Sex differences in type 2 diabetes: an opportunity for personalized medicine.

Over the past several decades, substantial ground has been gained in understanding the biology of sex differences. With new mandates to include sex as a biological variable in NIH-funded research, greater knowledge is forthcoming on how sex chromosomes, sex hormones, and social and societal differences between sexes can affect the pathophysiology of health and disease. A detailed picture of how biological sex impacts disease pathophysiology will directly inform clinicians in their treatment approaches and challenge canonical therapeutic strategies. Thus, a profound opportunity to explore sex as a variable in personalized medicine now presents itself. While many sex differences are apparent in humans and have been described at length, we are only beginning to see how such differences impact disease progression, treatment efficacy, and outcomes in obesity, type 2 diabetes, and cardiovascular disease. Here, we briefly present the most salient and convincing evidence of sex differences in type 2 diabetes detection, diagnostics, disease course, and therapeutics. We then offer commentary on how this evidence can inform clinicians on how to approach the clinical workup and management of different patients with diabetes. Finally, we discuss some gaps that remain in the literature and propose several research questions to guide basic and translational researchers as they continue in this growing area of scientific exploration.

For decades, most research in the laboratory and clinical settings focused primarily on males. However, more recently, grant-funding agencies, including the National Institutes of Health, have prioritized research that studies both males and females. This has dramatically improved our understanding of how biological sex impacts whether a person is at higher risk for developing a particular disease and what treatment options may be best to achieve the healthiest outcomes. This article offers the perspectives of practicing physicians and scientists on how our knowledge about biological sex may impact disease incidence, progression, treatment options, and outcomes in obesity, diabetes, and heart disease. The piece will offer a broad overview of the current science and personalized medicine approaches in these areas. It then discusses gaps in our knowledge and proposes several questions to guide future research.

Virilization of a 46,XX Fetus Following Aromatase Inhibitor Treatment of Breast Cancer.

Virilization of the 46,XX infant may be attributed to maternal or fetoplacental origin. Maternal sources may be endogenous, as with an androgen-producing tumor, or drug-related. Iatrogenic virilization by maternal drug exposure is rarely reported, with individual case reports and case series demonstrating the effects of progesterone and other medications affecting the pituitary-ovarian axis.1-3 The class of medications known as aromatase inhibitors are recognized as effective in treating hormone receptor-positive breast cancer by preventing the conversion of androgens into estrogens by aromatase. In fetal development, placental aromatase plays a critical role in preventing virilization of the XX fetus by maternal and fetal androgens during development. In the setting of placental aromatase deficiency, the XX fetus may be virilized. It is conceivable, therefore, that maternal exposure to aromatase inhibitors early in gestation may lead to in utero virilization, though there have been no known reports of this phenomenon to date. We present a case of virilization of a 46,XX infant attributed to pharmacologic aromatase inhibition. The infant's parents provided informed consent for the reporting of this case.

The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine.

Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in adults with pancreatic α cell hyperplasia and PNETs. We describe a 7-year-old girl with persistent hyperaminoacidemia, notable for elevations of glutamine (normal ammonia), alanine (normal lactate), dibasic amino acids (arginine, lysine and ornithine), threonine and serine. She initially was brought to medical attention by an elevated arginine on newborn screening (NBS) and treated for presumed arginase deficiency with a low protein diet, essential amino acids formula and an ammonia scavenger drug. This treatment normalized plasma amino acids. She had intermittent emesis and anorexia, but was intellectually normal. Arginase enzyme assay and ARG1 sequencing and deletion/duplication analysis were normal. Treatments were stopped, but similar pattern of hyperaminoacidemia recurred. She also had hypercholesterolemia type IIa, with only elevated LDL cholesterol, despite an extremely lean body habitus. Exome sequencing was initially non-diagnostic. Through a literature search, we recognized the pattern of hyperaminoacidemia was strikingly similar to that reported in the Gcgr -/- knockout mice. Subsequently the patient was found to have an extremely elevated plasma glucagon and a novel, homozygous c.958_960del (p.Phe320del) variant in GCGR. Functional studies confirmed the pathogenicity of this variant. This case expands the clinical phenotype of GCGR defect in children and emphasizes the clinical utility of plasma amino acids in screening, diagnosis and monitoring glucagon signaling interruption. Early identification of a GCGR defect may provide an opportunity for potential beneficial treatment for an adult onset tumor predisposition disease.

Intractable Hypoglycemia in the Setting of Autoimmune Overlap Syndrome.

Evaluation of hypoglycemia in a patient with known diabetes mellitus, although usually straightforward, can at times be challenging. We present the case of an 8 year-old Latina girl initially diagnosed with type 1 diabetes mellitus in the setting of multiple autoimmune disorders, including dermatomyositis and lupus nephritis. She subsequently developed signs of insulin resistance and severe hypoglycemia, which was found to be due to insulin-receptor autoantibodies. This condition, known as type B insulin resistance, is a rare, heterogeneous metabolic disease that may feature hypoglycemia in the setting of extreme insulin resistance and hyperinsulinemia and, in this case, masqueraded as type 1 diabetes mellitus. The presence of hypoglycemia in the setting of multiple autoimmune disorders should prompt consideration of autoimmune-mediated hypoglycemia. In addition to immunologic modifying therapies, advances in diabetes care in the form of continuous glucose monitoring have provided an additional tool to manage recurrent hypoglycemia.

High Overweight and Obesity in Fontan Patients: A 20-Year History.

The prevalence of obesity in long-term survivors with complex congenital heart disease may be increasing, and little is known about the timing and onset of weight gain and growth patterns in these high-risk patients. Prevalence rates of overweight/obesity and longitudinal changes in body mass index (BMI) with age were determined in 606 patients with Fontan circulation seen at a tertiary care cardiology center from 1992 to 2012. The number of clinic encounters (n) was stratified by age group (n = 401, 2-5 years; n = 333, 6-11 years; n = 217, 12-19 years; and n = 129, >20 years). Among adults, 39% were overweight/obese at last clinic visit; 22% overweight, and 17% obese. Childhood anthropometric data were available for 82 adults, of which 15% (n = 12/82) were overweight/obese in childhood. The likelihood of being overweight/obese as an adult was three times higher if there was a BMI ≥ 85th percentile in childhood (CI 2.1-4.5, P < 0.01). Overweight/obesity in adulthood was associated with lower heart failure rates (4 vs. 19%, P = 0.03). Pediatric rates of overweight/obesity were comparable to national data (NHANES 2011-2012) in every age group: at 2-5 years, (25 vs. 23%), 6-11 years (26 vs. 34%), and 12-19 years (15 vs. 35%). Systolic blood pressure was higher in overweight/obese children as young as 2-5 years of age. Childhood and adult survivors with Fontan circulation have high rates of overweight/obesity. Childhood obesity is a strong predictor of future adiposity and is linked to changes in systolic blood pressure at a very young age.

Permanent neonatal diabetes mellitus in monozygotic twins achieving low-dose sulfonylurea therapy.

Although KCNJ11 mutations of the KATP channel within the ß cell are known to prevent insulin secretion and cause permanent neonatal diabetes mellitus, the genotype-phenotype correlation continues to be of clinical interest. We report the clinical outcomes in monozygotic twins with neonatal diabetes due to heterozygous mutations in KCNJ11 at R201H. The twins demonstrated concordant clinical outcomes after transitioning from insulin to oral sulfonylurea therapy at 4 months of age. Both twins remained on sulfonylurea therapy while achieving similar growth, development, and metabolic goals. They exhibit marked sensitivity to sulfonylurea therapy with current dosing at 0.05 and 0.06 mg/kg per day at age 5 years which deviates from the approximate maintenance dose of 0.4 mg/kg per day at the time of transition and subsequent follow-up. Metabolic control provided by low-dose sulfonylurea therapy is likely due to early age at transition from insulin to sulfonylurea therapy and possible preservation of endogenous insulin secretion.

Exendin-4 normalizes islet vascularity in intrauterine growth restricted rats: potential role of VEGF.

Intrauterine growth restriction (IUGR) induced by uterine artery ligation in pregnant rats leads to low birth weight and early insulin secretory defects followed by the development of insulin resistance, decline in beta-cell mass, and diabetes in adulthood. Neonatal administration of Exendin-4 (Ex-4) prevents the deterioration of beta-cell mass and the onset of adult-onset diabetes. Our aim was to determine whether this effect occurs through preservation of islet vascularization. In 2 wk-old IUGR rats, endothelial-specific lectin staining revealed a 40% reduction in islet vascular density (p = 0.027), which was normalized by neonatal Ex-4. VEGF-A protein expression was reduced in IUGR islets compared with controls at postnatal d 1 (P). Neonatal Ex-4 normalized islet VEGF protein expression at P7. Neither IUGR nor Ex-4 administration to IUGR rats affected relative VEGF splice isoform RNA levels. Together, the reduced vascularity in IUGR islets before the deterioration of beta-cell mass, and the enhancement of VEGF expression and normalization of islet vascularity by neonatal Ex-4, suggest islet vascularity as an early determinant of beta-cell mass and as a potential therapeutic target for diabetes prevention.

Growth hormone releasing hormone plus arginine stimulation testing in young adults treated in childhood with cranio-spinal radiation therapy.

OBJECTIVE: Growth hormone deficiency (GHD) secondary to cranio-spinal radiation therapy (CSRT) is a complication seen in medulloblastoma survivors. The standard for diagnosis of adult GHD is a peak GH < 3 microg/l by the insulin tolerance test (ITT). However, insulin tolerance testing exposes patients to the risks of hypoglycaemia. Recent studies suggest that the GH releasing hormone + arginine (GHRH + ARG) test can identify GHD in cranially irradiated patients at longer time intervals after radiation. We evaluated the GHRH + ARG stimulation test compared to the ITT in young adults diagnosed with medulloblastoma during childhood. PATIENTS: We evaluated 10 young adult patients (age range 17-26 years) who were treated with CSRT during childhood for medulloblastoma, and who had resultant childhood-onset GHD. MEASUREMENTS: Subjects underwent GH provocative testing with the ITT and the GHRH + ARG test. IGF-I and IGFBP3 levels were also measured at baseline. RESULTS: Insulin tolerance testing and GHRH + arginine stimulation were performed at a mean +/- SD 14 +/- 4.4 years after cranial radiation. All patients failed the ITT with median peak GH 0.40 microg/l (range < 0.05-2.2). GHRH + arginine gave higher peak GH levels with a mean of 7.9 +/- 5.7 microg/l (P = 0.003). Four patients had peak GH > 9 microg/l and were between 7.8 and 19.6 years from cranial radiation. There was no correlation of peak GH levels with time interval since CSRT. Thirty-three per cent of subjects had normal IGF-I; neither IGF-I nor IGFBP3 standard deviation scores (SDS) correlated with ITT results. CONCLUSIONS: Using a GHRH + arginine cut-off for GHD of 9 microg/l, four patients would have been misclassified as GH sufficient, despite being > 7 years (with two patients being nearly 20 years) out from CSRT. These findings suggest that the pituitary GH-producing cells of young adults continue to maintain responsiveness to GHRH + arginine more than 5-10 years after cranial irradiation.