Parity and diabetes risk among hispanic women from Colombia: cross-sectional evidence.

OBJECTIVE: The association between parity and type 2 diabetes has been studied in developed countries and in Singapore and Chinese women but not in Hispanics. Herein we evaluated the association between parity (number of live births) with diabetes in a group of Hispanic postmenopausal women from Colombia. RESEARCH DESIGN AND METHODS: Herein we evaluated the association between parity and diabetes in a population of 1,795 women from Colombia. Women were divided in birth categories (0 [referent], 1 or 2, 3-5, 6 or > births). Medical history of diabetes and anthropometric characteristics were recorded. Logistic regressions were performed in order to find the association between parity and diabetes in bivariable and multivariable models after controlling for age, body mass index (BMI), waist hip ratio (WHR) and diabetes family history, among other variables. RESULTS: In our study, there was an association between parity and diabetes after adjusting for age, BMI and diabetes family history in the multiparous women groups when compared to the women with no births (Referent group) [1-2 births vs. referent OR 5.2 (95 CI 1.2-22.9), 3-5 births vs. referent OR 5.5 (1.3-23.0) and ≥6 births vs. referent OR 7.5 (1.8-31.8), respectively]. The association was maintained in two of the groups in the multivariable analysis [OR 5.0 (1.1-22.9) and 5.3 (1.2-23.5)], for 1 or 2 births and 6 or > births versus 0 births, respectively. Positive diabetes family history and WHR were also associated with an increased risk of diabetes [OR 4.6 (3.0-7.0) and 4.1 (2.0-8.1), respectively]. CONCLUSIONS: In postmenopausal Hispanic women, multiparity, as well as a positive family history of diabetes and a high waist-hip ratio were associated with higher diabetes risk.

"Creating hope" and other incentives for drug development for children.

Enhancing drug development for pediatric disease is a priority and a public responsibility. The Creating Hope Act of 2010 is important new proposed legislation that adds drugs and biologics for treating rare diseases in children to those for neglected tropical diseases as eligible for a priority review voucher from the U.S. Food and Drug Administration. The Act enhances existing incentive programs through specific financial benefits to companies who seek a pediatric indication for a new drug to treat an orphan disease that occurs specifically in children.

Nonalbumin proteinuria in islet transplant recipients.

The aim of this study was to evaluate the importance of nonalbumin-predominant proteinuria on kidney function (KF) after islet transplantation (ITx). Twenty-four-hour proteinuria and albuminuria were available in 27 recipients. KF was assessed by serum creatinine and estimated glomerular filtration rate (eGFR) was calculated by Modification of Diet in Renal Disease formula. Correlations between eGFR and albuminuria (r = -0.422, p < 0.001) were higher than with proteinuria (r = -0.223, p < 0.001; p = 0.006 for comparison between correlations). Nineteen (70%) subjects had proteinuria >or= 300 mg/24 h during the follow-up. Subjects were divided into three groups according to urinary protein excretion patterns: no proteinuria (n = 8), nonalbumin-predominant (n = 8), and albumin-predominant (n = 11) proteinuria. Proteinuria >or= 500 mg/24 h was observed only among patients with albumin-predominant proteinuria (64%; p = 0.002) and these patients had the lowest eGFR means post-ITx (no proteinuria: 84.2 +/- 16.4 vs. nonalbumin: 69.1 +/- 13.8 vs. albumin-predominant proteinuria: 65.5 +/- 16.6 ml/min/1.73 m(2), p = 0.044 for first vs. last group). In conclusion, high frequency of proteinuria was observed after ITx. However, it seems to be milder and have less impact on KF when albumin is not the major source of proteinuria. Prospective evaluation of proteinuria, including tubular function markers, should be performed to elucidate the mechanisms of kidney damage in this population.

Lipotoxicity and decreased islet graft survival.

OBJECTIVE To evaluate if baseline serum lipids are associated with islet graft survival in type 1 diabetes islet transplant (ITx) recipients. RESEARCH DESIGN AND METHODS Baseline fasting lipid profile was collected from 44 ITx recipients. Comparisons were performed between subjects below and above the median values of each lipid fraction. Differences in outcomes were compared by Kaplan-Meier curves and Cox regression analysis. RESULTS Subjects with baseline fasting plasma triglycerides and VLDL cholesterol above the median had shorter islet graft survival (triglycerides: 39.7 +/- 6.1 vs. 61.3 +/- 6.6 months, P = 0.029, and VLDL: 41.5 +/- 5.7 vs. 62.8 +/- 7.3 months, P = 0.032). Total, LDL, and HDL cholesterol did not influence islet function. Triglycerides (odds ratio 2.97 [95% CI 1.03-8.52], P = 0.044) maintained its association with graft failure after adjustments for confounders. CONCLUSIONS Higher baseline triglycerides are associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is directly caused by lipotoxicity and if strategies focusing on lowering serum lipids may prolong islet graft survival.

Clinical use of fructosamine in islet transplantation.

Many islet transplant recipients have medical conditions that could interfere with the accuracy of HbA1c measurements (e.g., anemia/dapsone use). Fructosamine is less prone to have clinical interferences and reflects glucose control in a shorter period of time than HbA1c. This study aimed to validate fructosamine use in islet transplant subjects and to evaluate its effectiveness as a predictor for islet graft dysfunction. Thirty-three islet transplant recipients who had concomitant fructosamine and HbA1c data available were retrospectively analyzed. HbA1c, fructosamine, mean capillary blood glucose, and islet graft function (fasting C-peptide/glucose ratio) were assessed. There was a significant and positive association between fructosamine and HbA1c (p < 0.0001). Both variables were also positively associated with mean overall and fasting capillary glucose. Neither fructosamine nor HbA1c was shown by ROC analysis to significantly discriminate between periods with and without subsequent graft dysfunction. HbA1c >6% was predictive of this outcome 1 month in advance (OR 2.95, p = 0.003). However, although significantly associated with graft dysfunction, use of this cutoff as a predictor of dysfunction has poor sensitivity (50%) and specificity (77.6%). Fructosamine above the normal range (>270 mumol/L Quest Diagnostics) was also predictive of ensuing dysfunction (OR 2.47, p = 0.03); however, it had similarly poor sensitivity (62%) and specificity (64%). Fructosamine can be used as an alternative to HbA1c for glycemic assessment in islet transplant recipients in situations with HbA1c assay interference. Neither HbA1c nor fructosamine are good predictors of islet graft dysfunction.

Type 2 diabetes mellitus phenotype and graft survival after islet transplantation.

BACKGROUND: Body fat accumulation decreases insulin sensitivity. It has being associated with earlier onset of type 1 diabetes mellitus (DM) and islet graft failure. The aim of this study was to evaluate whether insulin resistance, characterized by risk factors for type 2 DM, can predict islet graft survival in type 1 DM islet transplant (ITx) recipients. METHODS: Demographic, anthropometrical, and laboratory data, as well as family history of type 2 DM (first degree relatives), were collected from 44 ITx recipients. Risk factors for type 2 DM, such as positive family history of type 2 DM (n=11) and overweight (body mass index >25 kg/m2; n=14), were analyzed separately and in combination, which was designated as "type 2 DM phenotype" (n=5). Differences in outcomes (time-to-graft dysfunction and failure) were compared using Kaplan-Meier curves. Cox regression analysis was performed to control for possible confounding factors. RESULTS: Neither positive family history of type 2 DM nor overweight at baseline could predict islet function outcomes after ITx. However, when both risk factors were grouped, the "type 2 DM phenotype" was associated with earlier islet graft failure (mean estimate graft survival 25.7+/-9.1 vs. 54.1+/-5.2 months, P=0.022). These results were sustained after adjustments for confounding variables (OR 5.20, 95% CI 1.12-24.0). CONCLUSIONS: Predisposition for type 2 DM can coexist with the type 1 DM phenotype and is associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is associated with decreased insulin sensitivity and if insulin sensitizers play a role in prolonging islet graft survival.

Stable renal function after islet transplantation: importance of patient selection and aggressive clinical management.

BACKGROUND: Proteinuria development and decrease in glomerular filtration rate (GFR) have been observed after successful islet transplantation. The aim of this study was to determine clinical, laboratory, and immunosuppressant-related factors associated with kidney dysfunction in islet transplant recipients. METHODS: A retrospective cohort study was conducted in 35 subjects submitted to pancreatic islet transplantation for treatment of unstable type 1 diabetes mellitus. Demographic, anthropometrical, and laboratory data, as well as immunosuppressive and antihypertensive therapy were recorded. Kidney function was assessed by albuminuria and estimated GFR (eGFR), calculated by modification of diet in renal disease formula. RESULTS: Age was the only independent risk factor for low eGFR (<60 mL/min/1.73 m2) (odds ratio [OR]=1.78 [1.22-2.61]). Low-density lipoprotein cholesterol (OR=2.90 [1.37-6.12]) and previous microalbuminuria (OR=6.42 [1.42-29.11]) were risk factors for transient macroalbuminuria. Interestingly, tacrolimus was a protective factor for macroalbuminuria (OR=0.12 [0.06-0.26]). Six of 30 (20%) normoalbuminuric subjects at baseline progressed to microalbuminuria. No subject developed sustained macroalbuminuria. Surprisingly, overall eGFR remained stable during follow-up (before transplant: 74.0+/-2.0; during immunosuppressive therapy: 75.4+/-2.8; and after withdrawal: 76.3+/-5.3 mL/min/1.73 m2; P>0.05). Even subjects with low eGFR and microalbuminuria at baseline (n=10) maintained stable values posttransplantation (61.13+/-3.25 mL/min/1.73 m2 vs. 63.32+/-4.36 mL/min/1.73 m2, P=0.500). CONCLUSIONS: Kidney function remained stable after islet transplantation alone. The unchanged kidney function found in this sample may be attributed to healthier kidney status at baseline and possibly to prompt treatment of modifiable risk factors. Aggressive treatment of risk factors for nephropathy, such as blood pressure, low-density lipoprotein cholesterol, and careful tacrolimus levels monitorization, should be part of islet transplant recipient care.

Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept.

BACKGROUND: Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the "Edmonton protocol." To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial. METHODS: Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up. RESULTS: Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test. CONCLUSION: These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.

Islet transplantation with alemtuzumab induction and calcineurin-free maintenance immunosuppression results in improved short- and long-term outcomes.

BACKGROUND: Only a minority of islet transplant recipients maintain insulin independence at 5 years under the Edmonton protocol of immunosuppression. New immunosuppressive strategies are required to improve long-term outcomes. MATERIALS AND METHODS: Three subjects with unstable type 1 diabetes mellitus underwent islet transplantation with alemtuzumab induction and sirolimus-tacrolimus maintenance for 3 months and then sirolimus-mycophenolic acid maintenance thereafter. Follow-up was more than 2 years. Comparison was with 16 historical subjects transplanted under the Miami version of the Edmonton protocol. RESULTS: Insulin independence was achieved in 2 of 3 alemtuzumab and 14 of 16 historical subjects. Those who did not achieve insulin independence only received a single islet infusion. Insulin-independence rates remained unchanged in the alemtuzumab group, but decreased from 14 of 16 (88%) to 6 of 16 (38%) in the historical group over 2 years. Insulin requirements increased in the historical group while remaining stable in the alemtuzumab group. Comparison of functional measures at 3 months suggested better engraftment with alemtuzumab (P=NS). Further comparison of alemtuzumab versus historical groups, up to 24 months, demonstrated significantly better: Mixed meal stimulation index (24 months, 1.0+/-0.08 [n=3] vs. 0.5+/-0.06 pmol/mL [n=6], P<0.01), mixed meal peak C-peptide (24 months, 5.0+/-0.5 [n=3] vs. 3.1+/-0.3 nmol/mL [n=6], P<0.05), HbA1c (24 months, 5.4+/-0.15 [n=3] vs. 6.3+/-0.12 pmol/mL [n=10], P<0.01). Administration of alemtuzumab was well tolerated. There was no increased incidence of infections in alemtuzumab subjects despite profound, prolonged lymphocyte depletion. CONCLUSIONS: Islet transplantation with alemtuzumab induction was well tolerated and resulted in improved short- and long-term outcomes. Further investigation is underway for validation.

Improved long-term health-related quality of life after islet transplantation.

BACKGROUND: Health related quality of life (HRQoL) is one of the most important outcomes to measure effectiveness of an intervention, especially for islet transplantation in which benefits should outweigh risks of long-term immunosuppression. This study aimed to evaluate long-term effects of islet transplantation and to outline possible influential factors. METHODS: Forty islet transplant recipients who completed 344 Health Status Questionnaires (HSQ 2.0) and 384 Diabetes Quality of Life Questionnaires (DQoL) between 2000 and 2007 were retrospectively reviewed. Assessments were analyzed in pretransplantation period, then every 3 months after the first infusion for 18 months and every 6 months thereafter. The mean follow-up posttransplantation was 40.8+/-21.9 months (9-72 months). RESULTS: Sustained improvement in DQoL-impact score was observed at all time-points posttransplantation. Similarly, worry and satisfaction scales were significantly better than pretransplant evaluation for most time-points. Four of eight HSQ 2.0 scales demonstrated a significant improvement at some time-points. Longitudinal analysis, after adjustments for potential confounding factors, showed significantly sustained improvement in impact scale up to 72 months. Longer diabetes duration, higher insulin dosage, and occurrence of adverse events had negative effects on HRQoL. Single islet infusion or islet after kidney transplant recipients showed the lowest values in HSQ 2.0. In contrast, subjects on exenatide therapy had significantly higher HSQ 2.0 scores. CONCLUSIONS: Islet transplantation is associated with long-term improvement in HRQoL. Exenatide usage had a positive effect whereas single islet infusion, islet after kidney transplantation, longer diabetes duration, higher insulin dosage, and adverse events had a negative impact on HRQoL scores.

Restoration of hypoglycemia awareness after islet transplantation.

OBJECTIVE: To determine the impact of islet transplantation (ITx) on hypoglycemia awareness in patients with unstable type 1 diabetes and its relation to islet function. RESEARCH DESIGN AND METHODS: A total of 31 ITx recipients were studied. Hypoglycemia unawareness was assessed using the Clarke hypoglycemic score (0 = no hypoglycemia; >or=4 = hypoglycemia unawareness). Subjects were grouped based on graft function: off-insulin (n = 8), graft dysfunction (on-insulin and stimulated C-peptide >or=0.3 ng/ml, n = 13), and graft failure (stimulated C-peptide <0.3 ng/ml, n = 10, evaluated 11.5 +/- 14.5 months after graft failure). RESULTS: The hypoglycemia score improved after ITx when compared with baseline values (before vs. after: 5.29 +/- 1.51 vs. 1.35 +/- 1.92, P < 0.001). This result was sustained even after patient stratification based on islet function (pre vs. post off-insulin: 5.63 +/- 2.00 vs. no hypoglycemia reported; graft dysfunction: 5.31 +/- 1.49 vs. 1.15 +/- 1.63, P < 0.001; and graft failure: 5.00 +/- 1.16 vs. 2.70 +/- 2.26, P = 0.014). CONCLUSIONS: The improved metabolic control achieved with ITx can restore hypoglycemia awareness in patients with type 1 diabetes, persisting even after islet graft failure.

The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects.

BACKGROUND: A current limitation of islet transplantation is reduced long-term graft function. The glucagon-like peptide-1 receptor agonist, exenatide (Byetta, Amylin Pharmaceuticals, CA) has properties that could improve existing islet function, prevent further loss of islet mass and possibly even stimulate islet regeneration. METHODS: This prospective study evaluated the safety, efficacy, and metabolic effects of exenatide in subjects with type 1 diabetes mellitus and islet allograft dysfunction requiring exogenous insulin. RESULTS: Sixteen subjects commenced exenatide, 12 continue (follow-up 214+/-57 days; range 108-287), four (25%) discontinued medication because of side effects. At 6 months, exogenous insulin was significantly reduced with stable glycemic control (0.15+/-0.02 vs. 0.11+/-0.025 U/kg per day; P<0.0001); three subjects discontinued insulin from 4, 5, and 9 U/day, respectively, two sustained insulin independence with A1c reduction below graft dysfunction criteria. Postprandial capillary blood glucose was significantly decreased (129.4+/-3.8 vs. 118.7+/-4.6 mg/dL; P<0.001), C-peptide and C-peptide-to-glucose ratio increased significantly by 5th and 6th months of treatment (ratio, 1.09+/-0.15 vs. 1.52+/-0.18; P<0.05). Weight loss more than 3 kg occurred in 8 of 12 (67%) subjects. Stimulation testing demonstrated improved glucose disposal and C-peptide secretion (glucose area under the curve 52,332+/-3,219 vs. 42,072+/-1,965; P=0.002 mg x min x dL, mixed meal stimulation index 0.50+/-0.06 vs. 0.66+/-0.09; P=0.03 pmol x mL), with marked suppression of glucagon secretion and progressive increase in amylin secretion. Side effects were more frequent and severe compared with published reports in type 2 diabetes, tolerated doses were lower. CONCLUSIONS: Exenatide was tolerated in this patient population after appropriate dose titration and there appeared to be gradual but sustained positive effects on glycemic control and islet graft function.

Current challenges in islet transplantation.

Allogeneic islet transplantation is becoming a treatment option for patients with unstable type 1 diabetes mellitus (T1DM). Around 80% of the islet recipients achieve insulin independence after one or two islet infusions under "Edmonton-like" immunosuppressive protocol, but only 10% will remain insulin independent over the long term. Islet transplantation leads to glucose stabilization, and severe hypoglycemia is prevented even in patients back on insulin injections. Thus, islet transplantation has achieved the proposed targets in patients with unstable T1DM: normalizing blood glucose and hemoglobin A(1c), preventing severe hypoglycemic episodes, and improving quality of life. The current aims of islet transplantation programs are to maintain the success achieved and to overcome remaining obstacles and limitations.

Association between low lean body mass and osteoporotic fractures after menopause.

OBJECTIVE: This study evaluated dual-energy x-ray absorptiometry-assessed whole-body bone-muscle relationship (bone mineral content/lean mass [BMC/LM]) as an indicator of its nonmechanical perturbations (ie, systemic) in pre- and postmenopausal women. A total of 3,205 women were studied, either healthy (no fracture [No Fx] groups, 1,035 premenopausal, 1,556 postmenopausal) or with recent fractures (Fx groups, 139 premenopausal, 475 postmenopausal) located at osteoporotic sites (hip, spine, long-bone metaphyses; Type II Fx, n = 386) or at other skeletal sites (Type I Fx, n = 228) to evaluate the impact of decreased muscle mass on fracture incidence before and after menopause. DESIGN: SD-scored graphs of BMC/LM proportionality were obtained from the No Fx groups as normal references. Based on the reference BMC versus LM curves obtained from their respective No Fx pre- and postmenopausal controls, BMC-LM SD scores were calculated for all women with fractures. RESULTS: BMC-LM SD scores in all premenopausal women with fractures and in Type I Fx postmenopausal women were similar to the reference. In contrast, SD scores in Type II Fx postmenopausal women were lower than the reference, especially in those with hip fractures. Except for Type II Fx postmenopausal women, all groups showed linear and similar BMC versus LM curves. Type II Fx postmenopausal women showed nonlinear relationships, with progressively decreasing BMC and BMC-LM SD scores as their LM decreased. CONCLUSIONS: Results suggest that both LM and BMC-LM SD scores can help to differentiate between systemic and mechanical (disuse-related) osteopenia/osteoporosis after menopause. Low LM values or BMC-LM SD scores seem to constitute additional fracture risk factors beyond those usually detected in premenopausal women or in women with other types of fractures. This application of dual-energy x-ray absorptiometry technology may lead to more effective diagnosis and treatment at low cost.

Nutritional status and behavior in subjects with type 1 diabetes, before and after islet transplantation.

BACKGROUND: To investigate whether changes of nutritional status and behavior are associated with islet transplantation (ITx) and to assess their possible mechanisms. METHODS: In this observational study, 52 subjects with type 1 diabetes, 30 of whom received ITx, underwent nutritional assessments. The study consisted of questionnaires complemented by a dietary intake recording, anthropometric measurements, and body composition analysis. Laboratory tests were also reviewed as part of the follow up. RESULTS: After ITx, significant reductions in body weight (3.7 kg; P<0.0001), body mass index (1.39 kg/m2; P<0.0001), waist circumference (3.96 cm; P=0.006), and fat weight (3.28 kg; P<0.01) were observed. The average consumption of carbohydrate and protein were also lower than pretransplant, together with some micronutrients (vitamins B12 and B6, zinc, and phosphorus). Insulin administration and changes in A1C were not associated with a significant change in anthropometric measurements. Subjects on exenatide after ITx showed significantly lower weight and body mass index than those not taking exenatide. CONCLUSIONS: ITx is associated with modifications in nutritional behavior and status. Drugs and health conditions are likely to be at least in part responsible for these changes, but a voluntary modification of eating habits by the patients also plays a role. Strict monitoring of nutritional parameters, counseling by experts in nutrition, and multivitamin/mineral supplement after ITx could be of benefit to the patients.