Fight against Diabetes: July 2008

Monday, July 21, 2008

Sex Disparities in the Treatment and Control of Cardiovascular Risk Factors in Type 2 Diabetes

OBJECTIVE: To assess whether sex differences exist in the effective control and medication treatment intensity of cardiovascular disease (CVD) risk factors.

RESEARCH DESIGN AND METHODS: We performed a cross-sectional analysis including 44,893 patients with type 2 diabetes (51% women). End points included uncontrolled CVD risk factors (LDL cholesterol >=130 mg/dl, systolic blood pressure [SBP] >=140 mmHg, and A1C >=8%) and the intensity of medical management in patients with uncontrolled CVD risk factors. Multiple-adjusted odds ratios were calculated after stratification for the presence of CVD (present in 39% of the patients).

RESULTS: Women with CVD were less likely to have SBP, LDL cholesterol, and A1C controlled and less likely to receive intensive lipid-lowering treatment. Women without CVD were less likely than men to have LDL cholesterol controlled with no differences in SBP or A1C control.

CONCLUSIONS: Women with diabetes and CVD have poorer control of important modifiable risk factors than men and receive less intensified lipid-lowering treatment.

Trends in High-Risk HLA Susceptibility Genes Among Colorado Youth With Type 1 Diabetes

OBJECTIVE: Type 1 diabetes is associated with a wide spectrum of susceptibility and protective genotypes within the HLA class II system. It has been reported that adults diagnosed with youth-onset type 1 diabetes more recently have been found to have fewer classical high-risk HLA class II genotypes than those diagnosed several decades ago. We hypothesized that such temporal trends in the distribution of HLA-DR, DQ genotypes would be evident, and perhaps even stronger, among 5- to 17-year-old Hispanic and non-Hispanic white (NHW) youth diagnosed with type 1 diabetes in Colorado between 1978 and 2004.

RESEARCH DESIGN AND METHODS: HLA-DR, DQ was typed using PCR and sequence-specific oligonucleotide hybridization in 100 youth diagnosed during the period of 1978-1988 and 264 diagnosed during 2002-2004. Logistic regression was used to adjust for confounders and assess temporal trends.

RESULTS: The frequency of the highest-risk genotype (DRB1*03-DQB1*02/DRB1*04-DQB1*03) was higher (39%) in children diagnosed during the period 1978-1988 than in those diagnosed during 2002-2004 (28%). A similar pattern was observed in NHWs and Hispanics.

CONCLUSIONS: We found that high-risk HLA genotypes are becoming less frequent over time in youth with type 1 diabetes of NHW and Hispanic origin. This temporal trend may suggest that increasing environmental exposure is now able to trigger type 1 diabetes in subjects who are less genetically susceptible.

Increased Shear Rate Resistance and Fastest Kinetics of Erythrocyte Aggregation in Diabetes Measured With Ultrasound

OBJECTIVE: To measure with ultrasound the increased erythrocyte aggregation (EA) kinetics and adhesion energy between erythrocytes in patients with type 2 diabetes and poor metabolic control.

RESEARCH DESIGN AND METHODS: Blood samples were analyzed in a Couette rheometer at 32 MHz following shear rate reductions from 500 s-1 to residual shears of 0 (stasis), 1, 2, 10, 50, 100, and 200 s-1. The increase in EA was determined with the integrated backscatter coefficient as a function of time and shear rate.

RESULTS: The time required to form aggregates was shorter in diabetic patients at shear rates below 200 s-1 (P <>

CONCLUSIONS: Ultrasound can potentially noninvasively demonstrate, in vivo and in situ, the impact of local abnormal EA on arteriovenous flow disorders in diabetes.

Too Much Glucagon, Too Little Insulin: Time course of pancreatic islet dysfunction in new-onset type 1 diabetes

OBJECTIVE: To determine the time course of changes in glucagon and insulin secretion in children with recently diagnosed type 1 diabetes.

RESEARCH DESIGN AND METHODS: Glucagon and C-peptide concentrations were determined in response to standard mixed meals in 23 patients with type 1 diabetes aged 9.4 +/- 4.6 years, beginning within 6 weeks of diagnosis, and every 3 months thereafter for 1 year.

RESULTS: Glucagon secretion in response to a physiologic stimulus (mixed meal) increased by 37% over 12 months, while C-peptide secretion declined by 45%. Fasting glucagon concentrations remained within the normal (nondiabetic) reference range.

CONCLUSIONS: Postprandial hyperglucagonemia worsens significantly during the first year after diagnosis of type 1 diabetes and may represent a distinct therapeutic target. Fasting glucagon values may underestimate the severity of hyperglucagonemia. The opposing directions of abnormal glucagon and C-peptide secretion over time support the link between dysregulated glucagon secretion and declining [beta]-cell function.

Adipokines and Incident Type 2 Diabetes in a Canadian Aborigine Population: The Sandy Lake Health and Diabetes Project.

OBJECTIVE: The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in a Canadian Aborigine population.

RESEARCH DESIGN AND METHODS: Of the 606 Sandy Lake Health and Diabetes Project cohort subjects who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Concentrations of fasting adiponectin, leptin, CRP, IL-6, SAA, and covariates were measured at baseline. Fasting glucose and a 75-g oral glucose tolerance test were obtained at baseline and follow-up to determine incident type 2 diabetes, defined as clinically diagnosed type 2 diabetes or as fasting plasma glucose >=7.0 mmol/l or 2-h postload plasma glucose >=11.1 mmol/l at follow-up.

RESULTS: Low adiponectin, high leptin, and low adiponectin-to-leptin ratio at baseline were associated with increased risk of incident type 2 diabetes after adjustment for age, sex, triglycerides, HDL cholesterol, hypertension, and impaired glucose tolerance (odds ratio 0.63 [95% CI 0.48-0.83], 1.50 [1.02-2.21], and 0.54 [0.37-0.77], respectively). When the models were additionally adjusted for waist circumference or BMI, however, only low adiponectin remained significantly associated with increased incident diabetes (0.68 [0.51-0.90]). Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction.

CONCLUSIONS: Low baseline adiponectin is associated with increased risk of incident type 2 diabetes independent of leptin, CRP, IL-6, SAA, and metabolic syndrome variables including obesity.

Sex Differences in Diabetes Risk and the Effect of Intensive Lifestyle Modification in the Diabetes Prevention Program

OBJECTIVE: In participants of the Diabetes Prevention Program (DPP) randomized to intensive lifestyle modification (ILS), meeting ILS goals strongly correlated with prevention of diabetes in the group as a whole. Men met significantly more ILS goals than women but had a similar incidence of diabetes. Therefore, we explored sex differences in risk factors for diabetes and the effect of ILS on risk factors.

RESEARCH DESIGN AND METHODS: Baseline risk factors for diabetes and percent change in risk factors over the first year in men versus women were compared using Wilcoxon's rank-sum tests.

RESULTS: At baseline, men were older and had a larger waist circumference; higher fasting plasma glucose concentration, caloric intake, and blood pressure; and lower HDL cholesterol and corrected insulin response than women, who were less physically active and had a higher BMI (P < class="bibrecord-passage-highlight-user">diabetes was observed for those who lost <3%>7% body weight resulted in greater decreases in 2-h glucose (P <>

CONCLUSIONS: Weight loss >3% body weight yielded greater reduction in risk factors for diabetes in men than in women. Despite the more favorable effects of ILS in men, baseline risk factors were more numerous in men and likely obscured any sex difference in incident diabetes.

Association of Intrauterine Exposure to Maternal Diabetes and Obesity With Type 2 Diabetes in Youth: The SEARCH Case-Control Study.

OBJECTIVE: Limited data exist on the association between in utero exposure to maternal diabetes and obesity and type 2 diabetes in diverse youth. These associations were explored in African-American, Hispanic, and non-Hispanic white youth participating in the SEARCH Case-Control Study.

RESEARCH DESIGN AND METHODS: A total of 79 youth with type 2 diabetes and 190 nondiabetic control youth aged 10-22 years attended a research visit. In utero exposures to maternal diabetes and obesity were recalled by biological mothers.

RESULTS: Youth with type 2 diabetes were more likely to have been exposed to maternal diabetes or obesity in utero than were nondiabetic control youth (P < class="bibrecord-passage-highlight-user">diabetes (odds ratio [OR] 5.7 [95% CI 2.4-13.4]) and exposure to maternal obesity (2.8 [1.5-5.2]) were independently associated with type 2 diabetes. Adjustment for other perinatal and socioeconomic factors did not alter these associations. When offspring BMI was added, the OR for the association between in utero exposure to obesity and type 2 diabetes was attenuated toward the null (OR 1.1 [0.5-2.4]). Overall, 47.2% (95% CI 30.9-63.5) of type 2 diabetes in youth could be attributed to intrauterine exposure to maternal diabetes and obesity.

CONCLUSIONS: Intrauterine exposures to maternal diabetes and obesity are strongly associated with type 2 diabetes in youth. Prevention efforts may need to target, in addition to childhood obesity, the increasing number of pregnancies complicated by obesity and diabetes.

A New Look at Screening and Diagnosing Diabetes Mellitus

Objective: Diabetes is underdiagnosed. About one third of people with diabetes do not know they have it, and the average lag between onset and diagnosis is 7 yr. This report reconsiders the criteria for diagnosing diabetes and recommends screening criteria to make case finding easier for clinicians and patients.

Participants: R.M.B. invited experts in the area of diagnosis, monitoring, and management of diabetes to form a panel to review the literature and develop consensus regarding the screening and diagnosis of diabetes with particular reference to the use of hemoglobin A1c (HbA1c). Participants met in open session and by E-mail thereafter. Metrika, Inc. sponsored the meeting.

Evidence: A literature search was performed using standard search engines.

Consensus Process: The panel heard each member's discussion of the issues, reviewing evidence prior to drafting conclusions. Principal conclusions were agreed on, and then specific cut points were discussed in an iterative consensus process.

Conclusions: The main factors in support of using HbA1c as a screening and diagnostic test include: 1) HbA1c does not require patients to be fasting; 2) HbA1c reflects longer-term glycemia than does plasma glucose; 3) HbA1c laboratory methods are now well standardized and reliable; and 4) errors caused by nonglycemic factors affecting HbA1c such as hemoglobinopathies are infrequent and can be minimized by confirming the diagnosis of diabetes with a plasma glucose (PG)-specific test. Specific recommendations include: 1) screening standards should be established that prompt further testing and closer follow-up, including fasting PG of 100 mg/dl or greater, random PG of 130 mg/dl or greater, or HbA1c greater than 6.0%; 2) HbA1c of 6.5-6.9% or greater, confirmed by a PG-specific test (fasting plasma glucose or oral glucose tolerance test), should establish the diagnosis of diabetes; and 3) HbA1c of 7% or greater, confirmed by another HbA1c- or a PG-specific test (fasting plasma glucose or oral glucose tolerance test) should establish the diagnosis of diabetes. The recommendations are offered for consideration of the clinical community and interested associations and societies.

Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes

Context: Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels.

Objective: Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss.

Design and Methods: Obese women with T2DM studied before and 1 month after GBP (n = 9), or after a diet-induced equivalent weight loss (n = 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss.

Setting: This outpatient study was conducted at the General Clinical Research Center.

Main Outcome Measures: Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load.

Results: At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 +/- 6 to 112 +/- 54 pmol/liter; P < p =" 0.001)">

Conclusions: These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP.

Health-Related Quality of Life of Children and Adolescents With Type 1 or Type 2 Diabetes Mellitus: SEARCH for Diabetes in Youth Study

Objective: To examine the associations between demographic and diabetes management variables and the health-related quality of life (HRQOL) of youths with type 1 or type 2 diabetes mellitus (DM).

Design: Cross-sectional study.

Settings: Selected populations in Ohio, Washington, South Carolina, Colorado, Hawaii, and California; health service beneficiaries in 3 American Indian populations; and participants in the Pima Indian Study in Arizona.

Participants: Two thousand four hundred forty-five participants aged 8 to 22 years in the SEARCH for Diabetes in Youth Study.

Main Outcome Measure: Pediatric Quality of Life Inventory scores.

Results: Among youths with type 2 DM, HRQOL was lower compared with those with type 1. Among those with type 1 DM, worse HRQOL was associated with a primary insurance source of Medicaid or another government-funded insurance, use of insulin injections vs an insulin pump, a hemoglobin A1c value of at least 9%, and more comorbidities and diabetes complications. There was a significant age x sex interaction, such that, in older groups, HRQOL was lower for girls but higher for boys. For youths with type 2 DM, injecting insulin at least 3 times a day compared with using an oral or no diabetes medication was associated with better HRQOL, and having 2 or more emergency department visits in the past 6 months was associated with worse HRQOL.

Conclusions: Youths with types 1 and 2 DM reported HRQOL differences by type of treatment and complications. The significant age x sex interaction suggests that interventions to improve HRQOL should consider gender differences in diabetes adjustment and management in different age groups.

Using a Multidisciplinary Team and Clinical Redesign to Improve Blood Pressure Control in Patients With Diabetes

Objective: Optimal blood pressure (BP) control in patients with diabetes poses a challenge in primary care clinics because of the complexity of the disease and competing patient care demands. We used a multidisciplinary team to standardize and improve hypertension care for patients with diabetes by implementing a visual and action-oriented high BP prompt, collaborative practice agreement, medication intensification protocol, and home BP monitoring machine loan program.

Design: Prospective, pre-/poststudy.

Setting: General medicine clinic affiliated with a large academic healthcare system.

Patients: Two hundred sixty-three patients with type 2 diabetes mellitus.

Results: Hypertension control (ie, BP < class="bibrecord-passage-highlight-user">diabetes improved from 53.6% to 69.3% (P < .001) after implementing a standardized BP assessment and treatment process. There was also a significant decrease of 4 mm Hg in both the mean systolic and diastolic BPs after the intervention. The improvement in BP control was associated with an increase in the average number of antihypertensive medications from 1.56 to 1.93.

Conclusions: The use of a process-oriented clinical redesign and a multidisciplinary team approach resulted in improved BP management in patients with diabetes in a primary care setting.

Optimum management of type 2 diabetes - timely introduction, optimization and intensification of basal insulin

The natural progression of type 2 diabetes mellitus (T2DM) requires continuing medical care, early insulin intensification and patient self-management education to reduce the risk of long-term complications, including microvascular and macrovascular complications. However, too few people are on insulin, and all too commonly have poor glycaemic control. This paradigm significantly increases the risk for long-term complications. It is becoming increasingly apparent that the early introduction of basal insulin, such as insulin glargine, is essential to provide clinically important improvements in glycaemic control. In this review, we discuss the rationale for the earlier insulinization in T2DM in order to reach and maintain treatment targets and to provide further support for the recent American Diabetes Association and European Association for the Study of Diabetes consensus statement.

Reaching glycaemic targets while minimizing hypoglycaemia in insulin-treated type 2 diabetes patients.

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by both insulin resistance and [beta]-cell failure, resulting in a decline in insulin secretion and increased blood glucose levels. By the time T2DM is clinically diagnosed, only 50% of normal [beta]-cell function remains, leading to altered control of fasting and/or postprandial glucose. The aim of this review is to summarize the options for introduction of basal insulin, in particular insulin glargine, and the advantages and disadvantages of using insulin glargine vs. alternative insulins or vs. oral agents. Overall, the studies included in this review show that insulin glargine is associated with a lower risk of hypoglycaemia vs. both neutral protamine Hagedorn insulin and premixed insulin formulations, alongside clinically important improvements in glycaemic control. Furthermore, insulin glargine is associated with greater improvements in glycaemic control vs. intensification of oral therapy. Thus, insulin glargine should be a preferred option when starting insulin therapy for people with T2DM.

Insulin glargine in type 2 diabetes in everyday clinical practice: 7 years experience

Insulin therapy is often essential in people with type 2 diabetes mellitus (T2DM) but is typically not initiated early enough or aggressive enough, leading to worsening of glycaemic control and the majority of people staying above recommended haemoglobin A1c (HbA1c) targets of <7%. class="bibrecord-passage-highlight-user">diabetes are discussed. The advantages of insulin glargine in randomized controlled trials and how these have translated into everyday clinical practice are also discussed.

Insulin therapy in elderly patients with type 2 diabetes: the role of insulin glargine.

Within the USA, between 1980 and 2005, the prevalence of diagnosed diabetes has increased in all age groups, with the age group 65-74 years having the highest prevalence. The treatment of type 2 diabetes mellitus (T2DM) in elderly people is made more difficult than in their younger counterparts, primarily owing to the impact of co-morbidities, complications and hypoglycaemia as well as technical difficulties with insulin injections. Accordingly, the treatment approach for elderly patients with T2DM may need to be modified to accommodate co-morbidities and illnesses associated with ageing. Risks associated with insulin therapy, particularly hypoglycaemia, have traditionally limited the use of insulin in this patient population. Insulin glargine is associated with a low risk of hypoglycaemia compared with neutral protamine Hagedorn insulin, for example, and could thus provide a treatment of choice for healthcare providers when considering the increasing prevalence of diabetes in the elderly population. A regimen based on insulin glargine plus oral agents provides clinicians with a tool to help meet therapeutic targets in this population without increasing risk of hypoglycaemia.

Insulin management in overweight or obese type 2 diabetes patients: the role of insulin glargine

Type 2 diabetes mellitus (T2DM) and obesity commonly co-exist. Improved clinical management of T2DM and improved glycaemic control with traditional therapies including insulin usually result in some weight gain - a frequently perceived barrier to the introduction of insulin by both patient and healthcare professionals. Weight gain of 2.5 kg per 1% change in haemoglobin A1c (HbA1c) is common in many studies. Strategies to minimize weight gain, particularly in obese patients, are essential to help patients better manage their diabetes and improve quality of life. Insulin analogues with lower risk of hypoglycaemia and better within-patient variability compared with human insulin may help facilitate reaching treatment goals. Moreover, weight gain can be minimized by earlier insulinization and the use of basal insulin, such as insulin glargine, instead of premixed insulin. Data specific to the obese patient with T2DM are presented; they are currently limited but do indicate that insulin glargine therapy is associated with improved glycaemic control as well as less weight gain than other insulins, such as premixed insulin and prandial insulin regimens. Retrospective subanalyses of earlier trials and ongoing studies would shed further light on the impact of insulin therapy in obese people with T2DM in addition to determination of optimal therapeutic strategies.

Improving treatment satisfaction and other patient-reported outcomes in people with type 2 diabetes: the role of once-daily insulin glargine

Insulin therapy becomes essential for many people with type 2 diabetes. After starting insulin, people with diabetes that is poorly controlled with oral agents typically report improved well-being and treatment satisfaction. However, healthcare professionals and people with type 2 diabetes are often reluctant to begin insulin treatment, citing concerns such as time/resources needed to educate patients, increased risks of hypoglycaemia and fear of injections, which lead them to focus on intensifying conventional oral therapy. Insulin glargine, which offers people with diabetes a once-a-day injection regimen with low risk of hypoglycaemia, is more likely to overcome such initial barriers than other more complex insulin regimens. Once-daily insulin glargine, in combination with modern glucose-dependent oral agents that do not need to be chased with food to prevent hypoglycaemia, does not require the fixed mealtimes and set amounts of carbohydrates necessary with twice-daily injection mixes and older sulphonylureas. We know that it is such dietary restrictions that cause the most damage to quality of life (QoL). To avoid damaging QoL unnecessarily and to ensure optimal satisfaction with treatment, it is important to evaluate the effects of treatment on QoL, treatment satisfaction and other patient-reported outcomes (PROs) using questionnaires validated for this purpose, such as the widely used Diabetes Treatment Satisfaction Questionnaire and the Audit of Diabetes-Dependent Quality of Life measure. A systematic electronic literature search identified reports of studies evaluating PROs associated with insulin glargine in comparison with other treatments. The studies show that insulin glargine is usually associated with greater improvements in treatment satisfaction and other PROs compared with intensifying oral therapy or alternative insulin regimens.

The cost-effectiveness of insulin glargine vs. neutral protamine Hagedorn insulin in type 2 diabetes: a focus on health economics

Diabetes mellitus is a major public health problem, in particular because of long-term complications affecting essential organs, such as the eyes and kidneys, which can lead to a reduction in life expectancy and high healthcare costs. The number of individuals with diabetes mellitus is projected to rise worldwide from 171 million people in 2000 to 366 million people in 2030. With the number of patients with diabetes continually growing, the burden of pressure on worldwide health systems is huge. Accordingly, regulatory and marketing approvals of new medicines are beginning to incorporate economic evaluation techniques to determine their cost-effectiveness. Overall, the studies included in this review show that the initiation of insulin glargine is cost-effective and is expected to lead to substantial improvements in both life years (LYs) and quality-adjusted LYs compared with neutral protamine Hagedorn insulin.

Options for the intensification of insulin therapy when basal insulin is not enough in type 2 diabetes mellitus

In the early treatment of type 2 diabetes mellitus (T2DM), the addition of a basal insulin, such as insulin glargine, to existing oral therapy can help patients attain recommended glycaemic control targets, including haemoglobin A1c (HbA1c) <7%>

Beyond insulin replacement: addressing the additional needs of the diabetes patient

The management of type 2 diabetes mellitus (T2DM) typically focuses on correcting dysglycaemia to reduce risk for microvascular and macrovascular complications, possibly by reducing glucose-mediated oxidative stress. However, other cardiometabolic risk factors, including abdominal obesity and dyslipidaemia are often overlooked in the quest for perfect glucose control. The currently used antidiabetic agents, including insulin, metformin, sulphonylureas and thiazolidinediones, have limited efficacy on these risk factors. A number of new therapeutic agents are undergoing clinical development, including glucagon-like peptide 1 mimetics (exenatide and liraglutide) and dipeptidyl peptidase 4 inhibitors (sitagliptin and vildagliptin), which target the incretin system, and the cannabinoid-1 receptor antagonists (rimonabant), which target the endocannabinoid system, may hold some promise for meeting these unmet needs. In this review, the clinical properties of these agents and potential treatment pathways to best use these agents are discussed for improving the management of T2DM and cardiovascular risk.

Epidemiology of Walking and Type 2 Diabetes

Purpose: Diabetes is prevalent, deadly, serious, and costly. It affects an estimated 20.8 million Americans in 2005, having doubled from 1980, and is expected to reach at least 29 million by 2050. In 2002, diabetes was responsible for an estimated $132 billion in costs. Diabetes concerns leaders in public health and clinicians, and its personal, social, and economic burdens require preventive efforts such as the promotion of walking. As such, we reviewed the limited epidemiologic data of walking and incident diabetes (two studies) and walking and mortality outcomes among diabetic persons (three studies).

Methods: We abstracted information from each paper to identify characteristics of the study population, details of the disease outcomes (diabetes incidence, mortality outcomes, or cardiovascular disease events among persons with diabetes), relative risks, risk reductions, and adjustment for covariates.

Results: The reviewed studies were adjusted for important covariates such as age, body mass index, the coexistence of other nonwalking and vigorous activities, and so on and for biases such as differential misclassification of exposure. The strength of the observed reductions in risk were between approximately 20% and 40% for incident diabetes and between 40% and 55% for mortality due to all causes and due to cardiovascular disease (and related nonfatal events). Moderate to faster pace of walking seemed to enhance risk reduction. These reductions fit well with results of earlier reviews of physical activity and diabetes, and basically corresponded to 2-3 h of weekly walking.

Conclusion: Available dose-response data between walking and the aforementioned outcomes suggest that public health recommendations for physical activity might also apply to walking in particular. Regardless, important areas remain for future research on walking and diabetes.

Diabetes and Hearing Impairment in the United States: Audiometric Evidence from the National Health and Nutrition Examination Survey, 1999 to 2004

Background: Diabetes might affect the vasculature and neural system of the inner ear, leading to hearing impairment.

Objective: To determine whether hearing impairment is more prevalent among U.S. adults with diabetes.

Design: Cross-sectional analysis of nationally representative data.

Setting: National Health and Nutrition Examination Survey, 1999 to 2004.

Participants: 5140 noninstitutionalized adults age 20 to 69 years who had audiometric testing.

Measurements: Hearing impairment was assessed from the pure tone average of thresholds over low or mid-frequencies (500, 1000, and 2000 Hz) and high frequencies (3000, 4000, 6000, and 8000 Hz) and was defined as mild or greater severity (pure tone average >25 decibels hearing level [dB HL]) and moderate or greater severity (pure tone average >40 dB HL).

Results: Hearing impairment was more prevalent among adults with diabetes. Age-adjusted prevalence of low- or mid-frequency hearing impairment of mild or greater severity in the worse ear was 21.3% (95% CI, 15.0% to 27.5%) among 399 adults with diabetes compared with 9.4% (CI, 8.2% to 10.5%) among 4741 adults without diabetes. Similarly, age-adjusted prevalence of high-frequency hearing impairment of mild or greater severity in the worse ear was 54.1% (CI, 45.9% to 62.3%) among those with diabetes compared with 32.0% (CI, 30.5% to 33.5%) among those without diabetes. The association between diabetes and hearing impairment was independent of known risk factors for hearing impairment, such as noise exposure, ototoxic medication use, and smoking (adjusted odds ratios for low- or mid-frequency and high-frequency hearing impairment were 1.82 [CI, 1.27 to 2.60] and 2.16 [CI, 1.47 to 3.18], respectively).

Limitations: The diagnosis of diabetes was based on self-report. The investigators could not distinguish between type 1 and type 2 diabetes. Noise exposure was based on participant recall.

Conclusion: Hearing impairment is common in adults with diabetes, and diabetes seems to be an independent risk factor for the condition.

The Effect of Comorbid Illness and Functional Status on the Expected Benefits of Intensive Glucose Control in Older Patients with Type 2 Diabetes

Background: Physicians are uncertain about when to pursue intensive glucose control among older patients with diabetes.

Objective: To assess the effect of comorbid illnesses and functional status, mediated through background mortality, on the expected benefits of intensive glucose control.

Design: Decision analysis.

Data Sources: Major clinical studies in diabetes and geriatrics.

Target Population: Patients 60 to 80 years of age who have type 2 diabetes and varied life expectancies estimated from a mortality index that was validated at the population level.

Time Horizon: Patient lifetime.

Perspective: Health care system.

Intervention: Intensive glucose control (hemoglobin A1c [HbA1c] level of 7.0) versus moderate glucose control (HbA1c level of 7.9).

Outcome Measures: Lifetime differences in incidence of complications and average quality-adjusted days.

Results of Base-Case Analysis: Healthy older patients of different age groups had expected benefits of intensive glucose control ranging from 51 to 116 quality-adjusted days. Within each age group, the expected benefits of intensive control steadily declined as the level of comorbid illness and functional impairment increased (mortality index score, 1 to 26 points). For patients 60 to 64 years of age with new-onset diabetes, the benefits declined from 106 days at baseline good health (life expectancy, 14.6 years) to 44 days with 3 additional index points (life expectancy, 9.7 years) and 8 days with 7 additional index points (life expectancy, 4.8 years). A similar decline in benefits occurred among patients with prolonged duration of diabetes.

Results of Sensitivity Analysis: With alternative model assumptions (such as Framingham models), expected benefits of intensive control declined as mortality index scores increased.

Limitations: Diabetes clinical trial data were lacking for frail, older patients. The mortality index was not validated for use in predicting individual-level life expectancies. Adverse effects of intensive control were not taken into account.

Conclusion: Among older diabetic patients, the presence of multiple comorbid illnesses or functional impairments is a more important predictor of limited life expectancy and diminishing expected benefits of intensive glucose control than is age alone.

The impact of type 1 diabetes and eating disorders: the perspective of individuals

Aim: To describe the perspective of individuals living with the chronic conditions of both type 1 diabetes (T1D) and eating disorders.

Background: The TID and eating disorders are major concerns in Western society with the consequence of more prevalent and severe health complications. This paper arose from research on the impact of T1D on the self of adolescents and young adults.

Design: In a larger longitudinal study (doctoral) of 27 participants (both male and females), data were collected from 1994 from 2001 using in-depth semi-structured interviews and a grounded theory approach; four female participants reported that they were experiencing T1D and an eating disorder. This subset of four participants from the original study was case analysed and the issues that arose for the participants are described using secondary analysis.

Conclusions: Issues uncovered included the complexity of managing the interactions of the physical, emotional and social dimensions as well as personal relationships for the participants. These interrelated issues interfere with all-round management of T1D and eating disorders. Recognition and management of the comorbidity that exits in substantial numbers are of paramount importance in clinical practice. It is also necessary to incorporate the support of significant others in the health care partnership.

Relevance to clinical practice: Health professionals who treat individuals with T1D need to be aware of the incidence of eating disorders among people with TID. Unhealthy weight control practices are of particular concern because they lead to poorer metabolic control which has a flow on effect causing micro vascular complications.

Autonomy through identification: a qualitative study of the process of identification used by people with type 2 diabetes

Aims and objectives: The aim of this study is to clarify the process of identification with diabetes as a dimension of autonomy as described by people with type 2 diabetes.

Background: People with type 2 diabetes view autonomy as competency in shaping one's life. This concept of autonomy has seven dimensions, which emerged as categories in prior research. Dynamic processes shape these dimensions of autonomy. One of the dimensions of autonomy is identification.

Method: This study has a qualitative descriptive and exploratory design and an inductive approach as described in grounded theory. Data were collected by means of in-depth interviews. The sample consisted of 15 people with type 2 diabetes mellitus in a nurse-led, shared-care setting in the Netherlands.

Results: The phases of identification are comprehending, struggling, evaluating and mastering. Each phase has its own characteristics. Identifying with the diabetes is a non-linear, cyclical and continuous process because people with diabetes have to deal with changing conditions.

Conclusion: The dynamics of identification is directed to a process of identifying with diabetes and its care requirement. Recognizing identification as an element of autonomy enables nurses to adopt a more patient-oriented view of autonomy.

Relevance to clinical practice: Nursing that fosters the process of identification promotes autonomy. This implies that a person with diabetes should be able to identify with the nurse's interventions. Hence it is vital that nurses build supportive partnerships when providing care for such a patient.

Isolation, motivation and balance: living with type 1 or cystic fibrosis-related diabetes

Aims and objectives: To explore patients' responses to developing and managing cystic fibrosis-related diabetes and to contrast their views with those of individuals with type 1 diabetes mellitus.

Background: The incidence of diabetes among people with cystic fibrosis has increased with improvement in life expectancy. However, little is known about how patients respond to and manage cystic fibrosis-related diabetes, and how this compares with people living with type 1 diabetes mellitus.

Design: Qualitative research was undertaken in order to fully explore meanings and views.

Methods: Semi-structured telephone or face-to-face interviews were conducted with patients who had cystic fibrosis-related diabetes or type 1 diabetes mellitus, during which, they discussed diagnosis and management of diabetes. Framework analysis was employed to identify themes and to consider similarities and differences between the two groups.

Results: Eleven cystic fibrosis-related diabetes and 12 type 1 diabetes mellitus patients were interviewed in 2006. Patients with cystic fibrosis-related diabetes described their diabetes diagnosis as a progression of their primary illness, management of which was important owing to the benefits it brought to their cystic fibrosis. Those with type 1 diabetes mellitus were more likely to report feeling psychologically low because of diabetes and to list long-term complications as a key factor motivating self-management. Both groups struggled to balance the demands of diabetes with other life and health obligations, and experienced isolation because of diabetes.

Conclusions: Variation in perceptions recalled during interviews stemmed from diabetes being part of an existing life-threatening chronic illness in people with cystic fibrosis-related diabetes. Similarities and differences in attitudes and management practices were found, with less urgency regarding glucose monitoring and fewer information resources available for those with cystic fibrosis-related diabetes.

Relevance to clinical practice: Both groups need support for optimal diabetes management and access to appropriate resources outside specialist clinics. Web-based technologies could prove useful for those with cystic fibrosis-related diabetes as face-to-face interaction may be prevented owing to the risk of cross-infection.

Fetuin-A and Incident Diabetes Mellitus in Older Persons

Context: Fetuin-A is a hepatic secretory protein that binds the insulin receptor and inhibits insulin action in vitro. In prior cross-sectional studies in humans, higher fetuin-A levels were associated with insulin resistance. However, the longitudinal association of fetuin-A with incident type 2 diabetes mellitus is unknown.

Objective: To determine whether fetuin-A levels are associated with incident diabetes in older persons.

Design, Setting, and Participants: Observational study among 3075 well-functioning persons aged 70 to 79 years. In this case-cohort study, we retrospectively measured fetuin-A levels in baseline serum among 406 randomly selected participants without prevalent diabetes, and all participants who developed incident diabetes mellitus during a 6-year follow-up (to August 31, 2005).

Main Outcome Measure: Incident diabetes mellitus.

Results: Incident diabetes developed in 135 participants (10.1 cases/1000 person-years). Participants with fetuin-A levels within the highest tertile (> 0.97 g/L) had an increased risk of incident diabetes (13.3 cases/1000 person-years) compared with participants in the lowest tertile (<= 0.76 g/L) (6.5 cases/1000 person-years) in models adjusted for age, sex, race, waist circumference, body weight, physical activity, blood pressure level, fasting glucose level, high-density lipoprotein cholesterol concentration, triglyceride concentration, and C-reactive protein level (adjusted hazard ratio, 2.41; 95% confidence interval, 1.28-4.53; P = .007). The association was not affected by adipocytokine levels but was moderately attenuated by adjustment for visceral adiposity (adjusted hazard ratio of highest vs lowest tertile 1.72; 95% confidence interval, 0.98-3.05; P = .06).

Conclusion: Among well-functioning older persons, serum fetuin-A is associated with incident diabetes, independent of other markers of insulin resistance.

Secular decline in mortality from coronary heart disease in adults with diabetes mellitus: cohort study

Objective: To examine trends in fatal coronary heart disease in adults with and without diabetes.

Design: Cohort study.

Setting: Two surveys of the Nord-Trondelag health study (HUNT), a population based study in Norway.

Participants: 74 914 men and women from the first survey (1984-6) and 64 829 from the second survey (1995-7).

Main outcome measure: Age specific mortality from coronary heart disease among adults with and without diabetes during two consecutive nine year follow-up periods.

Results: A total of 2623 men and 1583 women died from coronary heart disease. Mortality rates were substantially lower during the most recent follow-up period: among men aged 70-79 without diabetes, deaths per 1000 person years declined from 16.38 to 8.79 (reduction 48%, 95% confidence interval 39% to 55%) and among women aged 70-79 from 6.84 to 2.68 (62%, 52% to 70%). Among the same age group with diabetes, deaths per 1000 person years in men declined from 38.97 to 17.89 (54%, 32% to 69%) and in women from 28.15 to 11.83 (59%, 37% to 73%). The reduction was more noticeable in age groups younger than 70 at baseline, and less pronounced among people aged 80 or more. Mortality from coronary heart disease was more than twofold higher in people with than without diabetes, with a slightly stronger association in women. The difference in mortality by diabetes status remained almost unchanged from the first to the second survey.

Conclusion: The strong general reduction in mortality rates from coronary heart disease from the first to the second follow-up period also benefited people with diabetes, but the more than twofold higher mortality from coronary heart disease associated with diabetes persisted over time.

Monogenic diabetes: implications for therapy of rare types of disease.

There are two major forms of diabetes: type 1 and type 2. However, monogenic diabetes, associated with severe [beta]-cell dysfunction or with severe resistance to insulin action, is diagnosed with increasing frequency by genetic testing. The list of such forms of diabetes includes MODY, mitochondrial diabetes, permanent neonatal diabetes (PNDM) and transient neonatal diabetes, familial lipodystrophies and some others. These rare forms constitute probably at least a few per cent of all diabetes cases seen in diabetic clinics. The identification of the molecular background of specific forms of diabetes gives new insight into the underlying aetiology. This knowledge helps to optimize treatment in specific clinical situations. The proper differential diagnosis also helps to predict the progress of diabetes in affected individuals and defines the prognosis in the family. For example, in patients with MODY2 because of glucokinase mutations who have very mild diabetes characterized by modest fasting, hyperglycaemia diet is frequently sufficient. Some other forms of monogenic diabetes associated with impaired function of the [beta]-cell, such as MODY3 and PNDM linked to mutations in Kir6.2 and SUR1 genes, can be successfully managed by sulphonylurea agents. Although the examples of pharmacogenetics seem to be less spectacular in rare syndromes of insulin resistance, those patients can also benefit from genetic testing. In this paper, the aetiology of some monogenic diabetes forms is reviewed together with the clinical aspects of management of the affected individuals.

Association between oral antidiabetic use, adverse events and outcomes in patients with type 2 diabetes

Objective: To quantify adverse events (AEs) associated with the use of metformin (MET), sulphonylureas (SUs) and thiazolidinediones (TZDs) in a usual care setting, and to assess the relationship of AEs to treatment patterns and glycaemic response in patients with type 2 diabetes.

Research design and methods: An electronic medical record database was used to identify patients with type 2 diabetes age >=18 years from 1996 to 2005. Patients naive to oral antidiabetic therapy were followed for 395 days postinitiation of MET, SU or TZD treatment. AEs related to study drugs were evaluated during the follow-up period. Baseline and follow-up A1C levels were compared by drug regimen. Associations between the change in A1C, drug regimen changes and AEs were evaluated.

Results: A total of 14 512 patients (mean age 60.8 years, 52.9% female) were identified. During the follow-up period, 12.7% of patients experienced an AE (8.6% MET, 15.9% SU and 19.8% TZD patients). SU and TZD patients were more likely to experience an AE than MET (p < or =" 1.37," or =" 1.91;">

Conclusions: The occurrence of AEs did not significantly impact glycaemic response to therapy. However, AEs may lead to greater treatment switches for patients receiving MET and add-on therapy for MET-treated and SU-treated patients.

Effects of aspirin on serum C-reactive protein and interleukin-6 levels in patients with type 2 diabetes without cardiovascular disease: a randomized

Aim: Low-grade inflammation plays a pivotal role in atherogenesis in type 2 diabetes. Next to its antithrombotic effects, several lines of evidence demonstrate anti-inflammatory properties of aspirin. We determined the effects of aspirin on inflammation - represented by C-reactive protein (CRP) and interleukin-6 (IL-6) - in type 2 diabetic subjects without cardiovascular disease and assessed differential effects of aspirin 300 mg compared with 100 mg.

Methods: A randomized, placebo-controlled, double-blind, crossover trial was performed in 40 type 2 diabetic patients. In two periods of 6 weeks, patients used 100 or 300 mg aspirin and placebo. Plasma CRP and IL-6 levels were measured before and after both periods.

Results: Use of aspirin resulted in a CRP reduction of 1.23 +/- 1.02 mg/l (mean +/- s.e.m.), whereas use of placebo resulted in a mean increase of 0.04 +/- 1.32 mg/l (P= 0.366). Aspirin reduced IL-6 with 0.7 +/- 0.5 pg/ml, whereas use of placebo resulted in a mean increase of 0.2 +/- 0.8 pg/ml (P= 0.302). There were no significant differences in effects on CRP and IL-6 between 100 and 300 mg aspirin.

Conclusions: Our results indicate that a 6-week course of aspirin does not improve low-grade inflammation in patients with type 2 diabetes without cardiovascular disease, although a modest effect could not be excluded. No significant differential effects between aspirin 100 and 300 mg were found.

The metabolic syndrome as a tool for predicting future diabetes: the AusDiab study

Objective: To compare the ability of the metabolic syndrome (MetS), a diabetes prediction model (DPM), a noninvasive risk questionnaire and individual glucose measurements to predict future diabetes.

Design: Five-year longitudinal cohort study. Tools tested included MetS definitions [World Health Organization, International Diabetes Federation, ATPIII and European Group for the study of Insulin Resistance (EGIR)], the FINnish Diabetes RIsk SCore risk questionnaire, the DPM, fasting and 2-h post load plasma glucose.

Setting: Adult Australian population.

Subjects: A total of 5842 men and women without diabetes >=25 years. Response 58%. A total of 224 incident cases of diabetes.

Results: In receiver operating characteristic curve analysis, the MetS was not a better predictor of incident diabetes than the DPM or measurement of glucose. The risk for diabetes among those with prediabetes but not MetS was almost triple that of those with MetS but not prediabetes (9.0% vs. 3.4%). Adjusted for component parts, the MetS was not a significant predictor of incident diabetes, except for EGIR in men [OR 2.1 (95% CI 1.2-3.7)].

Conclusions: A single fasting glucose measurement may be more effective and efficient than published definitions of the MetS or other risk constructs in predicting incident diabetes. Diagnosis of the MetS did not confer increased risk for incident diabetes independent of its individual components, with an exception for EGIR in men. Given these results, debate surrounding the public health utility of a MetS diagnosis, at least for identification of incident diabetes, is required.

New antigenic targets in type 1 diabetes

Purpose of review: The [beta]-cell-specific zinc transporter isoform 8 (SLC30A8) has recently emerged both as a major autoantigenic target of type 1 diabetes and also as a genetic marker for type 2 diabetes. We examine the hypothesis that the cell specificity and cellular localization of this granule membrane protein are significant factors in its contribution to the pathogenesis of these diseases.

Recent findings: Both type 1 diabetes and type 2 diabetes are associated with islet functional failure and both diseases may be linked to stress responses and changes in the secretory pathway, which lead to cell apoptosis and thus directly to reduction of [beta]-cell mass or activation of underlying autoimmunity. In both cases, the common polymorphism at aa 325 has been implicated in disease, in type 1 diabetes by determining the autoantibody epitope specificity and in type 2 diabetes through association with altered [beta]-cell mass and impaired secretion.

Summary: Functional studies of the transporter will be key to understanding the role of ZnT8 in type 2 diabetes. Investigation of the cellular immune response to ZnT8 will be essential in evaluating its contribution to type 1 diabetes. Measurement of autoantibodies to ZnT8 takes us a step closer to detection of prediabetes in the general population.

The accelerator hypothesis and increasing incidence of type 1 diabetes. Current Opinion in Endocrinology, Diabetes & Obesity

Purpose of review: To summarize the relevance of the 'accelerator hypothesis' to type 1 diabetes pathogenesis and examine if recent evidence supports the hypothesis. The 'accelerator hypothesis' proposes 'three processes in type 1 diabetes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity'.

Recent findings: Insulin resistance is an independent risk factor for progression to clinical type 1 diabetes in people with islet autoimmunity. Higher bodyweight is also associated with type 1 diabetes development although no longitudinal studies have simultaneously assessed bodyweight and insulin resistance in preclinical diabetes. Currently, there is no evidence for the view that accelerated beta-cell apoptosis is due to insulin resistance in the pathogenesis of type 1 diabetes.

Summary: Insulin resistance accelerates development of type 1 diabetes in people with islet autoimmunity and insulin deficiency. The increasingly 'obesogenic' environment which promotes insulin resistance could account for the rising incidence of type 1 diabetes.

Innate immunity and its role in type 1 diabetes

Purpose of review: Over the last 2 decades, studies addressing mechanisms of type 1 diabetes have focused primarily on the role of T lymphocytes in disease mechanisms. Recent investigations, however, suggest that the innate immune system plays a key role in promoting the response of autoreactive T cells triggering type 1 diabetes. The discovery of toll-like receptors in the 1990s has led to a better understanding of signaling pathways involved in initiating innate immune pathways and how these pathways may be associated with mechanisms leading to autoimmune disease. This review focuses on recent studies on the role of Toll-like receptors and innate pathways in triggering type 1 diabetes.

Recent findings: Data from animal models of type 1 diabetes provide strong support to the hypothesis that Toll-like receptor-induced innate signaling pathways are involved in the proinflammatory process leading to autoimmune diabetes. Studies performed in peripheral blood cells and sera from patients with type 1 diabetes indicate that aberrant innate functions might exist in such patients, but the relevance of these alterations to the mechanism leading to type 1 diabetes is currently unclear.

Summary: The discovery that innate signaling pathways are involved in the mechanism that may trigger islet inflammation and destruction holds great promise for the identification of new innate signaling molecules that could be targeted to specifically inhibit the autoimmune process to prevent autoimmune diabetes.

Relationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment

Introduction: The aim of this study was to assess the relationship between serum glycemic levels and subgingival microbial profile alteration following periodontal treatment in patients with type 2 diabetes mellitus.

Methods: We studied 30 periodontitis patients with type 2 diabetes mellitus who received full-mouth subgingival debridement by analyzing their subgingival microbial profiles using a polymerase chain reaction method at baseline and various time-points for 12 months following treatment. Concurrently, probing pocket depth, bleeding on probing, and metabolic parameters, including glycated hemoglobin A1c (HbA1c), blood sugar level, C-reactive proteins, total cholesterol, triglyceride, and high-density and low-density lipoprotein cholesterol, were recorded.

Results: Periodontal conditions were significantly improved after treatment, and the occurrence rates of periodontal bacterial species, including Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, and Prevotella intermedia, were also reduced. Interestingly, P. gingivalis was detected more frequently in subjects with increased HbA1c values after periodontal treatment than in those patients with decreased HbA1c values. Furthermore, P. gingivalis with type II fimbriae was detected only in HbA1c-increased subjects, while improvements in HbA1c values were observed only in subjects without type II clones.

Conclusions: These results suggest that glycemic level in diabetes is affected by the persistence of P. gingivalis, especially clones with type II fimbriae, in periodontal pockets.

Long-term risk of diabetes, hypertension and left ventricular hypertrophy associated with the metabolic syndrome in a general population

Objectives: Metabolic syndrome is accompanied by an increased risk of developing diabetes mellitus. Limited or no evidence exists on whether and to what extent metabolic syndrome increases the risk of developing office hypertension, daily-life hypertension and left ventricular hypertrophy.

Methods: In 1412 individuals representative of the population of Monza, plasma glucose, office, home and ambulatory blood pressure, and echocardiographic left ventricular mass index were measured between 1990 and 1992 and 10 years later. New onset diabetes mellitus, new onset office, home and ambulatory hypertension as well as new onset left ventricular hypertrophy were assessed in individuals with and without metabolic syndrome (Adult Treatment Panel criteria) at the first examination.

Results: New onset diabetes mellitus, hypertension and left ventricular hypertrophy were all much more frequent in individuals with metabolic syndrome than in those without. In patients with metabolic syndrome, the adjusted risk of new onset diabetes mellitus was five to six times greater (P < class="bibrecord-passage-highlight-user">diabetes mellitus, hypertension and left ventricular hypertrophy were the baseline blood glucose, blood pressure and left ventricular mass index, respectively, with an independent contribution, in each condition, from other metabolic syndrome components. The metabolic syndrome as such did not have an additional predictive value.

Conclusion: In the general population, metabolic syndrome is associated with a marked increase in the risk not only of new onset diabetes mellitus but also of new onset office and daily-life hypertension, and left ventricular hypertrophy. This may account for the increased rate of cardiovascular morbidity and mortality exhibited with this condition in long-term studies.

Impact of the endothelial nitric oxide synthase gene G894T polymorphism on renal endothelial function in patients with type 2 diabetes

Objective: Endothelial dysfunction and increased oxidative stress contribute to the progression of diabetic nephropathy. To analyze the functional significance of the G894T polymorphism of NOS3, the gene encoding endothelial nitric oxide synthase (NOS), we assessed basal nitric oxide activity and the amount of oxidative stress in the renal circulation of patients with type 2 diabetes.

Methods: Renal plasma flow (RPF) was assessed by steady-state input clearance technique with sodium para-aminohippurate in 84 patients with type 2 diabetes and 84 patients without diabetes. RPF was measured at baseline and after the infusion of the NOS inhibitor N-monomethyl-L-arginine (4.25 mg/kg); the substrate of NOS L-arginine (100 mg/kg); and coinfusion of vitamin C (3 g) with L-arginine (100 mg/kg).

Results: The decrease of RPF to N-monomethyl-L-arginine was similar between carriers of the T allele and homozygous carriers of the G allele in patients with diabetes (-56+/-40 vs. -68.1+/-74 ml/min/1.73 m2, P=0.342) and patients without diabetes (-66.7+/-81 vs. -58.3+/-63 ml/min/1.73 m2, P=0.606). In patients with diabetes, however, carriers of the T allele revealed a more pronounced increase of RPF to coinfusion of vitamin C with L-arginine than homozygous carriers of the G allele (61.8+/-75 vs. 22.3+/-73 ml/min/1.73 m2, P=0.021), whereas in patients without diabetes the response of RPF to coinfusion of vitamin C with L-arginine was similar between both groups (46.2+/-80 vs. 70.7+/-86 ml/min/1.73 m2, P=0.217). Gene-environment interaction between disease (diabetes) and genotype (genotype GG vs. genotype GT/TT) was observed for increase of RPF to coinfusion of vitamin C with L-arginine (P=0.020).

Conclusion: G894T polymorphism of NOS3 has no impact on the basal nitric oxide activity of renal circulation. In contrast, the T allele is associated with increased oxidative stress in the renal circulation in patients with diabetes suggesting a specific role of the G894T polymorphism in the pathogenesis of diabetic nephropathy.

Glucagon-like peptide-1 in type 2 diabetes: the [beta]-cell and beyond. Diabetes

Many traditional treatments for type 2 diabetes fail to achieve and maintain effective glycaemic control, witnessed by a progressive decline in [beta]-cell functionality and a corresponding rise in blood glucose levels over time. The routine loss of 50% of [beta]-cell function at diagnosis lends new urgency that both diagnosis and treatment initiation take place as early as possible in the course of the disease, before [beta]-cell decline proceeds too far. This review describes the role of the [beta]-cell and glucagon-like peptide-1 (GLP-1) in both normal metabolism and type 2 diabetes, highlights available and anticipated therapies and explores the prospect that certain incretin-derived therapies, which seek to harness the therapeutic potential of native GLP-1, may offer more than glycaemic control alone: they may also facilitate weight loss, improve the cardiovascular profile and, ideally, treat the [beta]-cell in such a way as to modify the natural history of the disease itself.

The physiology and pharmacology of incretins in type 2 diabetes mellitus. Diabetes

Two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1, help control blood glucose levels by affecting plasma insulin levels in response to oral glucose intake - this is known as the incretin effect. Incretins increase plasma insulin by a number of mechanisms, most of which are mediated through GIP and GLP-1 receptors (GIPR and GLP-1R respectively). Incretins act through the pancreas to stimulate insulin release and can also act at the cellular level by increasing insulin gene transcription and insulin biosynthesis. Incretins can also lower plasma glucose through non-insulin routes including inhibition of gastric emptying and reduced food intake. In type 2 diabetes, the incretin effect is reduced; as a result, insulin secretion is reduced and plasma glucose levels rise. However, the incretin effect can be restored in such individuals by the administration of exogenous incretins. Intravenous GLP-1 can stimulate insulin secretion, reduce glucagon secretion and normalize fasting plasma glucose in individuals with type 2 diabetes who were previously poorly controlled. The therapeutic potential of such agents is currently being explored.

Insulin Analog Preparations and Their Use in Children and Adolescents with Type 1 Diabetes Mellitus

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus.

The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.

Gestational diabetes and the risk of breast cancer among women in the Jerusalem Perinatal Study

Gestational diabetes is becoming increasingly common; it is important to determine how it relates to future risk of disease. We investigated the relation of gestational diabetes to breast cancer in 37,926 women who had one or more live births in 1964-1976 for whom information had been collected on complications of pregnancy. In this cohort there were 1,626 cases of breast cancer reported to the Israel Cancer Registry before January 1, 2005 and 410 cases of gestational diabetes recorded from birth records. There were 29 cases of breast cancer among women diagnosed with gestational diabetes. Using Cox proportional hazards models to control for age and birth order at the first observed birth and other characteristics, we found that the incidence of breast cancer was increased among women diagnosed with gestational diabetes (relative rate = 1.5, 95% confidence interval 1.0-2.1). This effect was seen only among women 50 years and older (relative rate 1.7, 95% confidence interval 1.1-2.5) but not among women <50 rate =" 1.0," class="bibrecord-passage-highlight-user">diabetes may be an important early marker of breast cancer risk among post-menopausal women, but these results need to be confirmed in future studies.

Pharmacokinetic/Pharmacodynamic Modelling in Diabetes Mellitus

Diabetes mellitus is a major health risk in many countries, and the incidence rates are increasing. Diverse therapeutic agents are applied to treat this condition. Since 1960, numerous mathematical models have been developed to describe the glucose-insulin system, analyse data from diagnostic tests and quantify drug effects. This review summarizes the present state-of-the-art in diabetes modelling, with a focus on models describing drug effects, and identifies major strengths and limitations of the published models.

For diagnostic purposes, the minimal model has remained the most popular choice for several decades, and numerous extensions have been developed. Use of the minimal model is limited for applications other than diagnostic tests. More mechanistic models that include glucose-insulin feedback in both directions have been applied. The use of biophase distribution models for the description of drug effects is not always appropriate. More recently, the effects of various antidiabetic agents on glucose and insulin have been modelled with indirect response models. Such models provide good curve fits and mechanistic descriptions of the effects of antidiabetic drugs on glucose-insulin homeostasis. These and other types of models were used to describe secondary drug effects on glucose and insulin, and effects on ancillary biomarkers. Modelling of disease progression in diabetes can utilize indirect response models as a disturbance of homeostasis.

Future needs are to include glucose-insulin feedback more often, develop mechanistic models for new drug groups, consider dual drug effects on complementary subsystems, and incorporate elements of disease progression.

Sunday, July 20, 2008

The impact of diabetes on survival following breast cancer

Purpose: It has been suggested that type 2 diabetes may affect breast cancer prognosis, possibly due to increased diabetes-related comorbidity, or direct effects of insulin resistance and/or hyperinsulinemia. The purpose of this study was to examine the impact of diabetes on survival following breast cancer.

Methods: Using population-based health databases from Ontario, Canada, this retrospective cohort study compared deaths between women with breast cancer aged 55-79 years with diabetes and without diabetes. Women were followed for all cause mortality from breast cancer diagnosis until March 31st 2006.

Results: Of the 6,107 women with breast cancer, 1,011 had diabetes and 5,096 did not have diabetes. Women with diabetes were slightly older, were more likely to reside in a lower income neighborhood, and had greater comorbidity compared to women without diabetes. After a mean follow-up of 5.0 years and adjustment for age, prior mammograms and other covariates, mortality following breast cancer was significantly higher among women with versus without diabetes (hazard ratio, HR 1.39, 95% confidence interval, CI 1.22-1.59, P < class="bibrecord-passage-highlight-user">diabetes on mortality was comparable to that seen in women with diabetes without breast cancer over a 7-year follow-up.

Conclusion: This study found that diabetes was associated with a close to 40% increase in mortality within the first 5 years following breast cancer, which was similar to that seen in women with diabetes without breast cancer. These findings suggest that early survival following breast cancer is reduced in women with diabetes, possibly due to diabetes-related causes.

Lucica(R) MI Urinary Myoinositol Kit: A New Diagnostic Test for Diabetes Mellitus and Glucose Intolerance.

[middle dot] Diabetes mellitus is a growing healthcare problem internationally, and poses a major burden from both a individual and societal perspective.

[middle dot] Diabetes causes potentially life-threatening complications that are preventable if the disease is detected early and appropriate interventions are put in place. Early detection is therefore imperative for preventing diabetes-related morbidity and mortality.

[middle dot] Current methods of detection, including the oral glucose tolerance test (OGTT), and measures of fasting plasma glucose, glycated hemoglobin (HbA1c), or glycated albumin, can be time-consuming and uncomfortable for patients.

[middle dot] Myoinositol can be measured in urine and has been found to be elevated in patients with diabetes and glucose intolerance; it has thus proven useful as a marker for the early detection of these conditions.

[middle dot] Lucica(R) MI is a diagnostic kit for the measurement of urinary myoinositol; it is used to detect glucose intolerance and diabetes mellitus at an early stage in disease progression. The test is based on an enzymatic method that uses liquid reagents requiring no preparation. Clinical trial results demonstrate that the test could be used to detect not only diabetes mellitus, but also to distinguish impaired fasting glucose and impaired glucose tolerance from normal glucose tolerance.

The Clinical Significance of New-Onset Diabetes Mellitus in Hypertension: Drug-Induced Diabetes is Important

Several intervention trials found that some antihypertensive drugs, mostly ACE inhibitors, calcium-channel blockers and angiotensin II receptor blockers, are associated to a lesser risk of developing diabetes mellitus in comparison with other drug classes, including diuretics and [beta]-blockers. This finding is clinically relevant because it has been demonstrated that patients who develop new-onset diabetes during therapy rapidly become a high-risk population, not dissimilar from patients with prior diagnosis of diabetes. In a recent analysis of the PIUMA (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale) study, pre-treatment glucose levels and use of diuretic drugs were independent predictors of new-onset diabetes. Although there is some controversy on this topic, prevention of new-onset diabetes could contribute to explain at least part of the benefit attributed to ACE inhibitors, calcium-channel blockers and angiotensin II receptor blockers in some intervention trials. In clinical practice, when faced with subjects at high risk of diabetes, it is important to implement non-pharmacological strategies whenever appropriate (diet, physical activity, weight loss). In these subjects, ACE inhibitors, calcium-channel blockers and angiotensin II receptor blockers could be considered first-line drugs.

Received for publication 21 December 2007; accepted for publication 20 January 2008.

Key words: hypertension, new-onset diabetes mellitus, antihypertensive drugs, diuretics, [beta]-blockers, ACE inhibitors, angiotensin II receptor blockers.

Is New-Onset Diabetes Mellitus Important?: Yes, but..

Diabetes mellitus is a powerful risk factor for cardiovascular disease (CVD), and most persons with diabetes ultimately succumb to coronary artery disease or stroke. The coincidence of hypertension and diabetes is common and, over the long term, sharply increases cardiovascular risk. The incidence of diabetes (new-onset diabetes [NOD]) among hypertensive persons is high, and appears to be increased during antihypertensive therapy. NOD is a distressing clinical event, provoking psychological distress, more clinical testing, and, sometimes, the need for hypoglycaemic therapy. Diuretics and [beta]-blockers are more likely to provoke NOD than other drugs that block the renin angiotensin system, or calcium channel blocking agents, It is important to note that the alternative agents have not been shown to prevent the emergence of hyperglycaemia, but seem to be metabolically neutral. It is also true that because diuretic-induced NOD may be due to hypokalaemia, it can sometimes be reversed without sacrificing diuretic therapy. The evidence suggests that most NOD appearing during antihypertensive therapy is not drug induced, but rather part of the natural history of disease. Since diabetes is such a powerful CVD risk factor, it can hardly be surprising that, over the long term, NOD is associated with increased CVD. However, there is no evidence in short-term clinical trials that diuretic-induced NOD increases CVD or detracts from the cardioprotective effects of these agents. Indeed, long-term follow-up of participants in a large placebo-controlled trial of diuretic therapy in elderly hypertensive subjects suggests that this antihypertensive therapy actually eliminates the expected increase in CVD. In summary, although NOD can hardly be dismissed as a trivial event, concern about its possible occurrence is not a reason to influence initial antihypertensive drug selection, nor does its appearance provide a reason to compromise antihypertensive therapy. Indeed, the available evidence suggests that blood pressure control trumps hypoglycaemic therapy as the very best tool for CVD prevention in new or established diabetic subjects.

Received for publication 21 December 2007; accepted for publication 20 January 2008.

Key words: hypertension, new-onset diabetes mellitus, antihypertensive drugs, diuretics, [beta]-blockers, ACE inhibitors, angiotensin II receptor blockers.

Intensified Diabetes Care Monitoring and Physician Education: Impact on Outcomes and Costs of Care

Background and objectives: Diabetes mellitus is a growing medical and economic burden that requires ongoing vigilant screening and effective management to prevent the development of serious and costly complications. In 2002, the Genesys Physician-Health Organization (PHO) implemented a quality initiative called the Clinical Excellence Program (CEP) with the purpose of increasing and documenting the quality of care provided to patients with particular health issues, including diabetes. This 5-year analysis (2002-6) of CEP findings was conducted to assess physician compliance with mandated screening/testing guidelines, evaluate the clinical impact for members with diabetes, and identify any potential economic effects.

Methods: Internal goals are set annually for specific diabetes care-related metrics (measurement of glycosylated hemoglobin [HbA1c], low-density lipoprotein-cholesterol [LDL-C] levels and blood pressure; retinal exams and foot exams; nephropathy screening) and communicated to Genesys PHO primary care physicians, who are then audited twice yearly for compliance with these measures. Physicians are given credit for any documentation showing that a given screening/test/referral was carried out or facilitated in good faith. CEP scores are compared against the 'index year' (2002) as an internal standard, and various national and regional benchmark datasets as external standards. Audit results are communicated to the physicians, and those scoring below preset deviation limits for compliance are subject to more frequent review.

Results: Physician compliance with diabetes screening parameters generally showed consistent annual improvement. Rates of HbA1c and LDL-C level testing were already favorable in the index year, but steadily improved over the 5-year period. The most dramatic increase was observed in the nephropathy screening rate, which nearly doubled from 43% in 2002 to 81% in 2003. Overall costs for medical and pharmacy claims, as well as emergency department visit costs and hospitalization rates, all demonstrated downward trends from 2003 through 2006, possibly reflecting the improvements in care and screening.

Conclusion: This analysis of the first 5 years of the Genesys CEP suggests that the program is meeting its primary goal of providing high-quality care, while realizing some degree of cost savings.

Clinical Depressive Symptoms and Diabetes in a Binational Border Population

Background: Depression affects more Hispanics with type 2 diabetes than other ethnic groups. This exploratory, binational study examined the prevalence and correlates of clinical depressive symptoms in Hispanics of Mexican origin with type 2 diabetes living on both sides of the Texas Mexico border.

Methods: Two binational samples, consisting of 172 adult patients of Mexican origin with type 2 diabetes in South Texas and 200 from the Northeastern region of Mexico, were compared. Logistic regression analyses were used to test personal and social correlates to clinical depressive symptoms.

Results: The rate of clinical depressive symptoms was similar in both South Texas and Northeastern Mexico patients (39% and 40.5%, respectively). Gender, education, emergency department visits, and burden of diabetes symptoms were predictors of clinical depressive symptoms in the South Texas sample. Among respondents in the Northeastern Mexico sample, the only statistically significant correlate to clinical depressive symptoms was the burden of diabetes symptoms.

Conclusions: Diabetes and depression must be addressed as priorities in diabetes initiatives at the US Mexico border region. Further research is warranted to examine the extent and impact of involving family practice physicians from both sides of the border in depression screenings among patients with type 2 diabetes.

The burden of diabetes-related mortality in France in 2002: An analysis using both underlying and multiple causes of death

Aim: To describe the burden of diabetes-related mortality in France.

Methods: Underlying and multiple causes (all causes listed) of death were extracted from the 2002 French national mortality registry. Death rates were standardized on the age structure of the European population.

Results: Diabetes was reported as the underlying cause of death in 11,177 certificates (2.1%), and as multiple causes in 29,357 certificates (5.3%), giving a ratio (multiple/underlying causes) of 2.6. When diabetes was a multiple cause, the mean age at death was 75 years in men, 81 years in women. The age-standardized mortality rates were 41.0/100,000 in men, 24.6/100,000 in women. The excess mortality observed in men (men/women ratio = 1.7) decreased with age. Geographic differences were observed: higher rates in the North-East, lower rates in the West of the country. In certificates mentioning diabetes, the most frequent cause of death was diseases of the circulatory system (76%). Coronary heart diseases, foot ulcers and renal diseases were more likely to be mentioned in certificates referring to diabetes than in those that did not.

Discussion: The use of multiple rather than underlying causes of death more than doubled diabetes-related mortality rates. While probably still under-estimated, the burden of diabetes-related mortality corresponds to a high proportion of the total mortality, especially in men. Geographic differences partially reflect disparities in diabetes prevalence. Causes more frequently associated with diabetes include coronary heart disease and complications related to neuropathy and nephropathy.

Histological Features of Symptomatic Carotid Plaques in Patients with Impaired Glucose Tolerance and Diabetes (Oxford Plaque Study)

Background: Diabetes is associated with an increased risk of incident stroke and both early and late recurrent stroke after transient ischaemic attack. Some small studies have suggested that atherosclerotic plaques from diabetics have a higher prevalence of unstable features than plaques from non-diabetics but results have been inconsistent.

Method: We made detailed histological assessments of 526 plaques from consecutive patients undergoing carotid endarterectomy for recently symptomatic stenosis and related these to the presence of diabetes and impaired glucose tolerance (IGT).

Results: 53 (10.1%) patients had diabetes, 26 (5%) had IGT and 447 (84.9%) had normal glucose tolerance (NGT). The overall prevalence of unstable plaque features was similar across these groups. However, whereas plaques removed >60 days after last symptoms in patients with NGT had less surface thrombus (OR = 0.61, 95% CI = 0.40-0.92, p = 0.02), fewer plaque macrophages (OR = 0.78, 95% CI = 0.51-1.19, p < or =" 0.57," ci =" 0.35-0.88," p =" 0.009)" class="bibrecord-passage-highlight-user">diabetes/IGT (OR = 1.08, 95% CI = 0.42-2.77, OR = 1.16, 95% CI = 0.46-2.96 and OR = 1.51, 95% CI = 0.60-3.77, respectively).

Conclusion: Overall, the prevalence of unstable histology features in recently symptomatic carotid plaques is similar in patients with diabetes, IGT and NGT. However, surface thrombus and plaque macrophages appear to persist for longer after ischaemic symptoms in plaques from patients with diabetes/IGT compared to plaques from patients with NGT. This may contribute to the increased risk of recurrent stroke that is associated with diabetes/IGT.

Monday, July 21, 2008

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