Diabetes Intervention Study Research Articles

An α-glucosidase inhibitor, acarbose treatment decreases serum levels of glyceraldehyde-derived advanced glycation end products (AGEs) in patients with type 2 diabetes

Diabetes is a major risk factor for cardiovascular disease (CVD) morbidity and mortality, and the incidence of CVD is 2–4 times greater in diabetic patients than in a general population [1]. There is a growing body of evidence that postprandial hyperglycemia plays an important role in the development and progression of CVD [2, 3]. Indeed, the DECODE study revealed that 2-h postload hyperglycemia was associated with an increased risk of mortality from CVD, independent of fasting plasma glucose [2]. Further, the Diabetes Intervention Study identified postprandial hyperglycemia to be an independent risk factor for myocardial infarction and all-cause mortality [3]. Since postprandial hyperglycemia is associated with endothelial dysfunction and increased intima-media thickness (IMT) of the common carotid arteries [4], postprandial hyperglycemia is a therapeutic target for preventing CVD in type 2 diabetes. Acarbose, an a-glucosidase inhibitor, which delays the absorption of carbohydrate from the small intestine, reduces postprandial hyperglycemia in patients with type 2 diabetes [4]. Recently, acarbose treatment was reported to slow the progression of IMT of the carotid arteries and to reduce the incidence of CVD in patients with impaired glucose tolerance or type 2 diabetes [4], thus suggesting that acarbose treatment could inhibit the development and progression of CVD by suppressing postprandial hyperglycemia. We have previously shown that glyceraldehyde can rapidly react with amino groups of proteins to form glyceraldehyde-derived advanced glycation end products (AGEs) in vivo, which evoke vascular inflammation and oxidative stress generation, thereby being implicated in accelerated atherosclerosis in diabetes [5, 6]. Further, recently, we found that serum levels of glyceraldehydederived AGEs rather than HbA1c could reflect cumulative postprandial hyperglycemia in type 2 diabetic rats [7]. These observations led us to speculate that acarbose treatment reduced serum levels of glyceraldehyde-derived AGEs, which could contribute to its cardioprotective properties in vivo. To address this issue, we investigated the effects of acarbose on anthropometric and metabolic variables, including glyceraldehyde-derived AGE levels in oral hypoglycemic agent (OHA)-naive type 2 diabetic patients. The study protocol was approved by our institutional ethics committee, and informed consent was obtained from all patients. Thirteen OHA-naive Japanese type 2 diabetic patients (mean age of 63.6 ± 2.4 years, 10 males and 3 females) without microangiopathy, coronary artery disease or any active inflammatory disease were enrolled for the present study. The patients were treated with 50 mg acarbose three times a day for 12 weeks. Blood pressure (BP) was measured in the sitting position using an upright M. Tsunosue N. Mashiko Y. Ohta Y. Matsuo K. Ueda M. Ninomiya S. Tanaka M. Hoshiko Y. Yoshiyama YY Research Group, Yanagawa-Yamato, Japan

Challenges in developing endpoints for type 1 diabetes intervention studies

Development of efficient and safe intervention strategies for preserving and/or restoring endogenous insulin production in type 1 diabetes has encountered a wide range of challenges, including lack of standardized trial protocols and of consensus on appropriate efficacy endpoints. For the greatest part, difficulties resided in choosing the most suitable assay(s) and parameter(s) to assess the beta-cell function. It is now an accepted approach to evaluate endogenous insulin secretion by measuring C-peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed-meal) under standardized conditions. Preventive interventions mandate the identification of well-defined, reliable and validated mechanistic or immunological markers of efficacy that would correlate with (and predict) the clinical outcome. This has not been consistently achieved to date. However, it has been generally agreed that for preventive studies performed very early in the disease course (in subjects without signs of autoimmunity against beta-cells) development of two or more islet related autoantibodies could be employed as biomarkers of disease and thereafter, diagnostic criteria of diabetes serve as suitable endpoints.This report summarizes the conclusions of the D-Cure workshop of international experts held in Barcelona in April 2007 and the current recommendations and updates in the field.

Genome-Wide Association Identifies the ABO Blood Group as a Major Locus Associated With Serum Levels of Soluble E-Selectin

Elevated serum soluble E-selectin levels have been associated with a number of diseases. Although E-selectin levels are heritable, little is known about the specific genetic factors involved. E-selectin levels have been associated with the ABO blood group phenotype. We performed a high-resolution genome-wide association study of serum soluble E-selectin levels in 685 white individuals with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study to identify major loci influencing levels. Highly significant evidence for association (P=10(-29)) was observed for rs579459 near the ABO blood group gene, accounting for 19% of the variance in E-selectin levels. Levels of E-selectin were higher in O/O than O/A heterozygotes, which were likewise higher than A/A genotypes. Analysis of subgroups of A alleles reveals heterogeneity in the association, and even after this was accounted for, an intron 1 SNP remained significantly associated. We replicate the ABO association in nondiabetic individuals. ABO is a major locus for serum soluble E-selectin levels. We excluded population stratification, fine-mapped the association to sub-A alleles, and also document association with additional variation in the ABO region.

The KID Study. I: Structural baseline characteristics of the Federal Insurance for Salaried Employees' Institution (BfA) diabetic patients in inpatient rehabilitation. Kissingen Diabetes Intervention Study.

% of type I diabetics are not administering insulin according to the intensified conventional therapy schedules, only 16.8% of all type II diabetics are treated with diet only. Type II diabetics are much too often treated with pre-mixed insulins of too high dosage (26.2%) or with oral hypoglycemics (46.2%) of which 90% were sulphonylureas and nearly exclusively glibenclamide. Oral hypoglycemics with extrapancreatic activity or combined therapies were not common among the patients.

The KID Study. II: Socioeconomic baseline characteristics, psycho-social strain, standard of current medical care and education of the Federal Insurance for Salaried Employees' Institution (BfA) diabetic patients in inpatient rehabilitation. Kissingen Diabetes Intervention Study.

The Kissingen Diabetes Intervention Study (KID) evaluated 1050 diabetic patients of the German Federal Insurance for Salaried Employees' Institution (BfA) admitted for inpatient rehabilitation. A single-center prospective, longitudinal study collected data concerning baseline characteristics of patient cohort, socioeconomic factors and mode of intervention at the time of admission, discharge and outcome 6 and 12 months after discharge with consecutively obtained random tests. This cohort of patients is especially interesting for aspects of health policy because it is composed of rather young diabetics engaged in professional work. The data suggest that on the one hand considerably fewer type I diabetics than type II diabetics are married, but that on the other hand constant relationships are equally common in both groups when not considering the marital status. 70% of all diabetics have regular working hours, only 10% of the type II diabetics and negligible 3.9% of the type 1 diabetics work nightshifts. Nevertheless, 29.4% of the type I diabetics and 36.4% of the type II diabetics were unfit for work for at least 4 weeks in the 6 months prior to admission. Only 35.5% of all diabetics see their doctor once or twice monthly. The disease was first diagnosed by the general practitioner in 70% of all cases. Thorough information concerning the disease was provided only in 33.7% of type II diabetics and 26.1% of type I diabetics. 50.6% of type I diabetics and 68.4% of type II diabetics did not receive any education during the all important first year after diagnosis. Most of the diabetic education which had taken place was provided by general hospitals but also by specialized diabetes hospitals and rehabilitation hospitals. 65.6% of all type II diabetics do not monitor urine glucose and those who do so, monitor only once to twice weekly or less. Fortunately 96.3% of all type I diabetics monitor blood glucose, but only 41.0% of them monitor as frequently as is appropriate. 28.3% receive material for monitoring glucose levels only after asking for this. In 32% of the type II diabetics monitoring urine glucose, the general practitioner does not discuss the results with them. Regular controls of glycolysated hemoglobin is part of the diabetic management in 84.4% of all type I diabetics, but carried out in only 34.9% of all type II diabetics, among which the checking of fasting glucose dominates laboratory controls with 50.9%. However, blood lipids are monitored in half of the patients. Huge deficits have been found in the monitoring of urinary albumin excretion in type I diabetics, but especially in type II diabetics. Fear of the future and depression are the predominant strains in everyday life for type I diabetics as well as for type II diabetics. Next most important is the fear of hypoglycemias for type I diabetics, who also feel significantly more restricted in leisure time activities than type II diabetics do. No difference was found between the two groups concerning the demands of treatment. Differences were marked in that more type I than type II diabetics complain of strain in professional life due to their disease, and that a higher proportion of type II diabetics feel impaired by physical complaints (higher incidence of multimorbidity) and consider their relationships more strained by the diabetes than type I diabetics. Surprisingly, problems with accepting the disease and problems in the doctor-patient relationship were of similarly low importance in both groups. We will soon report the changes of the parameters discussed here found after inpatient rehabilitation with intensive diabetic education, promotion of physical activities and psychological measures.

The KID Study. III: Impact of inpatient rehabilitation on the metabolic control of type I and type II diabetics--a one-year follow-up.

The Kissingen Diabetes Intervention Study (KID) evaluated 1050 diabetic patients of the German Federal Insurance Institution for Salaried Employees (BfA) admitted for inpatient rehabilitation. The data for the prospective longitudinal study (which was collected in a single center) relate to the structure of the patient cohort, socio-economic and psychological factors and the mode of medical management at the time of admission and discharge. Data regarding the same variables was checked by random testing six and twelve months after discharge and used in this part of the study. This cohort of patients is especially interesting for aspects of health policy because it comprises rather young diabetics engaged in highly qualified professional work. Therapy modifications entailing a more intensive insulin regimen were necessary in 20.7% of all type I diabetics. Most of these alterations were maintained over the following 12 months of management by the general practitioner. Improvement of HbA1 levels was related to the number of daily insulin administrations. The results obtained during inpatient treatment in patients on ICT are maintained even one year after their discharge. For type I diabetics, the first training measure especially results in a long-term improvement of the metabolic situation, whereas patients who have already received training several times previously benefit continuously less with increasing repetition of training. After twelve months the intensified insulin therapy of type I diabetics had no further effect on the BMI or the already previously normal serum lipids. In 55.5% of all type II diabetics, the therapy had to be modified. Inpatient rehabilitation resulted in raising the low number of type II diabetics treated just with diet by 5.3%. This proportion was again slightly reduced 12 months later. During inpatient residence the number of overweight type II diabetics treated with drugs was reduced both in the group on oral hypoglycemics and in the group on pre-mixed insulin, according to the weight loss achieved. On the other hand, it was often necessary to intensify the usual insulin regimen twice daily in the group of younger patients with normal body weight. These modifications were maintained twelve months after the stay in hospital for most of these patients. Virtually all type II diabetics on oral hypoglycemics are overweight as a reflection of too early prescriptions of oral hypoglycemics which often neglects the chance of a dietary management only. In this group, therapy modifications were directed towards treatment with diet only and with oral hypoglycemics having an extra-pancreatic action. On metformin, the HbA1 was reduced by 0.3% and the BMI by 0.9 kg/m2 even 12 months later. In the 90% of type II diabetics previously treated with sulphonylureas (almost exclusively glibenclamide), re-modification of therapy from metformin back to the old regimen (16:9%) was especially high. This is probably due to the uncertainty with and general restrictions in the prescription of metformin in the relevant period 1991 to 1995. The results 12 months after inpatient treatment show the small improvement of HbA1 and serum lipids as already seen in other larger interventional studies. The BMI does not change significantly within the relatively short follow-up period. The best long-term results are achieved by a combined therapy with sulphonylurea compounds and metformin. The KID study demonstrates major deficits in intensifying the insulin regimen of type I diabetics and in the individual adaptation to therapy of type II diabetes in Germany, even when younger patients of higher professional status are considered. Interventional inpatient rehabilitation improves their metabolic situation with lasting effect and can compensate deficits in outpatient management by the general practitioner. However, future concepts have to be improved at all levels of diabetic management, with a view to achieving an optimum interaction.

Mobile diabetes intervention study: Testing a personalized treatment/behavioral communication intervention for blood glucose control

Background: National data find glycemic control is within target (A1c < 7.0%) for 37% of patients with diabetes, and only 7% meet recommended glycemic, lipid, and blood pressure goals. Objectives: To compare active interventions and usual care for glucose control in a randomized clinical trial (RCT) among persons with diabetes cared for by primary care physicians (PCPs) over the course of 1 year. Methods: Physician practices ( n = 36) in 4 geographic areas are randomly assigned to 1 of 4 study groups. The intervention is a diabetes communication system, using mobile phones and patient/physician portals to allow patient-specific treatment and communication. All physicians receive American Diabetes Association (ADA) Guidelines for diabetes care. Patients with poor diabetes control (A1c ≥ 7.5%) at baseline ( n = 260) are enrolled in study groups based on PCP randomization. All study patients receive blood glucose (BG) meters and a year's supply of testing materials. Patients in three treatment groups select one of two mobile phone models, receive one-year unlimited mobile phone data and service plan, register on the web-based individual patient portal and receive study treatment phone software based on study assignment. Control group patients receive usual care from their PCP. The primary outcome is mean change in A1c over a 12-month intervention period. Conclusion: Traditional methods of disease management have not achieved adequate control for BG and other conditions important to persons with diabetes. Tools to improve communication between patients and PCPs may improve patient outcomes and be satisfactory to patients and physicians. This RCT is ongoing.

Insulin Therapy, Hyperglycemia, and Hypertension in Type 1 Diabetes Mellitus

Diabetes mellitus and hypertension are closely linked, but the long-term blood pressure effects of glucose-lowering therapy and hyperglycemia are not clear. We examined the effects of intensive insulin therapy and hyperglycemia on the development of hypertension in the Diabetes Control and Complications Trial (DCCT) and its observational follow-up, the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Incident hypertension was defined as 2 consecutive study visits with a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or use of antihypertensive medications to treat high blood pressure. Participants were enrolled from August 23, 1983, through June 30, 1989. During a 15.8-year median follow-up, 630 of 1441 participants developed hypertension. During the DCCT, the incidence of hypertension was similar comparing participants assigned to intensive vs conventional therapy. However, intensive therapy during the DCCT reduced the risk of incident hypertension by 24% during EDIC study follow-up (hazard ratio, 0.76; 95% confidence interval [CI], 0.64-0.92). A higher hemoglobin A(1c) level, measured at baseline or throughout follow-up, was associated with increased risk for incident hypertension (adjusted hazard ratios, 1.11 [95% CI, 1.06-1.17] and 1.25 [95% CI, 1.14-1.37], respectively, for each 1% higher hemoglobin A(1c) level), and glycemic control appeared to mediate the antihypertensive benefit of intensive therapy. Older age, male sex, family history of hypertension, greater baseline body mass index, weight gain, and greater albumin excretion rate were independently associated with increased risk of hypertension. Hyperglycemia is a risk factor for incident hypertension in type 1 diabetes, and intensive insulin therapy reduces the long-term risk of developing hypertension.

Risk Factors Related to Inflammation and Endothelial Dysfunction in the DCCT/EDIC Cohort and Their Relationship With Nephropathy and Macrovascular Complications

OBJECTIVE—Because endothelial cell dysfunction and inflammation are key contributors to the development of complications in type 1 diabetes, we studied risk factors related to endothelial dysfunction and inflammation (C-reactive protein and fibrinogen, soluble vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin, and fibrinolytic markers) in a subgroup of patients from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study cohort.RESEARCH DESIGN AND METHODS—We determined which of these risk factors or clusters thereof are associated with the presence of and subsequent development of nephropathy and macrovascular complications (reflected by carotid intima-media thickness [IMT]).RESULTS—After adjustment for conventional risk factors (age, sex, DCCT treatment group, diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, total and HDL cholesterol, and smoking status), fibrinogen remained strongly associated with progression of internal and common carotid IMT (P < 0.01) and soluble E-selectin had a strong association with nephropathy (P < 0.01).CONCLUSIONS—The best predictor for IMT progression in the DCCT/EDIC cohort was plasma fibrinogen, and the levels of soluble E-selectin discriminate patients with albuminuria better than conventional risk factors.

Type 1 diabetes intervention trials 2007: where are we and where are we going?

Type 1 diabetes (T1D) is characterized by autoimmune-mediated destruction of pancreatic beta cells culminating in absolute insulin deficiency. Despite enhanced knowledge of the natural history of type 1 diabetes we have yet to develop an intervention to consistently and safely prevent or reverse type 1 diabetes. This review explores the lessons learned from recent type 1 diabetes interventional studies, sets out controversial issues and seeks to provide a roadmap for future interventions. The type 1 diabetes intervention studies of the 1980s demonstrated potential for preserving c-peptide, but were abandoned due to unacceptable side-effect profiles of the agents being used. Pilot studies of new immunosuppressive and immunomodulatory agents with improved side-effect profiles have recently demonstrated promise in preserving c-peptide in new-onset type 1 diabetes patients. Several of these agents, including insulin, anti-CD3, mycophenolate mofetil, daclizumab and anti-CD20, are currently being tested in multicenter intervention trials. The inability to cure type 1 diabetes underscores the complex pathophysiology of the disease, and our poor knowledge of the precise etiological triggers and immunological mechanisms which culminate in the disease. While ongoing efforts to test individual agents with potential to ameliorate diabetes are needed, combination therapies employing multiple safe agents are likely to be the future of type 1 diabetes intervention studies.

Neuropathy Among the Diabetes Control and Complications Trial Cohort 8 Years After Trial Completion

To evaluate the impact of prior intensive diabetes therapy on neuropathy among former Diabetes Control and Complications Trial (DCCT) participants. At the conclusion of the DCCT, subjects in the intensive group were encouraged to maintain intensive therapy, and subjects in the conventional group were encouraged to begin intensive therapy. Thereafter, we annually assessed neuropathy as part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Neuropathy was defined using the Michigan Neuropathy Screening Instrument (MNSI). We recorded potential adverse consequences of neuropathy. At the first EDIC examination, 1,257 subjects participated in the neuropathy assessment. Consistent with DCCT results, the former intensive group showed a lower prevalence of neuropathy than the conventional group based on positive questionnaire (1.8 vs. 4.7%; P = 0.003) or examination (17.8 vs. 28.0%; P < 0.0001) results. Despite similar levels of glycemic control, symptoms and signs of neuropathy remained less prevalent among the former intensive group compared with the conventional group. At the beginning of the EDIC study, prior intensive therapy reduced the odds of having symptoms and signs of neuropathy using MNSI criteria by 64% (P = 0.0044) and 45% (P < 0.0001), respectively, with similar odds reductions observed for both neuropathic symptoms (51%, P < 0.0001) and neuropathic signs (43%, P < 0.0001) across 8 years of EDIC follow-up. The benefits of 6.5 years of intensive therapy on neuropathy status extended for at least 8 years beyond the end of the DCCT, similar to the findings described for diabetic retinopathy and nephropathy.

Total glucose control: the role of post-prandial glucose

The basis of strict glucose control and the achievement of a favorable HgbAlc must involve the control of both fasting and post-prandial glucose levels. Most of the day is spent in the post-prandial state. The most important predictor of post prandial glycemia is the pre-prandial glucose. Glucose control in the United States is far from optimal with a minority of patients achieving either the ADA goal of 7.0% or the ACE/AACE goal of 6.5%. There is evidence that post-meal glucose has a better correlation with A1C than fasting glucose levels especially when the A1C is less than 8%. A reduced early insulin release leads to high postprandial glucose. The evidence that lowering Hgb A1C results in lower microvascular risk is substantial. The DCC T demonstrated a clear association, of retinopathy with A1C . The study also demonstrated that for the same Al C, intensive glucose control using short-acting insulin pre-meals was associated with reduced complications compared to conventional treatment without short acting insulin. Further evidence from the Kumamoto Study and the UKPDS confirm reduced microvascular complications with lower A1C levels. Elevated mealtime glucose is an unappreciated concern at all levels of A1C including A1C levels at normal or near normal values. Elevated mealtime glucose is of special concern in the elderly. There is strong epidemiologic evidence linking post challenge hyperglycemia to macro-vascular risk. These include the Rancho Bernardo study the Honolulu Heart Study, the Paris Prospective Heart Study, The Diabetes Intervention Study, and the DECODE Study. There are many other studies going back to the 1980s that relate post-challenge or post-prandial blood glucose to cardiovascular disease risk and mortality. Possible effects of acute hyperglycemia responsible for increased microvascular and macrovascular risk include endothelial dysfunction, increased oxidative load, a pro-inflammatory state, protein glycosylation and altered coagulation. There is evidence that oral glucose loading adversely affects endothelial function. Oxidative load in the form of reactive oxygen species is increased following a glucose challenge. The pro-inflammatory state relates to quintiles of dietary glycemic load as it does to the 2- hour post challenge glucose category. There is evidence that in intimal media thickness increases more with the 2 hour glucose than A 1С. In summary, post mealtime glucose spikes are to be prevented because lowering A1C reduces microvascular complications, A1C reflects post mealtime glucose as well as fasting plasma group glucose, elevated post-meal glucose is a highly prevalent issue and elevated blood glucose 2 hours after a glucose load is associated with increased risk of death independent of fasting blood glucose. The Epic- Norfork study raises questions as to the level of A1C associated with risk.

The lipid triad in type 2 diabetes - prevalence and relevance of hypertriglyceridaemia/low high-density lipoprotein syndrome in type 2 diabetes.

Cardiovascular disease is the major cause of morbidity and mortality in type 2 diabetes mellitus. Among the established risk factors, the lipid triad (elevated triglycerides, decreased high-density lipoprotein cholesterol, and small dense low-density lipoprotein cholesterol) is a powerful risk factor for atherosclerosis in type 2 diabetes. The prevalence of hypertriglyceridaemia (HTG) in type 2 diabetes is two to three times higher than in non-diabetics. The Copenhagen Male study, the AMORIS study, and several other trials showed hypertriglyceridaemia to be an independent predictor of coronary heart disease (CHD). HTG may promote risk both directly and indirectly through association with alterations of lipoprotein size and composition. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) demonstrated that raising high-density lipoprotein cholesterol (HDL-C) in patients with low (HDL-C) and low-density lipoprotein cholesterol (LDL-C) is associated with a significant reduction in CHD risk. It was shown in the Diabetes Intervention Study, AFCAPS/TexCAPS, and PROCAM studies that decreased HDL-C and elevated triglycerides are independent risk factors for atherosclerosis, particularly in patients with diabetes mellitus. Several epidemiological studies demonstrated that total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratios or low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratios could be better predictors of atherosclerosis than any single lipid parameter. Intima-media thickness (IMT), a well established marker of early atherosclerosis, is associated with HTG/low HDL-cholesterol. In the Risk factors in IGT for Atherosclerosis and Diabetes (RIAD) study total and HDL-cholesterol were independent determinants of IMT in subjects at risk for type 2 diabetes. Postprandial HTG was also shown to be correlated with increased IMT in type 2 diabetic patients.

Influence of glucose control, lipoproteins, and haemostasis function on brachial endothelial reactivity and carotid intima-media area, stiffness and diameter in Type 1 diabetes mellitus patients.

The objectives of this study were to determine the influence of glucose control on lipoprotein and haemostasis variables in Type 1 diabetes mellitus patients and to evaluate the global impact of these metabolic risk factors on brachial artery reactivity and carotid artery atherosclerosis, stiffness and diameter. Follow up of Type 1 diabetes patients randomized to insulin-intensive conventional treatment (ICT, n = 29) or insulin-standard treatment (ST, n = 25) in the Stockholm Diabetes Intervention Study (SDIS) more than 14 years ago. The intensive conventional treatment patients had lower glycosylated haemoglobin (HbA1c) compared with the ST patients, i.e. 7.01 (SD 0.51) vs. 8.31 (0.97), while concentrations of the lipoprotein and haemostasis variables analyzed were virtually similar. The carotid artery intima-media area was associated with high HbA1c, high serum (S)-cholesterol levels, and low high-density lipoprotein (HDL)-cholesterol levels. Carotid artery stiffness was associated with high systolic blood pressure, high HbA1c, high fibrinogen, and high HDL-cholesterol. Brachial artery endothelial reactivity was higher for women and those with low S-cholesterol. In patients with Type 1 diabetes, glucose control appeared to have no effect on either lipoproteins or haemostasis variable concentrations. Poor glucose control, and high levels of S-cholesterol, systolic blood pressure and plasma fibrinogen were associated with development of atherosclerosis, thus emphasising the importance of global risk factor control in patients with Type 1 diabetes mellitus.

Plasma prekallikrein: a risk marker for hypertension and nephropathy in type 1 diabetes.

The relevance and significance of the plasma kallikrein/kinin system as a risk factor for the development of vascular complications in diabetic patients was explored in a cross-sectional study. We measured the circulating levels of plasma prekallikrein (PK) activity, factor XII, and high-molecular weight kininogen in the plasma of 636 type 1 diabetic patients from the Diabetes Control and Complications Trial/Epidemiology and Diabetes Intervention and Complications Study cohort. The findings demonstrated that type 1 diabetic patients with blood pressure > or =140/90 mmHg have increased PK levels compared with type 1 diabetic patients with blood pressure <140/90 (1.53 +/- 0.07 vs. 1.27 +/- 0.02 units/ml; P < 0.0001). Regression analysis also determined that plasma PK levels positively and significantly correlated with diastolic (DBP) and systolic blood pressures (SBP) as continuous variables (r = 0.17 and 0.18, respectively; P < 0.0001). In multivariate regression analysis, the semipartial r(2) value for PK was 2.93% for SBP and 2.92% for DBP (P < 0.0001). A positive correlation between plasma PK levels and the urinary albumin excretion rate (AER) was also observed (r = 0.16, P < 0.0001). In categorical analysis, patients with macroalbuminuria had a significantly higher level of plasma PK than normoalbuminuric patients (1.45 +/- 0.08 vs. 1.27 +/- 0.02 units/ml; P < 0.01), whereas microalbuminuric patients had an intermediate PK value (1.38 +/- 0.05 units/ml; P = NS). Among patients in the microalbuminuric subgroup, we observed a positive and independent correlation between PK and AER in univariate and multivariate regression analysis (r = 0.27, P < 0.03; n = 63). We concluded that in type 1 diabetes, 1) PK levels are elevated in association with increased blood pressure; 2) PK levels are independently correlated with AER and are categorically elevated in patients with macroalbuminuria; and 3) although the positive correlation between PK and AER within the subgroups of patients with microalbuminuria suggest that PK could be a marker for progressive nephropathy, longitudinal studies will be necessary to address this issue.

Prevention of type 2 diabetes in young people: a theoretical perspective.

Type 2 diabetes in youth is an increasing public health concern, especially in certain minority populations. The current paper consists of four sections. First, we establish the significance of the problem by presenting an overview of epidemiological and physiological evidence. Second, we discuss behavioral issues relevant to the prevention of type 2 diabetes in youth. Third, a qualitative review of existing prevention interventions specific to type 2 diabetes in youth is presented. Results suggest that modest improvements in social cognitive, dietary, and exercise outcomes are possible with diabetes intervention studies, although beneficial changes are difficult to sustain over the long term. Although theoretical frameworks are not always explicit, most studies have utilized elements of the social cognitive theory. Less attention has been paid to sociocultural and community organization variables. Finally, the paper discusses issues of risk definition and intervention sustainability, and presents a comprehensive, theoretically diverse model for the prevention of type 2 diabetes in youth. In summary, we suggest that theories of the natural history and pathophysiology of type 2 diabetes are important to identify modifiable risk factors, while theories of behavioral change are essential to modify the risk factors identified. The combination of sound physiological and behavioral theories should form the basis of prevention intervention design. In addition, an ecologic approach that takes into consideration the dynamic interactions of personal, social, and environmental factors would best promote the long-term adoption of healthful behaviors in a supportive, meaningful, and personally enjoyable context.

Responsiveness of the Problem Areas In Diabetes (PAID) questionnaire.

Responsiveness (sensitivity to change over time) is a key psychometric quality for an outcome measure. We examined the responsiveness of the Problem Areas In Diabetes (PAID) questionnaire, a measure of diabetes-specific emotional distress. PAID data were obtained from seven diabetes intervention studies following a literature search that included both published papers and conference abstracts. To estimate responsiveness we used two indices: (i) a statistical test (the dependent t-test), and (ii) a commonly used effect size index (Cohen's d). Mean patient PAID scores improved from baseline to follow-up for all seven studies. Specifically, t-statistics ranged from t= 8.5 (P < 0.001) to t= 2.1 (P < 0.06). Effect size results ranged from 0.32 (i.e. small) for a disease management intervention to 0.65 (i.e. moderate) for an intensive medical/educational intervention. Despite the pilot nature of the studies, the pattern of findings provided strong support for the responsiveness of the PAID. Information on responsiveness helps clinical researchers select measures, accurately estimate sample size to ensure adequate statistical power, and prioritize outcomes to be assessed.

Evolution in the American Diabetes Association Standards of Care

Glycemic treatment goals have been discussed twice annually for at least the past 3 years that I have served on the Professional Practice Committee of the American Diabetes Association (ADA). These were first established over a decade ago without the benefit of any of the landmark outcomes studies that are available for review today. The overall recommendations have been subsequently well supported by the Stockholm Diabetes Intervention Study,1 the Diabetes Control and Complications Trial,2 the Kumamoto study,3 and, most recently, the U.K. Prospective Diabetes Study (UKPDS).4,5 In each of these trials, a more intensively treated group achieved an average hemoglobin A1c (A1C) of ∼7%, and there was an associated reduction in microvascular endpoints and trend toward improvement in macrovascular endpoints. In each, the more stringently controlled group had a higher incidence of hypoglycemia, greater weight gain, and increased costs, although the net benefit with respect to endpoint reduction was felt to adequately compensate for these adverse effects. However, the trend towards reduction in cardiovascular events in these trials is in part counterbalanced by the Veterans Administration Cooperative Study,6 a feasibility study of modest size and short duration, in which there was a nonstatistically significant increase in cardiovascular events in the intensive treatment group. Furthermore, interpretation of the UKPDS results is complicated by the fact that there was a statistically significant reduction in cardiovascular disease (CVD) events in the obese group treated with metformin (Glucophage), but a lesser effect in those treated with insulin and sulfonylurea despite their having a modestly greater reduction in A1C. Thus, it remains uncertain whether more intensive glycemic control is associated with cardiovascular benefit. At least three large-scale multicenter trials are underway to examine the effect of glycemic control on CVD events, and they will hopefully provide a …

Glucose peaks – the hidden danger in type 2 diabetes

Glucose peaks – the hidden danger in type 2 diabetes

Postprandial hyperglycemia but not fasting blood glucose is a risk factor for cardiovascular death in type 2 diabetes: The diabetes intervention study (DIS)

Postprandial hyperglycemia but not fasting blood glucose is a risk factor for cardiovascular death in type 2 diabetes: The diabetes intervention study (DIS)