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Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). LEARNING OBJECTIVES: Upon completion of this educational activity, participants should be able to: Identify risk factors and learn when to suspect MODY-monogenic diabetes. Obtain appropriate diagnostic testing and evaluation prior to treatment. Determine appropriate monitoring and treatment for microvascular and macrovascular comorbidities. Recognize the recommended approach to treatment and monitoring that was performed in a patient with MODY-monogenic diabetes. TARGET AUDIENCE: This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.

Elderly patients with diabetes and poor glycemic control are at higher risk of complications. We examined the effects of utilizing a 3-month multidisciplinary team, including an endocrinologist, diabetes educator, and pharmacist, on glycemic control in order to extend specialized care and reduce therapeutic inertia in high-risk patients cared for by primary care physicians. The purpose of our study was intensification of medical management of high-risk elderly patients with diabetes through a quality improvement (QI) project with HbA1c value as the primary outcome. We identified 176 patients with diabetes in our primary care clinics who were >/= 50 years old and had a HbA1C >/= 9%. Of these, 22 patients were agreeable to be scheduled to follow up with a provider in our Endocrinology and Metabolism Institute as a new patient. In April 2020, baseline data was obtained (HbA1c, Albumin: Creatinine, blood pressure, BMI, lipid panel and 10-year ASCVD risk %). They were then seen by an endocrinologist and sequentially followed up by a clinical diabetes educator and a pharmacist. At the end of 12 weeks, post-intervention data was collected. Patients were then followed by their primary care physician as needed. Results: We enrolled 22 eligible patients with type 2 diabetes in our study. The mean age was 72 +/- 7 years with a pre-study HbA1c of 9.6 +/- 1.3%, BMI of 31.0 + 5.6 kg/m2, average albumin: creatinine of 195.1 +/- 298.3 mg/g. At the end of the study, the average HbA1c value was 7.6 +/- 0.9%, and represented a 2.0% decline (95% CI 8.0-9.3, p-value < 0.01). There was a 74.4 mg/g reduction in albuminuria (95% CI 61.1-282.4, p = 0.48) and a 0.5 kg/m2 increase in BMI (95% CI 29.0-33.4, p = 0.76). Conclusion: Through use of a 3-month strategic multi-disciplinary QI initiative in high-risk patients with diabetes, we significantly improved glycemic control measured by HbA1c. A limitation of our study was the small study size. Disclosure A. Iqbal: None. D. T. Broome: None. D. Isaacs: Consultant; Self; InPen, Insulet Corporation, LifeScan, Speaker’s Bureau; Self; Abbott Diabetes, Dexcom, Inc., Novo Nordisk, Xeris Pharmaceuticals, Inc. P. Rao: None.

Allgrove’s syndrome is an inherited condition caused by mutations in the AAAS gene (encoding the protein ALADIN) and is inherited in an autosomal recessive pattern (1). It classically is characterized by three specific features: achalasia, Addison’s disease, and alacrima (reduced or absent ability to secrete tears). This has led to the name “Triple A syndrome”, and some have suggested a 4th ‘A’ of autonomic disturbance (2). It is important to note that the phenotype of this condition is variable, and some patients may have all three (or four) of the manifestations at initial presentation, and that other patients may develop or have worsening of the ‘As’ over time. In this clinical vignette, we present a patient with Allgrove’s syndrome who developed clinical manifestations of the third ‘A’ of Addison’s disease later in life. A 46-year-old female patient presented to our tertiary referral center for follow-up of Allgrove’s disease after having been diagnosed with genetic testing as an adolescent. Prior to presentation, she underwent esophagectomy in 1995 and additionally had confirmed alacrima with ophthalmology. She was undergoing annual surveillance testing with 8 am cortisol and ACTH stimulation testing to monitor for the development of adrenal insufficiency. Prior to consultation, her baseline cortisol was 8.7 ug/dL. At presentation and the age of 46, her ACTH stimulation test (0.25 mg cosyntropin, 3 timepoints) was positive for adrenal insufficiency with a baseline cortisol of < 0.5 ug/dL (8 am), with 30-minute value of 4.4 ug/dL and 60-minute value of 6.3 ug/dL (peak). She was started on replacement dosing of hydrocortisone 20 mg at 8 am and 10 mg at 2 pm, in addition to calcium and vitamin D supplementation. Of note, her adrenal antibody (21-hydroxylase antibodies) were negative on two separate occasions. Allgrove’s syndrome is a rare condition described by the development of three, or at times four, characteristics with support of genetic testing. This case demonstrates that patients with Allgrove’s syndrome can present with two clinical manifestations of the condition (alicrima and achalasia) and develop the third (adrenal insufficiency) later in life. Therefore, regular screening for the missing clinical manifestation of this disease should be considered. References: 1. National Institute of Health: Genetic and Rare Disease Information Center. Triple A Syndrome. Genetics Home Reference. February 2010; http://ghr.nlm.nih.gov/condition/triple-a-syndrome. Accessed 2/1/2020. 2. Kimber J, McLean BN, Prevett M, Hammans SR. Allgrove or 4 “A” syndrome: an autosomal recessive syndrome causing multisystem neurological disease. J Neurol Neurosurg Psychiatry. 2003;74:654-657.

Context Preoperative imaging is performed routinely to guide surgical management in primary hyperparathyroidism, but the optimal imaging modalities are debated. Objective Our objectives were to evaluate which imaging modalities are associated with improved cure rate and higher concordance rates with intraoperative findings. A secondary aim was to determine whether additive imaging is associated with higher cure rate. Design, Setting, and Patients This is a retrospective cohort review of 1485 adult patients during a 14-year period (2004-2017) at an academic tertiary referral center that presented for initial parathyroidectomy for de novo primary hyperparathyroidism. Main Outcome Measures Surgical cure rate, concordance of imaging with operative findings, and imaging performance. Results The overall cure rate was 94.1% (95% confidence interval, 0.93-0.95). Cure rate was significantly improved if sestamibi/single-photon emission computed tomography (SPECT) was concordant with operative findings (95.9% vs. 92.5%, P = 0.010). Adding a third imaging modality did not improve cure rate (1 imaging type 91.8% vs. 2 imaging types 94.4% vs. 3 imaging types 87.2%, P = 0.59). Despite having a low number of cases (n = 28), 4-dimensional (4D) CT scan outperformed (higher sensitivity, specificity, positive predictive value, negative predictive value) all imaging modalities in multiglandular disease and double adenomas, and sestamibi/SPECT in single adenomas. Conclusions Preoperative ultrasound combined with sestamibi/SPECT were associated with the highest cure and concordance rates. If pathology was not found on ultrasound and sestamibi/SPECT, additional imaging did not improve the cure rate or concordance. 4D CT scan outperformed all imaging modalities in multiglandular disease and double adenomas, and sestamibi/SPECT in single adenomas, but these findings were underpowered.

Monogenic Diabetes (MODY) results from mutations or changes in a single gene, and currently account for about 1 to 4% of all cases of diabetes (1). Our group has previously published on the successful use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in three consecutive generations of a family with an HNF1A mutation (MODY-3) (2). Although GLP-1 RA therapy has been studied in patients with HNF1A mutations (MODY-3) (3), it has not been studied in patients with HNF4A mutations (MODY-1). In this father-son cohort, we demonstrate successful use of GLP-1 RA therapy in two patients with c.790:1 bp deletion of G; codon:264 mutations of HNF4A. The son first presented with neonatal hypoglycemia, then later developed diabetes and presented to our clinic at age 20, when genetic testing was performed and confirmatory for an HNF4A mutation. He was prescribed glimepiride and titrated to 4 mg twice daily, and two years later, his hemoglobin A1c (HbA1c) rose to 8.7%. He was switched to semaglutide 0.25 mg once weekly and was titrated to a maximum dose of 1 mg weekly over 8 weeks. The patient reports improvement in his post-prandial blood glucose values at this time, but HbA1c has not yet been repeated. The father had been diagnosed with monogenic diabetes in his early 20s and had been on sulfonylurea therapy until age 40, at which time he was transitioned to a regimen of long- and short-acting insulin therapy. Thereafter, he presented to our clinic in July, 2018 with a HbA1c of 9.6% and was transitioned to long-acting insulin once daily and liraglutide 0.6 mg once daily which was subsequently titrated to 1.8 mg once daily over 3 weeks. The patient tolerated this well and has been off short acting insulin since December 2018, with notable improvement in his HbA1c to 5.9% and marked improvement in his post-prandial glycemic control. To our knowledge this is the first report demonstrating the benefits of GLP-1 RA therapy in patients with the HNF4A mutations (MODY-1). Based on this report, it appears that GLP-1 RA therapy could be an effective therapy in patients with MODY-1. 1). Pihoker C, Gilliam LK, Ellard S, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. The Journal of Clinical Endocrinology and Metabolism. 2013;98(10):4055–4062. 2). Maricor Docena, Charles Faiman, Christine Stanley, and Kevin Pantalone (2014) Mody-3: Novel HNF1A Mutation and the Utility of Glucagon-Like Peptide (GLP)-1 Receptor Agonist Therapy. Endocrine Practice: February 2014, Vol. 20, No. 2, pp. 107–111. 3). Ostoft SH, Bagger JI, Hansen T, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37(7):1797–17805.

Primary hyperparathyroidism is characterized by excessive dysregulated production of parathyroid hormone (PTH) by 1 or more abnormal parathyroid glands. Preoperative localization is important for surgical planning in primary hyperparathyroidism. Previously, it had been published that ultrasound (sensitivity of 76.1%, positive predictive value of 93.2%) and nuclear scintigraphy (Sestamibi-SPECT) (sensitivity of 78.9%, and a positive predictive value of 90.7%) are first line imaging modalities1. Currently, the imaging modality of choice varies according to region and institutional protocol. The aim of this study was to evaluate the imaging modality that is associated with an improved remission rate based on concordance with operative findings. A secondary aim was to determine the effect of additive imaging on remission rates. This was an IRB-approved retrospective review of 2657 patients with primary hyperparathyroidism undergoing surgery at a tertiary referral center from 2004–2017. Analyses were performed with SAS software using a 95% confidence interval (p 1Kuzminski SJ, Sosa JA, Hoang JK. Update in Parathyroid Imaging. Magn Reson Imaging Clin N Am. 2018;26(1): 151–166.

Introduction: Hyponatremia is the most frequent electrolyte abnormality among hospitalized patients associated with increased morbidity and mortality. There is a demanding need for affordable and well-tolerated therapies, and urea is a compelling alternative for the syndrome of inappropriate diuretic hormone (SIADH). Urea increases renal water excretion due to osmotic diuresis and reduce urinary sodium leading to an increase in serum sodium. This case illustrates the effect and safe use of urea in a hospitalized patient with SIADH. Clinical Case: An 80-year-old male with history of recurrent anterior chest wall chondrosarcoma despite 3 chest wall resections presented to the hospital for a 4th anterior chest wall resection with reconstruction. Physical examination was notable for euvolemia with no neurologic deficits. Pre-operative labs were significant for a plasma sodium (PNa) 118 mmol/L, potassium 4 mmol/L, BUN 9 mg/dL, Cr 0.72 mg/dL, TSH 2.9 mIU/L, cortisol 21.3 mcg/dL, serum osmolality 267 mOsm/kg, urine osmolality 423 mOsm/kg, and urine sodium 115 mmol/L. Underlying SIADH was initially treated with water restriction of 800 mL/24 h. Previously, he was given a trial of salt tabs, which he did not tolerate due to nausea and emesis. Due to profound hyponatremia, he was started on 2% hypertonic saline. Once PNa levels reached 130 mmol/L, 2% saline was discontinued. Repeated PNa showed a decrease to 128mmol/L. Tolvaptan was not initiated due to lack of insurance coverage and hepatotoxicity, and demeclocycline was not considered due to his known allergy. He was ultimately started on urea powder at 15 g/day and tittered to 30 g/day. In one week PNa improved to 135 mmol/L and remained stable until discharge. Clinical Lessons: The cornerstone of therapy for SIADH relies on reducing free water intake but this is not always feasible or sufficient. Winzer et al. [1] showed that fluid restriction is effective in only 59% of the patient with SIADH. As a result, pharmacology therapy is often needed. European guidelines, as compared to American guidelines, recommend the use of urea instead of vaptans therapy as second-line treatment. The above is based on different studies [2] that have shown that urea has similar efficacy, is more cost-effective, and safer since it does not cause liver toxicity like vaptans. Given this response, it appears that urea should be considered as a second-line therapy to fluid restriction given its tolerability and cost-effectiveness when compared to its alternatives. References: 1. Winzeler B, Lengsfeld S, Nigro N, Suter-Widmer I, et al. Predictors of nonresponse to fluid restriction in hyponatremia due to the syndrome of inappropriate antidiuresis. J Intern Med 280: 609–617, 20162. Soupart A, Coffernils M, Couturier B, Gankam-Kengne F, et al. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol 7: 742–747

Objective The coexistence of insulinoma and insulin antibodies is extremely rare. The aim of this novel case report is to inform physicians of the possibility of an insulinoma with concomitant insulin antibodies. Methods In this report, we describe a patient with symptomatic hypoglycemia confirmed with a 72-hour fast, who was subsequently found to have an insulinoma with concomitant elevation in his immunoglobulin G insulin antibody titer. Results The patient presented with initial symptoms of diaphoresis, confusion, and disorientation and was found unresponsive by a bystander. He had a fingerstick blood glucose of 36 mg/dL (reference 74-99 mg/dL), without exogenous insulin or sulfonylurea use. His symptoms resolved with administration of glucose. He was subsequently admitted for a 72-hour fast in which he developed neuroglycopenic symptoms 4 hours into the fast with fingerstick glucose of 47 mg/dL and serum glucose of 44 mg/dL (reference 74-99 mg/dL), C-peptide of 10.8 ng/mL (reference 0.5-2.7 ng/mL), insulin level of 106 μIU/mL (reference

Machine learning (ML) is increasingly being studied for the screening, diagnosis, and management of diabetes and its complications. Although various models of ML have been developed, most have not led to practical solutions for real-world problems. There has been a disconnect between ML developers, regulatory bodies, health services researchers, clinicians, and patients in their efforts. Our aim is to review the current status of ML in various aspects of diabetes care and identify key challenges that must be overcome to leverage ML to its full potential. ML has led to impressive progress in development of automated insulin delivery systems and diabetic retinopathy screening tools. Compared with these, use of ML in other aspects of diabetes is still at an early stage. The Food & Drug Administration (FDA) is adopting some innovative models to help bring technologies to the market in an expeditious and safe manner. ML has great potential in managing diabetes and the future is in furthering the partnership of regulatory bodies with health service researchers, clinicians, developers, and patients to improve the outcomes of populations and individual patients with diabetes.

Objective: Clomiphene citrate-induced hypertriglyceridemia causing acute pancreatitis is rare. The aim of this case report is to alert physicians to the possibility of clomiphene citrate-induced hypertriglyceridemia that can lead to acute, and even chronic, pancreatitis.Methods: We describe a patient with known mild hypertriglyceridemia who presented with acute pancreatitis and severe hypertriglyceridemia after initiation of clomiphene citrate.Results: The patient had mid-epigastric tenderness with radiation around her bilateral flanks in a band-like distribution. Lab studies showed a triglyceride level greater than 4,425 mg/dL, a lipase level greater than 3,000 U/L, and computed tomography of the abdomen showed acute interstitial edematous pancreatitis. The patient's Naranjo Adverse Drug Reaction score was calculated to be a 7, and was therefore probable as clomiphene being the causative agent. The patient's triglyceride levels improved after initiation of fibrate therapy and discontinuation of clomiphene at first; however, she continued to develop acute episodes of pancreatitis that progressed to chronic pancreatitis despite stopping clomiphene citrate. This is the second report of recurrent pancreatitis with hypertriglyceridemia induced by clomiphene citrate and, in this case specifically, each episode of pancreatitis was associated with hypertriglyceridemia.Conclusion: Clomiphene citrate-induced hypertriglyceridemia rarely occurs and can progress to acute, and even chronic, pancreatitis with significant morbidity. Clomiphene citrate should be used with caution in patients with elevated triglycerides, and should be avoided in patients with triglyceride levels greater than 400 mg/dL.

Objective: To determine predictors of prolonged length of stay (LOS), 30-day readmission, and 30-day mortality in a multihospital health system. Methods: We performed a retrospective review of 531 adults admitted with diabetic ketoacidosis (DKA) to a multihospital health system between November 2015 and December 2016. Demographic and clinical data were collected. Linear regression was used to calculate odds ratios (ORs) for predictors and their association with prolonged LOS (3.2 days), 30-day readmission, and 30-day mortality. Results: Significant predictors for prolonged LOS included: intensive care unit (ICU) admission (OR, 2.12; 95% confidence interval [CI], 1.38 to 3.27), disease duration (nonlinear) (OR, 1.28; 95% CI, 1.10 to 1.49), non-white race (OR, 1.73; 95% CI, 1.15 to 2.60), age at admission (OR, 1.03; 95% CI, 1.01 to 1.04), and Elixhauser index (EI) (OR, 1.21; 95% CI, 1.13 to 1.29). Shorter time to consult after admission (median [Q1, Q3] of 11.3 [3.9, 20.7] vs. 14.8 [7.4, 37.3] hours, P

Tetratricopeptide repeat domain-7A (TTC7A) deficiency causing combined immunodeficiency with inflammatory bowel disease (IBD) is rare. This case report alerts physicians to the possibility of TTC7A deficiency causing combined immunodeficiency with IBD and also highlights some of the current treatment options. We describe a 19-year-old patient with a compound heterozygote TTC7A mutation causing combined immunodeficiency, IBD, and multiple intestinal atresia. Compound heterozygote TTC7A mutations are known to cause combined immunodeficiency and IBD. Although rare, clinicians should be alerted to this variant and should understand the general approach to treatment.

In this review, we have highlighted work that has clearly demonstrated that mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), a negative regulator of MAPKs, is an important signaling mediator in bone, muscle, and fat tissue homeostasis and differentiation. Further, we examined recent studies with particular focus on MKP-1 overexpression or deletion and its impact on tissues connected to bone. We also summarized regulation of MKP-1 by known skeletal regulators like parathyroid hormone (PTH)/PTH-related peptide (PTHrP) and bone morphogenic proteins. MKP-1's integration into the pathophysiological state of osteoporosis, osteoarthritis, rheumatoid arthritis, obesity, and muscular dystrophy are examined to emphasize possible involvement of MKP-1 both at the molecular level and in disease complications such as sarcopenia- or diabetes-related osteoporosis. We predict that understanding the mechanism of MKP-1-mediated signaling in bone-muscle-fat crosstalk will be a key in coordinating their activities and developing therapeutics to improve clinical outcomes for diseases associated with advanced age.

Maturity-onset diabetes of the young (MODY) is an inherited form of diabetes caused by a mutation in a single gene. The frequency of mutation carriers for HNF4A-MODY has been reported to be 1.2% (1). Our group has previously published on the successful use of glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy in three consecutive generations of a family with an HNF1A-MODY (2). Although GLP-1 RA therapy has been studied in patients with HNF1A-MODY (3), it has not been studied in patients with HNF4A-MODY. In this father-son cohort, we demonstrate successful use of GLP-1 RA therapy in two patients with c.790:1 bp deletion of G; codon:264 mutations of HNF4A. The son first presented with neonatal hypoglycemia, then later developed diabetes and …

Differentiation of adipocytes from preadipocytes contributes to adipose tissue expansion in obesity. Impaired adipogenesis may underlie the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mechanistically, a well defined transcriptional network coordinates adipocyte differentiation. The family of paired-related homeobox transcription factors, which includes Prrx1a, Prrx1b, and Prrx2, is implicated with regulation of mesenchymal cell fate, including myogenesis and skeletogenesis; however, whether these proteins impact adipogenesis remains to be addressed. In this study, we identify Prrx1a and Prrx1b as negative regulators of adipogenesis. We show that Prrx1a and Prrx1b are down-regulated during adipogenesis in vitro and in vivo. Stable knockdown of Prrx1a/b enhances adipogenesis, with increased expression of peroxisome proliferator-activated receptor-γ, CCAAT/enhancer-binding protein-α and FABP4 and increased secretion of the adipokines adiponectin and chemerin. Although stable low-level expression of Prrx1a, Prrx1b, or Prrx2 does not affect 3T3-L1 adipogenesis, transient overexpression of Prrx1a or Prrx1b inhibits peroxisome proliferator-activated receptor-γ activity. Prrx1 knockdown decreases expression of Tgfb2 and Tgfb3, and inhibition of TGFβ signaling during adipogenesis mimics the effects of Prrx1 knockdown. These data support the hypothesis that endogenous Prrx1 restrains adipogenesis by regulating expression of TGFβ ligands and thereby activating TGFβ signaling. Finally, we find that expression of Prrx1a or Prrx1b in adipose tissue increases during obesity and strongly correlates with Tgfb3 expression in BL6 mice. These observations suggest that increased Prrx1 expression may promote TGFβ activity in adipose tissue and thereby contribute to aberrant adipocyte function during obesity.

SummaryThe adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states.