The Importance of Exclusion of Obstructive Sleep Apnea During Screening for Adrenal Adenoma and Diagnosis of Pheochromocytoma

Context . As catecholamine elevation is a key element in the diagnosis of pheochromocytoma, more commonplace causes of sympathetic excess, such as obstructive sleep apnea (OSA), should be excluded as standard practice prior to diagnosis. This is essential to avoid misdiagnosis of adrenal incidentalomas identified in the estimated 42 million Americans with OSA, with greater than 4 million projected to undergo a computed tomography study annually. Case Description . A 56-year-old woman presented with a several year history of paroxysmal hypertension, palpitations, and diaphoresis. Abdominal/pelvic computed tomography performed during an unrelated hospitalization revealed a 2-cm left-sided adrenal nodule initially quantified at 37 Hounsfield units. Posthospitalization, 24-hour urine normetanephrine level was markedly elevated. Reassessment 2 weeks later revealed continued normetanephrine excess. Following normal thyroid function tests, morning cortisol, aldosterone, and plasma renin activity, laparoscopic adrenalectomy was performed. Surgical pathology identified an adrenal cortical adenoma. As paroxysms continued postoperatively, repeat 24-hour urine metanephrines were measured, demonstrating essentially unchanged normetanephrine elevation. Search for an alternate cause ensued, revealing OSA with progressive continuous positive airway pressure noncompliance over the preceding year. Regular continuous positive airway pressure therapy was resumed, and at the end of 7 weeks, 24-hour urine normetanephrine levels had declined. Conclusion . Pheochromocytomas are rare and sleep apnea is common. However, the overlap of clinical symptoms between these disorders is substantial, as is their ability to produce catecholamine excess. Thus, excluding uncontrolled or undiagnosed OSA in high-risk patients should be standard practice before diagnosing pheochromocytoma

Roux en Y gastric bypass hypoglycemia resolves with gastric feeding or reversal: Confirming a non-pancreatic etiology

Objective: Postprandial hypoglycemia is an infrequent but disabling complication of Roux-en-Y gastric bypass (RYGB) surgery. Controversy still exists as to whether the postprandial hyperinsulinemia observed is due to inherent changes in pancreatic β-cell mass or function or to reversible alterations caused by RYGB anatomy. We aimed to determine if gastric feeding or reversal of RYGB would normalize postprandial glucose and hormone excursions in patients with symptomatic hypoglycemia. Methods: We completed a prospective study of six patients with severe symptomatic RYGB hypoglycemia who underwent RYGB reversal. An additional subject without hypoglycemia who underwent RYGB reversal was also studied prospectively. Mixed meal tolerance testing (MTT) was done orally (RYGB anatomy), via gastrostomy tube in the excluded stomach in the setting of RYGB, and several months after RYGB reversal. Results: All subjects reported symptomatic improvement of hypoglycemia after reversal of RYGB. Weight gain after reversal was moderate and variable. Postprandial glucose, insulin, and GLP-1 excursions were significantly diminished with gastric feeding and after reversal. Insulin secretion changed proportional to glucose levels and insulin clearance increased after reversal. Glucagon/insulin ratios were similar throughout study. We further compared the impact of modified sleeve gastrectomy reversal surgery to those with restoration of complete stomach and found no significant differences in weight regain or in postprandial glucose or hormone levels. Conclusions: Reversal of RYGB is an effective treatment option for severe postprandial hypoglycemia. The pathophysiology of this disorder is primarily due to RYGB anatomy resulting in altered glucose, gut, and pancreatic hormone levels and decreased insulin clearance, rather than inherent β-cell hyperplasia or hyperfunction. Keywords: Hypoglycemia, Insulin, Glucagon-like peptide 1, Roux en Y gastric bypass, Gastric bypass reversal, Bariatric surger

Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy

IL-6 is a pleiotropic cytokine with complex roles in inflammation and metabolic disease. The role of IL-6 as a pro- or anti-inflammatory cytokine is still unclear. Within the pancreatic islet, IL-6 stimulates secretion of the prosurvival incretin hormone glucagon-like peptide 1 (GLP-1) by α cells and acts directly on β cells to stimulate insulin secretion in vitro. Uncovering physiologic mechanisms promoting β-cell survival under conditions of inflammation and stress can identify important pathways for diabetes prevention and treatment. Given the established role of GLP-1 in promoting β-cell survival, we hypothesized that IL-6 may also directly protect β cells from apoptosis. Herein, we show that IL-6 robustly activates signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in autophagy. IL-6 stimulates LC3 conversion and autophagosome formation in cultured β cells. In vivo IL-6 infusion stimulates a robust increase in lysosomes in the pancreas that is restricted to the islet. Autophagy is critical for β-cell homeostasis, particularly under conditions of stress and increased insulin demand. The stimulation of autophagy by IL-6 is regulated via multiple complementary mechanisms including inhibition of mammalian target of rapamycin complex 1 (mTORC1) and activation of Akt, ultimately leading to increases in autophagy enzyme production. Pretreatment with IL-6 renders β cells resistant to apoptosis induced by proinflammatory cytokines, and inhibition of autophagy with chloroquine prevents the ability of IL-6 to protect from apoptosis. Importantly, we find that IL-6 can activate STAT3 and the autophagy enzyme GABARAPL1 in human islets. We also see evidence of decreased IL-6 pathway signaling in islets from donors with type 2 diabetes. On the basis of our results, we propose direct stimulation of autophagy as a novel mechanism for IL-6-mediated protection of β cells from stress-induced apoptosis.—Linnemann, A. K., Blumer, J., Marasco, M. R., Battiola, T. J., Umhoefer, H. M., Han, J. Y., Lamming, D. W., Davis, D. B. Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy

What the BTBR/J mouse has taught us about diabetes and diabetic complications

Summary: Human and mouse genetics have delivered numerous diabetogenic loci, but it is mainly through the use of animal models that the pathophysiological basis for their contribution to diabetes has been investigated. More than 20 years ago, we serendipidously identified a mouse strain that could serve as a model of obesity-prone type 2 diabetes, the BTBR (Black and Tan Brachyury) mouse (BTBR T+ Itpr3tf/J, 2018) carrying the Lepob mutation. We went on to discover that the BTBR-Lepob mouse is an excellent model of diabetic nephropathy and is now widely used by nephrologists in academia and the pharmaceutical industry. In this review, we describe the motivation for developing this animal model, the many genes identified and the insights about diabetes and diabetes complications derived from >100 studies conducted in this remarkable animal model

Plasma Prostaglandin E2 Metabolite Levels Predict Type 2 Diabetes Status and One-Year Therapeutic Response Independent of Clinical Markers of Inflammation

Over half of patients with type 2 diabetes (T2D) are unable to achieve blood glucose targets despite therapeutic compliance, significantly increasing their risk of long-term complications. Discovering ways to identify and properly treat these individuals is a critical problem in the field. The arachidonic acid metabolite, prostaglandin E2 (PGE2), has shown great promise as a biomarker of β-cell dysfunction in T2D. PGE2 synthesis, secretion, and downstream signaling are all upregulated in pancreatic islets isolated from T2D mice and human organ donors. In these islets, preventing β-cell PGE2 signaling via a prostaglandin EP3 receptor antagonist significantly improves their glucose-stimulated and hormone-potentiated insulin secretion response. In this clinical cohort study, 167 participants, 35 non-diabetic, and 132 with T2D, were recruited from the University of Wisconsin Hospital and Clinics. At enrollment, a standard set of demographic, biometric, and clinical measurements were performed to quantify obesity status and glucose control. C reactive protein was measured to exclude acute inflammation/illness, and white cell count (WBC), erythrocyte sedimentation rate (ESR), and fasting triglycerides were used as markers of systemic inflammation. Finally, a plasma sample for research was used to determine circulating PGE2 metabolite (PGEM) levels. At baseline, PGEM levels were not correlated with WBC and triglycerides, only weakly correlated with ESR, and were the strongest predictor of T2D disease status. One year after enrollment, blood glucose management was assessed by chart review, with a clinically-relevant change in hemoglobin A1c (HbA1c) defined as ≥0.5%. PGEM levels were strongly predictive of therapeutic response, independent of age, obesity, glucose control, and systemic inflammation at enrollment. Our results provide strong support for future research in this area

Overexpression of Pre-Pro-Cholecystokinin Stimulates β-Cell Proliferation in Mouse and Human Islets with Retention of Islet Function

Type 1 and type 2 diabetes result from a deficit in insulin production and β-cell mass. Methods to expand β-cell mass are under intensive investigation for the treatment of type 1 and type 2 diabetes. We tested the hypothesis that cholecystokinin (CCK) can promote β-cell proliferation. We treated isolated mouse and human islets with an adenovirus containing the CCK cDNA (AdCMV-CCK). We measured [3H]thymidine and BrdU incorporation into DNA and additionally, performed flow cytometry analysis to determine whether CCK overexpression stimulates β-cell proliferation. We studied islet function by measuring glucose-stimulated insulin secretion and investigated the cell cycle regulation of proliferating β-cells by quantitative RT-PCR and Western blot analysis. Overexpression of CCK stimulated [3H]thymidine incorporation into DNA 5.0-fold and 15.8-fold in mouse and human islets, respectively. AdCMV-CCK treatment also stimulated BrdU incorporation into DNA 10-fold and 21-fold in mouse and human β-cells, respectively. Glucose-stimulated insulin secretion was unaffected by CCK expression. Analysis of cyclin and cdk mRNA and protein abundance revealed that CCK overexpression increased cyclin A, cyclin B, cyclin E, cdk1, and cdk2 with no change in cyclin D1, cyclin D2, cyclin D3, cdk4, or cdk6 in mouse and human islets. Additionally, AdCMV-CCK treatment of CCK receptor knockout and wild-type mice resulted in equal [3H]thymidine incorporation. CCK is a β-cell proliferative factor that is effective in both mouse and human islets. CCK triggers β-cell proliferation without disrupting islet function, up-regulates a distinct set of cell cycle regulators in islets, and signals independently of the CCK receptors