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Adeva-Andany MM, Domínguez-Montero A, Adeva-Contreras L, Fernández-Fernández C, Carneiro-Freire N, González-Lucán M. Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases. Curr Diabetes Rev 2024; 20:e160823219824. [PMID: 37587805 DOI: 10.2174/1573399820666230816111624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/28/2023] [Accepted: 05/31/2023] [Indexed: 08/18/2023]
Abstract
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Alberto Domínguez-Montero
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | | | - Carlos Fernández-Fernández
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Natalia Carneiro-Freire
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Manuel González-Lucán
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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Yu L, Yu F, Ma Z, Lu H, Luo J, Sun T, Liu Q, Gan S. INSR novel mutations identified in a Chinese family with severe INSR-related insulin resistance syndromes: A case report. Medicine (Baltimore) 2022; 101:e32266. [PMID: 36626508 PMCID: PMC9750703 DOI: 10.1097/md.0000000000032266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
RATIONALE Severe insulin receptor gene (INSR)-related insulin resistance syndromes (SIR) include Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS), and type A insulin resistance. The incidence of DS is about 1 in 4 million births. We identified novel INSR mutations (c.2246delG and c.2646 + 5G > A) in a patient with SIR, which expanded the variant spectrum and helped to improve the understanding of the diagnosis and treatment of this condition. PATIENT CONCERNS A 10-year-old Chinese boy was admitted to the hospital for deepening skin color. He presented with growth retardation, peculiar facial features, acanthosis nigricans, hypertrichosis, extremely high insulin levels, fasting hypoglycemia, and postprandial hyperglycemia, Whole-exome gene testing suggested compound heterozygous mutations in INSR (c.2246delG and c.2646 + 5G > A). DIAGNOSIS The diagnosis was SIR. What's more, based on the phenotypic and biographical results, this child did not present typical RMS and DS but rather an intermediate phenotype between the 2 conditions. INTERVENTIONS On the basis of a sensible diet and exercise, the patient was prescribed metformin (250 mg) at breakfast and lunch, which was increased to 500 mg after 1 month. OUTCOMES After 2 months of treatment, the patient's glycated hemoglobin (HbA1c) levels decreased to 6% but his insulin resistance did not improve significantly. LESSONS In children who are not obese but with severe insulin resistance, growth retardation, hirsutism, and hyperglycemia, genetic testing should be performed for early diagnosis, active treatment, and follow-up.
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Affiliation(s)
- Lu Yu
- Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
| | - Fang Yu
- Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
| | - Zongrui Ma
- Department of Ophthalmology, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
| | - Huilin Lu
- Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
| | - Jian Luo
- Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
| | - Ting Sun
- Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
| | - Qin Liu
- Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
| | - Shenglian Gan
- Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Changde, Hunan, P. R. China
- * Correspondence: Shenglian Gan, Department of Endocrinology and Metabolism, The First People’s Hospital of Changde City, Renmin Middle Road 818, Changde, Hunan 415000, P. R. China (e-mail: )
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Xu Y, Zhu H, Li W, Chen D, Xu Y, Xu A, Ye D. Targeting adipokines in polycystic ovary syndrome and related metabolic disorders: from experimental insights to clinical studies. Pharmacol Ther 2022; 240:108284. [PMID: 36162728 DOI: 10.1016/j.pharmthera.2022.108284] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 09/13/2022] [Accepted: 09/20/2022] [Indexed: 12/15/2022]
Abstract
Polycystic ovary syndrome (PCOS) affects approximately 15% of women of reproductive age worldwide. It is the most prevalent endocrine disorder with marked risks for female infertility, type 2 diabetes mellitus (T2DM), psychiatric disorders and gynecological cancers. Although the pathophysiology of PCOS remains largely elusive, growing evidence suggests a close link with obesity and its related metabolic disorders. As a highly active endocrine cell population, hypertrophic adipocytes in obesity have disturbed production of a vast array of adipokines, biologically active peptides that exert pleiotropic effects on homeostatic regulation of glucose and lipid metabolism. In parallel with their crucial roles in the pathophysiology of obesity-induced metabolic diseases, adipokines have recently been identified as promising targets for novel therapeutic strategies for multiple diseases. Current treatments for PCOS are suboptimal with insufficient alleviation of all symptoms. Novel findings in adipokine-targeted agents may provide important insight into the development of new drugs for PCOS. This Review presents an overview of the current understanding of mechanisms that link PCOS to obesity and highlights emerging evidence of adipose-ovary crosstalk as a pivotal mediator of PCOS pathogenesis. We summarize recent findings of preclinical and clinical studies that reveal the therapeutic potential of adipokine-targeted novel approaches to PCOS and its related metabolic disorders. We also discuss the critical gaps in knowledge that need to be addressed to guide the development of adipokine-based novel therapies for PCOS.
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Affiliation(s)
- Yidan Xu
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China; Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Huiqiu Zhu
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China; Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Weiwei Li
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China; Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Danxia Chen
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China; Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ying Xu
- School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Dewei Ye
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China; Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China.
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Galderisi A, Tamborlane W, Taylor SI, Attia N, Moretti C, Barbetti F. SGLT2i Improves Glycemic Control in Patients With Congenital Severe Insulin Resistance. Pediatrics 2022; 150:188231. [PMID: 35652305 DOI: 10.1542/peds.2021-055671] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/31/2022] [Indexed: 01/05/2023] Open
Abstract
Insulin-resistant diabetes in Rabson-Mendenhall syndrome (RMS) is relatively unresponsive to first-line antidiabetic treatments, including metformin and insulin. We report 2 patients with RMS treated with 2 different sodium-glucose cotransporter inhibitors 2: empagliflozin in an 11-year-old boy and dapagliflozin in a 12-year-old girl. In the first patient, we began empagliflozin at 2.5 mg/day and increased the dose to 10 mg/day over 3 months. During treatment with empagliflozin, the amount of time during which the patient maintained serum glucose in the 70 to 180 mg/dL target range increased by 2 hours per day. Hemoglobin A1C dropped from >14% to 11.9%, urinary calcium increased almost twofold, and β-hydroxybutyrate remained <2.5 mmol/L. Because glycemic control did not further improve with dose escalation, we reverted to the 2.5 mg/day dose. We initiated dapagliflozin in a second patient at 5 mg/day and witnessed a reduction of hemoglobin A1C from 8.5% to 6.2% after 6 months and a mild increase in urinary excretion of phosphorus but not calcium. Insulin levels fell by >50%. In 2 patients with RMS, empagliflozin and dapagliflozin were well tolerated and improved glycemic control without significantly increasing ketonemia. Renal calcium excretion should be carefully monitored.
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Affiliation(s)
- Alfonso Galderisi
- Department of Woman and Child's Health, University of Padova, Padova, Veneto, Italy
| | | | - Simeon I Taylor
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Najya Attia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Carlo Moretti
- Department of Woman and Child's Health, University of Padova, Padova, Veneto, Italy
| | - Fabrizio Barbetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.,Clinical Laboratory Unit, Bambino Gesù Childrens' Hospital, IRCCS, Rome, Italy
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Okawa MC, Cochran E, Lightbourne M, Brown RJ. Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function. J Clin Endocrinol Metab 2022; 107:e1032-e1046. [PMID: 34718628 PMCID: PMC8852213 DOI: 10.1210/clinem/dgab782] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that 1-year treatment with recombinant leptin (metreleptin) improves glycemia in RMS. OBJECTIVE This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function. METHODS We compared RMS patients during nonrandomized open-label treatment with metreleptin (≥ 0.15 mg/kg/day) vs no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main outcome measures were A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, body mass index (BMI), and insulin-like growth factor 1 (IGF-1); growth hormone; and estimated glomerular filtration rate. RESULTS Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. Growth hormone increased after metreleptin treatment vs control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher growth hormone, while reduced A1c predicted higher IGF-1. CONCLUSION Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.
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Affiliation(s)
- Marinna C Okawa
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Elaine Cochran
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Marissa Lightbourne
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Rebecca J Brown
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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6
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Al-Hussaniy HA, Alburghaif AH, Naji MA. Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions. J Med Life 2022; 14:600-605. [PMID: 35027962 PMCID: PMC8742898 DOI: 10.25122/jml-2021-0153] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/30/2021] [Indexed: 12/29/2022] Open
Abstract
Leptin is a hormone derived from adipose tissue and the small intestine, mainly in enterocytes; it helps regulate the energy balance by suppressing hunger, resulting in decreased fat mass in adipocytes. Leptin has specific receptors in the ventromedial and arcuate nuclei and other parts of the hypothalamus and the feeding center in the ventral tegmental area. It also plays a role in regulatory aspects other than fat cells, such as obesity, which is linked to a loss of sensitivity of leptin receptors, resulting in an inability to produce satiety and an increase in food intake. Moreover, leptin plays a part in lactation, bone density, the immune system, diabetes treatments, and hypertriglyceridemia. The latest studies in leptin suggest that an analog of leptin may treat DM and hypertriglyceridemia. Further research should be conducted on the effectiveness of leptin on other related diseases.
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Affiliation(s)
| | | | - Meena Akeel Naji
- Department of Family Medicine, University of Baghdad, Baghdad, Iraq
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7
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Diener JL, Mowbray S, Huang WJ, Yowe D, Xu J, Caplan S, Misra A, Kapur A, Shapiro J, Ke X, Wu X, Bose A, Panza D, Chen M, Beaulieu V, Gao J. FGF21 Normalizes Plasma Glucose in Mouse Models of Type 1 Diabetes and Insulin Receptor Dysfunction. Endocrinology 2021; 162:6267686. [PMID: 33951176 DOI: 10.1210/endocr/bqab092] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Indexed: 11/19/2022]
Abstract
Fibroblast growth factor (FGF) 21 is a member of the FGF family of proteins. The biological activity of FGF21 was first shown to induce insulin-independent glucose uptake in adipocytes through the GLUT1 transporter. Subsequently, it was shown to have effects on the liver to increase fatty acid oxidation. FGF21 treatment provides beneficial metabolic effects in both animal models and patients with obesity, type 2 diabetes mellitus (T2D) and/or fatty liver disease. In this paper, we revisited the original finding and found that insulin-independent glucose uptake in adipocytes is preserved in the presence of an insulin receptor antagonist. Using a 40-kDa PEGylated (PEG) and half-life extended form of FGF21 (FGF21-PEG), we extended these in vitro results to 2 different mouse models of diabetes. FGF21-PEG normalized plasma glucose in streptozotocin-treated mice, a model of type 1 diabetes (T1D), without restoring pancreatic β-cell function. FGF21-PEG also normalized plasma glucose levels and improved glucose tolerance in mice chronically treated with an insulin competitive insulin receptor antagonist, a model of autoimmune/type-B insulin resistance. These data extend the pharmacological potential of FGF21 beyond the settings of T2D, fatty liver, and obesity.
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MESH Headings
- 3T3-L1 Cells
- Adipocytes/drug effects
- Adipocytes/metabolism
- Animals
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Fibroblast Growth Factors/pharmacology
- HEK293 Cells
- Humans
- Hyperglycemia/blood
- Hyperglycemia/etiology
- Hyperglycemia/pathology
- Hyperglycemia/prevention & control
- Insulin/metabolism
- Insulin Resistance/physiology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Obese
- Obesity/blood
- Obesity/complications
- Obesity/pathology
- Receptor, Insulin/antagonists & inhibitors
- Receptor, Insulin/drug effects
- Receptor, Insulin/physiology
- Streptozocin
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Affiliation(s)
- John L Diener
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Sarah Mowbray
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Waan-Jeng Huang
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - David Yowe
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Jian Xu
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Shari Caplan
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Abhay Misra
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Ankur Kapur
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Jeffrey Shapiro
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Xiaoling Ke
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Xiaoping Wu
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Avirup Bose
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Darrell Panza
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Min Chen
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Valerie Beaulieu
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Jiaping Gao
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
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Huang-Doran I, Kinzer AB, Jimenez-Linan M, Thackray K, Harris J, Adams CL, de Kerdanet M, Stears A, O’Rahilly S, Savage DB, Gorden P, Brown RJ, Semple RK. Ovarian Hyperandrogenism and Response to Gonadotropin-releasing Hormone Analogues in Primary Severe Insulin Resistance. J Clin Endocrinol Metab 2021; 106:2367-2383. [PMID: 33901270 PMCID: PMC8277216 DOI: 10.1210/clinem/dgab275] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Indexed: 01/26/2023]
Abstract
CONTEXT Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited. OBJECTIVE To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR. METHODS Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration. RESULTS Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone-binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology. CONCLUSION SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.
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Affiliation(s)
- Isabel Huang-Doran
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Alexandra B Kinzer
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Mercedes Jimenez-Linan
- Histopathology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Kerrie Thackray
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Julie Harris
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Claire L Adams
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Marc de Kerdanet
- Pediatric Endocrinology Unit, University Hospital, Rennes, France
| | - Anna Stears
- National Severe Insulin Resistance Service, Wolfson Diabetes & Endocrine Clinic, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Stephen O’Rahilly
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - David B Savage
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Phillip Gorden
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Rebecca J Brown
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
- Rebecca J. Brown, Building 10-CRC, Room 6-5942, 10 Center Drive, Bethesda, MD, USA 20892.
| | - Robert K Semple
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Correspondence: Robert K. Semple, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK EH16 4TJ.
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9
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Wolfsdorf JI, Stanley CA. Hypoglycemia in the Toddler and Child. SPERLING PEDIATRIC ENDOCRINOLOGY 2021:904-938. [DOI: 10.1016/b978-0-323-62520-3.00023-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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10
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Brierley GV, Webber H, Rasijeff E, Grocott S, Siddle K, Semple RK. Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy. Diabetes 2020; 69:2481-2489. [PMID: 32816962 PMCID: PMC7576564 DOI: 10.2337/db20-0345] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
Loss-of-function mutations in both alleles of the human insulin receptor gene (INSR) cause extreme insulin resistance (IR) and usually death in childhood, with few effective therapeutic options. Bivalent antireceptor antibodies can elicit insulin-like signaling by mutant INSR in cultured cells, but whether this translates into meaningful metabolic benefits in vivo, wherein the dynamics of insulin signaling and receptor recycling are more complex, is unknown. To address this, we adopted a strategy to model human insulin receptoropathy in mice, using Cre recombinase delivered by adeno-associated virus to knockout endogenous hepatic Insr acutely in floxed Insr mice (liver insulin receptor knockout [L-IRKO] + GFP), before adenovirus-mediated add back of wild-type (WT) or mutant human INSR Two murine anti-INSR monoclonal antibodies, previously shown to be surrogate agonists for mutant INSR, were then tested by intraperitoneal injections. As expected, L-IRKO + GFP mice showed glucose intolerance and severe hyperinsulinemia. This was fully corrected by add back of WT but not with either D734A or S350L mutant INSR. Antibody injection improved glucose tolerance in D734A INSR-expressing mice and reduced hyperinsulinemia in both S350L and D734A INSR-expressing animals. It did not cause hypoglycemia in WT INSR-expressing mice. Antibody treatment also downregulated both WT and mutant INSR protein, attenuating its beneficial metabolic effects. Anti-INSR antibodies thus improve IR in an acute model of insulin receptoropathy, but these findings imply a narrow therapeutic window determined by competing effects of antibodies to stimulate receptors and induce their downregulation.
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Affiliation(s)
- Gemma V Brierley
- The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
| | - Hannah Webber
- MRC Disease Model Core, Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K
| | - Eerika Rasijeff
- MRC Disease Model Core, Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K
| | - Sarah Grocott
- MRC Disease Model Core, Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K
| | - Kenneth Siddle
- The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K
| | - Robert K Semple
- The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
- University of Edinburgh Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, U.K
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11
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Yan FF, Huang BK, Chen YL, Zhuang YZ, You XY, Liu CQ, Li XJ. Coexistence of ovarian serous papillary cystadenofibroma and type A insulin resistance syndrome in a 14-year-old girl: A case report. World J Clin Cases 2020; 8:3334-3340. [PMID: 32874990 PMCID: PMC7441255 DOI: 10.12998/wjcc.v8.i15.3334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/27/2020] [Accepted: 07/14/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Type A insulin resistance syndrome is a rare disorder caused by mutations in the gene encoding the insulin receptor. Its coexistence with ovarian serous papillary cystadenofibroma is even rarer.
CASE SUMMARY A 14-year-old girl developed type A insulin resistance syndrome and showed high fasting insulin, glucose, and hemoglobin A1c (HbA1c) levels. The girl suffered from ovarian serous papillary cystadenofibroma. The laboratory results were as follows: fasting insulin was 2624.90 pmol/L and HbA1c was 8.5%. A heterozygous missense mutation on exon 20 of the insulin receptor gene (c.3601C>T, Arg1201Trp) was observed. The histopathological diagnosis was a cystic lesion that extended to the upper right uterus, indicating a right ovarian serous papillary cystadefibroma accompanied by focal interstitial hyperplasia. The patient was treated with metformin for over 6 mo. Additionally, laparoscopic resection (bilateral) of the ovarian lesion and laparoscopic intestinal adhesiolysis were performed under general anesthesia. Diet therapy combined with exercise was then initiated. The patient had an uneventful recovery. The patient also showed improved blood glucose control, with reduced levels of fasting insulin (857.84 pmol/L) and HbA1c (7.0%).
CONCLUSION Insulin resistance may play a significant role in the induction of tumors. It is important to investigate further the association between insulin resistance and tumors and the underlying mechanism.
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Affiliation(s)
- Fang-Fang Yan
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Bing-Kun Huang
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Yin-Ling Chen
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Yan-Zhen Zhuang
- Department of Pathology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Xue-Ye You
- Department of Pathology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Chang-Qin Liu
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Xue-Jun Li
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
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12
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Kushchayeva YS, Startzell M, Cochran E, Auh S, Sekizkardes H, Soldin SJ, Kushchayev SV, Dieckmann W, Skarulis M, Abdul Sater Z, Brychta RJ, Cypess AM, Lin TC, Lightbourne M, Millo C, Brown RJ. Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations. J Clin Endocrinol Metab 2020; 105:5582247. [PMID: 31588494 PMCID: PMC7093053 DOI: 10.1210/clinem/dgz079] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 10/01/2019] [Indexed: 01/16/2023]
Abstract
CONTEXT Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. OBJECTIVE To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. DESIGN Single-arm, open-label study of liothyronine. SETTING National Institutes of Health. PARTICIPANTS Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. INTERVENTION Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). OUTCOMES Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. RESULTS There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. CONCLUSION Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.
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Affiliation(s)
| | - Megan Startzell
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Elaine Cochran
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Sungyoung Auh
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Hilal Sekizkardes
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Steven J Soldin
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | | | - William Dieckmann
- Positron Emission Tomography Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Monica Skarulis
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Zahraa Abdul Sater
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Robert J Brychta
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Aaron M Cypess
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Tzu-Chun Lin
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Marissa Lightbourne
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Corina Millo
- Positron Emission Tomography Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
- Correspondence and Reprint Requests: Rebecca J. Brown, MD, MHSc, Building 10, Room 6-5940, 10 Center Dr., Bethesda, MD 20892. E-mail:
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13
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Iwanishi M, Kusakabe T, Azuma C, Tezuka Y, Yamamoto Y, Ito-Kobayashi J, Washiyama M, Morimoto M, Ebihara K. Clinical characteristics in two patients with partial lipodystrophy and Type A insulin resistance syndrome due to a novel heterozygous missense mutation in the insulin receptor gene. Diabetes Res Clin Pract 2019; 152:79-87. [PMID: 31102683 DOI: 10.1016/j.diabres.2019.04.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/09/2019] [Accepted: 04/30/2019] [Indexed: 11/25/2022]
Abstract
AIMS The present report aimed to clarify the clinical characteristics in a girl at the age of 12 and her mother with partial lipodystrophy and Type A insulin resistance syndrome. METHODS We examined fat distribution in the patients using dual-energy X-ray absorptiometry, magnetic resonance imaging, and computed tomography. We performed genetic analysis to examine the causal gene for lipodystrophy and insulin resistance. RESULTS Both patients had partial lipodystrophy and a novel heterozygous missense mutation (Asn1137 → Lys1137) in the insulin receptor gene. Because Asn1137 in the catalytic loop is conserved in all protein kinases, this mutation was thought to impair insulin receptor function. By whole-exome sequencing, we found the proband had neither mutations in candidate genes known to be associated with familial partial lipodystrophy nor novel likely candidate causal genes. Taken together, we thought that fat loss in these two patients might be caused by insulin receptor dysfunction. The proband had amenorrhea due to polycystic ovary syndrome. Her menstruation improved, as fat loss was restored during adolescence. This might be caused by improving insulin resistance due to increased levels of leptin and fat mass. CONCLUSIONS This case might help to understand the mechanisms insulin receptor dysfunction that cause lipodystrophy.
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Affiliation(s)
- Masanori Iwanishi
- Department of Diabetes and Endocrinology, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan.
| | - Toru Kusakabe
- Department of Endocrinology, Metabolism and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan
| | - Choka Azuma
- Department of Diabetes and Endocrinology, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan
| | - Yuji Tezuka
- Department of Diabetes and Endocrinology, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan
| | - Yukako Yamamoto
- Department of Diabetes and Endocrinology, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan
| | - Jun Ito-Kobayashi
- Department of Diabetes and Endocrinology, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan
| | - Miki Washiyama
- Department of Diabetes and Endocrinology, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan
| | - Mayumi Morimoto
- Department of Pediatrics, Kusatsu General Hospital, 1660 Yabase, Kusatsu, Shiga 525-8585, Japan
| | - Ken Ebihara
- Division of Endocrinology and Metabolism, Jichi Medical University 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
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14
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Kushchayeva YS, Kushchayev SV, Startzell M, Cochran E, Auh S, Dai Y, Lightbourne M, Skarulis M, Brown RJ. Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes. J Clin Endocrinol Metab 2019; 104:2216-2228. [PMID: 30657911 PMCID: PMC6482021 DOI: 10.1210/jc.2018-02289] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 01/11/2019] [Indexed: 12/16/2022]
Abstract
CONTEXT Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia. OBJECTIVE The aim of this study was to analyze thyroid structural abnormalities in patients with lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy contribute to the thyroid growth and neoplasia in this population. DESIGN Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11 with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin. RESULTS The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30, 16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no difference between lipodystrophy and INSR. Body surface area-adjusted thyroid volume was larger in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 ± 5.1, 3.9 ± 1.5, and 6.2 ± 3.4 cm2, respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no differences in thyroid ultrasound features in patients treated vs not treated with metreleptin. CONCLUSION Children with extreme insulin resistance had a high prevalence of thyroid nodules, which were not associated with metreleptin treatment. Patients with homozygous INSR mutation had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.
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Affiliation(s)
- Yevgeniya S Kushchayeva
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland
| | | | - Megan Startzell
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland
| | - Elaine Cochran
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland
| | - Sungyoung Auh
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland
| | - Yuhai Dai
- Clinical Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland
| | - Marissa Lightbourne
- National Institute of Child Health and Human Development/National Institutes of Health, Bethesda, Maryland
| | - Monica Skarulis
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland
| | - Rebecca J Brown
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland
- Correspondence and Reprint Requests: Rebecca J. Brown, MD, National Institutes of Health, Building 10, Room 6-5940, 10 Center Drive, Bethesda, Maryland 20892. E-mail:
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15
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Takasawa K, Tsuji-Hosokawa A, Takishima S, Wada Y, Nagasaki K, Dateki S, Numakura C, Hijikata A, Shirai T, Kashimada K, Morio T. Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of the insulin receptor (INSR) gene. J Diabetes 2019; 11:46-54. [PMID: 29877041 DOI: 10.1111/1753-0407.12797] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 05/02/2018] [Accepted: 06/01/2018] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required. METHODS Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients. RESULTS Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment. CONCLUSIONS The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.
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Affiliation(s)
- Kei Takasawa
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Atsumi Tsuji-Hosokawa
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shigeru Takishima
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Pediatrics, Soka Municipal Hospital, Soka, Japan
| | - Yasunori Wada
- Department of Pediatrics, Iwate Medical University School of Medicine, Morioka, Japan
| | - Keisuke Nagasaki
- Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Sumito Dateki
- Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Chikahiko Numakura
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Atsushi Hijikata
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
| | - Tsuyoshi Shirai
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
| | - Kenichi Kashimada
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Morio
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
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16
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Huang Z, Liu J, Ng K, Wan X, Xu L, He X, Liao Z, Li Y. Glimepiride treatment in a patient with type A insulin resistance syndrome due to a novel heterozygous missense mutation in the insulin receptor gene. J Diabetes Investig 2018; 9:1075-1083. [PMID: 29469970 PMCID: PMC6123050 DOI: 10.1111/jdi.12824] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/26/2018] [Accepted: 02/18/2018] [Indexed: 02/01/2023] Open
Abstract
AIMS/INTRODUCTION Glimepiride is a sulfonylurea known to have unique insulin mimetic and sensitizing effects. We aimed to study the efficacy of glimepiride in a patient with type A insulin resistance syndrome. MATERIALS AND METHODS A 15-year-old girl with type A insulin resistance syndrome was treated with glimpiride for 6 months. Self-monitoring of blood glucose was recorded, and oral glucose tolerance tests on glucose and insulin were measured during the treatment. Hyperinsulinemic euglycemic clamp was used to evaluate whole-body insulin sensitivity before and after the treatment. RESULTS A novel heterozygous missense mutation at exon 19 (c.3427A>T) in the tyrosine kinase domain of the INSR gene was identified, causing an amino acid replacement of phenylalanine for isoleucine at codon 1143 (Ile1143Phe). Before the treatment, the patient's glycated hemoglobin was 7.0%, plasma glucose during oral glucose tolerance test was 6.7, 12.8 and 17.3 mmol/L, and simultaneous serum insulin was 80.7, 137.5 and >300 μU/mL. There were no significant differences between self-monitored blood glucose measured at each time-point among different glimepiride dosages, or during the 14 weeks when glimepiride was used at its maximal dosage (6 mg/day). Oral glucose tolerance test showed little change in plasma glucose and serum insulin. Glycated hemoglobin decreased by 0.8% after the treatment. However, a euglycemic clamp study showed that the M value decreased from 5.25 to 2.90 mg/kg/min, showing increased insulin resistance. CONCLUSIONS Treatment with glimepiride did not improve insulin sensitivity in a patient with type A insulin resistance syndrome carrying Ile1143Phe heterozygous mutation in the INSR gene. Large-scale long-term studies assembled worldwide are required to optimize treatment algorithms for patients with type A insulin resistance syndrome.
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Affiliation(s)
- Zhimin Huang
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Juan Liu
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Kaka Ng
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Xuesi Wan
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Lijuan Xu
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Xiaoying He
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Zhihong Liao
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yanbing Li
- Department of Endocrinology and Diabetes CenterThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
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17
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Chen X, Wang H, Wu B, Dong X, Liu B, Chen H, Lu Y, Zhou W, Yang L. One Novel 2.43Kb Deletion and One Single Nucleotide Mutation of the INSR Gene in a Chinese Neonate with Rabson-Mendenhall Syndrome. J Clin Res Pediatr Endocrinol 2018; 10:183-187. [PMID: 29082893 PMCID: PMC5985390 DOI: 10.4274/jcrpe.5080] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mutations in the insulin receptor (INSR) gene are responsible for Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). Insulin resistance is a feature of both diseases. Our patient was a Chinese neonate suffering from abnormal glucose homeostasis, hyperinsulinemia, dry skin, heavy hair, growth retardation and an elevated testosterone level. To search for candidate point mutations, small insertions or deletions and copy number variants, 2742 inherited disease-gene panel sequencing was performed. One pathogenic mutation (c.3355C>T, p.Arg1119Trp) and a novel 2.43Kb deletion (chr19:7150507-7152938) in INSR were found. The patient was diagnosed as RMS. Sanger sequencing and real-time quantitative polymerase chain reaction (PCR) confirmed the missense variant and microdeletion, respectively. We therefore supposed that these variants were candidate mutations in this case. We report a novel 2.43Kb deletion in INSR gene and provide further proof of the power of next generation sequencing in rare disease diagnosis.
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Affiliation(s)
- Xiang Chen
- Children’s Hospital of Fudan University, Clinic of Neonatology, Shanghai, China
| | - Huijun Wang
- Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China
| | - Bingbing Wu
- Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China
| | - Xinran Dong
- Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China
| | - Bo Liu
- Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China
| | - Hongbo Chen
- Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China
| | - Yulan Lu
- Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China
| | - Wenhao Zhou
- Children’s Hospital of Fudan University, Clinic of Neonatology, Shanghai, China,Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China,Children’s Hospital of Fudan University, Key Laboratory of Neonatal Diseases, Shanghai, China
| | - Lin Yang
- Children’s Hospital of Fudan University, Key Laboratory of Birth Defects, Shanghai, China,Children’s Hospital of Fudan University, Clinic of Endocrinology, Genetics and Metabolic Diseases, Shanghai, China,* Address for Correspondence: Children’s Hospital of Fudan University, Key Laboratory of Birth Defects; Clinic of Endocrinology, Genetics and Metabolic Diseases, Shanghai, China Phone: +86-21-64931003 E-mail:
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18
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Güemes M, Rahman SA, Shah P, Hussain K. Enteroinsular hormones in two siblings with Donohue syndrome and complete leptin deficiency. Pediatr Diabetes 2018; 19:675-679. [PMID: 29226618 DOI: 10.1111/pedi.12619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 10/29/2017] [Accepted: 11/10/2017] [Indexed: 11/30/2022] Open
Abstract
The main biochemical hallmark of the rare and lethal condition of Donohue syndrome (DS) is hyperinsulinemia. The roles of the gut and other pancreatic hormones involved in glucose metabolism, satiety and energy expenditure have not been previously reported in DS. Two siblings with genetically confirmed DS and extremely low weight underwent a mixed meal (MM) test where pancreatic hormones insulin, C-peptide, glucagon, active amylin, pancreatic polypeptide (PP) as well as gut hormones active glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, peptide YY (PYY) and leptin were analyzed using a Multiplex assay. Results were compared to those of 2 pediatric controls. As expected, concentrations of insulin, C-peptide and amylin were very high in DS cases. The serum glucagon concentration was undetectable at the time of hypoglycemia. GIPs concentrations were lower in the DS, however, this was not mimicked by the other incretin, GLP-1. Ghrelin concentrations were mainly undetectable (<13.7 pg/mL) in all participants. DS cases had higher PYY and dampened PP concentrations. Leptin levels remained completely undetectable (<137.0 pg/mL). Patients with DS have extremely high amylin levels, completely undetectable serum glucagon and leptin levels with abnormal satiety regulating hormone PP with a relatively normal ghrelin response during a MM test. The low serum GIP might be acting as physiological brake on insulin secretion. The undetectable serum leptin levels suggest the potential of using leptin analogues as therapy for DS patients.
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Affiliation(s)
- M Güemes
- Genetics and Genomic Medicine Programme, Genetics and Epigenetics in Health and Disease Section, Institute of Child Health, University College London, London, UK.,Endocrinology Department, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | - S A Rahman
- Genetics and Genomic Medicine Programme, Genetics and Epigenetics in Health and Disease Section, Institute of Child Health, University College London, London, UK.,Endocrinology Department, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | - P Shah
- Genetics and Genomic Medicine Programme, Genetics and Epigenetics in Health and Disease Section, Institute of Child Health, University College London, London, UK.,Endocrinology Department, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | - K Hussain
- Genetics and Genomic Medicine Programme, Genetics and Epigenetics in Health and Disease Section, Institute of Child Health, University College London, London, UK.,Division of Endocrinology, Department of Pediatric Medicine, Sidra Medical & Research Center, Doha, Qatar
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19
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Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature. Int J Mol Sci 2018; 19:ijms19051268. [PMID: 29695048 PMCID: PMC5983765 DOI: 10.3390/ijms19051268] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 04/16/2018] [Accepted: 04/18/2018] [Indexed: 02/07/2023] Open
Abstract
Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson–Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections.
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Mechanick JI, Zhao S, Garvey WT. Leptin, An Adipokine With Central Importance in the Global Obesity Problem. Glob Heart 2017; 13:113-127. [PMID: 29248361 DOI: 10.1016/j.gheart.2017.10.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 10/25/2017] [Indexed: 02/08/2023] Open
Abstract
Leptin has central importance in the global obesity and cardiovascular disease problem. Leptin is principally secreted by adipocytes and acts in the hypothalamus to suppress appetite and food intake, increase energy expenditure, and regulate body weight. Based on clinical translation of specific and networked actions, leptin affects the cardiovascular system and may be a marker and driver of cardiometabolic risk factors with interventions that are actionable by cardiologists. Leptin subnetwork analysis demonstrates a statistically significant role for ethnoculturally and socioeconomically appropriate lifestyle intervention in cardiovascular disease. Emergent mechanistic components and potential diagnostic or therapeutic targets include hexokinase 3, urocortins, clusterin, sialic acid-binding immunoglobulin-like lectin 6, C-reactive protein, platelet glycoprotein VI, albumin, pentraxin 3, ghrelin, obestatin prepropeptide, leptin receptor, neuropeptide Y, and corticotropin-releasing factor receptor 1. Emergent associated symptoms include weight change, eating disorders, vascular necrosis, chronic fatigue, and chest pain. Leptin-targeted therapies are reported for lipodystrophy and leptin deficiency, but they are investigational for leptin resistance, obesity, and other chronic diseases.
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Affiliation(s)
- Jeffrey I Mechanick
- Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Shan Zhao
- Basepaws Inc., Redondo Beach, CA, USA
| | - W Timothy Garvey
- Department of Nutritional Sciences and Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Geriatric Research Education and Clinical Center, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
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Tuhan H, Ceylaner S, Nalbantoğlu Ö, Acar S, Abacı A, Böber E, Demir K. A Mutation in INSR in a Child Presenting with Severe Acanthosis Nigricans. J Clin Res Pediatr Endocrinol 2017; 9:371-374. [PMID: 28663160 PMCID: PMC5785646 DOI: 10.4274/jcrpe.4577] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder due to mutations in the insulin receptor gene (INSR) which is mapped to 19p13.2. RMS is characterized by acanthosis nigricans, generalized lanugo, tooth and nail dysplasia, high nasal bridge, and growth retardation. A 5-year-old female patient was referred due to acanthosis nigricans and generalized lanugo. On her physical examination, severe acanthosis nigricans of the neck, axillae, the external genitalia and antecubital regions, generalized lanugo, mildly decreased subcutaneous fat, dysmorphic facial features, and polydactyly on her left hand were noted. Insulin resistance and impaired glucose tolerance were found. Sequence analysis of the INSR in the patient revealed c.3529+5G>A mutation in homozygous state. RMS should be suspected in a patient with characteristic physical features and insulin resistance.
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Affiliation(s)
- Hale Tuhan
- Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey
| | | | - Özlem Nalbantoğlu
- University of Health Sciences, Dr. Behçet Uz Children Diseases and Surgery Training and Research Hospital, Department of Pediatric Endocrinology, İzmir, Turkey
| | - Sezer Acar
- Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey
| | - Ayhan Abacı
- Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey
| | - Ece Böber
- Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey
| | - Korcan Demir
- Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey
,* Address for Correspondence: Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey Phone: +90 232 412 60 77 E-mail:
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Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice. Proc Natl Acad Sci U S A 2017; 114:2753-2758. [PMID: 28115707 DOI: 10.1073/pnas.1621069114] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show that glucagon receptor (GCGR) inhibition with a monoclonal antibody normalized blood glucose and β-hydroxybutyrate levels. Insulin receptor antagonism increased pancreatic β-cell mass threefold. Normalization of blood glucose levels with GCGR-blocking antibody unexpectedly doubled β-cell mass relative to that observed with S961 alone and 5.8-fold over control. GCGR antibody blockage expanded α-cell mass 5.7-fold, and S961 had no additional effects. Collectively, these data show that GCGR antibody inhibition represents a potential therapeutic option for treatment of patients with extreme insulin-resistance syndromes.
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Moore MM, Bailey AM, Flannery AH, Baum RA. Treatment of Diabetic Ketoacidosis With Intravenous U-500 Insulin in a Patient With Rabson-Mendenhall Syndrome: A Case Report. J Pharm Pract 2016; 30:468-475. [PMID: 27112737 DOI: 10.1177/0897190016645036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Rabson-Mendenhall syndrome is a rare genetic disorder resulting from mutations in the insulin receptor and is associated with high degrees of insulin resistance. These patients are prone to complications secondary to their hyperglycemia including diabetic ketoacidosis (DKA). We report the case of a 19-year-old male with Rabson-Mendenhall syndrome presenting with DKA who required doses of up to 500 U/h (10.6 U/kg/h) of insulin. The patient's insulin infusion was originally compounded with U-100 regular insulin, although to minimize volume, the product was compounded with U-500 insulin. The DKA eventually resolved requiring infusion rates ranging from 400 to 500 U/h. Although numerous opportunities for medication errors exist with the use of U-500 insulin, this case outlines the safe use of concentrated intravenous insulin when clinically indicated for patients requiring extremely high doses of insulin to control blood glucose.
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Affiliation(s)
- Megan M Moore
- 1 University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Abby M Bailey
- 2 Department of Pharmacy, University of Kentucky HealthCare, Lexington, KY, USA.,3 Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Alexander H Flannery
- 2 Department of Pharmacy, University of Kentucky HealthCare, Lexington, KY, USA.,3 Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Regan A Baum
- 2 Department of Pharmacy, University of Kentucky HealthCare, Lexington, KY, USA.,3 Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA
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Meehan CA, Cochran E, Kassai A, Brown RJ, Gorden P. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Expert Rev Clin Pharmacol 2015; 9:59-68. [PMID: 26465174 PMCID: PMC4931926 DOI: 10.1586/17512433.2016.1096772] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The lipodystrophies represent a class of diseases characterized by leptin deficiency. Leptin deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. Metreleptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreleptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties. Finally, we speculate on future uses and development of metreleptin.
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Affiliation(s)
- Cristina Adelia Meehan
- a Diabetes, Endocrinology, and Obesity Branch , National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health , Bethesda , MD , USA
| | - Elaine Cochran
- a Diabetes, Endocrinology, and Obesity Branch , National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health , Bethesda , MD , USA
| | - Andrea Kassai
- a Diabetes, Endocrinology, and Obesity Branch , National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health , Bethesda , MD , USA
| | - Rebecca J Brown
- a Diabetes, Endocrinology, and Obesity Branch , National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health , Bethesda , MD , USA
| | - Phillip Gorden
- a Diabetes, Endocrinology, and Obesity Branch , National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health , Bethesda , MD , USA
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Ros P, Colino-Alcol E, Grasso V, Barbetti F, Argente J. Síndrome de insulinorresistencia severa tipo A debido a mutación del gen del receptor de insulina. An Pediatr (Barc) 2015; 82:e30-4. [DOI: 10.1016/j.anpedi.2014.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/01/2014] [Accepted: 03/11/2014] [Indexed: 02/05/2023] Open
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Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism 2015; 64:146-56. [PMID: 25156686 DOI: 10.1016/j.metabol.2014.07.014] [Citation(s) in RCA: 149] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/03/2014] [Accepted: 07/29/2014] [Indexed: 12/20/2022]
Abstract
Leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function. Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analog) has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis. Remarkable weight loss has been observed in patients with CLD. Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated nonalcoholic fatty liver disease, depression and dementia.
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Affiliation(s)
- Gilberto Paz-Filho
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
| | - Claudio A Mastronardi
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
| | - Julio Licinio
- South Australian Health and Medical Research Institute and Flinders University, Adelaide, Australia.
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Blüher M, Mantzoros CS. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 2015; 64:131-45. [PMID: 25497344 DOI: 10.1016/j.metabol.2014.10.016] [Citation(s) in RCA: 280] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 10/15/2014] [Accepted: 10/20/2014] [Indexed: 12/20/2022]
Abstract
This year marks the 20th anniversary of the discovery of leptin, which has tremendously stimulated translational obesity research. The discovery of leptin has led to realizations that have established adipose tissue as an endocrine organ, secreting bioactive molecules including hormones now termed adipokines. Through adipokines, the adipose tissue influences the regulation of several important physiological functions including but not limited to appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion, glucose and lipid metabolism, fat distribution, endothelial function, hemostasis, blood pressure, neuroendocrine regulation, and function of the immune system. Adipokines have a great potential for clinical use as potential therapeutics for obesity, obesity related metabolic, cardiovascular and other diseases. After 20 years of intense research efforts, recombinant leptin and the leptin analog metreleptin are already available for the treatment of congenital leptin deficiency and lipodystrophy. Other adipokines are also emerging as promising candidates for urgently needed novel pharmacological treatment strategies not only in obesity but also other disease states associated with and influenced by adipose tissue size and activity. In addition, prediction of reduced type 2 diabetes risk by high circulating adiponectin concentrations suggests that adipokines have the potential to be used as biomarkers for individual treatment success and disease progression, to monitor clinical responses and to identify non-responders to anti-obesity interventions. With the growing number of adipokines there is an increasing need to define their function, molecular targets and translational potential for the treatment of obesity and other diseases. In this review we present research data on adipose tissue secreted hormones, the discovery of which followed the discovery of leptin 20 years ago pointing to future research directions to unravel mechanisms of action for adipokines.
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Affiliation(s)
- Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany; Department of Endocrinology, Metabolism and Diabetes, VA Boston Medical Health Center, Boston, MA, USA.
| | - Christos S Mantzoros
- Department of Medicine, University of Leipzig, Leipzig, Germany; Department of Endocrinology, Metabolism and Diabetes, VA Boston Medical Health Center, Boston, MA, USA
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Muniyappa R, Brown RJ, Mari A, Joseph J, Warren MA, Cochran EK, Skarulis MC, Gorden P. Effects of leptin replacement therapy on pancreatic β-cell function in patients with lipodystrophy. Diabetes Care 2014; 37:1101-7. [PMID: 24496806 PMCID: PMC3964492 DOI: 10.2337/dc13-2040] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Leptin administration is known to directly modulate pancreatic β-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on β-cell function are lacking. In this study, we examined the effects (16-20 weeks) of leptin replacement on β-cell function in patients with lipodystrophy. RESEARCH DESIGN AND METHODS In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on β-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16-20 weeks of leptin replacement. β-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT. RESULTS There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, β-cell glucose sensitivity, rate sensitivity, or insulin clearance. CONCLUSIONS In contrast to the suppressive effects of leptin on β-cell function in rodents, 16-20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or β-cell function in leptin-deficient individuals with lipodystrophy.
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