Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice.

Dysregulated glucagon secretion deteriorates glycemic control in type 1 and type 2 diabetes. Although insulin is known to regulate glucagon secretion via its cognate receptor (insulin receptor, INSR) in pancreatic alpha cells, the role of downstream proteins and signaling pathways underlying insulin's activities are not fully defined. Using in vivo (knockout) and in vitro (knockdown) studies targeting insulin receptor substrate (IRS) proteins, we compared the relative roles of IRS1 and IRS2 in regulating alpha cell function. Alpha cell-specific IRS1-knockout mice exhibited glucose intolerance and inappropriate glucagon suppression during glucose tolerance tests. In contrast, alpha cell-specific IRS2-knockout animals manifested normal glucose tolerance and suppression of glucagon secretion after glucose administration. Alpha cell lines with stable IRS1 knockdown could not repress glucagon mRNA expression and exhibited a reduction in phosphorylation of AKT Ser/Thr kinase (AKT, at Ser-473 and Thr-308). AlphaIRS1KD cells also displayed suppressed global protein translation, including reduced glucagon expression, impaired cytoplasmic Ca2+ response, and mitochondrial dysfunction. This was supported by the identification of novel IRS1-specific downstream target genes, Trpc3 and Cartpt, that are associated with glucagon regulation in alpha cells. These results provide evidence that IRS1, rather than IRS2, is a dominant regulator of pancreatic alpha cell function.

Signaling between pancreatic ß cells and macrophages via S100 calcium-binding protein A8 exacerbates ß-cell apoptosis and islet inflammation.

Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic ß cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in ß-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked ß-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives ß-cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent ß-cell loss in patients with diabetes.

Eplerenone improves carotid intima-media thickness (IMT) in patients with primary aldosteronism.

Primary aldosteronism (PA) is associated with a higher rate of cardiovascular events than essential hypertension. Although adrenalectomy has been reported to reduce carotid intima-media thickness (IMT) in patients with PA, the effects of the selective aldosterone blocker, eplerenone, on vascular damage in these patients remains unclear. To evaluate the effects of eplerenone on vascular status in PA patients, we sequentially measured carotid IMT (using computer software to calculate an average IMT for accurate and reproducible evaluation) in 22 patients including 8 patients treated by unilateral adrenalectomy and 14 patients treated with eplerenone for 12 months. Patients who underwent adrenalectomy showed significant reductions in aldosterone concentration (from 345 ± 176 pg/mL to 67 ± 34 pg/mL; P<0.01) and IMT (from 0.67 ± 0.07 mm to 0.63 ± 0.09 mm; P<0.05) 6 months after surgery. Patients treated with eplerenone showed significant reductions in IMT from baseline (0.75 ± 0.10 mm) to 6 (0.71 ± 0.11 mm; P<0.05) and 12 (0.65 ± 0.09 mm; P<0.01) months, although plasma aldosterone level increased significantly, from 141 ± 105 pg/mL to 207 ± 98 pg/mL (P<0.05). Eplerenone treatment of patients with PA reduces blood pressure, increases serum potassium level, and improves vascular status. Carotid IMT may be a useful marker for evaluating the effectiveness of eplerenone in patients with PA.

Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion.

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K cells in response to nutrient intake, especially fat. GIP is one of the contributing factors inducing fat accumulation that results in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secretion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in a 40% reduction of GIP response to fat but not to glucose in whole body FABP5-knockout (FABP5(-/-)) mice, with no change in K cell count or GIP content in K cells. In an ex vivo experiment using isolated upper small intestine, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid together with attenuated GIP response in the FABP5(-/-) sample. FABP5(-/-) mice exhibited a 24% reduction in body weight gain and body fat mass under a high-fat diet compared with wild-type (FABP5(+/+)) mice; the difference was not observed between GIP-GFP homozygous knock-in (GIP(gfp/gfp))-FABP5(+/+) mice and GIP(gfp/gfp)-FABP5(-/-) mice, in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat-induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner.

Transcriptional regulatory factor X6 (Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K-cells and is involved in GIP hypersecretion in high fat diet-induced obesity.

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K-cells in response to nutrient ingestion. GIP potentiates glucose-stimulated insulin secretion and induces energy accumulation into adipose tissue, resulting in obesity. Plasma GIP levels are reported to be increased in the obese state. However, the molecular mechanisms of GIP secretion and high fat diet (HFD)-induced GIP hypersecretion remain unclear, primarily due to difficulties in separating K-cells from other intestinal epithelial cells in vivo. In this study, GIP-GFP knock-in mice that enable us to visualize K-cells by enhanced GFP were established. Microarray analysis of isolated K-cells from these mice revealed that transcriptional regulatory factor X6 (Rfx6) is expressed exclusively in K-cells. In vitro experiments using the mouse intestinal cell line STC-1 showed that knockdown of Rfx6 decreased mRNA expression, cellular content, and secretion of GIP. Rfx6 bound to the region in the gip promoter that regulates gip promoter activity, and overexpression of Rfx6 increased GIP mRNA expression. HFD induced obesity and GIP hypersecretion in GIP-GFP heterozygous mice in vivo. Immunohistochemical and flow cytometry analysis showed no significant difference in K-cell number between control fat diet-fed (CFD) and HFD-fed mice. However, GIP content in the upper small intestine and GIP mRNA expression in K-cells were significantly increased in HFD-fed mice compared with those in CFD-fed mice. Furthermore, expression levels of Rfx6 mRNA were increased in K-cells of HFD-fed mice. These results suggest that Rfx6 increases GIP expression and content in K-cells and is involved in GIP hypersecretion in HFD-induced obesity.

Isolated Adrenocorticotropic Hormone (ACTH) Deficiency as an Immune-Related Adverse Event Following Combination Immune Checkpoint Inhibitor Therapy.

Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare condition characterized by the sole impairment of ACTH secretion among the various hormones produced by the pituitary gland. This leads to secondary hypoadrenocorticism, manifesting symptoms such as fatigue, anorexia, weight loss, and altered consciousness. Recently isolated ACTH deficiency has emerged as an immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs). In this report, we detail a case of isolated ACTH deficiency as a result of irAE. A 65-year-old man received nivolumab and ipilimumab combination therapy for esophageal cancer and approximately six weeks later, presented fatigue and anorexia, and was shown hyponatremia and hyperkalemia on blood test, and was diagnosed as isolated ACTH deficiency. Retrospective examination indicated an increase in eosinophils and a slight decrease in sodium levels shortly before thyrotoxicosis was diagnosed. These findings suggest the possibility of mild hypoadrenocorticism, potentially due to decreased ACTH secretion, existing prior to the recognition of adrenal insufficiency symptoms. Healthcare providers should maintain a heightened vigilance for eosinophilia and electrolyte imbalances during the administration of ICIs. The detection of even subtle abnormalities in these parameters should prompt immediate consultation with an endocrinologist.

Diabetic striatopathy: Hyperglycemic chorea/ballism successfully treated with L-dopa.

Diabetic striatopathy, a rare hyperglycemia complication, is characterized by chorea/ballism and striatal anomalies on neuroimaging, usually managed with glycemic control and haloperidol. However, practical strategies for haloperidol-resistant cases are scarce. We describe a 76-year-old Japanese woman with diabetic striatopathy who initially presented with polydipsia, polyuria, and lower-extremity weakness. Despite pronounced hyperglycemia (725 mg/dL), her blood glucose levels were reduced through saline infusion and intravenous insulin. Subsequently, she developed whole-body ballism concomitant with striatal hyperintensity on T1-weighted magnetic resonance imaging, which initially responded to haloperidol. Upon discontinuation of haloperidol, her symptoms relapsed and did not improve with the reintroduction of haloperidol. Dopamine transporter single photon emission computed tomography revealed diminished bilateral striatal uptake, suggesting presynaptic dopaminergic dysfunction. This finding prompted the initiation of L-dopa, which significantly improved her symptoms. This case underlines the need to consider presynaptic dopaminergic dysfunction in diabetic striatopathy patients unresponsive to standard treatments, highlighting the effectiveness of L-dopa in such scenarios.

Gestational Ectopic Hyperparathyroidism: A Case Report of Perioperative and Perinatal Outcomes.

In the realm of obstetric care, discerning the subtle signs of primary hyperparathyroidism (PHPT) amidst common pregnancy symptoms remains a formidable challenge. Our exploration into a case of gestational hypercalcemia peels back the layers of this complexity, revealing the clinical conundrum posed by overlapping gastrointestinal manifestations. The journey from diagnosis through surgical intervention to the resolution of symptoms underscores the importance of vigilance for PHPT in pregnant patients. This case further prompts consideration of gamma-aminobutyric acid (GABA) as a potential piece in the puzzle of persistent symptoms post-calcium normalization, inviting a broader dialogue on the intricacies of parathyroid pathology in pregnancy.

Reduced arterial stiffness in patients with acromegaly: non-invasive assessment by the cardio-ankle vascular index (CAVI).

In patients with acromegaly, cardiovascular diseases are the most common cause of death. Arterial stiffness is increasingly recognized as a valuable surrogate marker for predicting cardiovascular events. To evaluate the vascular status of acromegalic patients, we used the cardio-ankle vascular index (CAVI) to reflect the arterial stiffness from the heart to the ankles. We analyzed 21 acromegalic patients, comprising five patients with untreated active acromegaly, one patient treated with medication and 15 patients who underwent transsphenoidal surgery. Among the 15 patients with surgery, 10 received additional therapies with dopamine agonists and/or somatostatin analogs. All patients with acromegaly unexpectedly showed significant reductions in the CAVI, indicating reduced arterial stiffness, compared with age- and sex-matched controls, regardless of whether they underwent surgery. There was a significant negative correlation between the CAVI and the serum insulin-like growth factor (IGF)-I level in these patients. Active acromegalic patients were associated with lower CAVI than controlled patients. Sequential measurements of the CAVI and serum IGF-I before and after treatment with octreotide and transsphenoidal surgery revealed that a reduced IGF-I level after treatment was accompanied by CAVI elevation. The present findings indicate that the CAVI is negatively correlated with the serum IGF-I level in acromegaly. These findings are consistent with previous reports indicating that the GH/IGF-I axis reduces peripheral vascular resistance. This non-invasive assessment can reflect the present vascular status and would be a useful marker for evaluation of therapeutic effects in patients with acromegaly.

A Case of Lymphocytic Infundibulo-neurohypophysitis Exhibiting Spontaneous Regression.

Lymphocytic infundibulo-neurohypophysitis (LINH) is a rare autoimmune inflammatory process that selectively affects the neurohypophysis and the pituitary stalk, typically presenting with central diabetes insipidus (CDI). LINH is considered underdiagnosed because the definitive diagnosis requires invasive pituitary surgery with a high risk of complications. We present a case of CDI resulting from LINH, which was treated with conservative management, eschewing both glucocorticoid treatment and pituitary surgery. At presentation, the hormonal assessment indicated the presence of CDI without anterior pituitary dysfunction. Magnetic resonance imaging revealed stalk thickening without a posterior pituitary bright spot, and anti-rabphilin-3A antibodies were positive in serum. Collectively, we made a diagnosis of LINH. Considering that the patient did not exhibit any symptoms of mass effect, we chose conservative treatment with desmopressin acetate. One year later, the stalk thickening regressed spontaneously without surgical or glucocorticoid treatment, although the posterior pituitary bright spot remained absent, and CDI did not improve. The inflammatory process of LINH is mostly self-limited and recovers spontaneously, whereas life-long desmopressin treatment may be required because of pituitary stalk fibrosis and atrophy. Our case highlights the importance of noninvasive diagnosis and careful follow-up in preventing unnecessary interventions for patients with LINH.

Successful Treatment of Postprandial Hyperinsulinemic Hypoglycemia After Billroth-II Gastrojejunostomy Using Octreotide.

Postprandial hyperinsulinemic hypoglycemia, although rare, is a well-documented complication that can manifest after upper gastrointestinal surgery. Despite its potential for severe morbidity, the underlying pathogenesis and optimal treatment strategies for this condition remain insufficiently understood. This report presents a compelling case of postprandial hypoglycemia following Billroth-II gastrojejunostomy, characterized by a marked increase in postprandial insulin levels, accompanied by the exaggerated response of incretin hormones. The incretin effect in this patient was found to be exceptionally high, measuring at approximately 90%. While nutritional interventions proved ineffective in alleviating the patient's symptoms, the administration of octreotide significantly attenuated the exaggerated postprandial insulin and incretin response, substantially ameliorating both the symptoms and postprandial hypoglycemia. Monthly subcutaneous injections of long-acting repeatable octreotide were initiated, resulting in the complete resolution of symptomatic postprandial hypoglycemia. Although the patient developed acalculous cholecystitis and gallstone cholangitis 2 years after commencing octreotide therapy, she has remained free from symptomatic postprandial hypoglycemia for more than 4 years. Our case underscores the efficacy of somatostatin analogs in the management of postprandial hyperinsulinemia after gastrointestinal surgery, shedding light on the potential involvement of incretin hormones in the pathophysiology of this condition.

An unusual concomitance of acute heart failure: prolactinoma in a patient with left ventricular dysfunction-a case report.

Background: Heart failure concomitant with prolactinoma is extremely rare. Case summary: We present the case of a 29-year-old man who had acute decompensated heart failure concomitant with visual loss in his right eye. Transthoracic echocardiography indicated severely decreased left ventricular (LV) function. A massive tumour on the sella turcica was detected by brain computed tomography. The findings of the laboratory tests showed hyperprolactinaemia with hypopituitarism, and the antigen test for coronavirus disease 2019 was positive as an incidental finding. Medication for heart failure and cabergoline therapy were started immediately. His LV function significantly improved, and he had no symptoms after a year. Discussion: Prolactinoma in men, which can cause visual loss and hypopituitarism, is frequently substantial when diagnosed. The cardiac manifestation of prolactinoma is uncommon. It is believed that a major contributing component to the pathogenesis of peripartum cardiomyopathy is hyperprolactinaemia. Hyperprolactinaemia may cause endothelial damage and cardiomyocyte dysfunction, eventually resulting in LV dysfunction. The success of LV reverse remodelling may be significantly impacted by heart failure and hormone treatments. Heart failure and endocrine therapy should be administered concurrently to patients who have prolactinoma and congestive heart failure.

Fluorescein-based sensors to purify human α-cells for functional and transcriptomic analyses.

Pancreatic α-cells secrete glucagon, an insulin counter-regulatory peptide hormone critical for the maintenance of glucose homeostasis. Investigation of the function of human α-cells remains a challenge due to the lack of cost-effective purification methods to isolate high-quality α-cells from islets. Here, we use the reaction-based probe diacetylated Zinpyr1 (DA-ZP1) to introduce a novel and simple method for enriching live α-cells from dissociated human islet cells with ~95% purity. The α-cells, confirmed by sorting and immunostaining for glucagon, were cultured up to 10 days to form α-pseudoislets. The α-pseudoislets could be maintained in culture without significant loss of viability, and responded to glucose challenge by secreting appropriate levels of glucagon. RNA-sequencing analyses (RNA-seq) revealed that expression levels of key α-cell identity genes were sustained in culture while some of the genes such as DLK1, GSN, SMIM24 were altered in α-pseudoislets in a time-dependent manner. In conclusion, we report a method to sort human primary α-cells with high purity that can be used for downstream analyses such as functional and transcriptional studies.

Resolution of Visual Field Defect in Macroprolactinoma After Treatment With Cabergoline.

We report the case of a 49-year-old woman presenting with amenorrhea and progressive visual field defect for one month. Endocrinological workup revealed a high concentration of serum prolactin, and magnetic resonance imaging (MRI) showed pituitary macroadenoma with extrasellar extension as well as compression of optic nerves. Treatment with a dopamine agonist, cabergoline, for eight weeks led to the resolution of the visual field defect accompanied by a rapid decrease in the serum prolactin level. Follow-up MRI three months after the initial diagnosis revealed alleviation of visible mechanical compression of the optic chiasm by the tumor. We considered that the absence of retinal nerve damage and prompt initiation of cabergoline contributed to the rapid recovery of the visual acuity.

Exploring a Suitable Marker of Glycemic Response to Dulaglutide in Patients with Type 2 Diabetes: A Retrospective Study.

INTRODUCTION: Previous studies suggested that ß-cell function markers such as fasting and postprandial serum C-peptide and C-peptide increment (FCPR, PCPR, and ΔCPR, respectively) may be useful in estimating glycemic response to glucagon-like peptide-1 receptor agonists. However, it remains elusive whether baseline glycemic control confounds these markers. Here we aimed to identify the least confounded ß-cell function markers and investigate whether these markers could predict glycemic response to dulaglutide. METHODS: We evaluated FCPR, PCPR, and ΔCPR levels in patients with type 2 diabetes who initiated dulaglutide treatment after a standardized meal tolerance test (MTT). We first investigated the confounding effects of baseline HbA1c on ß-cell function markers using Pearson's correlation test. Then, we evaluated the association between each ß-cell function marker and glycemic response (HbA1c change 0-6 months) to dulaglutide using generalized linear model and logistic regression analysis with adjustment for baseline HbA1c. RESULTS: In 141 patients, baseline HbA1c was significantly inversely correlated with PCPR and ΔCPR (P < 0.01 for both) but not with FCPR (r = 0.02; P = 0.853), suggesting that FCPR was the marker least confounded by baseline glycemic control. Of all patients, 59 continued dulaglutide for at least 6 months without initiating any additional glucose-lowering medications. Mean ± SE HbA1c change 0-6 months was - 1.16 ± 0.17% (P < 0.001 vs. baseline). The ß-cell function markers were significantly associated with HbA1c change 0-6 months in the generalized linear model. FCPR was also a significant predictor for achieving a reduction in HbA1c of at least 1% (P = 0.044) with an area under the receiver operating characteristic curve of 0.83 (sensitivity = 0.81 and specificity = 0.79). CONCLUSION: Fasting and meal-induced C-peptide levels are associated with glycemic response to dulaglutide, among which FCPR is least confounded by baseline glycemic control, suggesting its utility as a marker for glycemic response to dulaglutide.

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19.

SARS-CoV-2 vaccinations have greatly reduced COVID-19 cases, but we must continue to develop our understanding of the nature of the disease and its effects on human immunity. Previously, we suggested that a dysregulated STAT3 pathway following SARS-Co-2 infection ultimately leads to PAI-1 activation and cascades of pathologies. The major COVID-19-associated metabolic risks (old age, hypertension, cardiovascular diseases, diabetes, and obesity) share high PAI-1 levels and could predispose certain groups to severe COVID-19 complications. In this review article, we describe the common metabolic profile that is shared between all of these high-risk groups and COVID-19. This profile not only involves high levels of PAI-1 and STAT3 as previously described, but also includes low levels of glutamine and NAD+, coupled with overproduction of hyaluronan (HA). SARS-CoV-2 infection exacerbates this metabolic imbalance and predisposes these patients to the severe pathophysiologies of COVID-19, including the involvement of NETs (neutrophil extracellular traps) and HA overproduction in the lung. While hyperinflammation due to proinflammatory cytokine overproduction has been frequently documented, it is recently recognized that the immune response is markedly suppressed in some cases by the expansion and activity of MDSCs (myeloid-derived suppressor cells) and FoxP3+ Tregs (regulatory T cells). The metabolomics profiles of severe COVID-19 patients and patients with advanced cancer are similar, and in high-risk patients, SARS-CoV-2 infection leads to aberrant STAT3 activation, which promotes a cancer-like metabolism. We propose that glutamine deficiency and overproduced HA is the central metabolic characteristic of COVID-19 and its high-risk groups. We suggest the usage of glutamine supplementation and the repurposing of cancer drugs to prevent the development of severe COVID-19 pneumonia.

A case of systemic lupus erythematosus complicated by subclinical Cushing's syndrome: case report.

An 18-year-old female was diagnosed with subclinical Cushing's syndrome (CS) due to a left adrenal adenoma. When she was 20 years old, she developed lupus nephritis. She was treated with high-dose prednisolone (PSL) and soon developed the symptoms of CS. When she was 25 years old, we evaluated her serum glucocorticoid level while she continued to take oral PSL. The result suggested her CS was affected by both the oral PSL and the endogenous cortisol secreted by the adrenocortical adenoma, which was therefore resected. Seven months after the operation, the patient's body weight was decreasing, and her SLE remained in clinical remission. CS complicated by SLE is rare, and the decision to surgically remove an adrenal tumor in such a case is even more rare.