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The incidence of obesity is rapidly increasing worldwide. Obesity-associated insulin resistance has long been established as a significant risk factor for obesity-related disorders such as type 2 diabetes and atherosclerosis. Insulin plays a key role in systemic glucose metabolism, with the liver, skeletal muscle, and adipose tissue as the major acting tissues. Insulin receptors and the downstream insulin signaling-related molecules are expressed in various tissues, including vascular endothelial cells, vascular smooth muscle cells, and monocytes/macrophages. In obesity, decreased insulin action is considered a driver for associated disorders. However, whether insulin action has a positive or negative effect on obesity-related disorders depends on the tissue in which it acts. While an enhancement of insulin signaling in the liver increases hepatic fat accumulation and exacerbates dyslipidemia, enhancement of insulin signaling in adipose tissue protects against obesity-related dysfunction of various organs by increasing the capacity for fat accumulation in the adipose tissue and inhibiting ectopic fat accumulation. Thus, this "healthy adipose tissue expansion" by enhancing insulin sensitivity in adipose tissue, but not in the liver, may be an effective therapeutic strategy for obesity-related disorders. To effectively address obesity-related metabolic disorders, the mechanisms of insulin resistance in various tissues of obese patients must be understood and drugs that enhance insulin action must be developed. In this article, we review the potential of interventions that enhance insulin signaling as a therapeutic strategy for obesity-related disorders, focusing on the molecular mechanisms of insulin action in each tissue.

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Context: Moon-like facies (MLF) are a typical side effect of glucocorticoid (GC) therapy; however, its predisposing factors, relationship with GC-induced complications, and effects on body image are not well understood. Objective: This study aimed to determine the predisposing factors for MLF during GC therapy; its association with GC-induced diabetes, hypertension, and dyslipidemia; and its effects on body image. Methods: This prospective observational study spanned 24 weeks and targeted patients who received GC therapy at the University of Yamanashi Hospital from June 2020 to August 2022. The MLF was defined based on the following 3 factors: (1) an increase in facial measurement lengths, (2) subjective facial changes by patients' self-assessment using a visual analog scale; (3) objective and qualitative facial changes assessed by physicians. We examined the predisposing factors for MLF and the association of MLF with GC-induced diabetes, hypertension, dyslipidemia, and body image. Results: The cumulative incidence rate of MLF at 24 weeks was 37.6%. Predisposing factors for MLF were an initial oral prednisolone dosage of ≥ 30 mg/day [odds ratio (OR) 63.91, 95% confidence interval (CI) 5.82-701.81] and female (OR 6.66, 95% CI 1.35-32.79). MLF showed a significant association with the onset of GC-induced diabetes (OR 6.58, 95% CI 1.25-34.74). MLF was also an independent factor contributing to body image disturbance (ß = -18.94, P = .01). Conclusion: MLF contributes to body image disturbance and is associated with the development of GC-induced diabetes; therefore, it is clinically important as a physical manifestation of GC therapy.

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A 36-year-old woman presented to the emergency room with a consciousness disorder after developing abdominal pain with diarrhea for 2 days. She presented with marked hyperglycemia, ketoacidosis, and increased serum free fatty acid (FFA) levels; however, no elevation in the glycated hemoglobin (HbA1c) levels was observed. Based on the marked depletion of insulin secretion, the patient was diagnosed as diabetic ketoacidosis attributed to fulminant type 1 diabetes (FT1D). Computed tomography on admission revealed severe fatty liver (FL), which improved 17 h following insulin treatment. Insulin treatment also suppressed the serum FFA levels. Some cases of FT1D with FL and liver dysfunction have been reported previously; however, its pathogenesis and clinical course remain unclear. Compared to previous reports, this case reported the shortest time for FL improvement. In this case, rapid and severe insulin deficiency led to a markedly high FFA level and significant accumulation of triglycerides in the hepatocytes, resulting in severe FL. A rapid and large dose of insulin was administered when systemic insulin sensitivity was nearly maximal owing to insulin deficiency, increased insulin efficacy, early reduction of FFA, suppressed triglyceride accumulation in the hepatocytes, and increased triglyceride excretion from the liver. All these factors could have contributed to the rapid improvement in FL.

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Obesity is recognized as an independent risk factor for abdominal aortic aneurysm (AAA). While mutations in the melanocortin-4 receptor (MC4R) gene is the most common cause of obesity caused by mutations in a single gene, the link between MC4R function and vascular disease has still remained unclear. Here, by using melanocortin-4 receptor (MC4R) deficient mice, we confirmed MC4R deficiency promotes AAA and atherosclerosis. We demonstrated the contribution of two novel factors towards vascular vulnerability in this model: leptin signaling in vascular smooth muscle cells (VSMCs) and loss of MC4R signaling in macrophages. Leptin was shown to promote vascular vulnerability via PI3K-dependent upregulation of Spp1 expression in VSMC. Additionally, Ang II-induced AAA incidence was significantly reduced when MC4R gene expression was myeloid cell-specifically rescued in MC4R deficient (MC4RTB/TB) mice. Ex vivo analysis showed a suppression in NF-κB activity in bone marrow-derived macrophages from LysM(+);MC4RTB/TB mice compared to LysM(-);MC4RTB/TB mice, which exaggerates with endogenous MC4R ligand treatment; α-MSH. These results suggest that MC4R signaling in macrophages attenuates AAA by inhibiting NF-κB activity and subsequent vascular inflammation.

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Sodium glucose cotransporter-2 (SGLT2) inhibitors inhibit the development of diabetic nephropathy (DN). We determined whether changes in perirenal fat (PRAT) by a SGLT2 inhibitor ipragliflozin (Ipra) contribute to the suppression of DN development. High-fat diet (HFD)-fed mice were used as a DN model and were treated with or without Ipra for 6 weeks. Ipra treatment reduced urinary albumin excretion (UAE) and glomerular hypertrophy in HFD-fed mice. In the PRAT of Ipra-treated mice, adipocyte size was increased, and inflammation, fibrosis, and adipocyte death were suppressed. In conditioned medium made from PRAT (PRAT-CM) of Ipra-treated mice, the concentration of leptin was significantly lower than PRAT-CM of mice without Ipra treatment. Serum leptin concentration in renal vein positively correlated with UAE. PRAT-CM from HFD-fed mice showed greater cell proliferation signaling in mouse glomerular endothelial cells (GECs) than PRAT-CM from standard diet-fed mice via p38MAPK and leptin-dependent pathways, whose effects were significantly attenuated in PRAT-CM from Ipra-treated mice. These findings suggest that Ipra-induced PRAT expansion may play an important role in the improvement of DN in HFD-fed mice. In vitro experiments suggest that reduced PRAT-derived leptin by Ipra could inhibit GECs proliferation, possibly contributing to the suppression of DN development.

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OBJECTIVE: It is unclear whether monocyte/macrophage insulin signaling in humans is affected by type 2 diabetes (T2DM), systemic insulin sensitivity, and other unknown factors. RESEARCH DESIGN AND METHODS: Fifty-three adult volunteers (control group) not taking any medication and without cardiovascular risk factors, and 59 patients with T2DM (T2DM group) were included. Monocytes were isolated and cultured from all participants. RESULTS: In cultured monocytes, insulin-stimulated AKT and FOXO3 phosphorylation was significantly suppressed in T2DM compared with that in the control group. Insulin-stimulated phosphorylation of AKT was significantly correlated with body mass index and serum insulin level only in the control group. In both groups, significant negative correlation between age and insulin-stimulated phosphorylation of AKT and FOXO3 was commonly observed. In the control group, lipopolysaccharide (LPS)-stimulated induction of TNFA, and NOS2 was significantly and negatively correlated with insulin-stimulated AKT phosphorylation. Age was also significantly correlated with LPS-stimulated induction of TNFA. DISCUSSION: Aging plays an important role in the development of monocyte insulin resistance, not only in patients with T2DM but also in healthy participants. Monocyte insulin sensitivity is negatively correlated with inflammatory responses and may be helpful for subclinical risk assessment of CVDs and/or insulin resistance in participants without risk factors.

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Refractory hypothyroidism is caused by decreased gut absorption, increased metabolism, and poor compliance. Previous studies suggested that the weekly oral, suppository, or intramuscular administration of levothyroxine (LT4) is an effective treatment for refractory hypothyroidism. However, limited information is currently available on treatment involving the weekly intravenous administration of LT4. We managed a case of refractory hypothyroidism due to poor compliance, for which, by weekly intravenous LT4 administration, LT4 was intravenously administered weekly at a dose of 300 µg without any adverse effects such as acute ischemic heart diseases or liver dysfunction and effectively maintained the euthyroid status for 14 months. The weekly oral administration of LT4 (700 µg) was also safely performed and was as effective as its intravenous administration. We herein present precise clinical course of the present case including pharmacokinetic data during the weekly intravenous and oral administration of LT4 and discuss the safety and efficacy of the treatments.

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A 29-year-old man was referred to our department due to adrenal insufficiency with the inappropriate secretion of TSH (SITSH). Magnetic resonance imaging revealed a pituitary tumor. A weak TSH response in the TRH test, elevated sex hormone binding globulin (SHBG) levels, and the absence of a family medical history of SITSH or TRß gene mutations supported the diagnosis of TSH-secreting pituitary adenoma (TSHoma). However, complete TSH suppression and a blunted cholesterol response in the T3 suppression test as well as normal glycoprotein α-subunit (α-GSU) levels were not compatible with TSHoma. Since TSH, FT3, and FT4 spontaneously returned to normal ranges after admission, he was discharged. One month after his discharge, thyrotoxicosis with elevated serum TSH levels relapsed. After admission, his serum TSH levels returned to within the normal range. After his discharge from the second admission, his serum TSH levels fluctuated in accordance with serum FT3 and FT4 levels and symptoms, such as palpitations. Ten months after his discharge, he was admitted to our department again due to adrenal insufficiency and thyrotoxicosis with elevated serum TSH levels, suggesting cyclic SITSH. Although resistance to thyroid hormone (RTH) was not completely excluded, the pituitary tumor was removed by transsphenoidal surgery (TSS). A pathological diagnosis confirmed TSHoma. We herein report a case of TSHoma in which serum TSH, FT3, and FT4 levels fluctuated periodically. To the best of our knowledge, this is the first case report of "cyclic TSHoma", which needs to be considered when making a differential diagnosis of SITSH.

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A 52-year-old woman was treated with sensor augmented pump therapy after undergoing total pancreatectomy for a nonfunctional pancreatic neuroendocrine tumor (NET). The secretion of both endogenous insulin and pancreatic glucagon were completely depleted. Octreotide long acting repeatable (Oct-LAR) was administered for the treatment of liver metastasis of NET. Both the fasting and postprandial glucagon levels decreased immediately after the administration of Oct-LAR. In a continuous glucose monitoring analysis, episodes of nocturnal hypoglycemia was found to increase and an improvement of postprandial hyperglycemia was observed. This case suggests that octreotide may reduce the glucose level in both the fasting and postprandial states, in part by the suppression of extrapancreatic glucagon.

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A 66-year-old woman, who was diagnosed with iritis, visited our hospital due to general malaise. A blood analysis revealed hypercalcemia. Computed tomography revealed mediastinal and hilar lymph node hyperplasia. Moreover, 67Gallium scintigraphy demonstrated strong accumulation in the lesions, suggesting sarcoidosis. A core needle biopsy (CNB) of the hypoechoic areas of the thyroid was performed because the patient refused to undergo a bronchoscopic examination. The scattering of slightly acidophilic epithelioid cell granulomas was observed in the pathological examination of the biopsy specimen. Based on this finding, the patient was diagnosed with sarcoidosis. Although sarcoidosis rarely involves the thyroid gland, in the present case, thyroid CNB was an alternative diagnostic method that allowed a pathological diagnosis to be obtained.

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