Jessica L. Hwang

Steroid-induced diabetes: a clinical and molecular approach to understanding and treatment

Since the advent of glucocorticoid therapy for autoimmune disease in the 1940s, their widespread application has led to the concurrent therapy‐limiting discovery of many adverse metabolic side effects. Unanticipated hyperglycemia associated with the initiation of glucocorticoids often leads to preventable hospital admissions, prolonged hospital stays, increased risks for infection and reduced graft function in solid organ transplant recipients. Challenges in managing steroid‐induced diabetes stem from wide fluctuations in post‐prandial hyperglycemia and the lack of clearly defined treatment protocols. The mainstay of treatment is insulin therapy coincident with meals.

Sulfonylurea Treatment Before Genetic Testing in Neonatal Diabetes: Pros and Cons

CONTEXT Diabetes in neonates nearly always has a monogenic etiology. Earlier sulfonylurea therapy can improve glycemic control and potential neurodevelopmental outcomes in children with KCNJ11 or ABCC8 mutations, the most common gene causes. OBJECTIVE Assess the risks and benefits of initiating sulfonylurea therapy before genetic testing results become available. DESIGN, SETTING, AND PATIENTS Observational retrospective study of subjects with neonatal diabetes within the University of Chicago Monogenic Diabetes Registry. MAIN OUTCOME MEASURES Response to sulfonylurea (determined by whether insulin could be discontinued) and treatment side effects in those treated empirically. RESULTS A total of 154 subjects were diagnosed with diabetes before 6 months of age. A genetic diagnosis had been determined in 118 (77%), with 73 (47%) having a mutation in KCNJ11 or ABCC8. The median time from clinical diagnosis to genetic diagnosis was 10.4 weeks (range, 1.6 to 58.2 wk). In nine probands, an empiric sulfonylurea trial was initiated within 28 days of diabetes diagnosis. A genetic cause was subsequently found in eight cases, and insulin was discontinued within 14 days of sulfonylurea initiation in all of these cases. CONCLUSIONS Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available; however, larger numbers of cases must be studied. Given the potential beneficial effect on neurodevelopmental outcome, glycemic control, and the current barriers to expeditious acquisition of genetic testing, an empiric inpatient trial of sulfonylurea can be considered. However, obtaining a genetic diagnosis remains imperative to inform long-term management and prognosis.

Role of Noninsulin Therapies Alone or in Combination in Chromosome 6q24-Related Transient Neonatal Diabetes: Sulfonylurea Improves but Does Not Always Normalize Insulin Secretion

Chromosome 6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes caused by an overexpression of PLAGL1 and HYMAI (1). After remitting in infancy, diabetes recurs in most patients later in life. While the best treatment remains unknown, many patients are managed with insulin (1). We sought to characterize β-cell function and glucose homeostasis in patients with 6q24-TND and assess their response to sulfonylurea (SU) therapy. Adults with 6q24-TND and recurrence of hyperglycemia requiring insulin therapy later in life were identified through The University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry) and invited to participate in a trial of SU therapy. Four patients with insulin doses of 0.41–0.76 units/kg/day attempted the trial. Three were available for a mixed-meal test (MMT) and arginine stimulation test (AST) on day one and day five of SU treatment. All insulin products were withheld on the morning of day one. Subjects ingested 7 mL/kg (maximal 360 mL) of BOOST High Protein (http://www.boost.com) within 5 …

Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls.

KCNJ11‐related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls.

Utility of Heel Dual-Energy X-ray Absorptiometry in Diagnosing Osteoporosis

Although peripheral dual-energy X-ray absorptiometry measurements have been found to predict fractures in population studies of white subjects, little is known about their utility in other races and in patients with greater risk of fracture. In a cross-sectional study of 874 women referred for bone mineral density (BMD) testing, we examined the utility of heel BMD in African-American (AA) compared with Caucasian (CA) women and in women using glucocorticoids. The ability of heel T-score to predict central osteoporosis was similar in AA and CA women (odds ratio [OR] per 1 unit decrease in T-score of 2.79 [95% confidence interval {CI} 2.16-3.60] and 3.15 [95% CI 2.53-3.92], respectively). The association between heel T-score and prevalent vertebral fractures was also similar in the 2 groups (OR 1.46 [95% CI 1.15-1.85] in AA and 1.42 [95% CI 1.16-1.74] in CA). In women using glucocorticoids heel T-score was better than central T-score in predicting vertebral fractures (OR 1.38 [95% CI 1.03-1.85] and 1.22 [95% CI 0.86-1.73], respectively). We conclude that in a multiracial referral population heel BMD predicts central osteoporosis and prevalent vertebral fractures equally well in AA as in CA women and may be better than central BMD in assessing fragility in glucocorticoid users.

FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause “immune dysregulation, polyendocrinopathy (including insulin‐requiring diabetes), enteropathy, X‐linked” (IPEX) syndrome. This condition is often fatal unless patients receive a bone‐marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin‐requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole‐exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT‐PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice‐site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT‐PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early‐onset insulin‐requiring diabetes with or without other features of IPEX syndrome.

MODY3 and Pancreatic Transplant: Making a Case for Universal MODY Screening Before Transplant

ABSTRACT Objective: Maturity onset diabetes of the young (MODY) comprise a group of autosomal dominant forms of diabetes and account for approximately 1 to 2% of diabetes. Of these, MODY3 is the most common form, and patients are often misdiagnosed as having type 1 diabetes mellitus (T1D). Moreover, many of these patients develop end-stage renal disease. Because of this, there is frequent clinical discussion as to whether simultaneous pancreas and kidney transplantation is warranted. Although MODY3 can often be treated with sulfonylureas, many of these patients have never received this class of drugs. This raises an important clinical question: should sulfonylureanaive MODY3 patients undergo pancreas transplants? Methods: We present the case of a 31-year-old female with a history of T1D and end-stage renal disease. Results: After receiving a living-donor kidney transplant, the patients C-peptide level was detectable during evaluation for a pancreas transplant. Genetic testing was performed due to an exte...

Laparoscopic renal cryoablation of small renal tumors: An alternative treatment option in elderly patients at high risk

4767 Background: Minimally invasive management of small renal tumor is a reasonable alternative to open surgery in select patients. We determined the clinical utility and safety of laparoscopic renal cryoablation in elderly patients at high risk. Methods: Since December 2003, a total of 16 patients underwent laparoscopic renal cryoablation, of which 12 were considered elderly and at high risk, as defined by age 70 years or greater and American Society of Anesthesiologists (ASA) classification of 3 or greater. All patients had a solitary renal tumor measuring 2.5 to 4cm in maximal diameter (mean of 3cm). We retrospectively examined intraoperative parameters, perioperative complications and postoperative course in this cohort. Results: Median age of the 12 patients was 80 years (range 70 to 87). ASA class was 3 in all patients. Depending on the location of renal tumors, a retroperitoneal (6), transperitoneal (5) and a combined retroperitoneal/transperitoneal (1) approach was used. Laparoscopic ultrasound wa...