this study, differences in lipid levels amongst diabetics with and without complications were assessed to determine lipid disorders that are associated with diabetic complications other than cardiovascular diseases. A Cross sectional study design was employed. The study included 288 diabetics and 108 non diabetics with different types of complications such as hypertension, nephropathy, neuropathy, and retinopathy. The mean serum total cholesterol was higher in patients with complications compared to those without complications and the non-diabetic controls. The normotensive diabetic patients had the lowest total cholesterol among the diabetic patients’ groups (4.65 ± 0.17 mmol/l) compared to the diabetics with hypertension (6.051 ± 0.20 mmol/l), retinopathy (6.26 ± 0.29 mmol/l), neuropathy (5.80 ± 0.17 mmol/l) and nephropathy patients 5.74 ± 0.26 mmol/l (P < 0.05). The prevalence of dyslipidaemia among diabetic subjects was between 19.2 and 84.0%. The study shows that, in addition to macrovascular complications, dyslipidaemia is common in type 2 diabetes mellitus patients with microvascular complications.
PMCID: PMC3162963  PMID: 22754190
Type 2 diabetes mellitus; Ghanaians; Dyslipidaemia; Complications
10.  Correlations between Glucagon Stimulated C-peptide Levels and Microvascular Complications in Type 2 Diabetes Patients 
Diabetes & Metabolism Journal  2012;36(5):379-387.
This study aimed to investigate whether stimulated C-peptide is associated with microvascular complications in type 2 diabetes mellitus (DM).
A cross-sectional study was conducted in 192 type 2 diabetic patients. Plasma basal C-peptide and stimulated C-peptide were measured before and 6 minutes after intravenous injection of 1 mg glucagon. The relationship between C-peptide and microvascular complications was statistically analyzed.
In patients with retinopathy, basal C-peptide was 1.9±1.2 ng/mL, and stimulated C-peptide was 2.7±1.6 ng/mL; values were significantly lower compared with patients without retinopathy (P=0.031 and P=0.002, respectively). In patients with nephropathy, basal C-peptide was 1.6±0.9 ng/mL, and stimulated C-peptide was 2.8±1.6 ng/mL; values were significantly lower than those recorded in patients without nephropathy (P=0.020 and P=0.026, respectively). Stimulated C-peptide level was associated with increased prevalence of microvascular complications. Age-, DM duration-, and hemoglobin A1c-adjusted odds ratios for retinopathy in stimulated C-peptide value were 4.18 (95% confidence interval [CI], 1.40 to 12.51) and 3.35 (95% CI, 1.09 to 10.25), respectively. The multiple regression analysis between nephropathy and C-peptide showed that stimulated C-peptide was statistically correlated with nephropathy (P=0.03).
In patients with type 2 diabetes, the glucagon stimulation test was a relatively simple method of short duration for stimulating C-peptide response. Stimulated C-peptide values were associated with microvascular complications to a greater extent than basal C-peptides.
PMCID: PMC3486985  PMID: 23130323
Basal C-peptide; Diabetes mellitus, type 2; Glucagon stimulation test; Microvascular complications; Stimulated C-peptide
11.  Prevalence of Microvascular Complications in Newly Diagnosed Patients with Type 2 Diabetes  
Background & Objective: Microvascular complications are the major outcome of type 2 Diabetes Mellitus progression, which reduce the quality of life, incur heavy economic burdens to the health care system and increase diabetic mortality. The aims of this study were to assess the prevalence of microvascular complications among newly diagnosed type 2 diabetic patients and to analyze the association between these complications and poor glycemic control.
Methods: This cross sectional hospital based study was carried out in Diabetic Clinic of Shaikh Zayed Postgraduate Medical Institute, Lahore Pakistan. The study was conducted from November 2011 to November 2012 among newly diagnosed type 2 diabetic patients. Relevant information of all patients was recorded with the help of a proforma. They were investigated for retinopathy, nephropathy and neuropathy.
Results: We have divided the patients into two groups: Group I with good glycemic control (HbA1c <6.5) and group II with poor glycemic control (HbA1c >6.5). In group II microvascular complications were 89.8%. Neuropathy, nephropathy and retinopathy were present in 68.5%, 56.2% and 31.4% respectively. These similar percentages in Group I were 50%, 0% and 31% respectively and are significantly lower.
Conclusion: The study showed that even in newly diagnosed type 2 diabetic patients who had poor glycemic control, frequency of microvascular complications is much higher as compared to those who had average glycemic control. Thus tight glycemic control does count even in newly diagnosed type 2 diabetics to prevent and minimize the occurrence of complications.
PMCID: PMC3817776  PMID: 24353655
Microvascular Diabetic Complications; Neuropathy; Nephropathy; Retinopathy; Type 2 Diabetes Mellitus
12.  Nonalcoholic fatty liver disease and microvascular complications in type 2 diabetes 
AIM: To evaluate the correlation between nonalcoholic fatty liver disease (NAFLD) and microvascular complications in type 2 diabetes mellitus (T2DM).
METHODS: Data were obtained from 1217 inpatients with T2DM (757 females, 460 males; aged 63.39 ± 12.28 years). NAFLD was diagnosed by hepatic ultrasonography. Diabetic nephropathy (DN), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (DR) were diagnosed according to their respective criteria. The prevalence of NAFLD and the independent correlations of clinical characteristics with NAFLD were determined by cross-tabulation and logistic regression, respectively.
RESULTS: Approximately 61% of inpatients with T2DM in Qingdao, China had NAFLD, which decreased significantly with increase in age and prolonged course of diabetes. The prevalence of NAFLD in patients presenting with DN, DPN and DR was 49.4%, 57.2% and 54.9%, respectively. These rates were significantly lower than those of patients without DN, DPN and DR (65.9%, 65.6% and 66.1%, respectively, P < 0.05). Participants with NAFLD had greater body weight, waist circumference (WC), body mass index (BMI), fasting blood glucose (FBG), hemoglobin A1c, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, blood pressure, as well as triglyceride (TG) levels and lower high-density lipoprotein (HDL) concentration than those without NAFLD (P < 0.05). NAFLD was positively correlated with BMI, WC, TG, FBG, diastolic blood pressure, and systolic blood pressure but negatively correlated with the duration of diabetes, DR, DPN, DN, and HDL.
CONCLUSION: Despite the benign nature of NAFLD, efforts should be directed toward early diagnosis, intensive blood glucose and blood pressure control, and effective dyslipidemia correction.
PMCID: PMC3662955  PMID: 23716995
Nonalcoholic fatty liver disease; Type 2 diabetes mellitus; Diabetic nephropathy; Diabetic retinopathy; Diabetic neuropathy
13.  Relationship between C peptide and chronic complications in type-2 diabetes mellitus. 
OBJECTIVE: The relationship between C peptide and micro- and macrovascular complications is poorly known in type-2 diabetes mellitus. The aim of the study was to evaluatethe relationship between serum C-peptide level and chronic complications in patients with type-2 diabetes mellitus. PATIENTS AND METHODS: Three-hundred-eighteen patients (138 male, 180 female) with type-2 diabetes mellitus were included in the study. Microvascular (nephropathy, retinopathy and neuropathy) and macrovascular complications (coronary artery disease and peripheral vascular disease) were determined in all patients. In addition, presence of hypertension and smoking habit was recorded. Fasting serum glucose, lipid levels, HbA1c and C-peptide levels were measured in all patients. RESULTS: There were 90 (28.3%) patients with sensorial neuropathy, 48 (15.1%) with autonomic neuropathy, 72 (22.7%) with nephropathy, 84 (26.4%) with retinopathy, 135 (42.5%) with hypertension, 270 (84.9%) with dyslipidemia, 33 (10.4%) with coronary artery disease and 18 (5.7%) with peripheral vascular disease. Serum C-peptide level was higher in patients with dyslipidemia (p = 0.045), hypertension (p = 0.001), coronary artery disease (p = 0.001), peripheral vascular disease (p = 0.001) and autonomic neuropathy (p = 0.001). Serum C-peptide level was not significantly different in patients with and without sensorial neuropathy, nephropathy and retinopathy. Serum C-peptide level was significantly associated with the presence of coronary artery disease (p = 0.001), peripheral vascular disease (p = 0.001) and autonomic neuropathy (p = 0.001). There was no relationship between C peptide and sensorial neuropathy, nephropathy and retinopathy. CONCLUSION: Our findings indicate a relationship between C peptide and macrovascular but not microvascular compli cations in patients with type-2 diabetes mellitus.
PMCID: PMC2575980  PMID: 16173326
14.  Relationship between inflammatory markers, metabolic and anthropometric variables in the Caribbean type 2 diabetic patients with and without microvascular complications 
Serum sialic acid and C reactive protein are the markers for inflammation. The main objective of this study was to determine the sialic acid level in Caribbean type 2 diabetic patients with and without microvascular complications and its relationship with metabolic and anthropometric variables.
Research design and methods
The Caribbean subjects aged 15–60 years with type 2 diabetes were recruited for the study. Fasting venous blood samples were collected from 162 subjects of which 44 were healthy individuals, 44 were of type 2 diabetes, 44 were of type 2 diabetes with nephropathy and 30 were of diabetes with retinopathy. Simultaneously urine samples were also collected from each of the subjects. All the blood samples were processed for lipid profile, glucose, HbA1C, C-reactive protein and sialic acid. The urine samples were analysed for sialic acid and microalbumin.
Serum sialic acid concentrations were significantly higher among diabetic subjects (66.0 ± 11.7 mg %) as compared to controls (55.2 ± 8.3 mg %). There was a significantly increasing trend of serum sialic acid with severity of nephropathy (71.6 ± 23.6 mg %) and degree of urinary albumin excretion (794.3 ± 805.9). The diabetic retinopathy patients also demonstrated significantly higher values of serum sialic acid (77.9 ± 29.0) and urine microalbumin (351.1 ± 559.9). Elevated serum sialic acid microalbumin concentrations were associated with cardiovascular risk factors such as hypertension, increased waist to hip ratios. (P < 0.05). Sialic acid had no correlation with CRP or any component of the lipid profile.
The increased serum sialic acid and microalbumin were strongly related to the presence of microvascular complications like diabetic nephropathy and diabetic retinopathy and cardiovascular risk factors like hypertension and waist to hip ratios in Caribbean type-2 diabetic patients. The serum sialic acid may be used as an inflammatory marker and possible indicator of microvascular complications in type-2 diabetic patients.
PMCID: PMC1764741  PMID: 17187674
15.  Platelet and coagulation factors in proliferative diabetic retinopathy. 
Journal of Clinical Pathology  1984;37(6):659-664.
Plasma beta-thromboglobulin, platelet factor 4, fibrinogen, fibrinopeptide A, antithrombin III, factor VIII related antigen, alpha 2-macroglobulin, platelet count, and total glycosylated haemoglobin were measured in three well matched groups of subjects: non-diabetic controls, diabetics without retinopathy, and diabetics with proliferative retinopathy. beta-thromboglobulin and platelet factor 4 concentrations were significantly higher in the diabetics with retinopathy than in the controls and platelet factor 4 was also increased in the diabetics without retinopathy compared with controls. Fibrinogen concentration was raised in diabetics without retinopathy compared with controls, diabetics with retinopathy compared with controls, and diabetics with retinopathy compared with those without. Fibrinopeptide A concentration did not differ significantly between groups. Antithrombin III levels were increased in diabetics with retinopathy compared with controls, and in diabetics with retinopathy compared with those without. Factor VIII related antigen values were higher in both the diabetic groups when compared with the controls. Fibrinopeptide A concentration correlated with both beta-thromboglobulin and platelet factor 4 in each of the three groups. Haemostatic abnormalities in diabetes have been shown, although a hypercoagulable state has not been confirmed. These changes in platelet and coagulation function may be secondary to the development of microvascular disease and their role in the pathogenesis of retinopathy remains uncertain.
PMCID: PMC498841  PMID: 6202721
16.  Hypovitaminosis D in Patients with Type 2 Diabetes Mellitus: A Relation to Disease Control and Complications 
ISRN Endocrinology  2013;2013:641098.
Aims. This study aims at assessing the relationship between 25 (OH) vitamin D (25-OHD) levels and microvascular complications in patients with type 2 diabetes mellitus (DM2). Methods. 136 patients (59 ± 11 years) with DM2 (disease duration 8.6 ± 7 years) participated in this cross-sectional study. Anthropometric data, HbA1c, 25-OHD levels, serum creatinine, and urine microalbumin/creatinine ratio were collected. Dilated retinal exam was performed, and diabetic neuropathy was assessed using the United Kingdom Screening Score. Results. Serum 25-OHD correlated negatively with HbA1c (r = −0.20,  P = 0.049). Mean 25-OHD levels were lower in subjects with diabetic retinopathy compared to those without retinopathy (12.3 ± 5.5 versus 21.8 ± 13.7, P < 0.001) and lower in subjects with diabetic neuropathy compared to those without neuropathy (16.4 ± 10.4 versus 23.5 ± 14.5, P = 0.004). After adjustment for BMI, diabetes duration, and smoking, 25-OHD was an independent predictor of HbA1c (β  −0.14; P = 0.03). After adjustment for HbA1c, age, smoking, BMI and disease duration, 25-OHD were independent predictors for diabetic retinopathy: OR 2.8 [95% CI 2.1–8.0] and neuropathy: OR 4.5 [95% CI 1.6–12] for vitamin D < 20 versus vitamin D ≥ 20 ng/mL. Conclusion. Low serum 25-OHD level was an independent predictor of HbA1c, diabetic neuropathy, and diabetic retinopathy in patients with DM2.
PMCID: PMC3819758  PMID: 24251044
17.  Relationship between Sialic acid and metabolic variables in Indian type 2 diabetic patients 
Plasma sialic acid is a marker of the acute phase response. Objective is to study the relationship between sialic acid relationship with metabolic variables in Indian type 2 diabetes with and without microvascular complications.
Research design and Methods
Fasting Venous blood samples were taken from 200 subjects of which 50 were of diabetes mellitus (DM) and nephropathy patients, 50 patients with type 2 diabetes and retinopathy, 50 patients with type 2 diabetes without any complications and 50 healthy individuals without diabetes. The Indian subject's aged 15–60 years with type 2 diabetes were recruited for the study. Simultaneously urine samples were also collected from each of the subjects. All the blood samples were analyzed for total cholesterol, triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), fasting and postprandial glucose on fully automated analyzer. Serum and urine sialic acid along with microalbumin levels were also estimated.
There was a significantly increasing trend of plasma and urine sialic acid with severity of nephropathy (P < 0.001) and with degree of urinary albumin excretion (P < 0.001). Serum sialic acid correlated with increasing serum creatinine concentration (P < 0.001). Elevated serum sialic acid concentrations were also associated with several risk factors for diabetic vascular disease: diabetes duration, HbA1c, serum triglyceride and cholesterol concentrations, waist-to-hip ratio and hypertension. Significant correlations were found between sialic acid concentration and cardiovascular risk factors like LDL and TG in the diabetic subjects.
The main finding of this study is that elevated serum and urinary sialic acid and microalbumin concentrations were strongly related to the presence of microvascular complications like diabetic nephropathy and retinopathy and cardiovascular risk factors in Indian type 2 diabetic subjects. Further study of acute-phase response markers and mediators as indicators or predictors of diabetic microvascular complications is therefore justified.
PMCID: PMC1201167  PMID: 16092968
Sialic acid; Microalbuminuria; microvascular; and type-2 diabetes mellitus
18.  The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus 
Few large-scale, real-world studies have assessed the relative associations of lipid fractions with diabetic microvascular events. The main objective of this study was to evaluate the association of the lipid profile components, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high density lipoprotein cholesterol (non-HDL-C) with microvascular complications (MVCs) in type 2 diabetes mellitus (T2DM) patients.
This observational cohort study queried the HealthCore Integrated Research Database (HIRDSM) for newly-diagnosed (Index Date) 18-64-year-old patients with diabetes mellitus between 01/01/2005-06/30/2010. Inclusion required ≥12 months pre-index continuous health plan eligibility and ≥1 pre-index lipid profile result. Patients with polycystic ovary syndrome and prior MVCs were excluded. Incident complications were defined as the earliest occurrence of diabetic retinopathy, peripheral neuropathy, and/or nephropathy post-index. Cox proportional models and Kaplan-Meier (KM) curves were used to evaluate associations among variables.
Of the patients (N = 72,267), 50.05 % achieved HDL-C, 64.28 % LDL-C, 59.82 % TG, and 56.79 % non-HDL-C American Diabetes Association goals at baseline. During follow-up (mean, 21.74 months), there were 5.21 microvascular events per 1,000 patient-months. A 1-mg/dL increase in HDL-C was associated with 1 % decrease in any MVC risk (P < .0001), but for LDL-C, TG, and non-HDL-C, 1-mg/dL increase resulted in increases of 0.2 % (P < .0001), 0.1 % (P < 0.001) and 0.3 % (P < 0.001) in MVC risk. Patients achieving HDL-C goals had a 11 % lower risk of MVC versus non-achievers (RR 0.895, [95 % CI, 0.852-0.941], P < .0001). Similarly, TG goal attainment was associated with a lowered risk for any MVC (RR 0.849, [95 % CI, 0.808-0.892], P < .0001). Evaluation of KM survival curves demonstrated no significant difference in the risk of MVCs between patients achieving vs. not achieving LDL-C goals, but did demonstrate a difference in MVC risk between patients achieving vs. not achieving non-HDL-C goals.
This study demonstrates significant independent associations among lipid fractions and risk for microangiopathy. These findings suggest that attaining established ADA goals for HDL-C, TG, and non-HDL-C may reduce risk for microvascular events among patients with diabetes.
PMCID: PMC3473235  PMID: 22978715
Lipid subfractions; ADA treatment goals; Diabetes; Microvascular complications; Retinopathy; Neuropathy; Nephropathy
19.  Profile of Microvascular Disease in Type 2 Diabetes in a Tertiary Health Care Hospital in India 
Diabetes mellitus (DM) is a metabolic disorder complicated by microvascular and macrovascular diseases. The clinical profile of these complications has not been adequately studied in many tertiary health care centers in India.
The authors studied the clinical profile of microvascular diabetes complications [peripheral sensory neuropathy (PSN), diabetic retinopathy (DR), nephropathy] in patients attending a tertiary care hospital in India.
Subjects and Methods:
In this cross-sectional study, patients (n = 1529) with type 2 diabetes mellitus (T2DM) were studied for the presence of complications. PSN was diagnosed when the vibration perception threshold of big toe was >25 V. Retinopathy was diagnosed using direct ophthalmoscopy (presence of microaneurysms, exudates, and hemorrhages), and nephropathy with microalbuminuria (≥30 mg/l albumin in a spot urine sample) or low creatinine clearance (<90 ml/min) using Cockcroft-Gault formula.
PSN was present in 37% (565/1529), nephropathy in 20% (297/1529), and retinopathy in 17% (256/1529) of the study population. Microvascular complications are seen in 48% (734/1529) patients of the study population. Increasing age (P < 0.001), long duration of diabetes (P < 0.001), and higher HbA1c (P = 0.036) were the common risk factors for all complications. Hypertriglyceridemia (P = 0.016) and low body weight (P = 0.039) predisposed to retinopathy over other microangiopathies. Overall, nephropathy was associated strongly with retinopathy (P = 0.015).
The data showed that neuropathy was the most common microangiopathy and coexisted with other complications in many patients. Old age, long duration of disease, and poor glycemic control are the common risk factors for microvascular complications.
PMCID: PMC3573501  PMID: 23439986
Microangiopathy; Nephropathy; Retinopathy; Sensory neuropathy; Type 2 diabetes
20.  Hyperbaric Oxygen Therapy for Non-Healing Ulcers in Diabetes Mellitus 
Executive Summary
To examine the effectiveness and cost-effectiveness of hyperbaric oxygen therapy (HBOT) to treat people with diabetes mellitus (DM) and non-healing ulcers. This policy appraisal systematically reviews the published literature in the above patient population, and applies the results and conclusions of the review to current health care practices in Ontario, Canada.
Although HBOT is an insured service in Ontario, the costs for the technical provision of this technology are not covered publicly outside the hospital setting. Moreover, access to this treatment is limited, because many hospitals do not offer it, or are not expanding capacity to meet the demand.
Clinical Need
Diabetes mellitus is a chronic disease characterized by an increase in blood sugar that can lead to many severe conditions such as vision, cardiac, and vascular disorders. The prevalence of DM is difficult to estimate, because some people who have the condition are undiagnosed or may not be captured through data that reflect access to the health care system. The Canadian Diabetic Association estimates there are about 2 million people in Canada with diabetes (almost 7% of the population). According to recent data, the prevalence of DM increased from 4.72% of the population aged 20 years and over in 1995, to 6.19% of the population aged 20 years and over in 1999, or about 680,900 people in 1999. Prevalence estimates expanded to 700,000 in 2003.
About 10% to 15% of people with DM develop a foot wound in their lifetimes because of underlying peripheral neuropathy and peripheral vascular disease. This equals between 70,000 and 105,000 people in Ontario, based on the DM prevalence estimate of 700,000 people. Without early treatment, a foot ulcer may fester until it becomes infected and chronic. Chronic wounds are difficult to heal, despite medical and nursing care, and may lead to impaired quality of life and functioning, amputation, or even death.
The Technology
Hyperbaric oxygen therapy has been in use for about 40 years. It is thought to aid wound healing by supplying oxygen to the wound. According to the Hyperbaric Oxygen Therapy Association, HBOT acts as a bactericidal, stops toxin production, and promotes tissue growth to heal difficult wounds.
During the procedure, a patient is placed in a compression chamber with increased pressure between 2.0 and 2.5 atmospheres absolute for 60 to 120 minutes, once or twice daily. In the chamber, the patient inhales 100% oxygen. Treatment usually runs for 15 to 20 sessions.
Noted complications are rare but may include claustrophobia; ear, sinus, or lung damage due to pressure; temporary worsening of short sightedness; and oxygen poisoning. Careful monitoring during the treatment sessions and follow-up by a trained health care provider is recommended.
Review Strategy
The aims of this health technology policy appraisal were to assess the effectiveness, safety, and cost-effectiveness of HBOT, either alone, or as an adjunct, compared with the standard treatments for non-healing foot or leg ulcers in patients with DM. The following questions were asked:
Alone or as an adjunct therapy, is HBOT more effective than other therapies for non-healing foot or leg ulcers in patients with DM?
If HBOT is effective, what is the incremental benefit over and above currently used strategies?
When is the best time in a wound treatment strategy to use HBOT?
What is the best treatment algorithm with HBOT?
The Medical Advisory Secretariat searched for health technology assessments in the published and grey literature. The search yielded 4 reports, which were published from 2000 to 2005. The most recent from the Cochrane Collaboration had a literature review and analysis of randomized control trials to 2003.
As an update to this review, as per the standard Medical Advisory Secretariat systematic review strategy, the abstracts of peer-reviewed publications were identified using Ovid MEDLINE, EMBASE, MEDLINE in-process and not-yet-indexed citations, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, and INAHTA using key words and searching from January 1, 2003 to 2004.
The criteria for inclusion were as follows:
Patients with diabetes
Live human study
English-language study
HBOT as adjunctive therapy or alone
Randomized control trial
The number of excluded studies included the following:
2 animal studies
13 focus on condition other than DM
8 review/protocol for HBOT use
3 HBOT not focus of report
2 health technology assessments (2)
1 non-RCT
Outcomes of interest were wound healing and prevention of amputation.
The search yielded 29 articles published between 2003 and 2004. All 29 of these were excluded, as shown beside the exclusion criteria above. Therefore, this health technology policy assessment focused exclusively on the most recently published health technology assessments and systematic reviews.
Summary of Findings
Four health technology assessments and reviews were found. Cochrane Collaboration researchers published the most recent review in 2005. They included only randomized controlled trials and conducted a meta-analysis to examine wound healing and amputation outcomes. They found that, based on findings from 118 patients in 3 studies, HBOT may help to prevent major amputation (relative risk, 0.31; 95% confidence interval [CI], 0.13–0.71) with a number needed to treat (NNT) of 4 (95% CI, 3–11). They noted, however, that the point estimates derived from trials were not well reported, and had varying populations with respect to wound severity, HBOT regimens, and outcome measures. These noted limitations rendered the comparison of results from the trials difficult. Further, they suggested that the evidence was not strong enough to suggest a benefit for wound healing in general or for prevention of minor amputations.
The Medical Advisory Secretariat also evaluated the studies that the Cochrane Collaboration used in their analysis, and agreed with their evaluation that the quality of the evidence was low for major and minor amputations, but low to moderate for wound healing, suggesting that the results from new and well-conducted studies would likely change the estimates calculated by Cochrane and others.
In 2003, the Ontario Health Technology Advisory Committee recommended a more coordinated strategy for wound care in Ontario to the Ministry of Health and Long-term Care. This strategy has begun at the community care and long-term care institution levels, but is pending in other areas of the health care system.
There are about 700,000 people in Ontario with diabetes; of these, 10% to 15% may have a foot ulcer sometime in their lifetimes. Foot ulcers are treatable, however, when they are identified, diagnosed and treated early according to best practice guidelines. Routine follow-up for people with diabetes who may be at risk for neuropathy and/or peripheral vascular disease may prevent subsequent foot ulcers. There are 4 chambers that provide HBOT in Ontario. Fewer than 20 people with DM received HBOT in 2003.
The quality of the evidence assessing the effectiveness of HBOT as an adjunct to standard therapy for people with non-healing diabetic foot ulcers is low, and the results are inconsistent. The results of a recent meta-analysis that found benefit of HBOT to prevent amputation are therefore uncertain. Future well-conducted studies may change the currently published estimates of effectiveness for wound healing and prevention of amputation using HBOT in the treatment of non-healing diabetic foot ulcers.
Although HBOT is an insured service in Ontario, a well conducted, randomized controlled trial that has wound healing and amputation as the primary end-points is needed before this technology is used widely among patients with foot wounds due to diabetes.
PMCID: PMC3382405  PMID: 23074462
21.  Effects of physical activity on the development and progression of microvascular complications in type 1 diabetes: retrospective analysis of the DCCT study 
To examine the effects of physical activity on the development and progression of microvascular complications in patients with type 1 diabetes.
A retrospective analysis of data from the Diabetes Control and Complications trial was undertaken. Physical activity data was collected at baseline for each of 1441 recruits, converted to metabolic equivalent of task values, and categorised according to the American College of Sports Medicine recommendations. The rates of development/progression of diabetic retinopathy, nephropathy and neuropathy were compared in those who achieved over twice recommended, up to twice recommended, and less than recommended metabolic equivalent of task levels of activity. The DCCT study had a mean duration of follow up of 6.5 years ending in 1993.
A total of 271 subjects had a sustained three-step progression in diabetic retinopathy. The rates of development or progression of retinopathy showed no significant association with physical activity level. The number of outcomes for nephropathy and neuropathy were small and there was no significant association with physical activity level.
We found no evidence that physical activity improves microvascular outcomes in type 1 diabetes. However we demonstrate no evidence of harm. We suggest that physical activity continues to play an important role in the management of type 1 diabetes.
PMCID: PMC3850661  PMID: 24083407
Physical activity; Exercise; Complications; Retinopathy; Type 1 diabetes
22.  C-peptide, Na+,K+-ATPase, and Diabetes 
Na+,K+-ATPase is an ubiquitous membrane enzyme that allows the extrusion of three sodium ions from the cell and two potassium ions from the extracellular fluid. Its activity is decreased in many tissues of streptozotocin-induced diabetic animals. This impairment could be at least partly responsible for the development of diabetic complications. Na+,K+-ATPase activity is decreased in the red blood cell membranes of type 1 diabetic individuals, irrespective of the degree of diabetic control. It is less impaired or even normal in those of type 2 diabetic patients. The authors have shown that in the red blood cells of type 2 diabetic patients, Na+,K+-ATPase activity was strongly related to blood C-peptide levels in non–insulin-treated patients (in whom C-peptide concentration reflects that of insulin) as well as in insulin-treated patients. Furthermore, a gene-environment relationship has been observed. The alpha-1 isoform of the enzyme predominant in red blood cells and nerve tissue is encoded by the ATP1A1 gene.Apolymorphism in the intron 1 of this gene is associated with lower enzyme activity in patients with C-peptide deficiency either with type 1 or type 2 diabetes, but not in normal individuals. There are several lines of evidence for a low C-peptide level being responsible for low Na+,K+-ATPase activity in the red blood cells. Short-term C-peptide infusion to type 1 diabetic patients restores normal Na+,K+-ATPase activity. Islet transplantation, which restores endogenous C-peptide secretion, enhances Na+,K+-ATPase activity proportionally to the rise in C-peptide. This C-peptide effect is not indirect. In fact, incubation of diabetic red blood cells with C-peptide at physiological concentration leads to an increase of Na+,K+-ATPase activity. In isolated proximal tubules of rats or in the medullary thick ascending limb of the kidney, C-peptide stimulates in a dose-dependent manner Na+,K+-ATPase activity. This impairment in Na+,K+-ATPase activity, mainly secondary to the lack of C-peptide, plays probably a role in the development of diabetic complications. Arguments have been developed showing that the diabetesinduced decrease in Na+,K+-ATPase activity compromises microvascular blood flow by two mechanisms: by affecting microvascular regulation and by decreasing red blood cell deformability, which leads to an increase in blood viscosity. C-peptide infusion restores red blood cell deformability and microvascular blood flow concomitantly with Na+,K+-ATPase activity. The defect in ATPase is strongly related to diabetic neuropathy. Patients with neuropathy have lower ATPase activity than those without. The diabetes-induced impairment in Na+,K+-ATPase activity is identical in red blood cells and neural tissue. Red blood cell ATPase activity is related to nerve conduction velocity in the peroneal and the tibial nerve of diabetic patients. C-peptide infusion to diabetic rats increases endoneural ATPase activity in rat. Because the defect in Na+,K+-ATPase activity is also probably involved in the development of diabetic nephropathy and cardiomyopathy, physiological C-peptide infusion could be beneficial for the prevention of diabetic complications.
PMCID: PMC2478626  PMID: 15198370
23.  Cheiroarthropathy and long term diabetic complications in Nigerians. 
Two hundred and fifty six consecutively ambulant diabetic patients attending a Nigerian diabetic clinic for the presence of cheiroarthropathy were examined using standard criteria. Forty eight (19%) had limited joint mobility of the hand, a prevalence higher than the 4% (2/56) observed in a non-diabetic population matched for age and sex. Limited joint mobility was twice as prevalent in the insulin treated (16/50, 32%) than in the non-insulin dependent (32/206, 16%) diabetics. Indices such as age, duration of diabetes, and glycaemic control (as assessed by integrated blood glucose concentration over the previous 12 months and glycated haemoglobin (HbA1c concentrations) were the same in the diabetics with and without limited joint mobility. The prevalence of cataracts (18/48, 38%) and background retinopathy (8/48, 17%) was higher in diabetics with limited joint mobility than in those without (respectively 6-9% and 5-6%); hypertension, peripheral neuropathy, and foot ulcers, however, were about equally common in the two groups of diabetics (with and without limited joint mobility). Nephropathy appeared commoner in diabetic subjects without limited joint mobility. Our results confirm previous observations in Caucasians of an increased prevalence of limited joint mobility in diabetes, especially those receiving insulin treatment, and also showed that limited joint mobility could predict the presence of retinopathy and cataracts in those diabetics. Neuropathy and hypertension were not commoner in our diabetics with limited joint mobility (unlike in the Caucasian population), suggesting that racial factors may underlie the predictive value of limited joint mobility in diabetic microangiopathy.
PMCID: PMC1003959  PMID: 2310224
24.  The Association of Hypomagnesaemia, High Normal Uricaemia and Dyslipidaemia in the Patients with Diabetic Retinopathy 
Context: Diabetic retinopathy is fast becoming an important cause of a visual disability. The visual disability which results from diabetes is a significant public health problem; however, this morbidity is largely preventable and treatable. If it is managed with a timely intervention, the quality of life can be preserved.
Aims: The objective of this study was to investigate the association of serum uric acid, magnesium and the lipid profile in diabetic retinopathy with Normal subjects and Diabetes mellitus without retinopathy, among the south Indian population.
Settings and Design: The diabetic retinopathy patients were identified from the diabetic health camps which were held in rural areas, and they were compared with those with diabetes without complications and the normal subjects.
Material and Methods: The diabetic retinopathy patients were compared with the healthy subjects and with diabetes without retinopathy. Furthermore, the Diabetic retinopathy patients were grouped as proliferative and non-proliferative, based on the fundoscopic findings. Magnesium, uric acid, FPG, fructosamine and the lipid profile were measured in the above groups and they were analyzed.
Statistical Analysis: The statistical analysis was done by using the SPSS software, by applying the Student ‘t’ test.
Results: The mean serum magnesium concentration was observed to be low in the diabetic retinopathy group (1.43mg/dl) as compared to those in the controls and the diabetic subjects. The serum Uric acid concentration was high normal (4.84mg/dl), which was associated with the dyslipidaemia in diabetic retinopathy.
Conclusion: The poor glycaemic control in diabetes is associated with hypomagnesaemia, and increased uric acid concentration with dyslipidaemia, which can be an initial picture of the ongoing biochemical changes in the complication of diabetes, which can help in predicting the onset of diabetic retinopathy in diabetes.
PMCID: PMC3809619  PMID: 24179880
Diabetic Retinopathy; Hypomagnesaemia; Dyslipidaemia; Magnesium; Uric acid; Fructosamine
25.  Hemoglobin A1c variability as an independent correlate of cardiovascular disease in patients with type 2 diabetes: a cross-sectional analysis of the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study 
Previous reports have clearly indicated a significant relationship between hemoglobin (Hb) A1c change from one visit to the next and microvascular complications, especially nephropathy (albuminuria and albuminuric chronic kidney disease, CKD). In contrast, data on macrovascular disease are less clear. This study was aimed at examining the association of HbA1c variability with cardiovascular disease (CVD) in the large cohort of subjects with type 2 diabetes from the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study.
Serial (3–5) HbA1c values obtained during the 2-year period preceding recruitment, including that obtained at the enrolment, were available from 8,290 subjects from 9 centers (out of 15,773 patients from 19 centers). Average HbA1c and HbA1c variability were calculated as the intra-individual mean (HbA1c-MEAN) and standard deviation (HbA1c-SD), respectively, of 4.52±0.76 values. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. Diabetic retinopathy (DR) was assessed by dilated fundoscopy. CKD was defined based on albuminuria, as measured by immunonephelometry or immunoturbidimetry, and estimated glomerular filtration rate, as calculated from serum creatinine.
HbA1c-MEAN, but not HbA1c-SD, was significantly higher (P<0.0001) in subjects with history of any CVD (n. 2,133, 25.7%) than in those without CVD (n. 6,157, 74.3%). Median and interquartile range were 7.78 (7.04-8.56) and 7.49 (6.81-8.31), respectively, for HbA1c-MEAN, and 0.47 (0.29-0.75) and 0.46 (0.28-0.73), respectively, for HbA1c-SD. Logistic regression analyses showed that HbA1c-MEAN, but not HbA1c-SD (and independent of it), was a significant correlate of any CVD. Similar findings were observed in subjects with versus those without any coronary or cerebrovascular event or myocardial infarction. Conversely, none of these measures were associated with stroke, whereas both correlated with any lower limb vascular event and HbA1c-SD alone with ulceration/gangrene. All these associations were independent of known CVD risk factors and microvascular complications (DR and CKD).
In patients with type 2 diabetes, HbA1c variability has not a major impact on macrovascular complications, at variance with average HbA1c, an opposite finding as compared with microvascular disease, and particularly nephropathy.
Trial registration
ClinicalTrials.Gov NCT00715481
PMCID: PMC3750360  PMID: 23829205
Chronic kidney disease; Retinopathy; Hemoglobin A1c; Risk factors; Type 2 diabetes

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