Risk Factors For Diabetic Complications Research Articles

A National Progress Report on Diabetes: Successes and Challenges

Over the last few decades, numerous public health agencies and other private and public organizations have sought to prevent and delay the disabling complications of diabetes by increasing the use of preventive care practices and reducing risk factors for complications among people with diabetes. Now, federal diabetes surveillance activities are yielding encouraging reports that progress is being made in increasing the use of preventive care practices, reducing risk factors for complications, and preventing or delaying diabetes complications. However, although several gains have been noted, levels of preventive care practices remain suboptimal, risk factors for diabetes complications are too prevalent, and diabetes complications are too pervasive. Furthermore, with compelling evidence that the onset of diabetes can be prevented or delayed among adults at high risk, prevention of diabetes has become a major new challenge. Additional efforts are needed to address the growing problems of obesity and physical inactivity, to identify the most efficacious and cost-effective prevention strategies and interventions, and to implement surveillance activities that allow us to gauge our success. Although progress has been made against diabetes complications, the current epidemic of diabetes increases the urgency of primary prevention efforts.

Prevalence of diabetic complications in fibrocalculous pancreatic diabetic patients and type 2 diabetic patients: A cross-sectional comparative study

Objective To determine the prevalence of diabetes-related complications in subjects with fibrocalculous pancreatic diabetes (FCPD) and compare them with subjects with type 2 diabetes mellitus matched for age, sex, and duration of diabetes. Methods The study group comprised of 277 FCPD patients and 277 age, sex, and duration of diabetes-matched type 2 diabetic patients. All the study subjects underwent a detailed clinical examination, and fasting blood samples were obtained for biochemical studies. Peripheral Doppler was used for diagnosis of peripheral vascular disease (PVD). Vibratory perception threshold (VPT) was determined using biothesiometry for diagnosis of neuropathy. Diagnosis of coronary artery disease (CAD) was based on medical history and 12-lead resting ECG. Retinal photographs were used for diagnosis of retinopathy using a modified version of Early Treatment Diabetic Retinopathy Study (ETDRS) grading system. Results FCPD patients had lower body mass index (BMI) ( P<.001), systolic blood pressure ( P<.0001), diastolic blood pressure ( P<.001), serum cholesterol ( P<.001), serum triglyceride ( P<.001), and serum creatinine ( P<.01) but higher glycosylated hemoglobin ( P<.001) levels compared to patients with type 2 diabetes. Prevalence of CAD was significantly higher among type 2 diabetic patients (11.9%) compared to FCPD patients (5.1%), P<.003. There was no significant difference in the prevalence of other diabetic complications between the two study groups (type 2 diabetes vs. FCPD: retinopathy—37.2% vs. 30.1%, PVD—4.3% vs. 4.7%, Neuropathy—25.3% vs. 20.9%, Nephropathy—15.0% vs. 10.1%). Multiple logistic regression analysis revealed the following risk factors for diabetes complications among type 2 diabetic subjects—retinopathy: BMI ( P=.028), duration of diabetes ( P<.001), and glycosylated hemoglobin ( P=.026); nephropathy: diastolic blood pressure ( P=.016) and glycosylated hemoglobin ( P=.040); neuropathy: age ( P<.001), duration of diabetes ( P=.003), and glycosylated hemoglobin ( P=.001). Among subjects with FCPD, systolic blood pressure ( P=.013), glycosylated hemoglobin ( P=.021), and duration of diabetes ( P<.001) were associated with retinopathy; BMI ( P=.057), glycosylated hemoglobin ( P=.010), and duration of diabetes ( P=.024) with nephropathy and age ( P=.011) and BMI ( P=.010) with neuropathy. Conclusion: The prevalence of retinopathy, nephropathy, neuropathy, and PVD was similar among FCPD patients and type 2 diabetic patients, but the prevalence of CAD was lower among FCPD patients.

Nurture vs. nature in diabetic vasculopathy: roles of advanced glycation endproducts and the receptor for them

As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies conducted in this lab revealed advanced glycation endproducts (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes, and the receptor for AGE (RAGE) as the major genetic factor that responds to them. AGE fractions that caused the vascular derangement were proven to be RAGE ligands. When made diabetic, RAGE-overexpressing transgenic mice exhibited the exacerbation of the indices of nephropathy, and this was prevented by the inhibition of AGE formation. We also created RAGE-deficient mice. They showed marked amelioration of diabetic nephropathy. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A) + RNA, we came across a novel splice variant coding for a soluble RAGE protein, and named it endogenous secretory RAGE (esRAGE). esRAGE was able to capture AGE ligands and neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE–RAGE system should thus be regarded as a candidate molecular target for overcoming this life- and quality of life (QOL)-threatening disease.

Role of lipids in chemical modification of proteins and development of complications in diabetes.

Hyperglycaemia is the major risk factor for the development of complications in both Type I and Type II diabetes; however, there is growing evidence from several clinical trials that dyslipidaemia, including hypertriglyceridaemia, is a significant and independent risk factor for diabetic complications. In this paper, we propose that chemical modification of proteins by lipids may be a underlying pathogenic mechanism linking dyslipidaemia to diabetic complications. Thus the major AGEs (advanced glycation end-products) in tissues, such as carboxymethyl-lysine, carboxyethyl-lysine and hydroimidazolones, may, in fact, be ALEs (advanced lipoxidation end-products), derived from lipids. Increased lipid peroxidation and accelerated ALE formation, possibly catalysed by hyperglycaemia and oxidative stress, may be the mechanistic link between dyslipidaemia and diabetic complications. If correct, this proposal would suggest that inhibition or reversal of glycation, which is a central theme of this symposium, may not be sufficient for protection against diabetic complications.

The AGE-RAGE system and diabetic nephropathy.

As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies revealed advanced glycation end products (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes and the receptor for AGE (RAGE) as the major genic factor that responds to them. AGE fractions that caused the vascular derangement were proved to be RAGE ligands. When made diabetic, RAGE transgenic mice exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)(+)RNA, a novel splice variant coding for a soluble RAGE protein was found and was named endogenous secretory RAGE. Endogenous secretory RAGE was able to capture AGE ligands and to neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE-RAGE system, therefore, should be a candidate molecular target for overcoming this life- and quality-of-life-threatening disease.

Brachial-ankle pulse wave velocity is useful for evaluation of complications in type 2 diabetic patients.

Pulse wave velocity (PWV) is useful for the evaluation of aortic stiffness. The brachial-ankle PWV (baPWV) and carotid PWV (from heart to carotid) were compared to study the relation of these two types of PWVs to diabetic complications in patients with type 2 diabetes mellitus. The baPWV was determined by oscillometrically measuring the pulse volume record at the upper arm and ankles. The carotid PWV was measured tonometrically. Ninety patients with type 2 diabetes mellitus were divided into tertile groups on the basis of baPWV or carotid PWV. The correlations of these variables with albuminuria, peripheral neuropathy, coefficient of variation of R-R intervals (CV R-R) on the electrocardiogram at rest, and retinopathy were examined by logistic regression analysis. After adjustment for age, systolic blood pressure, and duration of diabetes, logistic regression analysis showed that baPWV was directly related to the frequencies of albuminuria, decreased CV R-R, peripheral neuropathy, and retinopathy. In contrast, carotid PWV did not significantly correlate with any diabetic complications. We conclude that oscillometrically determined baPWV is related to the risk of diabetic microvascular disease in patients with type 2 diabetes mellitus and suggested to be useful for assessing risk factors of diabetic complications.

Is Postprandial Glucose Control Important? Is It Practical In Primary Care Settings?

In Brief Large interventional studies have shown that achieving and maintaining near-normal glycemic levels reduces the risk for microvascular and macrovascular complications in type 2 diabetes. The impact of postprandial glucose on glycemic control has become a topic of much discussion among clinicians. This article examines the literature related to the role of postprandial glucose in type 2 diabetes, both as a contributor to overall glycemia and as an independent risk factor for diabetes complications, and discusses the practicality of managing postprandial hyperglycemia in primary care settings.

Risk Factors for Diabetic Complications in Juvenile-Onset Type 1 Diabetic Patients.

We investigated the incidence of diabetic retinopathy and nephropathy in juvenile-onset type 1 diabetic patients and the impact of metabolic control and other risk factors on the incidence of retinopathy and nephropathy. A clinic-based observational longitudinal study was performed. Patients visited our outpatient clinic at the Diabetes Center, Tokyo Women's Medical University from 1980 to 1998. Participants for the study were 533 patients with type 1 diabetes. Fukuda's classification for fundoscopic findings grade (A1, A2, and B1) corresponded to non-proliferative retinopathy and the other grades to proliferative retinopathy. Incipient nephropathy was defined as that in which the albumine-creatinine ratio (ACR) was 30-300 mg/g.Cr, and overt nephropathy was defined as that in which ACR was over 300 mg/g.Cr. The predictive effect of independent variables was explored using Cox's proportional hazard regression analysis. Independent predictors were HbA1c, total-cholesterol, triglyceride, duration of diabetes, systolic blood pressure (BP) for non-proliferative retinopathy, HbA1c, diastolic BP, and total-cholesterol for proliferative retinopathy, HbA1c and duration of diabetes for incipient nephropathy, and HbA1c and onset age for overt diabetic nephropathy. Systolic BP was a significant independent risk factor for non-proliferative retinopathy, and diastolic BP was an independent risk factor for proliferative retinopathy. Once retinal vascular injury has been initiated, greater diastolic pressure may promote progression. Duration of diabetes was an independent risk factor for both non-proliferative diabetic retinopathy and incipient diabetic nephropathy, but was not a risk factor for either proliferative diabetic retinopathy or overt diabetic nephropathy. Strict control of blood glucose, BP, and lipid metabolism are mandatory for reducing the risk of progression of diabetic complications.

An economic model of the long-term health care burden of Type II diabetes.

To develop a long-term economic model of health care for Type II diabetes initially for the United Kingdom; characterize experiences of diabetes-related morbidities and the use of health care resources among a typical Type II diabetes cohort; to estimate lifetime differences in expected health outcomes and costs attributable to Type II diabetes; and to facilitate evaluation of policies or interventions in treating Type II diabetes from the funder's perspective. A compact spreadsheet structure of interconnected Markov chain modules was developed to facilitate rapid estimation of costs and outcomes for whole populations. Recent clinical findings from the United Kingdom Prospective Diabetes Study and other sources were incorporated and a detailed costing module developed from United Kingdom observational data. The model allows the assessment of costs and long-term complications experienced by people suffering from Type II diabetes, including direct health care costs associated with the main diabetic complications and second-order effects on other health services required by such patients. Initial results suggest that the lifetime cost of health care for patients from the diagnosis of diabetes is more than double that for an equivalent non-diabetic population. The model is intended for use by health care policy makers and payers to assess the long-term budgetary impact of trends in a variety of demographic and epidemiological factors on future services, and is also useful to physicians when considering the impact of new treatment strategies or programmes to modify risk factors for diabetic complications.

The Risk Factors For Diabetic Complications

The major late complications of diabetes mellitus can be classified into those attributable to atherosclerosis (heart attacks, stroke, and peripheral vascular disease) and to microvascular disease (diabetic polyneuropathy [DPN], retinopathy, and nephropathy). The risk factors for diabetic polyneuropathy had not previously been adequately assessed by: 1) assessing representative population‐based cohorts; 2) assessing DPN comprehensively and quantitatively; 3) expressing nerve tests as a percentile and normal deviate value correcting for anthropometric characteristics as based on study of a randomly selected normal subject cohort from which neurologic disease had been excluded; 4) assessing risk factors serially over time; and 5) performing multivariate analysis of risk factors. For DPN we have found that the risk factors are: 1) markers of diabetic microvessel disease (diabetic retinopathy, 24‐hour proteinuria, or 24‐hour microalbuminuria); 2) chronic hyperglycemic exposure; and 3) type of DM. Excluding markers of microvessel disease and type of DM we found that the highest correlation coefficients were obtained by glycated hemoglobin (GH) × duration of DM 1/2 × 18/age of onset DM (lowest score = 1) × total plasma antioxidant activity. Similarly, major determinants for diabetic retinopathy and nephropathy also are GH × duration of DM. These results provide strong supportive evidence that the product of chronic hyperglycemic (especially GH) exposure × duration of DM are the main determinants of the diabetic complications of retinopathy, nephropathy, and neuropathy.

Maculopathy in patients with diabetes mellitus type 1 and type 2: associations with risk factors

AIMTo examine possible relation between diabetic maculopathy and various risk factors for diabetic complications in patients with diabetes mellitus type 1 and type 2.METHODSCross sectional study of two cohorts of...

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Este artigo revisa as evidências clínicas e farmacológicas para o uso da repaglinida, um regulador da glicose prandial. Repaglinida tem um início rápido de ação e curta duração - um perfil farmacocinético que permite sua administração em esquemas flexíveis no horário das alimentações limitando as flutuações pós-prandiais da glicemia, típicas do diabetes mellitus do tipo 2 (DM2). Estudos comparativos com repaglinida controlados por placebo demonstram que seu uso também controla os níveis médios da glicemia, conforme indicado por parâmetros essenciais de glicemia, como a glicemia de jejum e os níveis de hemoglobina A1c (HbA1c). O controle da glicemia pós-prandial é de grande importância clínica, uma vez que ela é um importante fator de risco independente para as complicações do DM. O controle glicêmico melhorou ainda mais em pacientes com DM2 resistente a drogas quando a repaglinida foi incorporada ao esquema terapêutico combinado com agentes sensibilizadores de insulina, como a metformina ou o troglitazone. Existem, também, dados sugerindo que o esquema de repaglinida durante as alimentações pode reduzir a possibilidade de hipoglicemia quando comparado com esquemas tradicionais baseados nas sulfoniluréias. Isto pode ser particularmente benéfico para deixar o paciente livre para adotar padrões alimentares variados. Enquanto as sulfoniluréias podem efetivamente melhorar o controle glicêmico global, sua ação prolongada pode resultar em estimulação inapropriada das células beta durante períodos de glicemia relativamente baixa, incorrendo em risco aumentado para hipogicemia. Embora este risco possa ser reduzido se as alimentações forem consumidas em espaços regulares, este esquema impõe restrições à rotina dos pacientes e à liberdade para implementar melhorias no estilo de vida, como a restrição calórica. A repaglinida é metabolizada no fígado produzindo metabólitos inativos e excretada na bile, uma vantagem potencial para pacientes com comprometimento da função renal. Em conclusão, razões óbvias para se considerar um esquema prandial para controle da glicemia incluem a redução dos riscos de complicações diabéticas e de hipoglicemia, e uma maior flexibilidade por o paciente. Dados já disponíveis sobre a repaglinida sugerem que muitos benefícios teóricos deste esquema prandial para regulação da glicemia pode ser obtido na prática clínica.

The burden of chronic hyperglycemia.

Diabetic complications constitute the principal clinical and economic burdens of diabetes. Available evidence indicates that sustained reduction in hyperglycemia (as measured by HbA1c) reduces the incidence of diabetic complications, including microvascular and neurological disease, and will likely reduce the risk of macrovascular disease. In the U.S., targeting interventions to aged and ethnic subpopulations, which are currently receiving suboptimal care, and increasing efforts to lower the average HbA1c concentrations one or two percentage points in people with diabetes would be a more cost-effective goal than aiming for a theoretical HbA1c threshold below which the risk of complications is negligible. Other risk factors for diabetic complications, such as obesity, hypertension, cigarette smoking, and hypercholesterolemia, must also be addressed to reduce the burden of diabetes.

Management of non-insulin-dependent diabetes mellitus. The United Kingdom experience.

Care of persons with non-insulin-dependent diabetes mellitus (NIDDM) in the United Kingdom resembles that in the United States. However, health care practice in Europe is being influenced by the Saint Vincent Declaration, the joint European World Health Organization-International Diabetes Federation initiative, which emphasizes prevention of diabetic complications. In recent years, the responsibility for care for NIDDM has shifted in the United Kingdom to general practice teams. The effect of this shift on the quality of care and the coordinating and educational role of local diabetes specialist teams is discussed, as is the importance of an individualized "menu" of care for each patient. This menu aims for optimum blood glucose level control as well as detection and correction of risk factors for diabetic complications. The pervasive and dangerous notion of NIDDM as a "mild" disease must be corrected. The importance of systematic auditing of process and outcomes in diabetes care is emphasized, as is the need for regular data acquisition, aggregation, and analysis to achieve continuous improvement in the quality of care. Although patient-health professional encounters are the core of good diabetes care, the need for larger-scale appraisal on a local, regional, and national basis is now apparent.

Effect of Glycemic Control on Early Diabetic Renal Lesions-Reply

In Reply. —Dr Poothullil questions the evidence supporting glycemia as a risk factor for diabetic complications. Furthermore, he asks whether other measures (such as lipid levels) correlated more closely with the prevention of the structure manifestations of diabetic nephropathy. Unfortunately, in bolstering his claim for a lack of correlation between a persistent hyperglycemic state and the development of diabetic nephropathy, he has chosen a reference nearly two decades old (his reference 4) that relates to non—insulin-independent diabetes mellitus. In addition to our work showing a strong relationship between glycemic control and the early lesions of diabetic nephropathy in humans, 1 the Diabetes Control and Complications Trial (DCCT) 2 and other studies 3-5 have demonstrated a strong correlation between improved glycemic control and the prevention or reversal of the complications of diabetes. The DCCT demonstrated that lipid levels did not relate as well to the development of complications as did the

Relationship Between Serum Levels of Methylguanidine and Glycemic Control in IDDM Children

To examine the serum levels of methylguanidine in IDDM children and compare them with markers for glycemic control. Reports have indicated that active oxygen, which damages various tissues, increases in diabetes mellitus. The increase of active oxygen is one of the risk factors for diabetic complications. The synthesis of methylguanidine, a metabolic product of guanidine, is mainly regulated by active oxygen. Forty-eight children with IDDM (mean age 13.3 yr) and 17 age-matched nondiabetic control subjects were studied. Diabetic children were divided into a well-controlled group (HbA1c < 8%, n = 24) and a poorly controlled group (HbA1c > 8%, n = 24). Serum concentrations of methylguanidine were measured by enzymatic assay. Levels of methylguanidine in the poorly controlled group (1.31 +/- 0.08 microM) were significantly higher than those in both the well-controlled group (0.85 +/- 0.08 microM) and the control group (0.59 +/- 0.11 microM), respectively (P < 0.01). Methylguanidine levels showed a positive correlation with the levels of HbA1c (P < 0.01) or fructosamine (P < 0.01). No significant correlations were noted between methylguanidine levels and age, sex, duration of diabetes, or insulin dose. Our data indicate that the levels of methylguanidine in IDDM children might be affected by glycemic control and that the determination of serum methylguanidine levels could be a useful test for evaluating the state of diabetic control.

Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis.

To investigate duration of the period between diabetes onset and its clinical diagnosis. Two population-based groups of white patients with non-insulin-dependent diabetes (NIDDM) in the United States and Australia were studied. Prevalence of retinopathy and duration of diabetes subsequent to clinical diagnosis were determined for all subjects. Weighted linear regression was used to examine the relationship between diabetes duration and prevalence of retinopathy. Prevalence of retinopathy at clinical diagnosis of diabetes was estimated to be 20.8% in the U.S. and 9.9% in Australia and increased linearly with longer duration of diabetes. By extrapolating this linear relationship to the time when retinopathy prevalence was estimated to be zero, onset of detectable retinopathy was calculated to have occurred approximately 4-7 yr before diagnosis of NIDDM. Because other data indicate that diabetes may be present for 5 yr before retinopathy becomes evident, onset of NIDDM may occur 9-12 yr before its clinical diagnosis. These findings suggest that undiagnosed NIDDM is not a benign condition. Clinically significant morbidity is present at diagnosis and for years before diagnosis. During this preclinical period, treatment is not being offered for diabetes or its specific complications, despite the fact that reduction in hyperglycemia, hypertension, and cardiovascular risk factors is believed to benefit patients. Imprecise dating of diabetes onset also obscures investigations of the etiology of NIDDM and studies of the nature and importance of risk factors for diabetes complications.

Insulin resistance: A risk factor for diabetic complications

Glucose tolerance, as estimated by the oral glucose tolerance test, depends upon several factors, the most important of which are insulin secretion and insulin action. A close correlation between the two variables, insulin secretion and insulin action, has been found in normal subjects, where they seem to compensate for each other. The result is that glucose tolerance is kept normal even if one of the variables is altered.3 Thus, most subjects with insulin resistance may compensate by hypersecretion of insulin. These subjects, therefore, will develop hyperinsulinemia both in the fasting state and after a meal. If beta cells are unable to produce enough insulin to overcome the insulin resistance, frank diabetes mellitus will be the result. Insulin resistance, therefore, may be present in a compensated form e.g., obesity, and an uncompensated form e.g., noninsulin-dependent diabetes mellitus (NIDDM). In between normal glucose tolerance and frank diabetes (fasting hyperglycemia), a clinical state characterized by partial compensation of insulin resistance has been defined, impaired glucose tolerance (IGT), a clinical state with normal fasting plasma glucose values, but postprandial hyperglycemia. Glucose intolerance, both as diabetes mellitus and IGT, has been shown to be linked to macrovascular diseases, especially CHD.4 Furthermore, glucose intolerance seems to be a common feature of subjects with arterial hypertension. In a recent paper, about 40% of the hypertensives were glucose intolerant,5 while dyslipoproteinemic subjects have been shown to be more glucose intolerant than controls.* Taken together, glucose intolerance seems to be a common characteristic of subjects with dyslipoproteinemia, arterial hypertension, and/or obesity. Since insulin resistance is the major underlying defect in glucose intolerance in the subjects described above, the following question may be raised: How can insulin resistance lead to hypertension, obesity, and dyslipoproinemia?