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Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

The burden of cardiovascular disease (CVD) among patients with diabetes is substantial. Individuals with diabetes are at two- to fourfold increased risk of cardiovascular events compared with age- and sex-matched individuals without diabetes. In diabetic patients over the age of 65 years, 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke (1). A number of mechanisms for the increased cardiovascular risk with diabetes have been proposed, including increased tendency toward intracoronary thrombus formation (2), increased platelet reactivity (3), and worsened endothelial dysfunction (4). The increased risk for cardiovascular events and mortality in patients with diabetes has led to considerable interest in identifying effective means for cardiovascular risk reduction. Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with myocardial infarction (MI) or stroke (secondary prevention) (5). The Food and Drug Administration has not approved aspirin for use in primary prevention, and its net benefit among patients with no previous cardiovascular events is more controversial, for both patients with and without a history of diabetes (5). The U.S. Preventive Services Task Force recently updated its recommendation about aspirin use for primary prevention. The Task Force recommended encouraging aspirin use in men age 45–79 years and women age 55–79 years and not encouraging aspirin use in younger adults. They did not differentiate their recommendations based on the presence or absence of diabetes (6,7). In 2007, the American Diabetes Association (ADA) and the American Heart Association (AHA) jointly recommended that aspirin therapy (75–162 mg/day) be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) (8). These recommendations were …

The burden of cardiovascular disease (CVD) among patients with diabetes is substantial. Individuals with diabetes are at two- to fourfold increased risk of cardiovascular events compared with age- and sex-matched individuals without diabetes. In diabetic patients over the age of 65 years, 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke (1). A number of mechanisms for the increased cardiovascular risk with diabetes have been proposed, including increased tendency toward intracoronary thrombus formation (2), increased platelet reactivity (3), and worsened endothelial dysfunction (4). The increased risk for cardiovascular events and mortality in patients with diabetes has led to considerable interest in identifying effective means for cardiovascular risk reduction. Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with myocardial infarction (MI) or stroke (secondary prevention) (5). The Food and Drug Administration has not approved aspirin for use in primary prevention, and its net benefit among patients with no previous cardiovascular events is more controversial, for both patients with and without a history of diabetes (5). The U.S. Preventive Services Task Force recently updated its recommendation about aspirin use for primary prevention. The Task Force recommended encouraging aspirin use in men age 45–79 years and women age 55–79 years and not encouraging aspirin use in younger adults. They did not differentiate their recommendations based on the presence or absence of diabetes (6,7). In 2007, the American Diabetes Association (ADA) and the American Heart Association (AHA) jointly recommended that aspirin therapy (75–162 mg/day) be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) (8). These recommendations were …

Background: The aims of this study are to compare the diabetes-related lower extremity amputation (LEA) rate trend in South Carolina (SC) to that of the United States (US) and to determine changes in LEA rates in SC according to age, race, gender, and amputation site. Methods: National Hospital Discharge Survey (NHDS) and SC hospital discharge data for 1996 to 2002 were analyzed. ICD-9-CM codes identified all diabetic patients and occurrences of LEA. Linear regression was used to compare the LEA rate trends between SC and the US. Results: LEA rates are decreasing throughout the study period. The slope is greater in SC compared with US (US slope = - 0.00082; SC slope = -0.0015; P = 0.002), signifying a decrease in LEA rates of 1.5/1000 per year in SC and 0.8/1000 per year in the US. Furthermore, LEA rate decreases in SC are significant throughout all ages, races, genders, and amputation levels. Conclusions: Diabetes-related LEA rates are decreasing in SC more rapidly than in the US. Ongoing community-level education may be assisting in the favorable trends.

PURPOSE Nearly one third of diabetes cases in the United States is undiagnosed, with mounting evidence that complications accrue even before clinical diagnosis. We wanted to determine whether persons with undiagnosed diabetes have signs of nephropathy and peripheral neuropathy METHODS We examined the prevalence of positive screening tests for nephropathy and peripheral neuropathy in adults aged ≥40 years with undiagnosed diabetes using secondary analysis of survey and examination data from the population-based United States National Health and Nutrition Examination Survey 1999-2002. We defined a positive screening test for nephropathy as a spot urine albumin-creatinine ratio >30.0 mg/g, representing at least microalbuminuria. We defined ≥1 insensate area on Semmes-Weinstein monofilament testing as a positive finding for neuropathy. Undiagnosed diabetes was defined as a combination of no history of diagnosed diabetes and a measured fasting glucose ≥126 mg/dL. We used SUDAAN for χ2 and regression analyses. RESULTS The prevalence of a positive test when screening for nephropathy among those with undiagnosed diabetes was 26.5% compared with 7.1% in those with no diabetes (χ2, P

Accelerated atherosclerosis and the increased risk of thrombotic vascular events in diabetes may result from dyslipidemia, endothelial dysfunction, platelet hyperreactivity, an impaired fibrinolytic balance, and abnormal blood flow. There is also a correlation between hyperglycemia and cardiovascular (CV) events. The importance of platelets in the atherothrombotic process has led to investigation of using antiplatelet agents to reduce CV risk. A meta-analysis conducted by the Antiplatelet Trialists’ Collaboration demonstrated that aspirin reduced the risk of ischemic vascular events as a secondary prevention strategy in numerous high-risk groups, including patients with diabetes. Based on results from placebo-controlled randomized trials, the American Diabetes Association recommends low-dose enteric-coated aspirin as a primary prevention strategy for people with diabetes at high risk for CV events. Clopidogrel is recommended if aspirin allergy is present. There is occasionally a need for an alternative to aspirin or for additive antiplatelet therapy. Aspirin in low doses inhibits thromboxane production by platelets but has little to no effect on other sites of platelet reactivity. Agents such as ticlopidine and clopidogrel inhibit ADP-induced platelet activation, whereas the platelet glycoprotein (Gp) IIb/IIIa complex receptor antagonists block activity at the fibrinogen binding site on the platelet. These agents appear to be useful in acute coronary syndromes (ACSs) in diabetic and nondiabetic patients. A combination of clopidogrel plus aspirin was more effective than placebo plus standard therapy (including aspirin) in reducing a composite CV outcome in patients with unstable angina and non-ST segment elevation myocardial infarction. In a meta-analysis of six trials in diabetic patients with ACSs, intravenous GpIIb-IIIa inhibitors reduced 30-day mortality when compared with control subjects. Results from controlled prospective clinical trials justify the use of enteric-coated low-dose aspirin (81–325 mg) as a primary or secondary prevention strategy in adult diabetic individuals (aged >30 years) at high risk for CV events. Recent studies support the use of clopidogrel in addition to standard therapy, as well as the use of GpIIb-IIIa inhibitors in ACS patients.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Summary Only recently are we beginning to understand the complex interplay of factors involved in vascular disease and diabetes. Insulin resistance provides a starting point to explain the many factors that lead to the more severe vascular disease characteristic of diabetes. Insulin resistance syndrome comprises insulin resistance and compensatory hyperinsulinaemia as well as hypertension, dyslipidaemia, macrovascular disease, and increased plasminogen activator inhibitor-1 activity. The development of type 2 diabetes may be viewed as the inability of the pancreas to continue to overcome insulin resistance, even with excessive insulin production.

OBJECTIVE: Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS: We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA(1c) 7.1%) or to standard treatment (ST) (goal HbA(1c) 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group. RESULTS: A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups. CONCLUSIONS: Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.

The use of aspirin for the primary prevention of cardiovascular events in patients with type 2 diabetes mellitus is controversial. According to the findings of a Japanese trial, aspirin does not reduce the risk of cardiovascular events in this group of patients, unless they are aged 65 years and above.

Basic and clinical research findings have led to an increased understanding about diabetes and its complications. Therapeutic approaches are now based not only on predicted effects from epidemiologic, correlative, or retrospective analyses, but often on prospective intervention trials comparing a new form of therapy to the standard methods. While this database may never be complete, partially due to the complexity and variability of the diabetic state, we now have excellent data that allow the development of aggressive new guidelines for care. Much of the material presented here reflects the views of the American Diabetes Association, as included in a recent publication (1). These guidelines are under review by a number of other organizations and will be subject to modification for special situations. Thus, the terminology "guidelines," rather than "standards of care," is chosen to indicate the flexibility necessary in developing such recommendations for general usage.

The rationale for intensive insulin therapy and results from major clinical trials in diabetes are reviewed. The Diabetes Control and Complications Trial (DCCT) has shown that intensive insulin therapy will prevent or delay the onset of retinopathy, nephropathy, and neuropathy in type I diabetes. The University Group Diabetes Program (UGDP) and the U.K. Prospective Diabetes Study (UKPDS) have addressed the issue of insulin versus oral agent or diet therapy in people with recently diagnosed type II diabetes. The UGDP showed that effective glycemie control could be achieved with intensive insulin therapy, but no effect on vascular end points was seen. Early data from the UKPDS also suggest that intensive insulin therapy may be more effective in lowering HbA1c toward normal than oral agents or diet. A pressing clinical problem is the question of the use of intensive insulin therapy in type II diabetic individuals who remain hyperglycemie despite pharmacological therapy. A Veterans Affairs Cooperative Study explored the feasibility of using intensive insulin therapy in 153 male type II diabetic patients with these characteristics. A 2% lowering of HbA1c was seen, with no increase in weight gain or in hypoglycemia. However, 40 of 153 patients (26.1%) had cardiovascular events during the 27-month trial; no difference in cardiovascular event rates was seen between the two treatment groups. A long-term multicenter collaborative trial is needed to assess the benefltcrisk ratio of intensive insulin therapy for type II diabetic patients in whom pharmacological therapy failed to provide glycemie management.

OBJECTIVE It is not clear whether intensive pharmacological therapy can be effectively sustained in non-insulin-dependent diabetes mellitus (NIDDM). The relative risks and benefits of intensive insulin therapy in NIDDM are not well defined. Accordingly, we designed a feasibility study that compared standard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycemia. RESEARCH DESIGN AND METHODS A prospective trial was conducted in five medical centers in 153 men of 60 ± 6 years of age who had a known diagnosis of diabetes for 7.8 ± 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: 1) an evening insulin injection, 2) the same injection adding daytime glipizide, 3) two injections of insulin alone, and 4) multiple daily injections. Patient accrual and adherence, glycohemoglobin (HbA1c), side effects, and measurements of endpoints for a prospective long-term trial were assessed. RESULTS Accrual goals were met, mean follow-up time was 27 months (range 18–35 months), and patients kept 98.6% of scheduled visits. After 6 months, the mean HbA1c in the intensive therapy group was at or below 7.3% and remained 2% lower than the standard group for the duration of the trial. Most of the decrease in the mean HbA1c in the intensive group was obtained by a single injection of evening intermediate insulin, alone or with daytime glipizide. By the end of the trial, 64% of the patients had advanced to two or more injections of insulin a day, aiming for normal HbA1c. However, only a small additional fall in HbA1c was attained. Severe hypoglycemia was rare (two events per 100 patients per year) and not significantly different between the groups, nor were changes in weight, blood pressure, or plasma lipids. There were 61 new cardiovascular events in 40 patients and 10 deaths (6 due to cardiovascular causes). CONCLUSIONS Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia, weight gain, hypertension, or dyslipidemia. Cardiovascular event rates are high at this stage of NIDDM. A long-term prospective trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin.

OBJECTIVE To compare platelet plasminogen activator inhibitor 1 (PAI-1) concentration in type 11 diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We studied a group of 12 diabetic patients whose disease was controlled by diet or sulfonylurea therapy and a group of 17 nondiabetic control subjects. All subjects were free of clinically advanced vascular disease. PAI-1 antigen concentrations were measured in 5 × 108 isolated platelets, which were lysed by 1% Triton X-100. RESULTS Mean platelet PAI-1 was significantly higher in diabetic patients (264 ± 83 ng/5 × 108 platelets) compared with control subjects (202 ±71 ng/5 × 108platelets) (P < 0.05). A significant independent positive correlation was found between platelet PAI-1 concentrations and fasting plasma specific insulin levels in the diabetic patients (r = 0.63, P = 0.03). CONCLUSIONS These findings suggest that 1) a higher platelet PAI-1 concentration may contribute to enhanced thrombosis in type II diabetes and 2) megakaryo-cyte PAI-1 synthesis may be under the control of insulin.

One hundred seventy-eight implants from three systems were placed in 89 type II diabetic patients at 13 Department of Veterans Affairs medical centers. Four failures (2.2 percent) were found at uncovering. The failure rate increased to 7.3 percent at the end of 1 year (nine additional failures). Study patients will be monitored for an additional 4 years. Initial results suggest that type II diabetic patients can be considered for dental implant therapy.

Objective— Patients with NIDDM have a two- to fourfold increased risk of macrovascular disease. The constellation of elevated TGs and decreased HDL cholesterol are recognized as risk factors and constitute the major dyslipidemia in NIDDM. We therefore sought to determine if gemfibrozil (600 mg b.i.d.) was effective in correcting the dyslipidemia of NIDDM. Research Design and Methods– After 8 wk of placebo stabilization, 442 patients from 46 study centers were randomized to double-blind treatment, in a designated 2:1 ratio, 295 received gemfibrozil and 147 received placebo for 20 wk. The primary end point was plasma TG; secondary end points were TC, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and HbA1c. No baseline differences were noted between groups in sex, age, weight, type of diabetic therapy, fasting plasma levels of TGs, HbA1c, or C-peptide. About two-thirds received oral hypoglycemic drugs, one-third insulin Results– TG fell 26.4% in the gemfibrozil group and rose 7.4% in the placebo group (P < 0.023), by an intent-to-treat analysis. When patients who were noncompliant or with inadequate data were excluded, similar results were found—a 30.4% fall with gemfibrozil and a 4.8% increase with placebo (P < 0.0001). TG levels fell within 4 wk and remained low for 20 wk (P < 0.001). Mean HDL cholesterol rose by 4 wk and increased further at 12 wk (8–12%), P < 0.0001. TC fell. We observed a significant rise in LDL cholesterol in both gemfibrozil- and placebo-treated groups, with no significant differences between these groups. Changes in HbA1c were similar in gemfibrozil and placebo groups. No differences were observed in responses in groups treated with insulin and or oral hypoglycemic drugs. Overall AEs that were clinically important occurred in 6.1% in the gemfibrozil group vs. 2.0% in the placebo group (NS). Conclusions– We conclude that gemfibrozil is an effective and safe agent in combating the dyslipidemia of NIDDM, irrespective of type of diabetic therapy.

OBJECTIVE To determine, after 1 yr of follow-up in type II diabetes patients, whether a statistically and clinically significant difference can be achieved in HbA1c between a standard therapy group and an intensively treated group, while maintaining HbA1c levels in both groups within ranges acceptable in regular community practice. Secondary objectives include assessment of patient adherence to protocol, side effects, and accuracy of data collection. RESEARCH DESIGN AND METHODS This is a prospective, randomized, controlled VA CS conducted with 151 patients at five VAMCs. Patients are males, age 40–69 yr, treated at entry with a maximum dose of sulfonylurea or with insulin, exhibiting an HbA1c level > 3 SDs above the normal mean (5.05 + 3 × 0.50 = > 6.55%). Standard control is achieved with insulin and intensive control with a step-up regimen including insulin alone or insulin/glipizide combinations. Education and management of cardiovascular risk factors are handled similarly in both groups. Primary macrovascular end points are nonfatal myocardial infarction, congestive heart failure, stroke, amputation, and cardiovascular death. Primary microvascular end points are appearance and progression of retinopathy, documented by centrally read seven-field-stereo fundus photographs. Other measured indicators include resting and ambulatory ECGs, ventricular function (MUGA scan), serum lipid and apolipoprotein levels, plasma fibrinogen, nonsymptomatic peripheral vasculopathy, neuroautonomic status by heart-beat variation on Valsalva maneuver, and microalbuminuria. CONCLUSIONS This study may be the basis for a long-term trial, involving 1400 patients, to assess the long-term effects of metabolic control on macro- and microvascular end points.

Diabetes mellitus is a major risk factor for coronary heart disease, peripheral vascular disease, and cardiovascular disease. The prevalence of these complications is increased about two- to four-fold in people with diabetes in the United States, and they contribute substantially to morbidity, mortality, and healthcare costs. The pathogenesis of macrovascular disease in diabetes is multifactorial. Endothelial injury is an early event, followed by macrophage adherence and uptake of lipids to produce a fatty streak. Platelet adherence, aggregation, and release of thromboxane and platelet-derived growth factors may then occur. Quantitative and qualitative alterations of lipoproteins are seen, particularly in uncontrolled insulin-dependent and non-insulin-dependent diabetes. Hyperinsulinemia may be contributory, as may elevated plasma proinsulin levels. Glycation of plasma proteins and of components of the vascular wall occurs, and altered coagulation and/or fibrinolysis may lead to thrombosis. The process is accelerated by hypertension, smoking, and hypercholesterolemia. Gliclazide is an oral sulfonylurea agent that has been reported to have actions on platelet function and fibrinolysis in addition to its effects on glycemia. The evidence for this is reviewed, and recommendations for future studies are made.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Various parameters of coagulation and fibrinolysis were measured in 13 men (aged 54 +/- 3 yr) with non-insulin-dependent diabetes mellitus (NIDDM) before and after 12-14 wk of exercise training. Subjects exercised for 30 min 3 times/wk at 70% of maximum O2 consumption (VO2max). Training increased VO2max by 12.5% but did not alter body weight, relative body fat, blood pressure, cholesterol, triglycerides, or high-density lipoprotein cholesterol. Slight downward trends were apparent for fasting glucose and insulin, but glycosylated hemoglobin was unchanged. There were no changes in coagulation parameters of plasminogen, hematocrit, or alpha 2-antiplasmin. Plasma fibrinogen (303 +/- 24.2 vs. 256 +/- 12.3 mg/dl) and fibronectin (380 +/- 41.9 vs. 301 +/- 22.2 micrograms/ml) were significantly reduced (P less than 0.02) by exercise conditioning. Three assays of fibrinolytic activity (tissue plasminogen activator, euglobulin lysis time, and an isotopic measure of fibrinolysis) confirmed that neither basal fibrinolysis nor the fibrinolytic responses to venous occlusion and maximal exercise were significantly altered. Exercise conditioning may have antithrombotic effects in NIDDM by reducing plasma fibrinogen and fibronectin. Although the significance of the fall in fibronectin awaits further studies, the reduction in plasma fibrinogen gives a rationale for the use of exercise training in men with NIDDM.

There is significant evidence that low-dose aspirin is effective in preventing the first myocardial infarction in men and ischemic stroke in women. There is also an increased risk for major gastrointestinal tract hemorrhage and a suggestive, but nonsignificant, increase in the risk for hemorrhagic stroke. If there is a history of ulcer disease or upper-gastrointestinal tract bleeding, Helicobacter pylori should be eradicated (if present) and a proton pump inhibitor used with aspirin therapy. In conclusion, the benefits of low-dose aspirin (75-162 mg/day) in the prevention of myocardial infarction in men and thrombotic stroke in women generally outweigh the risks of serious bleeding in adults with a coronary heart disease risk >1% per year or >1% in 10 years.

A procoagulant state has been found to exist in diabetes mellitus. There may be activation of the intrinsic coagulation system, decreased fibrinolytic activity, or alterations in platelet function. Intensive glycemic control with insulin is effective in reducing the impact of this procoagulant state by favorably affecting all three components of the system. Decreased fibrinolytic activity, as influenced by plasma PAI-1 levels, may be favorably affected by weight loss, exercise, a low-GI diet, or by metformin, thiazolidinediones, gemfibrozil, and ACE inhibitor therapy. Insulin has variable effects on plasma PAI-1 activity. Estrogens will lower the elevated PAI-1 levels seen in the menopausal state. Collaborative trial evidence supports the use of low-dose aspirin as a primary or secondary prevention strategy in diabetic persons who are at high cardiovascular risk. A recent study suggests that this category includes virtually every type 2 diabetic individual in the United States. The American Diabetes Association recommends enteric-coated aspirin, 81 to 325 mg/day, as the first choice. In the case of aspirin allergy, clopidrogel is an alternate choice. Thus, recognition of and therapy for a procoagulant state in diabetes mellitus is likely to result in a decrease in the atherothrombotic events that characterize the later stages of this disease.

To determine whether a difference in HbA(1c) could be safely sustained between a standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining HbA(1c) levels in both arms within a range acceptable in community practice. The effects of intensive treatment on various parameters were studied in this feasibility trial. We report here the results of 24 months of INT on peripheral and autonomic neuropathy.A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: (1) an evening insulin injection, (2) the same injection adding daytime glipizide, (3) two injections of insulin alone, and (4) multiple daily injections. Peripheral neuropathy was diagnosed clinically by a history and physical examination, and by abnormal autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10). An average HbA(1c) separation of 2.07% was achieved with INT, having HbA(1c) at or below 7.3% (p = 0. 001 versus STD). Baseline prevalence of peripheral neuropathy was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in STD (p = 0.005 versus baseline), and to 64% in INT (p = 0. 008 versus baseline, but no different than STD). Though INT did not reverse all elements of peripheral neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053 versus STD) and more frequent preservation of touch sensation in the upper extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD, the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p = 0.012 versus baseline and no different from STD). The prevalence of erectile dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD, and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from STD. There was no change in the frequency of abnormal gastrointestinal or sweating symptoms. Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy. In fact, the prevalence rose equivalently and significantly in both treatment arms. There was some benefit, however, in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT.

The Veterans Affairs Cooperative Study in Type II Diabetes Mellitus prospectively studied insulin-treated patients with type 2 (non-insulin-dependent) diabetes mellitus, achieving 2.1% glycosylated hemoglobin separation between intensive- and standard-treatment arms (P.001) for 2 years.To assess the effect of intensive therapy on serum fibrinogen and lipid levels, compared with standard treatment.One hundred fifty-three male subjects with type 2 diabetes mellitus and who required insulin treatment were recruited from 5 Veterans Affairs medical centers. The subjects were divided into intensive- and standard-treatment arms for a randomized prospective study. Dyslipidemia was managed identically in both arms (diet, drugs). Fibrinogen levels and lipid fractions were measured in the full cohort. Lipid fractions are separately reported in patients not treated with hypolipidemic agents.There were no baseline differences between arms. Fibrinogen levels rose in the intensive-treatment arm at 1 year (from 3.34+/-0.12 to 3.75+/-0.15 g/L; P.001) but returned to baseline at 2 years (3.47+/-0.12 g/L). There was no change in the standard-treatment arm. Triglyceride levels decreased in the intensive-treatment arm from 2.25+/-0.27 to 1.54+/-0.14 mmol/L (199+/-24 to 136+/-12 mg/ dL) at 1 year (P = .004) and to 1.74+/-0.18 mmol/L (154+/-16 mg/dL) at 2 years (P = .03); there was no change in the standard-treatment arm. Cholesterol levels decreased in the intensive-treatment arm at 1 year from 5.4+/-0.21 to 4.99+/-0.13 mmol/L (207+/-8 to 193+/-5 mg/dL) (P = .02); there was no change in the standard-treatment arm. Levels of low- and high-density lipoprotein cholesterol decreased in the standard-treatment arm only by 2 years, from 3.44+/-0.13 to 3.16+/-0.10 mmol/L (133+/-5 to 122+/-4 mg/ dL) (P =.02) and from 1.10+/-0.03 to 1.00+/-0.03 mmol/L (42+/-1 to 38+/-1 mg/dL) (P.001) for low-density and high-density lipoprotein cholesterol, respectively. Levels of apolipoprotein B decreased in both treatment arms (P.001), and apolipoprotein A1 levels decreased in the standard-treatment arm (P.01). Lipoprotein (a) levels did not change in either treatment arm. Lipid results were essentially identical whether examined in the full cohort or excluding those patients receiving hypolipidemic agents.Intensive insulin therapy led to a potentially beneficial reduction in serum triglyceride levels and preservation of high-density lipoprotein cholesterol and apolipoprotein A1 levels. However, it caused transient elevation in plasma fibrinogen levels, a possible thrombogenic effect.

OBJECTIVE The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus was conducted in NIDDM patients to determine if a significant difference in HbA1c could be achieved between groups receiving standard and intensive treatment. We observed differences in the response to exogenous insulin between African-Americans and other intensively treated patients. Therefore, we assessed the variations of response and correlated factors that might explain such differences. RESEARCH DESIGN AND METHODS One hundred fifty-three men aged 40–69 years with NIDDM for ≤15 years were randomized to either the standard therapy (n = 78) or the intensive therapy (n = 75) arm. Of the 75 patients in the intensive therapy group, 57 completed the study on insulin therapy alone. Of these, 18 were African-Americans and 39 were non-African-Americans. We conducted an analysis of the data collected to determine differences in baseline characteristics, glycemic response, insulin requirement, body weight, exercise, and basal C-peptide level, factors that may explain a difference in response to insulin therapy. RESULTS Glycemic control improved in all patients with intensive insulin therapy. African-Americans achieved a greater improvement in HbA1c compared with non-African-Americans with a similar increment in insulin. This difference could not be explained by differences in body weight, activity, concomitant use of other medicines, or insulin-secretory capacity of the pancreas. CONCLUSIONS We conclude that ethnic differences may exist in the response to insulin therapy. A knowledge of such differences may aid in achieving good glycemic control, especially since minorities have a greater prevalence of and burden from the microvascular complications of diabetes.

OBJECTIVE The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HbA1c levels. Age of patients was 60 ± 6 years, duration of diabetes 8 ± 3 years, and BMI 30.7 ± 4 kg/m2. A fourstep management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added daytime glipizide; phase III, two injections of insulin alone; and phase IV multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS Baseline HbA1c was 9.3 ± 1.8%, and fasting plus serum glucose was 11.4 ± 3.3 mmol/1. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA1c separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA1c levels below 7.3% (P = 0.001). Most of the decrease in HbA1c occurred with one injection of insulin alone (phase I, − 1.4%) or adding daytime glipizide (phase II, −1.9% compared with baseline). HbA1c did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA1c fall (−2.4% compared with baseline). However, two-thirds of the patients were still on one or two injections a day at the end of the study Changes in home glucose monitoring levels paralleled those of the HbA1c, as did the increments in number of reported hypoglycemic reactions, virtually all either “mild” or “moderate” in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA1c levels had an upward trend with doses >20 mg/day. CONCLUSIONS A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA1c for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA1c demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide >20 mg/day offered no additional benefit.

People with type II diabetes have a twofold to fourfold increased risk of dying from the complications of cardiovascular disease. Atherosclerosis and vascular thrombosis are major contributors. The increased risk is present before fasting hyperglycemia is seen. These individuals often have a sedentary life-style, poor physical conditioning, insulin resistance, centripetal obesity, hypertension, dyslipidemia, and a prothrombotic state. Chronic hyperglycemia is then added to these risk markers. Microalbuminuria may precede hyperglycemia in type II diabetes, occurs in 30% to 40% of these individuals after diabetes is established, and is a predictor of cardiovascular events. Early intervention in high-risk individuals may delay or prevent fasting hyperglycemia. An all-inclusive approach that focuses on early risk factor (or marker) identification and management to prevent or delay accelerated atherosclerosis and thrombosis in type II diabetes is an attractive strategy. However, the database to support this strategy is limited. In particular, large-scale prospective trial data are not available to support the concept of intensive glycemic regulation to prevent progression of macrovascular disease in type II diabetes. This is in contrast to the situation regarding microvascular disease of the eyes and kidneys. Recently, indirect data of a correlative nature have emerged, and short- and long-term prospective trials at early and late stages of type II diabetes are now being reported. These studies are analyzed and interpreted in this report. In contrast, the database to support an intensive antiplatelet regimen to prevent vascular thrombotic events in people with type II diabetes is large, and these studies are reviewed. They are of a type and magnitude to allow definite recommendations for aspirin therapy in type II diabetes. Aggressive therapy directed at hypertension, hyperlipidemia, and elevated urinary albumin in people with type II diabetes appears to be indicated. Increased attention to the multifactorial aspects of treatment of the type II diabetic patient is needed. Our present challenge is to translate these findings for patients and primary health care providers so that effective actions may be implemented.

The pathogenesis of atherosclerosis and vascular thrombosis in NIDDM is reviewed. Evidence that suggests a role for chronic hyperglycemia, in association with other vascular risk markers, is presented. Based on this framework, a multifactorial approach to the prevention of progression of macrovascular disease in NIDDM is discussed. Results from a recent consensus conference sponsored by the American Diabetes Association regarding approaches to glycemic regulation in people with NIDDM are reviewed. It is concluded that preventive approaches will materially alter the course of macrovascular disease, reduce health care costs, and improve the quality of life for people with NIDDM.

This report presents results of a study on the effectiveness of a prenatal group hypnosis smoking cessation program. The postpartum smoking behaviours of those who stopped smoking during the pregnancy are also presented. The multifactorial intervention emphasized is the use of multiple hypnosis sessions with accompanying information booklets and personal physician encouragement. This study group of 55 people included both pregnant women and their significant others who lived with them and smoked. Only 83% follow-up was achieved of the 47 patients eligible for analysis (n=39). Results showed a quit rate of 18% and positive smoking behaviour changes in 90% of the study group. Of those 7 individuals who quit during pregnancy, only two resumed smoking at three and six months, respectively. These preterm and postpartum preliminary results are promising given the small sample size of the study and the potential room for improvement of this intervention modality. Normal 0 false false false EN-CA X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0in; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;}

The participants of Forum Two addressed the unanswered research questions about metabolic control and non-insulin-dependent diabetes mellitus (NIDDM). The most compelling issue was the effect of metabolic control on both the development and progression of macrovascular disease in patients with NIDDM. Associated questions that could be answered by a well-controlled clinical trial related to the goal of blood glucose control in NIDDM in the elderly and in persons with clinical vascular disease. The specific suggestion was a trial similar to the Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM. Another important research issue that was discussed was the benefit of treating other risk factors such as hypertension and hyperlipidemia in diabetic patients. Yet another area discussed was the study of health services delivery to examine the best care-delivery methods for diabetes and other chronic diseases. Other areas of discussion centered on basic research, that is, the fundamental cause of insulin resistance and the genetics of NIDDM and the loss of protection against atherosclerosis in postmenopausal women with diabetes.

Objective : To review the results from the Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM (VACSDM) and to discuss the implications of the results from this feasibility trial. Design : A randomized clinical trial comprising 153 men with non-insulin-dependent diabetes mellitus (NIDDM) who remained hyperglycemic on usual pharmacologic therapy. Patients were randomized into two groups receiving either standard or intensive insulin therapy and were followed for 27 months. Setting : Five Veterans Affairs medical centers. Patients : 153 men with NIDDM, aged 40 to 69 years, who had hemoglobin A 1c (HbA 1c ) levels of greater than 6.55% while receiving sulfonylurea or insulin therapy. Intervention : Standard insulin therapy was one or two insulin injections daily. Intensive insulin therapy was done using a stepwise approach : 1) evening intermediate or long-acting insulin ; 2) addition of daytime glipizide ; 3) insulin twice daily, with no glipizide ; and 4) insulin three to four times daily, with no glipizide. Measurements : Fasting blood glucose and HbA 1c levels, retinopathy, lipid and urinary albumin levels, cardiovascular events, hypoglycemia, and body mass index. Results : In the intensive group, the HbA 1c level fell 2.07 percentage points ; the mean HbA 1c level was 7.3% from 6 months onward. The standard group experienced little change. These changes occurred without significant weight gain and with a very low rate of severe hypoglycemia. Sixteen patients (20.5%) in the standard group and 24 patients (32%) in the intensive group had cardiovascular events (P = 0.1). Conclusions : It is feasible to achieve excellent glycemic control in men with NIDDM in whom standard pharmacologic therapy has failed. The benefit/risk ratio of intensive insulin management in this patient group is not established and has been made the subject of a long-term prospective clinical trial.

Vascular endothelial cells have received increasing attention as potential contributors to the pathogenesis of vascular disease in diabetes mellitus. Early observations suggested that endothelial injury may be a very early stage in diabetic micro-and macroangiopathy, and subsequent data support this view. A complete review of this rapidly expanding literature is beyond the scope of this chapter; the reader is referred to previous reviews (1,2). Our focus is on recent evidence of endothelial dysfunction in diabetes mellitus.

OBJECTIVE To compare platelet plasminogen activator inhibitor 1 (PAI-1) release in type II diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We studied a group of 27 diabetic patients and a group of 16 nondiabetic control subjects. Whole-blood platelet aggregation, defined as a decrease in platelet count during shaking (180 rpm) of blood samples at 37°C, and plasma PAI-1 antigen concentrations were measured in parallel at time 0, 7.5, 15, 30, 60, 120, and 180 min. RESULTS Platelet aggregation did not differ significantly between the two groups at any time period. However, the increase in plasma PAI-1 antigen concentration over basal levels at time 0 was higher for the group of diabetic patients when compared with their matched control subjects. The increment of PAI-1 antigen was 61.8 ± 29.4 vs. 35.9 ± 13.4 ng/ml (P < 0.005, means ± SD) after 180 min for the diabetic and control subjects, respectively. Platelet PAI-1 release was correlated to very-low-density lipoprotein cholesterol and triglyceride plasma levels, but not to HbA1c levels. CONCLUSIONS Platelets of patients with type II diabetes release significantly more PAI-1 than platelets of healthy subjects at the same level of platelet aggregation. This may contribute to enhanced thrombosis in diabetes.

Accelerated atherosclerosis is characteristic of diabetes mellitus. People with diabetes have a risk of dying from cardiovascular disease that is about fourfold greater than the risk for age and sex-matched nondiabetic individuals. This increased risk is not explained by the coexistence of diabetes with the classical major vascular risk factors of hypertension, hypercholesterolemia, and cigarette smoking (26). It appears that there is something else about diabetes that makes this disease a major cardiovascular risk factor, and studies of the pathogenesis of atherosclerosis in diabetes have provided insight into this issue.