Shubhada Jagasia

Gestational diabetes mellitus resulting from impaired β-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen

OBJECTIVE The objectives of the study were to determine whether the cell cycle transcription factor, FoxM1, is required for glucose homeostasis and β-cell mass expansion in maternal islets during pregnancy and whether FoxM1 is essential for placental lactogen (PL)-induced β-cell proliferation. RESEARCH DESIGN AND METHODS β-Cell mass, β-cell proliferation, and glucose homeostasis were assessed in virgin, pregnant, and postpartum mice with a pancreas-wide Foxm1 deletion (FoxM1Δpanc). Wild-type islets were cultured with or without PL and examined for Foxm1 induction. Transgenic mice overexpressing PL in β-cells were bred with FoxM1Δpanc mice, and β-cell proliferation was examined. RESULTS Foxm1 was upregulated in maternal islets during pregnancy. In contrast to controls, β-cell proliferation did not increase in pregnant FoxM1Δpanc females. Mutant islets showed increased Menin and nuclear p27. FoxM1Δpanc females developed gestational diabetes mellitus as pregnancy progressed. After parturition, euglycemia was restored in FoxM1Δpanc females, but islet size was significantly reduced. Strikingly, β-cell mass was normal in postpartum FoxM1Δpanc pancreata due to a combination of increased β-cell size and islet neogenesis. Evidence for neogenesis included increased number of endocrine clusters, increased proportion of smaller islets, and increased neurogenin 3 or insulin expression in cells adjacent to ducts. PL induced Foxm1 expression in cultured islets, and FoxM1 was essential for PL-mediated increases in β-cell proliferation in vivo. CONCLUSIONS FoxM1 is essential for β-cell compensation during pregnancy. In the absence of increased β-cell proliferation, neogenesis is induced in postpartum FoxM1Δpanc pancreata. Our results suggest that FoxM1 functions downstream of PL to mediate its effects on β-cell proliferation.

How I treat late effects in adults after allogeneic stem cell transplantation

More than 25,000 allogeneic hematopoietic stem cell transplantations (allo-HCTs) are expected to be performed worldwide in 2010, a number that has been increasing yearly. With broadening indications, more options for allo-HCT, and improvement in survival, by 2020 there may be up to half a million long-term survivors after allo-HCT worldwide. These patients have increased risks for various late complications, which can cause morbidity and mortality. Most long-term survivors return to the care of their local hematologists/oncologists or primary care physicians, who may not be familiar with specialized monitoring recommendations for this patient population. The purpose of this article is to describe practical approaches to screening for and managing these late effects, with the goal of reducing preventable morbidity and mortality associated with allo-HCT.

Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: results of a retrospective case review.

Lenalidomide is an antiangiogenic drug associated with hypothyroidism. We describe a case‐series of lenalidomide use in hematological cancers and the prevalence of thyroid abnormalities. We reviewed medical records of patients treated with lenalidomide at a single center form 2005 to 2010 and extracted demographic, clinical, and laboratory data. Of 170 patients with confirmed lenalidomide use (age 64.9±15 years), 148 were treated for multiple myeloma and 6% had thyroid abnormalities attributable only to lenalidomide. In patients with a previous diagnosis of thyroid dysfunction, the addition of lenalidomide therapy was associated with a higher incidence of subsequent TFTF abnormality (17%) as compared to patients with no previous diagnosis of thyroid dysfunction (6%) (P=0.0001). Many patients (44%) with pre‐existing disease and a change in thyroid function before or while on lenalidomide had no further follow‐up of their thyroid abnormalities, Of 20 patients who did not undergo any thyroid finction testing either before starting or while on lenalidomide for a median of 9.4 months (±6.5), 35% developed new symptoms compatible with hypothyroidism, including worsened fating, constipation or cold intolerance. Symptoms of thyroid dysfunction overlap with side effects of lenalidomide. Thyroid hormone levele are not regularly evaluated in patients on lenalidomide. While on this treatment, thyroid abnormalities can occur in patients with no previous diagnoses and in patients with pre‐existing abnormalities. Because symptoms of thyroid dysfunction could be alleviated by appropriate treatment, thyroid function should be evaluated during the course of lenalidomide to improve patients quality of life. Am. J. Hematol. 2011.

Diabetes mellitus after hematopoietic stem cell transplantation.

OBJECTIVE To review the current literature on posttransplant diabetes mellitus after hematopoietic stem cell transplantation, including its epidemiologic features, transplant-related risk factors, and treatment. METHODS A literature search was conducted in PubMed for articles on diabetes mellitus after hematopoietic stem cell transplantation and effects of immunosuppressants on glucose metabolism. RESULTS Within 2 years after hematopoietic stem cell transplantation, up to 30% of patients may have diabetes. Although some of these cases resolve, the rates of diabetes and metabolic syndrome remain elevated in comparison with those in the nontransplant patient population during long-term follow-up. Traditional risk factors for diabetes as well as features related to the transplantation process, including immunosuppressive medications, are associated with posttransplant diabetes. Cardiovascular risk also appears to be increased in this population. Limited data are available on hypoglycemic agents for posttransplant diabetes; thus, treatment decisions must be based on safety, efficacy, and tolerability, with consideration of each patients transplant-related medications and comorbidities. CONCLUSION Treatment of diabetes mellitus in patients who have undergone hematopoietic stem cell transplantation necessitates attention to the posttransplant medication regimen and clinical course. Although no guidelines specific to treatment of posttransplant diabetes in this patient population currently exist, treatment to goals similar to those for nontransplant patients with diabetes should be considered in an attempt to help reduce long-term morbidity and mortality.

Pretransplantation C-Peptide Level Predicts Early Posttransplantation Diabetes Mellitus and Has an Impact on Survival after Allogeneic Stem Cell Transplantation

Posttransplantation diabetes mellitus (PTDM) is a frequent complication after allogeneic stem cell transplantation (allo-SCT), important for its negative impact on cardiovascular health. Risk factors for PTDM are not well defined. We conducted a prospective study to investigate the risk factors and incidence for PTDM in the first 100 days after allo-SCT. A total of 84 patients completed the study, 60% of whom developed PTDM. In a multivariate logistic regression model, pretransplantation c-peptide level (>3.6 ng/mL; odds ratio [OR], 5.9; 95% confidence interval [CI], 1.77-20.22; P = .004), unrelated donor allo-SCT (OR, 4.3; 95% CI, 1.34-14.2; P = .014), and peak steroid dose >1 mg/kg/day (OR, 5.09; 95% CI, 1.19-23.2; P = .035) were identified as independent predictors of PTDM. In addition, overall survival (OS) was inferior in patients with PTDM compared with those without PTDM (mean survival, 2.26 years vs 2.7 years; P = .021). Pretransplantation c-peptide level greater than the cohort median (>3.6 ng/mL) also was associated with inferior OS (mean, 1.7 years vs 2.9 years; P = .012). In a multivariate Cox proportional hazards model, high-risk disease (hazard ratio [HR], 2.34; 95% CI, 1.09-5.28; P = .029) and pretransplantation c-peptide level >3.6 ng/mL (HR, 1.05; 95% CI, 1.01-1.09; P = .013) were independent predictors of OS when adjusted for systemic steroids and regimen intensity. We suspect that diabetes mellitus in the immediate posttransplantation period may be mediated via an inflammatory pathway that contributes to insulin resistance in the host adipose tissue. Our study is the first to report the risk factors of early PTDM in patients undergoing allo-SCT and identifies pretransplantation c-peptide as an independent predictor of diabetes and survival.

Type B insulin resistance syndrome associated with systemic lupus erythematosus.

OBJECTIVE To document a case of type B insulin resistance syndrome associated with systemic lupus erythematosus. METHODS We present the clinical course of a female patient with type B insulin resistance syndrome, from the onset, diagnosis, and empiric treatment until remission of her disease. RESULTS A 40-year-old African American woman with systemic lupus erythematosus presented with a relatively acute onset of severe hyperglycemia in January 2004. Her hyperglycemia was resistant to treatment with high doses of insulin (up to an equivalent dose of regular insulin of 4,500 units daily). The diagnosis of type B insulin resistance syndrome was confirmed after her insulin receptor antibody was found to be strongly positive. The patients hemoglobin Ale level improved substantially after she had been treated with azathioprine for 3 months. By November 2004, she was able to discontinue insulin therapy. Repeated insulin receptor antibody testing in February 2005 revealed that her insulin receptor antibody had become negative. The patients fasting glucose level became normal, and only occasional mild postprandial hyperglycemic episodes have been noted. CONCLUSION Immunosuppressive therapy with azathioprine seems to be responsible for our patients remission of type B insulin resistance, although the possibility of the occurrence of a spontaneous remission cannot be completely excluded.

Predicting posttransplantation diabetes mellitus by regulatory T-cell phenotype: implications for metabolic intervention to modulate alloreactivity.

Chronic inflammation and decreased frequency of regulatory T cells (Tregs) in visceral adipose tissue contribute to the propagation of insulin resistance to diabetes mellitus. We tested the hypothesis that new-onset posttransplantation diabetes mellitus (PTDM) is associated with measurable changes in Treg subsets after allogeneic hematopoietic stem cell transplantation (HSCT). PTDM before day 100 and Treg phenotype at engraftment were determined in 36 HSCT recipients without preceding history of diabetes mellitus. Among patients with new-onset PTDM (N = 24), the frequency of circulating CLA(+) (skin-homing) Tregs was decreased (1.53% vs 3.99%; P = .002) and the percentage of α(4)β(7)(+) (gut-homing) Tregs was increased (17.9% vs 10.7%; P = .048). In multivariate analysis, patients with PTDM continued to demonstrate elevated ratios of α(4)β(7)(+) Tregs to CLA(+) Tregs (odds ratio, 18.1; P = .020). PTDM is associated with altered immune regulation after HSCT and could represent a target to modulate alloreactivity.

Endocrine Complications in Long-Term Survivors After Allogeneic Stem Cell Transplant

As survival rates continue to increase after allogeneic stem cell transplant (allo-SCT), the associated long-term complications of transplant need to be taken into consideration. Here, we review the endocrine and metabolic complications associated with transplant survivors, including diabetes, dyslipidemia, hypertension, cardiovascular disease, hypogonadism, vitamin D deficiency, osteoporosis, thyroid disease, adrenal dysfunction, and pituitary disorders, and provide a brief summary of evaluation and treatment of these conditions.

Clinical markers implying the need for treatment in women with gestational diabetes mellitus.

OBJECTIVE To assess the association of the point-of-care hemoglobin A1c (POC A1C), fasting blood glucose (FBG), and BMI with fetal macrosomia and the need for medication in women with gestational diabetes (GDM). METHODS POC A1C, FBG, and BMI values at GDM diagnosis and fetal weight at delivery were obtained for women identified from a prospective patient registry. These outcomes were compared between women who did not require medication for GDM and women who did require medication. RESULTS Mean values of POC A1C, FBG, and BMI in 67 patients who required medication were higher than those in 71 patients who did not require medication (POC A1C: 5.72 ± 0.45% vs 5.35 ± 0.46% [P<.001]; FBG: 97.4 ± 12.3 mg/dL vs 86.4 ± 9.5 mg/dL [P<.001]; BMI: 35.4 ± 6.4 kg/m2 vs 30.4 ± 6.2 kg/m(2) [P<.001]). There was a modest correlation between POC A1C and FBG (Spearman rho 0.4, P<.001) and between POC A1C and BMI (Spearman rho 0.366, P<.001). Maternal POC A1C was not correlated with fetal weight at delivery (Spearman rho -0.010, P = .915). CONCLUSIONS Higher POC A1C, FBG, and BMI values were associated with the need for medication in women with GDM. The use of clinical markers to assess glycemic control sooner in pregnancy may lead to the earlier identification of women at risk for GDM and earlier intervention to decrease the risk for complications.

Disparities in Postpartum Follow-Up in Women With Gestational Diabetes Mellitus

IN BRIEF Postpartum follow-up for patients with gestational diabetes mellitus (GDM) is essential to manage future disease risk. In a diverse, urban population of GDM patients at a major medical center, high fasting glucose, high BMI at diagnosis, and low education level were associated with not following up in the endocrinology clinic after delivery; patients least likely to follow up are, therefore, also at greatest risk of GDM complications. Although race/ethnicity was not a significant predictor of follow-up, Hispanic/Latina and African-American patients were more likely to have risk factors for postpartum clinical attrition.