Primary Care Diabetes Fellowship Programs: Developing National Standards.

The rapid and constant increase in the number of people living with diabetes has outstripped the capacity of specialists to fully address this chronic disease alone. Furthermore, although most people with diabetes are treated in the primary care setting, most primary care providers feel under-prepared and under-resourced to fully address the needs of their patients with diabetes. Addressing this care gap will require a multifaceted approach centering on primary care training in diabetes and its complications. One-year diabetology fellowship programs are well situated to provide this training. Previous research has shown that the higher the diabetes-specific volume of patients seeing a primary care physician was, the better the quality outcomes were across six quality indicators (eye examinations, LDL cholesterol testing, A1C testing, prescriptions for ACE inhibitors or angiotensin receptor blockers, prescriptions for statins, and emergency department visits for hypoglycemia or hyperglycemia). Primary care diabetes fellowships have existed for many years, but the number of fellowships and fellowship positions has recently grown dramatically. This article proposes a standardized curriculum for such programs and makes the case for increasing their number in the United States.

Continuous Glucose Monitoring for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes.

Context: Patients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms, in part mediated through exposure to hypoglycemia. Objective: To determine whether implementation of real-time continuous glucose monitoring (CGM) as a strategy for hypoglycemia avoidance could improve glucose counterregulation in patients with long-standing T1D and hypoglycemia unawareness. Design, Setting, Participants, and Intervention: Eleven patients with T1D disease duration of ∼31 years were studied longitudinally in the Clinical & Translational Research Center of the University of Pennsylvania before and 6 and 18 months after initiation of CGM and were compared with 12 nondiabetic control participants. Main Outcome Measure: Endogenous glucose production response derived from paired hyperinsulinemic stepped-hypoglycemic and euglycemic clamps with infusion of 6,6-2H2-glucose. Results: In patients with T1D, hypoglycemia awareness (Clarke score) and severity (HYPO score and severe events) improved (P < 0.01 for all) without change in hemoglobin A1c (baseline, 7.2% ± 0.2%). In response to insulin-induced hypoglycemia, endogenous glucose production did not change from before to 6 months (0.42 ± 0.08 vs 0.54 ± 0.07 mg·kg-1·min-1) but improved after 18 months (0.84 ± 0.15 mg·kg-1·min-1; P < 0.05 vs before CGM), albeit remaining less than in controls (1.39 ± 0.11 mg·kg-1·min-1; P ≤ 0.01 vs all). Conclusions: Real-time CGM can improve awareness and reduce the burden of problematic hypoglycemia in patients with long-standing T1D, but with only modest improvement in the endogenous glucose production response that is required to prevent or correct low blood glucose.

An Adult Health Care-Based Pediatric to Adult Transition Program for Emerging Adults With Type 1 Diabetes.

Purpose The purpose of the study was to evaluate an adult health care program model for emerging adults with type 1 diabetes transitioning from pediatric to adult care. Methods Evaluation of the Pediatric to Adult Diabetes Transition Clinic at the University of Pennsylvania included a cohort of 72 emerging adults with type 1 diabetes, ages 18 to 25 years. Data were extracted from transfer summaries and the electronic medical record, including sociodemographic, clinical, and follow-up characteristics. Pre- and postprogram assessment at 6 months included mean daily blood glucose monitoring frequency (BGMF) and glycemic control (A1C). Paired t tests were used to examine change in outcomes from baseline to 6 months, and multiple linear regression was utilized to adjust outcomes for baseline A1C or BGMF, sex, diabetes duration, race, and insulin regimen. Open-ended survey responses were used to assess acceptability amongst participants. Results From baseline to 6 months, mean A1C decreased by 0.7% (8 mmol/mol), and BGMF increased by 1 check per day. Eighty-eight percent of participants attended ≥2 visits in 6 months, and the program was rated highly by participants and providers (pediatric and adult). Conclusions This study highlights the promise of an adult health care program model for pediatric to adult diabetes transition.

Perspectives on care for young adults with type 1 diabetes transitioning from pediatric to adult health systems: A national survey of pediatric endocrinologists.

BACKGROUND: Healthcare transition from pediatric to adult care for young adults (YA) with type 1 diabetes (T1D) is associated with risk of adverse outcomes. Consensus recommendations exist from US professional societies on transition care for YA with T1D, but it is not known whether they have been widely adopted. We describe experiences, barriers, and provider characteristics associated with transition care in a national sample of pediatric endocrinologists. METHODS: US pediatric endocrinologists identified through the American Medical Association Physician Masterfile were sent an electronic survey. RESULTS: Response rate was 16% (164/1020) representing 32 states. The majority of pediatric endocrinologists (age 44 ± 10; years in practice 12 ± 11) were female (67%) and worked in academic centers (75%). Main reasons for transfer were age (49%) and glycemic control (18%). Barriers to transition included ending long-therapeutic relationships with patients (74%), lack of transition protocols (46%), and perceived deficiencies in adult care (42%). The majority of pediatric endocrinologists reported lack of transition training (68%); those who received training were less likely to have difficulty ending patient relationships [odds ratio (OR) = 0.39, P = .03], more likely to perform patient record transfer to adult systems (OR=1.27, P = .006), and less likely to report patient returns to pediatric care after transfer (OR=0.49, P = .01), independent of endocrinologist gender, years in practice, or practice type. CONCLUSIONS: There is wide variation in transition care for YA with T1D among US pediatric endocrinologists despite consensus recommendations. Dissemination of educational programming on transition care and provision of actionable solutions to overcome local health system and perceived barriers is needed.

Challenges in recruiting subjects to a pilot trial of patient-managed in-hospital insulin.

BACKGROUND: To examine the feasibility of implementing clinician-supported inpatient self-managed insulin to aid in the planning of a randomized clinical trial. RESULTS: We conducted a proof-of-concept interventional study of inpatients with diabetes mellitus who had hospital orders for basal-bolus or sliding scale insulin. Patients meeting inclusion criteria were offered the opportunity to manage their own basal-bolus insulin with support from a diabetes nurse practitioner. Over a three-month screening period, we conducted 361 screens in 336 patients, only eleven of whom met all inclusion criteria. None of these eleven eligible patients elected to enroll. The most common reason for refusal was lack of interest in self-managing insulin while acutely ill (36 %). DISCUSSION: Future studies of patient-managed in-hospital insulin should consider enrolling less acutely ill patients with longer anticipated lengths of stay. TRIALS REGISTRATION: NCT02144441.

Effect of exenatide, sitagliptin, or glimepiride on ß-cell secretory capacity in early type 2 diabetes.

OBJECTIVE: Agents that augment GLP-1 effects enhance glucose-dependent ß-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on ß-cell secretory capacity, an in vivo measure of functional ß-cell mass, early in the course of T2D. RESEARCH DESIGN AND METHODS: We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIRarg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIRpot]), and 340 mg/dL (maximum arginine-induced insulin release [AIRmax]) hyperglycemic clamp conditions, in which AIRmax provides the ß-cell secretory capacity. RESULTS: The change in AIRpot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIRmax (P = 0.1). Within each group, the primary outcome measure, AIRmax, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGRmin) was also increased with glimepiride treatment (P < 0.05), and the change in AGRmin trended higher with glimepiride than with exenatide (P = 0.06). CONCLUSIONS: After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional ß-cell mass as measured by ß-cell secretory capacity, whereas glimepiride appeared to enhance ß- and α-cell secretion.

Measurement of waist circumference predicts coronary atherosclerosis beyond plasma adipokines.

OBJECTIVE: The association of plasma adipokines beyond waist circumference (WC) with coronary artery calcification (CAC), a measure of subclinical atherosclerosis, is unknown. DESIGN AND METHODS: Asymptomatic Caucasian individuals from two community-based cross-sectional studies (n = 1,285) were examined and multivariate analysis of traditional risk factors was performed, then WC and adipokines (adiponectin and leptin) were added. Incremental value of each was tested with likelihood ratio testing. RESULTS: Beyond traditional risk factors, WC (Tobit regression ratio 1.69, P < 0.001) and plasma leptin (1.57, P < 0.001) but not plasma adiponectin (P = 0.75) were independently associated with CAC. In nested models, neither adiponectin (χ(2) = 0.76, P = 0.38) nor leptin (χ(2) = 1.32, P = 0.25) added value to WC beyond traditional risk factors, whereas WC added incremental value to adiponectin (χ(2) = 28.02, P < 0.0001) and leptin (χ(2) = 13.58, P = 0.0002). CONCLUSION: In the face of important biomarkers such as plasma adiponectin and leptin, WC remained a significant predictor of CAC beyond traditional risk factors underscoring the importance of WC measurement during cardiovascular risk assessment.

Severe insulin resistance and hypertriglyceridemia after childhood total body irradiation.

OBJECTIVE: To characterize the metabolic phenotype of 2 cases of normal weight young women who developed type 2 diabetes (T2D), severe insulin resistance (insulin requirement >200 units/day), marked hypertriglyceridemia (>2000 mg/dL), and hepatic steatosis beginning 9 years after undergoing total body irradiation (TBI) and bone marrow transplantation for childhood cancer. METHODS: Fasting plasma glucose, insulin, free fatty acids (FFAs), leptin, adiponectin, resistin, TNFα, and IL-6 were measured in each case and in 8 healthy women; Case 1 was also assessed after initiating pioglitazone. Coding regions and splice junctions of PPARG, LMNA, and AKT2 were sequenced in Case 1 and of PPARG in Case 2 to evaluate for familial partial lipodystrophies. Genotyping of APOE was performed in Case 1 to rule out type III hyperlipoproteinemia. RESULTS: Both cases had elevated plasma levels of insulin, leptin, resistin, and IL-6, high-normal to elevated TNFα, and low to low-normal adiponectin in keeping with post-receptor insulin resistance and adipose tissue inflammation. Case 1 experienced a biochemical response to pioglitazone. No causative mutations for partial lipodystrophies or type III hyperlipoproteinemia were identified. CONCLUSION: Though metabolic derangements have previously been reported in association with TBI, few cases have described insulin resistance and hypertriglyceridemia as severe as that seen in our patients. We speculate that early childhood TBI may impede adipose tissue development leading to metabolic complications from an attenuated ability of adipose tissue to accommodate caloric excess, and propose that this extreme metabolic syndrome be evaluated for as a late complication of TBI.

Comparison of high-density lipoprotein cholesterol to apolipoprotein A-I and A-II to predict coronary calcium and the effect of insulin resistance.

High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance.

Usefulness of insulin resistance estimation and the metabolic syndrome in predicting coronary atherosclerosis in type 2 diabetes mellitus.

Metabolic syndrome (MS) definitions predict cardiovascular events beyond traditional risk factors in patients with type 2 diabetes mellitus (DM) as well as subjects without DM. It has been shown that apolipoprotein B (apoB) and non-high-density lipoprotein cholesterol are associated with coronary artery calcification in DM. However, the relative value of MS, apoB lipoproteins, and estimates of insulin resistance is unknown in predicting atherosclerosis in DM. Cross-sectional analyses of white subjects in 2 community-based studies were performed (n = 611 patients with DM, n = 803 subjects without DM) using multivariate analysis of traditional risk factors and then adding MS, apoB, and homeostasis model assessment of insulin resistance (HOMA-IR). Incremental value was tested using likelihood ratio testing. Beyond traditional risk, HOMA-IR (tobit regression ratio 1.86, p = 0.002), apoB (tobit regression ratio 1.55, p = 0.001), and MS (tobit regression ratio 2.37, p = 0.007) were independently associated with coronary artery calcification in DM. In nested models, HOMA-IR added value to apoB (tobit regression ratio 1.72, p = 0.008), MS (tobit regression ratio 1.72, p = 0.011), and apoB and MS (tobit regression ratio 1.64, p = 0.021). ApoB showed a similar pattern when added to HOMA-IR (tobit regression ratio 1.51, p = 0.004), MS (tobit regression ratio 1.46, p = 0.005), and HOMA-IR and MS (tobit regression ratio 1.48, p = 0.006). MS added to apoB (tobit regression ratio 1.99, p = 0.032) but not HOMA-IR (tobit regression ratio 1.54, p = 0.221) or apoB and HOMA-IR (tobit regression ratio 1.32, p = 0.434). In conclusion, insulin resistance estimates add value to MS and apoB in predicting coronary artery calcification scores in DM and warrant further evaluation in clinic for identification of patients with DM at higher risk for atherosclerotic cardiovascular disease.

Gender differences in the association of C-reactive protein with coronary artery calcium in type-2 diabetes.

OBJECTIVES: Plasma C-reactive protein (CRP) is associated with cardiovascular disease (CVD), but effects may vary by gender and degree of CVD risk. Whether CRP has value as a CVD risk marker in type-2 diabetes (T2DM) is unclear. We examined whether CRP has gender differences in association with coronary artery calcium (CAC) in diabetic and nondiabetic samples without clinical CVD. METHODS: We performed cross-sectional analyses of gender influence on CRP association with CAC in the Penn Diabetes Heart Study (N = 1299 with T2DM), the Study of Inherited Risk of Coronary Atherosclerosis (N = 860 nondiabetic subjects) and a combined sample. RESULTS: Female gender was associated with higher plasma CRP in diabetic and nondiabetic samples after adjustment for covariates. There was a strong interaction by gender in the association of CRP with CAC (interaction P < 0·001). In diabetic women, CRP was associated with higher CAC even after further adjustment for age, race, medications, metabolic syndrome, Framingham risk score and body mass index [Tobit ratio 1·60, 95% CI (1·03-2·47)]. Although this relationship was attenuated in nondiabetic women, the combined sample maintained this association in fully adjusted models [1·44, 95% CI (1·13-1·83)]. There was no association of CRP with CAC in either diabetic or nondiabetic men. CONCLUSIONS: CRP may be a useful marker of cardiovascular risk in women, particularly in diabetic women who otherwise have no known CVD. Prospective studies are needed to better assess the gender differences in CRP utility and the use of CRP in T2DM.

Type 2 diabetes does not attenuate racial differences in coronary calcification.

AIMS: Coronary artery calcification (CAC) is a strong predictor of atherosclerotic cardiovascular disease (CVD). Whites appear to have a higher prevalence of CAC than African-Americans (AAs), but it is unknown if type 2 diabetes, a major cardiovascular risk factor, attenuates this difference. We investigated the relationship of race and CAC in a sample of patients with type 2 diabetes without clinical CVD. METHODS: multivariable analyses of self-reported ethnicity and CAC scores, stratified by gender, in 861 subjects [32% AA, 66.9% male] with type 2 diabetes. RESULTS: AA race was associated with lower CAC scores in age-adjusted models in males [Tobit ratio for AAs vs. Whites 0.14 (95% CI 0.08-0.24, p<0.001)] and females [Tobit ratio 0.26 (95% CI 0.09-0.77, p=0.015)]. This persisted in men after adjustment for traditional, metabolic and inflammatory risk factors, but adjustment for plasma triglycerides [0.48 (95% CI 0.15-1.49, p=0.201)] and HOMA-IR [0.28 (95% CI 0.08-1.03, p=0.055)] partially attenuated the association in women. CONCLUSIONS: relative to African-Americans, White race is a strong predictor of CAC, even in the presence of type 2 diabetes. The relationship in women appears less robust possibly due to gender differences in metabolic risk factors.

Lipoprotein(a) is strongly associated with coronary artery calcification in type-2 diabetic women.

BACKGROUND: Lp(a), implicated in both atherogenesis and thrombosis pathways, varies significantly by demographic and metabolic factors, providing challenges for its use in Coronary Heart Disease (CHD) risk. The purpose of this study was to investigate whether type-2 diabetic subjects, relative to non-diabetics, might benefit more from Lp(a) measurement in the prediction of CHD risk, as measured by coronary artery calcium (CAC). METHODS: We performed cross sectional analyses in two community-based studies: the Penn Diabetes Heart Study [N = 1299 with type-2 diabetes] and the Study of Inherited Risk of Coronary Atherosclerosis [N = 860 without diabetes]. RESULTS: Blacks had 2-3 fold higher Lp(a) levels than whites in diabetic and non-diabetic samples. There was significant difference by gender (interaction p<0.001), but not race, in the association of Lp(a) with CAC in type-2 diabetic subjects. In age and race adjusted analysis of diabetic women, Lp(a) was associated with CAC [Tobit regression ratio 2.76 (95% CI 1.73-4.40), p<0.001]. Adjustment for exercise, medications, Framingham risk score, metabolic syndrome, BMI, CRP and hemoglobin A1c attenuated this effect, but the association of Lp(a) with CAC remained significant [2.25, (1.34-3.79), p = 0.002]. This relationship was further maintained in women stratified by race, or by the use of HRT or lipid lowering drugs. In contrast, Lp(a) was not associated with CAC in diabetic men, nor in non-diabetic men and women. CONCLUSIONS: Lp(a) is a strong independent predictor of CAC in type-2 diabetic women, regardless of race, but not in men. Lp(a) does not relate to CAC in men or women without type-2 diabetes.

Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus.

Fatty acid-binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.

Association of lower plasma fetuin-a levels with peripheral arterial disease in type 2 diabetes.

OBJECTIVE: Fetuin-A is an inhibitor of vascular calcification and a mediator of insulin resistance. This study evaluated the association of plasma fetuin-A and peripheral arterial disease (PAD). RESEARCH DESIGN AND METHODS: A total of 738 individuals with type 2 diabetes (mean age 58.7 years, 37.1% female) without known cardiovascular or kidney disease were included in this cross-sectional analysis. RESULTS: Subjects with PAD had a significantly lower fetuin-A (264.3 vs. 293.4 ng/dl, P < 0.001). In multivariable analysis, a 1-SD decrease in fetuin-A increased the odds of PAD (odds ratio 1.6, P = 0.02). Subgroup analysis revealed an increased odds even in subjects with glomerular filtration rate >80 (odds ratio 1.9, P = 0.05) or high-sensitivity C-reactive protein <3 mg/dl (odds ratio 2.7, P = 0.002). CONCLUSIONS: Lower circulating fetuin-A is associated with PAD in type 2 diabetes beyond traditional and novel cardiovascular risk factors. Our findings suggest a potentially unique role for fetuin-A deficiency as a biomarker of PAD in patients with type 2 diabetes.

Apolipoprotein B but not LDL cholesterol is associated with coronary artery calcification in type 2 diabetic whites.

OBJECTIVE: Evidence favors apolipoprotein B (apoB) over LDL cholesterol as a predictor of cardiovascular events, but data are lacking on coronary artery calcification (CAC), especially in type 2 diabetes, where LDL cholesterol may underestimate atherosclerotic burden. We investigated the hypothesis that apoB is a superior marker of CAC relative to LDL cholesterol. RESEARCH DESIGN AND METHODS: We performed cross-sectional analyses of white subjects in two community-based studies: the Penn Diabetes Heart Study (N = 611 type 2 diabetic subjects, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (N = 803 nondiabetic subjects, 52.8% men) using multivariate analysis of apoB and LDL cholesterol stratified by diabetes status. RESULTS: In type 2 diabetes, apoB was associated with CAC after adjusting for age, sex, and medications [Tobit regression ratio of increased CAC for 1-SD increase in apoB; 1.36 (95% CI 1.06-1.75), P = 0.016] whereas LDL cholesterol was not [1.09 (0.85-1.41)]. In nondiabetic subjects, both were associated with CAC [apoB 1.65 (1.38-1.96), P < 0.001; LDL cholesterol 1.56 (1.30-1.86), P < 0.001]. In combined analysis of diabetic and nondiabetic subjects, apoB provided value in predicting CAC scores beyond LDL cholesterol, total cholesterol, the total cholesterol/HDL cholesterol and triglyceride/HDL cholesterol ratios, and marginally beyond non-HDL cholesterol. CONCLUSIONS: Plasma apoB, but not LDL cholesterol, levels were associated with CAC scores in type 2 diabetic whites. ApoB levels may be particularly useful in assessing atherosclerotic burden and cardiovascular risk in type 2 diabetes.