Probucol normalizes cholesteryl ester transfer in type 2 diabetes.

AIMS: Accelerated cholesteryl ester transfer (CET) protein (CETP) activity is believed to promote macrovascular disease in patients with type 2 diabetes (T2D) by increasing the cholesterol burden of the apoB - containing triglyceride-rich lipoprotein (TGRLP) CE acceptors and promoting small dense LDL formation. While previous studies have shown that this same abnormality is present in patients with type 1 diabetes (T1D) and was normalized by the anti-oxidant drug probucol, its effects on CET in T2D are unknown. PATIENTS AND METHODS: The net mass transfer of CE from HDL to the apoB lipoproteins (VLDL+LDL) was studied in intact plasma from seven T2D patients before and two months after treatment with probucol (1g/day). RESULTS: Before treatment, CET was significantly greater than controls at 1 and 2h (p<.005). Recombination studies showed that this disturbance was attributable to dysfunction of VLDL and not due to altered behavior of HDL or CETP. Probucol treatment normalized CET in all subjects and significantly lowered plasma cholesterol (pre-Rx: 197±4.5 vs post-Rx: 162±27.1mg/dL; mean±S.D.; p<.025) and HDL-C (pre-Rx: 46.4±7.5 vs post-Rx: 39.1±4.0; p<.025) without changing glycemic control. CONCLUSIONS: By normalizing CET in T2D, probucol likely reduces the formation of atherogenic lipoproteins. This effect on CET is achieved through qualitative alterations in CETP's lipoprotein substrates and not through changes in CETP or HDL. Since probucol also has potent anti-oxidative and anti-inflammatory properties, it may have a new role to play in lipoprotein remodeling that reduce cardiovascular risk in T2D.

Diabetes knowledge in young adults: associations with hemoglobin A1C.

The purpose of this study was to quantify associations between hemoglobin A1C (A1C) and diabetes knowledge score using an assessment tool developed to evaluate the level of diabetes knowledge in young adults with Type 1 diabetes (T1DM) and their parent/primary caregiver. Seventy-five participants with T1DM, ages 15-22 years, completed questionnaires. Two 25-item questionnaires were developed: one for patient and one for caregiver. Linear regression quantified associations between correct items on the tools and participant A1C and demographic characteristics. Mean age of participants was 16.7 ± 1.7 years, diabetes duration 5.9 ± 4.2 years, 46.7% male, 74.7% Caucasian, 69.3% on multiple daily injections, and 30.7% on continuous subcutaneous insulin infusion therapy; 78.7% of parents/caregivers completed the questionnaire. A significant interaction was observed between patient and caregiver scores with A1C by diabetes duration. Among patients with diabetes <6 years, higher patient and caregiver scores were associated with lower A1C (-0.25 ± 0.11, p = .03 and -0.59 ± 0.19, p = .005, respectively) accounting for age, gender, race, therapy, and insurance. Neither patient nor caregiver score was associated with A1C in patients with diabetes duration ≥6 years. Better performance on a diabetes knowledge assessment (for both patient and the caregiver) was found to be associated with more favorable levels of glycemic control among young adults with diabetes <6 years. Additional evaluation of these questionnaires and novel interventions to enhance knowledge in this population are needed.

A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes.

BACKGROUND: We conducted a randomized and unblinded 2 × 2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. METHODS: Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor-withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. RESULTS: Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose-rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. CONCLUSION: The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.

Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia.

BACKGROUND: Rabbit anti-thymocyte globulin (rATG) induction reduces reperfusion injury and improves renal function in kidney recipients by means of properties unrelated to T-cell lysis. Here, we analyze intensive rATG induction (single dose, rATG(S) , vs. divided dose, rATG(D) ) for improved renal function and protection against hyperglycemia. METHODS: Patients without diabetes (n = 98 of 180) in a prospective randomized trial of intensive rATG induction were followed for six months for the major secondary composite end point of impaired glucose regulation (hyperglycemia and new-onset diabetes after transplantation, NODAT). Prospectively collected data included fasting blood glucose and HbA(1c). Serum Mg(++) was routinely collected and retrospectively analyzed. RESULTS: Induction with rATG(S) produced less impaired glucose regulation (p = 0.05), delayed NODAT development (p = 0.02), less hyperglycemia (p = 0.02), better renal function (p = 0.04), and less hypomagnesemia (p = 0.02), a factor associated with a lower incidence of NODAT. Generalized linear modeling confirmed that rATG(S) protects against a synergistic interaction between tacrolimus and sirolimus that otherwise increased hypomagnesemia (p = 0.008) and hyperglycemia (p = 0.03). CONCLUSIONS: rATG(S) initiated before renal reperfusion improved early renal function and reduced impaired glucose regulation, an injury by diabetogenic maintenance agents (tacrolimus and sirolimus).

Approach to the patient with new-onset diabetes after transplant (NODAT).

New-onset diabetes after transplantation (NODAT) refers to the occurrence of diabetes in previously nondiabetic persons after organ transplantation. The incidence rates of NODAT vary by organ transplanted and posttransplant interval. The estimated rates at 12 months posttransplant are 20-50% for kidney transplants, 9-21% for liver transplants, and approximately 20% for lung transplants. NODAT is associated with increased risks of graft rejection, infection, cardiovascular disease, and death. Besides the traditional risk factors for type 2 diabetes (age, family history, obesity, and ethnicity), exposure to immunosuppressive agents often precedes the occurrence of NODAT. Identification of risk factors through pretransplant screening is desirable, as is prompt diagnosis and appropriate treatment. NODAT is consistent with type 2 diabetes and responds to the usual antidiabetes agents. However, severe hyperglycemia during the early posttransplant period may necessitate the use of iv insulin infusion. Also, high-dose glucocorticoid therapy for induction of immunosuppression (or treatment of acute rejection) may require the use of insulin therapy for glycemic control. After hospital discharge, close monitoring of blood glucose during the first month and every 3 months for the first year is recommended. Consideration should be given to drug toxicities or interactions when prescribing antidiabetes agents in the posttransplant patient. In addition to hyperglycemia, the control of comorbidities such as dyslipidemia and hypertension needs to be optimized. Future areas of investigation include the development of immunosuppressive regimens with minimal diabetogenic effects, determination of the role of glycemic control on graft survival, and interventions for primary prevention of NODAT.

Assessing treatment barriers in young adults with type 1 diabetes.

AIMS: The current study was designed to identify barriers that prevent young adults with DM1 from achieving glycemic control. METHODS: Eighty-three young adult patients with DM1 [age 22.2 ± 2.8 years (mean ± SD), duration diabetes 11.3 ± 5.6 years, HbA1c 8.8 ± 2.1%] completed a battery of surveys assessing potential barriers to achieving glycemic control. Results of questionnaires were correlated with the patient's most recent HbA1c, and a multiple regression analysis was conducted to determine what barriers were significantly associated with HbA1c levels. RESULTS: Questionnaires that significantly correlated with HbA1c levels included the Conflict Subscale of the Diabetes Responsibility and Conflict Scale (r = .55, p < .01), the Modified Barriers to Adherence Questionnaire (r = .42, p < .01), and the Hospital Anxiety and Depression Scale (r = .31, p < .05). An item analysis of the Modified Barriers to Adherence Scale suggested that patient confidence with carbohydrate counting was most statistically associated with HbA1c [F(3, 80) = 12.95, p < .01, R²=.35]. CONCLUSIONS: Results suggest that despite attempts to educate patients; barriers such as family conflict, psychological issues, and carbohydrate counting remain obstacles impeding glycemic control in young adults with DM1.

Intraocular pressure and aqueous humor flow during a euglycemic-hyperinsulinemic clamp in patients with type 1 diabetes and microvascular complications.

BACKGROUND: Microvascular complications, including retinopathy and nephropathy are seen with type 1 diabetes. It is unknown whether functional changes in aqueous humor flow or intraocular pressure (IOP) develop in parallel with these complications. This study was designed to test the hypothesis that clinical markers of microvascular complications coexist with the alteration in aqueous humor flow and IOP. METHODS: Ten patients with type 1 diabetes and ten healthy age- and weight-matched controls were studied. Aqueous flow was measured by fluorophotometry during a hyperinsulinemic-euglycemic clamp (insulin 2 mU/kg/min). Intraocular pressure was measured by tonometry at -10, 90 and 240 minutes from the start of the clamp, and outflow facility was measured by tonography at 240 minutes. RESULTS: During conditions of identical glucose and insulin concentrations, mean aqueous flow was lower by 0.58 microl/min in the diabetes group compared to controls (2.58 +/- 0.65 versus 3.16 +/- 0.66 microl/min, respectively, mean +/- SD, p = 0.07) but statistical significance was not reached. Before the clamp, IOP was higher in the diabetes group (22.6 +/- 3.0 mm Hg) than in the control group (19.3 +/- 1.8 mm Hg, p = 0.01) but at 90 minutes into the clamp, and for the remainder of the study, IOP was reduced in the diabetes group to the level of the control group. Ocular pulse amplitude and outflow facility were not different between groups. Systolic blood pressure was significantly higher in the diabetes group, but diastolic and mean arterial pressures were not different. CONCLUSIONS: We conclude that compared to healthy participants, patients with type 1 diabetes having microalbuminuria and retinopathy have higher IOPs that are normalized by hyperinsulinemia. During the clamp, a reduction in aqueous flow was not statistically significant.

Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report.

BACKGROUND: The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. METHODS: Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3+/-11.6 months). RESULTS: There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated DeltaGFR (POD 1-4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). CONCLUSIONS: This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Glycemic control over 3 years in a young adult clinic for patients with type 1 diabetes.

OBJECTIVE: To evaluate the effect of specialized young adult diabetes clinic (YAC) on glycemic control in a young adult patients with type 1 diabetes (DM1) transitioning from pediatric to adult diabetes care. RESEARCH DESIGN AND METHODS: HbA1c was retrospectively analyzed through 3 years in 15-25 y/o DM1 patients entering a YAC, and compared to similar patients entering general endocrine clinics (GEC) in a university diabetes center. RESULTS: Ninety-six patients were seen in the YAC, compared to 153 patients in the GEC. No difference in HbA1c was seen at entry (YAC 9.0+/-2.3% versus 8.8+/-2.3%). HbA1c did not change over time in either clinic (mean 3-year HbA1c 8.6+/-2.1% in YAC versus 8.4+/-2.3% in GEC). When the HbA1c values were divided into tertiles, no differences in distribution of baseline HbA1c were seen. Within the highest tertile, the YAC had a greater fall in HbA1c, compared to the GEC. Pump users from both clinics had HbA1c values 1% lower at each time point. CONCLUSIONS: Young adults with DM1 continue to have difficulty achieving target HbA1c values. Earlier use of pump therapy and a specialized YAC for those with the worst glycemic control will benefit this population.

Aqueous flow in galactose-fed dogs.

Dogs fed galactose develop diabetes-like ocular complications that include keratopathy, cataracts, and retinopathy. The purpose of this study was to investigate whether galactosemic dogs display reduced aqueous flow similar to that observed in patients with insulin-dependent diabetes mellitus. Twelve male beagles at 9 months of age were divided into three groups of four. The Galactose group was fed diet containing 30% galactose for 97 months and the Reversal group was fed the galactose diet for an initial 38 months then standard dog diet for the remaining period. The Control group was fed standard dog diet for 97 months. Aqueous flow was determined by fluorophotometry in one eye per dog at 96 and 97 months after the initiation of galactose feeding. Intraocular pressure (IOP) was measured once in the morning by pneumatonometry. Anterior chamber depth was measured by A-scan. At the end of the experiment, eyes were enucleated and processed for histological examination. Dogs fed galactose diet for 97 months had significantly (p<0.05) increased body weights but similar IOP and anterior chamber depth compared to the other groups, and significantly (p=0.05) reduced aqueous flow compared to the control group (4.4+/-2.2 vs. 6.8+/-2.4 microl/min, mean+/-standard deviation, respectively). Additionally, aqueous flow decreased in the Reversal group to 3.1+/-1.3 microl/min (p=0.002). This decrease correlated with morphological changes of the ciliary processes. Like patients with insulin-dependent diabetes mellitus, galactose-fed dogs demonstrate reduced aqueous flow. This reduction was irreversible and independent of the retinopathy present. This animal model may be useful for the study of aqueous humor dynamics in diabetes.

New-onset diabetes after kidney transplantation: an application of 2003 International Guidelines.

BACKGROUND: The 2003 International Consensus Guidelines defined new-onset diabetes after transplantation. This study determined the risk of new-onset diabetes following kidney transplantation using these criteria. METHODS: Consecutive nondiabetic patients who received kidney transplantation between August 2001 and March 2003 (recent, n=61) and before August 2001 (earlier, n=61) were retrospectively evaluated. RESULTS: In all, 74% in the recent group and 56% in the earlier group developed diabetes by 1 year posttransplant. Median time to diabetes development was 23 days in the recent vs. 134 days in the earlier group (P=0.0304). Most patients developed diabetes within 60 days after transplantation. Immunosuppression was the strongest correlate of diabetes development; tacrolimus and cyclosporine A treatments were associated with increased risk. The rate of development was also greater when rapamycin was added to tacrolimus, compared to when it was not. The risk was double in African-Americans compared to whites. Age, body mass index, family history of diabetes, and etiology of renal failure did not predict diabetes; however, the mean age of patients was greater than previously reported. CONCLUSIONS: The majority of patients are at risk of developing new-onset diabetes within a short time after kidney transplantation. The risk may be due to preexisting risk factors, immunosuppressive agents, or older age. The significance of these findings is not clear, but demands appropriate follow-up studies related to glycemia, end-organ complications, and graft function. It remains to be determined whether the 2003 International Consensus Guidelines are adequate to appropriately diagnose diabetes in the posttransplant time period, with special emphasis on the first 3 months.

Comparison of CT and dual-energy DEXA using a modified trunk compartment in the measurement of abdominal fat.

The quantification of abdominal fat is a marker of health risk. While dual-energy x-ray absorptiometry (DEXA) is easily applied, it measures overall fat, although abdominal fat may be a better indicator of health risk from obesity. We have evaluated whether a subcomponent of DEXA measurements correlates better with computed tomography (CT) for body fat than those traditionally used. Forty-seven healthy adults (22 M/25 F), aged 54.5+/-15.8 yr (mean+/-SD), with BMI of 27.1+/-4.6 kg/m2 participated in a cross-sectional study. Body fat was measured using abdominal CT and DEXA for total fat, trunk fat, and a modified trunk measurement that excludes the chest, termed "lower trunk," and compared. The coefficient of variation for DEXA measurements for trunk, lower trunk, and total body were 1.98, 3.12, and 0.85%, respectively. Mean DEXA for percentage fat ranged from 31.7% to 34.1% for trunk, lower trunk, and total body, compared to 54.2% for abdominal CT (p<0.003 for each pairwise comparison). Lower trunk, whole trunk, and total body DEXA measurements were not different. Measurement of subcomponents of fat content by DEXA is not superior to whole body measurements and remains consistently lower than measurements by CT.

Heel ultrasonography is not a good screening tool for bone loss after kidney and pancreas transplantation.

BACKGROUND: Solid organ transplant recipients, particularly simultaneous pancreas kidney recipients, are at high fracture risk. We tested whether quantitative ultrasonography (QUS) of the heel predicts bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) in solid organ transplant recipients. METHODS: Thirty-eight transplant recipients (22 Female/16 Male) were studied. Spine and hip BMD was measured with a Hologic DXA scanner. 'Stiffness' of the heel was measured with a Lunar Ultrasound densitometer and compared with BMD by DXA. Contributing factors to bone loss were also assessed. RESULTS: Mean age was 43.1 +/- 1.3 yr. Simultaneous pancreas-kidney, kidney, and pancreas alone transplant recipients were assessed. Mean time post-transplantation was 3.0 +/- 0.6 yr. Mean DXA spine T-score was -1.15 +/- 0.22 (mean +/- SEM) and hip T-score was -1.22 +/- 0.20. There was no difference in mean T-score between women and men at the hip or spine. Mean right heel stiffness T-score was -0.97 +/- 0.25. There was no correlation between QUS and DXA at either the hip or spine in women or men. QUS had a false negative rate for identifying osteopenia or osteoporosis of 17% compared with DXA. The false positive rate for identifying osteopenia was 61%. CONCLUSIONS: The QUS is an unacceptable tool for identifying those at risk for bone loss after kidney or pancreas transplantation.

Pancreas transplantation improves vascular disease in patients with type 1 diabetes.

OBJECTIVE: Pancreas transplantation (PTX) normalizes glucose and improves microvascular complications, but its impact on macrovascular disease is still debated. RESEARCH DESIGN AND METHODS: Carotid intima-media thickness (IMT), shown to correlate with cardiovascular disease (CVD) risk and events, was determined prospectively by ultrasonography in successful pancreas transplant recipients to evaluate the effect of PTX on CVD risk. Carotid IMT and CVD risk factors of pancreas transplant recipients (n = 25) were compared with three groups: individuals with type 1 diabetes without significant nephropathy (n = 20), nondiabetic kidney transplant recipients (n = 16), and normal control subjects (n = 32). Mean age of pancreas transplant recipients at the time of transplantation was 42.4 +/- 1.2 years (mean +/- SE) and duration of diabetes was 25.9 +/- 1.4 years. RESULTS: After PTX, HbA(1c) level (P < 0.0001) decreased to normal and, whereas creatinine level (P = 0.0002) decreased, it remained elevated compared with normal control subjects (P < 0.05). Blood pressure, BMI, fasting lipid levels, smoking frequency, and use of hypolipidemic agents were unchanged. Mean carotid IMT was increased in pancreas transplant candidates but decreased by 1.8 +/- 0.1 year after PTX (P = 0.0068), no longer different from that in normal control subjects or patients with type 1 diabetes. CONCLUSIONS: Carotid IMT improves after successful PTX within 2 years of the procedure, with normalization of HbA(1c) and improved renal function, independent of changes in lipid levels, BMI, blood pressure, smoking, or use of hypolipidemic agents. This study suggests that CVD risk, future events, and mortality should improve after PTX in the absence of other significant, untreated CVD risk factors.