RARE DISEASE
Rabson-Mendenhall syndrome
Rabson-Mendenhall syndrome
Rabson-Mendenhall syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the INSR gene, leading to severe insulin resistance and dysregulated glucose metabolism [1][6][7]. Characterized by growth retardation, acanthosis nigricans, dental dysplasia, and dysmorphic features, RMS manifests in early childhood with paradoxical hypoglycemia progressing to persistent hyperglycemia and diabetic ketoacidosis [2][4][12]. Prognosis remains poor due to limited treatment efficacy, with life expectancy typically <20 years [1][6][17].
Burden
High morbidity from metabolic instability, recurrent ketoacidosis, and end-organ complications [3][12][17]
Requires intensive daily management with frequent glucose monitoring and complex care coordination [9][12]
Limited treatment response: HbA1c often remains >10% despite aggressive therapy [3][16]
Therapies
Glycemic control: High-dose insulin (up to 4.6 U/kg/day), SGLT2 inhibitors (e.g., empagliflozin), and insulin sensitizers (metformin/pioglitazone) [3][9][16]
Adjunctive therapies: Recombinant IGF-1 (mecasermin) and leptin analogues show partial efficacy [2][16][18]
Supportive care: Surgical correction of dental/facial anomalies and multidisciplinary management [1][4]
Categories: rare endocrine diseases, rare genetic diseases, rare skin diseases
Research Papers
41 drug discovery papers about Rabson-Mendenhall syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
41 drug discovery papers about Rabson-Mendenhall syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-01-29 | Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience.
Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are extreme forms of insulin resistance (IR) caused by biallelic mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) treatment is often used but its long-term benefits and risks are still poorly delineated. We describe rhIGF-1 treatment outcomes of a cohort of patients with DS and RMS, and compare them to previously published patients. A single-center retrospective observational study with case note review was conducted. A literature search was performed for previously published DS and RMS patients treated with rhIGF-1. rhIGF-1 outcomes beyond 4 months have been reported for only 11 patients with DS and RMS to date. We provide outcome data for 3 more males, and report the long-term clinical course of a patient already described. Metabolic benefits of rhIGF-1 included improved glycemic control and fasting tolerance in early years of life, and some growth enhancement. Two patients exhibited poor response or intolerance to rhIGF-1 and died in infancy. The 2 longest-lived patients had progressive decompensation to diabetes mellitus, in 1 case despite long-term uninterrupted rhIGF-1 therapy. We also describe new features associated with severe insulin receptoropathies, such as cataract, liver hemangioma, and impaired hepatic protein synthesis. The phenotypes of DS and RMS are heterogeneous. Current treatment options remain unsatisfactory as high-dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus. More research is needed to identify alternative treatment strategies for extreme forms of IR.
2025-08-24 | Rabson-Mendenhall syndrome: A rare case with severe insulin resistance
A rare hereditary cause of insulin resistance, Rabson-Mendenhall syndrome (RMS) is manifested by extreme insulin resistance caused by mutations in the insulin receptor (INSR) gene. The characteristics of RMS are retarded growth, dysmorphisms, hirsutism, enlarged genitalia, acanthosis nigricans, dysplastic dentition, hyperglycemia, elevated insulin level, and hyperplasia of the pineal gland. RMS patients usually present in childhood, and most affected patients usually survive till the second decade of life. We are presenting here a unique case of a 10-year-old girl with very high blood sugar and crowding of teeth. She developed classical symptoms of diabetes for the last three years. On examination, she had syndromic coarse facies, prognathism, gingival hyperplasia, larger lower lip, hyperdontia, hyperpigmented skin, hypertrichosis, severe acanthosis nigricans & dystrophic nails. Biochemical investigations revealed insulin resistance by high fasting insulin, and high normal C-peptide with very high Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). She was treated with insulin with insulin sensitizer-Metformin & Pioglitazone, but her blood glucose was still poorly controlled. J Assoc Clin Endocrinol Diabetol Bangladesh, July 2025;4(2): 80-84
2022-11-03 | Management challenges of Rabson Mendenhall syndrome in a resource limited country: a case report.
Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate point on spectrum of insulin resistance with Donohue syndrome flanking the severe and Type A insulin resistance at the mild end. We are reporting a 3.5-month-old boy with RMS along with its management challenges in a resource limited country. An infant presented at 3.5-month of an age with failure to thrive and fluctuating blood glucose level (hyperglycaemia and hypoglycaemia) along with clinical features of insulin resistance. He was found to have raised HbA1C, high insulin and C peptide level and a homozygous mutation in INSR gene c.1049C>T, (p.Ser350 Leu) confirming the diagnosis of RMS. He was managed with long-acting insulin (Detemir) along with frequent feeding. RMS in resource limited countries could be managed with frequent feeding along with insulin. Early diagnosis and management can improve long term outcome.
2021-10-28 | Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function
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.This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function.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.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.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.
2021-02-04 | Insulin, Insulin Everywhere: A Rare Case Report of Rabson-Mendenhall Syndrome
Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond appropriately to the hormone insulin.Insulin resistance impairs blood sugar regulation and ultimately leads to diabetes mellitus.A 19year-old male presented with joint pain, blurring of vision, and generalized weakness.Investigations revealed hyperglycemia (random blood sugar (RBS) > 625 mg/dL, glycosylated hemoglobin (HbA1c) 18%), as well as sugars, protein, and ketone bodies in urine routine examination.An ultrasound of the abdomen was normal.Cardiac status was normal.Based on the clinical features, particularly the head to toe examination, skin changes, and the onset of type 2 diabetes mellitus, RMS syndrome was considered.The joint pain was alleviated with intravenous tramadol.Actrapid®, a fast-acting insulin, was given to control sugar levels, along with metformin.Vitamin B12 and pregabalin were also supplemented.A dermatological cream containing ammonium chloride, calcium lactate, glycerin, potassium chloride, sodium dihydrogen phosphate, and urea was given for skincare.It is an extremely rare disease with a frequency of fewer than one million people worldwide.Most patients survive only up to 15 years of age, although some can live into their third decade of life.Hepatic gluconeogenesis and fatty acid oxidation are affected, leading to ketoacidosis.The progression is much faster in RMS.In RMS, the genetic defect affects the insulin receptor (INSR) gene transcription with non-sense mutations and causes splicing defects.This results in premature chain termination and eventually to lower amounts of the insulin receptor messenger ribonucleic acid (mRNA).Ultimately, the number and density of insulin receptors in the plasma membrane are smaller, making the cells resistant to insulin.Herein, we report the case of a 19-year-old patient with RMS who was treated in our hospital, leading to a successful improvement in symptoms and discharge of the patient.
small molecules
2025-12-22 | The Use of Dapagliflozin in the Treatment of Children With Severe Insulin Resistance.
Managing severe insulin resistance (IR) is challenging, necessitating a multifaceted approach, including dietary restriction, exercise, and pharmacotherapy. This paper will detail our utilization of dapagliflozin in a series of cases involving patients with severe IR of various etiology and inadequate glycemic control. We describe six cases of extreme IR with distinct clinical diagnoses: four with Rabson-Mendenhall syndrome (RMS), one with IR type 1A, and a patient with type 1 diabetes mellitus (T1DM) and severe subcutaneous (SC) IR. These cases exhibit the observable characteristics of IR, characterized by an inability to effectively manage blood glucose (BG) with a standard treatment plan. Every case had a remarkable response to dapagliflozin. Subsequent assessment demonstrated improved HgbA1C, fasting glucose, insulin, and C-peptide concentrations. Furthermore, several cases demonstrated improvement in the clinical manifestations of IR following the administration of dapagliflozin, while others showed a reduction in the frequency of diabetic ketoacidosis (DKA). There were no documented adverse reactions with the use of dapagliflozin for a duration of 2-4 years in these patients. Dapagliflozin appeared both safe and effective as a standalone treatment or when used alongside other antidiabetes medications such as insulin in a case series of children with T1DM and severe IR or IR syndromes (IRS).
2025-04-17 | Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene.
We present a patient with Rabson-Mendenhall syndrome with unsatisfactory glycemic control of diabetes despite the use of metformin, pioglitazone, and sitagliptin. We investigated the long-term effects of treatment with an empagliflozin. After one year of empagliflozin therapy, an improvement in metabolic control of diabetes was detected. However, eleven months after implementation of empagliflozin, the patient was diagnosed with an early form of nephrocalcinosis. The empagliflozin dose was reduced, maintaining metabolic control and reducing hypercalciuria. We discuss the probable causes of nephrocalcinosis as well as the potential impact of SGLT-2 inhibitor therapy on the occurrence and progression of renal calcium deposition.
2025-01-29 | Insulin resistant diabetes mellitus in a girl with mild Rabson-Mendenhall syndrome: efficacy of sodium glucose co-transporter 2 inhibitor.
We report a beneficial effect of a sodium glucose co-transporter 2 (SGLT2) inhibitor in the management of insulin resistant diabetes mellitus (IRDM) in a Japanese girl with mild Rabson-Mendenhall syndrome (RMS). At 10 2/12 years of age, she was referred to us because of glucosuria, and was found to have marked acanthosis nigricans and RMS-like facial features such as proptosis, large ears, full lips, and gingival hypertrophy, but not other clinical features frequently found in RMS. At 11 9/12 years of age, her blood HbA1c level, though it remained ~ 6.5% until then, increased to 7.9% with pubertal development. She was treated with an SGLT2 inhibitor and metformin, which ameliorated overt hyperglycemia in the afternoon and the evening (postprandial time) as well as obvious hypoglycemia in the early morning (before breakfast), and reduced her blood HbA1c to 5.5%. Whole exome sequencing revealed probably disease-causing c.2465 T > C:p.(Leu822Pro) of paternal origin and c.3038C > T:p.(Pro1013Leu) of maternal origin in INSR. These findings imply the usefulness of SGLT2 inhibitor in the treatment of IRDM. It is likely that SGLT2 inhibitor mitigated hyperglycemia by increasing the urine glucose excretion and prevented severe hypoglycemia probably because of attenuated hyperinsulinemia in the absence of overt hyperglycemia.
2024-07-09 | Case report: A case of Rabson-Mendenhall syndrome: long-term follow-up and therapeutic management with empagliflozin.
Background: Rabson-Mendenhall syndrome (RMS), a rare disorder characterized by severe insulin resistance due to biallelic loss-of-function variants of the insulin receptor gene (INSR), presents therapeutic challenges (OMIM: 262190). This case study explores the efficacy of adjunctive therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in the management of RMS in an 11-year-old male patient with compound heterozygous pathogenic variants of INSR. Methods: Despite initial efforts to regulate glycemia with insulin therapy followed by metformin treatment, achieving stable glycemic control presented a critical challenge, characterized by persistent hyperinsulinism and variable fluctuations in glucose levels. Upon the addition of empagliflozin to metformin, notable improvements in glycated hemoglobin (HbA1c) and time in range (TIR) were observed over a 10-month period. Results: After 10 months of treatment, empagliflozin therapy led to a clinically meaningful reduction in HbA1c levels, decreasing from 8.5% to 7.1%, along with an improvement in TIR from 47% to 74%. Furthermore, regular monitoring effectively averted normoglycemic ketoacidosis, a rare complication associated with SGLT2 inhibitor therapy. Conclusion: This case highlights the potential of SGLT2i as adjunctive therapy in RMS management, particularly in stabilizing glycemic variability. However, further research is warranted to elucidate the long-term efficacy and safety of this therapeutic approach in RMS and similar insulin resistance syndromes.
2023-10-01 | THU350 Rapid Decrease Of Glycemic Levels In Three Patients With Severe Insulin Resistance Associated With Bell’s Palsy.
Abstract Disclosure: E. Chuki: None. M. Lightbourne: None. B. Abel: None. R.J. Brown: None. Bell’s palsy (BP) is associated with diabetic angiopathy and facial nerve ischemia and may be the first sign of diabetic mononeuropathy. Specific risk factors for diabetic mononeuropathy have not been well established. Rapid tightening of glycemic control has been associated with worsening diabetic retinopathy. However, this association has not been reported previously in the development of diabetic mononeuropathy or BP. We describe three patients with extreme insulin resistance, in whom rapid correction of hyperglycemia was temporally associated with development of BP. Case 1: A 63 year-old African American male with history of type 2 diabetes (T2D) and peripheral neuropathy was admitted with sudden onset severe insulin resistance and DKA, leading to a diagnosis of type B insulin resistance. Serum glucose was >600 mg/dl and A1c was 13.4%. He was treated with an insulin drip, then transitioned to subcutaneous insulin U-500 at a total daily dose of ∼3000 units, resulting in blood glucose between 140 and 180 mg/dl. On Day 5 after initiating U-500 and achieving tight control of glycemia, the patient developed bilateral Bell’s Palsy, which resolved after 4 years. Case 2: A 25 year-old African American female with history of T2D was admitted with sudden onset severe insulin resistance and DKA requiring an insulin drip of ∼3,000 units per day, leading to a diagnosis of type B insulin resistance. A1c on admission was 14%. After ∼5 days, she transitioned to U-500 that was titrated over 2 weeks to a total daily dose of 3,000 units with blood glucose between 98 and 177 mg/dL. She developed bilateral BP approximately 43 days from onset of DKA and 36 days after starting U-500 insulin with improved glycemic control. At last follow up 5 years later she still had residual facial weakness. Case 3: A 25 year-old Caucasian male with history of diabetes due to type A insulin resistance (Rabson-Mendenhall Syndrome) and recurrent ketosis on U500 insulin >1,000 units daily had poor adherence to insulin and diet with A1c of 14.3%. 3 weeks after A1c measurement he was started on a Continuous Glucose Monitor (CGM), leading to dramatic change in diet and medication adherence, with reduction in the estimated A1c based on glucose management indictor (GMI) to 7.7% within 3 weeks. 3 weeks after starting CGM use with improved compliance and glycemic control, he developed unilateral BP, which fully recovered after 1 month.We report 3 cases in which onset of BP was observed in rapid temporal correlation with massive increases in insulin dose and/or improvement in glycemia. Severe insulin resistance and rapid decrease of glycemic levels may lower intravascular volume and narrow vessels, leading to microvascular disruption of the vasa nervorum, ultimately causing mononeuropathy. A more gradual approach to glycemia management in patients with severe insulin resistance may be warranted to mitigate this risk. Presentation: Thursday, June 15, 2023
proteins
2026-01-29 | Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience.
Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are extreme forms of insulin resistance (IR) caused by biallelic mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) treatment is often used but its long-term benefits and risks are still poorly delineated. We describe rhIGF-1 treatment outcomes of a cohort of patients with DS and RMS, and compare them to previously published patients. A single-center retrospective observational study with case note review was conducted. A literature search was performed for previously published DS and RMS patients treated with rhIGF-1. rhIGF-1 outcomes beyond 4 months have been reported for only 11 patients with DS and RMS to date. We provide outcome data for 3 more males, and report the long-term clinical course of a patient already described. Metabolic benefits of rhIGF-1 included improved glycemic control and fasting tolerance in early years of life, and some growth enhancement. Two patients exhibited poor response or intolerance to rhIGF-1 and died in infancy. The 2 longest-lived patients had progressive decompensation to diabetes mellitus, in 1 case despite long-term uninterrupted rhIGF-1 therapy. We also describe new features associated with severe insulin receptoropathies, such as cataract, liver hemangioma, and impaired hepatic protein synthesis. The phenotypes of DS and RMS are heterogeneous. Current treatment options remain unsatisfactory as high-dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus. More research is needed to identify alternative treatment strategies for extreme forms of IR.
2025-08-24 | Rabson-Mendenhall syndrome: A rare case with severe insulin resistance
A rare hereditary cause of insulin resistance, Rabson-Mendenhall syndrome (RMS) is manifested by extreme insulin resistance caused by mutations in the insulin receptor (INSR) gene. The characteristics of RMS are retarded growth, dysmorphisms, hirsutism, enlarged genitalia, acanthosis nigricans, dysplastic dentition, hyperglycemia, elevated insulin level, and hyperplasia of the pineal gland. RMS patients usually present in childhood, and most affected patients usually survive till the second decade of life. We are presenting here a unique case of a 10-year-old girl with very high blood sugar and crowding of teeth. She developed classical symptoms of diabetes for the last three years. On examination, she had syndromic coarse facies, prognathism, gingival hyperplasia, larger lower lip, hyperdontia, hyperpigmented skin, hypertrichosis, severe acanthosis nigricans & dystrophic nails. Biochemical investigations revealed insulin resistance by high fasting insulin, and high normal C-peptide with very high Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). She was treated with insulin with insulin sensitizer-Metformin & Pioglitazone, but her blood glucose was still poorly controlled. J Assoc Clin Endocrinol Diabetol Bangladesh, July 2025;4(2): 80-84
2022-11-03 | Management challenges of Rabson Mendenhall syndrome in a resource limited country: a case report.
Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate point on spectrum of insulin resistance with Donohue syndrome flanking the severe and Type A insulin resistance at the mild end. We are reporting a 3.5-month-old boy with RMS along with its management challenges in a resource limited country. An infant presented at 3.5-month of an age with failure to thrive and fluctuating blood glucose level (hyperglycaemia and hypoglycaemia) along with clinical features of insulin resistance. He was found to have raised HbA1C, high insulin and C peptide level and a homozygous mutation in INSR gene c.1049C>T, (p.Ser350 Leu) confirming the diagnosis of RMS. He was managed with long-acting insulin (Detemir) along with frequent feeding. RMS in resource limited countries could be managed with frequent feeding along with insulin. Early diagnosis and management can improve long term outcome.
2021-10-28 | Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function
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.This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function.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.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.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.
2021-02-04 | Insulin, Insulin Everywhere: A Rare Case Report of Rabson-Mendenhall Syndrome
Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond appropriately to the hormone insulin.Insulin resistance impairs blood sugar regulation and ultimately leads to diabetes mellitus.A 19year-old male presented with joint pain, blurring of vision, and generalized weakness.Investigations revealed hyperglycemia (random blood sugar (RBS) > 625 mg/dL, glycosylated hemoglobin (HbA1c) 18%), as well as sugars, protein, and ketone bodies in urine routine examination.An ultrasound of the abdomen was normal.Cardiac status was normal.Based on the clinical features, particularly the head to toe examination, skin changes, and the onset of type 2 diabetes mellitus, RMS syndrome was considered.The joint pain was alleviated with intravenous tramadol.Actrapid®, a fast-acting insulin, was given to control sugar levels, along with metformin.Vitamin B12 and pregabalin were also supplemented.A dermatological cream containing ammonium chloride, calcium lactate, glycerin, potassium chloride, sodium dihydrogen phosphate, and urea was given for skincare.It is an extremely rare disease with a frequency of fewer than one million people worldwide.Most patients survive only up to 15 years of age, although some can live into their third decade of life.Hepatic gluconeogenesis and fatty acid oxidation are affected, leading to ketoacidosis.The progression is much faster in RMS.In RMS, the genetic defect affects the insulin receptor (INSR) gene transcription with non-sense mutations and causes splicing defects.This results in premature chain termination and eventually to lower amounts of the insulin receptor messenger ribonucleic acid (mRNA).Ultimately, the number and density of insulin receptors in the plasma membrane are smaller, making the cells resistant to insulin.Herein, we report the case of a 19-year-old patient with RMS who was treated in our hospital, leading to a successful improvement in symptoms and discharge of the patient.
small molecules
2025-12-22 | The Use of Dapagliflozin in the Treatment of Children With Severe Insulin Resistance.
Managing severe insulin resistance (IR) is challenging, necessitating a multifaceted approach, including dietary restriction, exercise, and pharmacotherapy. This paper will detail our utilization of dapagliflozin in a series of cases involving patients with severe IR of various etiology and inadequate glycemic control. We describe six cases of extreme IR with distinct clinical diagnoses: four with Rabson-Mendenhall syndrome (RMS), one with IR type 1A, and a patient with type 1 diabetes mellitus (T1DM) and severe subcutaneous (SC) IR. These cases exhibit the observable characteristics of IR, characterized by an inability to effectively manage blood glucose (BG) with a standard treatment plan. Every case had a remarkable response to dapagliflozin. Subsequent assessment demonstrated improved HgbA1C, fasting glucose, insulin, and C-peptide concentrations. Furthermore, several cases demonstrated improvement in the clinical manifestations of IR following the administration of dapagliflozin, while others showed a reduction in the frequency of diabetic ketoacidosis (DKA). There were no documented adverse reactions with the use of dapagliflozin for a duration of 2-4 years in these patients. Dapagliflozin appeared both safe and effective as a standalone treatment or when used alongside other antidiabetes medications such as insulin in a case series of children with T1DM and severe IR or IR syndromes (IRS).
2025-04-17 | Case Report: The long-term effects of the empagliflozin therapy on glycemia and renal function in a patient with Rabson-Mendenhall syndrome caused by two heterozygous variants in INSR gene.
We present a patient with Rabson-Mendenhall syndrome with unsatisfactory glycemic control of diabetes despite the use of metformin, pioglitazone, and sitagliptin. We investigated the long-term effects of treatment with an empagliflozin. After one year of empagliflozin therapy, an improvement in metabolic control of diabetes was detected. However, eleven months after implementation of empagliflozin, the patient was diagnosed with an early form of nephrocalcinosis. The empagliflozin dose was reduced, maintaining metabolic control and reducing hypercalciuria. We discuss the probable causes of nephrocalcinosis as well as the potential impact of SGLT-2 inhibitor therapy on the occurrence and progression of renal calcium deposition.
2025-01-29 | Insulin resistant diabetes mellitus in a girl with mild Rabson-Mendenhall syndrome: efficacy of sodium glucose co-transporter 2 inhibitor.
We report a beneficial effect of a sodium glucose co-transporter 2 (SGLT2) inhibitor in the management of insulin resistant diabetes mellitus (IRDM) in a Japanese girl with mild Rabson-Mendenhall syndrome (RMS). At 10 2/12 years of age, she was referred to us because of glucosuria, and was found to have marked acanthosis nigricans and RMS-like facial features such as proptosis, large ears, full lips, and gingival hypertrophy, but not other clinical features frequently found in RMS. At 11 9/12 years of age, her blood HbA1c level, though it remained ~ 6.5% until then, increased to 7.9% with pubertal development. She was treated with an SGLT2 inhibitor and metformin, which ameliorated overt hyperglycemia in the afternoon and the evening (postprandial time) as well as obvious hypoglycemia in the early morning (before breakfast), and reduced her blood HbA1c to 5.5%. Whole exome sequencing revealed probably disease-causing c.2465 T > C:p.(Leu822Pro) of paternal origin and c.3038C > T:p.(Pro1013Leu) of maternal origin in INSR. These findings imply the usefulness of SGLT2 inhibitor in the treatment of IRDM. It is likely that SGLT2 inhibitor mitigated hyperglycemia by increasing the urine glucose excretion and prevented severe hypoglycemia probably because of attenuated hyperinsulinemia in the absence of overt hyperglycemia.
2024-07-09 | Case report: A case of Rabson-Mendenhall syndrome: long-term follow-up and therapeutic management with empagliflozin.
Background: Rabson-Mendenhall syndrome (RMS), a rare disorder characterized by severe insulin resistance due to biallelic loss-of-function variants of the insulin receptor gene (INSR), presents therapeutic challenges (OMIM: 262190). This case study explores the efficacy of adjunctive therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in the management of RMS in an 11-year-old male patient with compound heterozygous pathogenic variants of INSR. Methods: Despite initial efforts to regulate glycemia with insulin therapy followed by metformin treatment, achieving stable glycemic control presented a critical challenge, characterized by persistent hyperinsulinism and variable fluctuations in glucose levels. Upon the addition of empagliflozin to metformin, notable improvements in glycated hemoglobin (HbA1c) and time in range (TIR) were observed over a 10-month period. Results: After 10 months of treatment, empagliflozin therapy led to a clinically meaningful reduction in HbA1c levels, decreasing from 8.5% to 7.1%, along with an improvement in TIR from 47% to 74%. Furthermore, regular monitoring effectively averted normoglycemic ketoacidosis, a rare complication associated with SGLT2 inhibitor therapy. Conclusion: This case highlights the potential of SGLT2i as adjunctive therapy in RMS management, particularly in stabilizing glycemic variability. However, further research is warranted to elucidate the long-term efficacy and safety of this therapeutic approach in RMS and similar insulin resistance syndromes.
2023-10-01 | THU350 Rapid Decrease Of Glycemic Levels In Three Patients With Severe Insulin Resistance Associated With Bell’s Palsy.
Abstract Disclosure: E. Chuki: None. M. Lightbourne: None. B. Abel: None. R.J. Brown: None. Bell’s palsy (BP) is associated with diabetic angiopathy and facial nerve ischemia and may be the first sign of diabetic mononeuropathy. Specific risk factors for diabetic mononeuropathy have not been well established. Rapid tightening of glycemic control has been associated with worsening diabetic retinopathy. However, this association has not been reported previously in the development of diabetic mononeuropathy or BP. We describe three patients with extreme insulin resistance, in whom rapid correction of hyperglycemia was temporally associated with development of BP. Case 1: A 63 year-old African American male with history of type 2 diabetes (T2D) and peripheral neuropathy was admitted with sudden onset severe insulin resistance and DKA, leading to a diagnosis of type B insulin resistance. Serum glucose was >600 mg/dl and A1c was 13.4%. He was treated with an insulin drip, then transitioned to subcutaneous insulin U-500 at a total daily dose of ∼3000 units, resulting in blood glucose between 140 and 180 mg/dl. On Day 5 after initiating U-500 and achieving tight control of glycemia, the patient developed bilateral Bell’s Palsy, which resolved after 4 years. Case 2: A 25 year-old African American female with history of T2D was admitted with sudden onset severe insulin resistance and DKA requiring an insulin drip of ∼3,000 units per day, leading to a diagnosis of type B insulin resistance. A1c on admission was 14%. After ∼5 days, she transitioned to U-500 that was titrated over 2 weeks to a total daily dose of 3,000 units with blood glucose between 98 and 177 mg/dL. She developed bilateral BP approximately 43 days from onset of DKA and 36 days after starting U-500 insulin with improved glycemic control. At last follow up 5 years later she still had residual facial weakness. Case 3: A 25 year-old Caucasian male with history of diabetes due to type A insulin resistance (Rabson-Mendenhall Syndrome) and recurrent ketosis on U500 insulin >1,000 units daily had poor adherence to insulin and diet with A1c of 14.3%. 3 weeks after A1c measurement he was started on a Continuous Glucose Monitor (CGM), leading to dramatic change in diet and medication adherence, with reduction in the estimated A1c based on glucose management indictor (GMI) to 7.7% within 3 weeks. 3 weeks after starting CGM use with improved compliance and glycemic control, he developed unilateral BP, which fully recovered after 1 month.We report 3 cases in which onset of BP was observed in rapid temporal correlation with massive increases in insulin dose and/or improvement in glycemia. Severe insulin resistance and rapid decrease of glycemic levels may lower intravascular volume and narrow vessels, leading to microvascular disruption of the vasa nervorum, ultimately causing mononeuropathy. A more gradual approach to glycemia management in patients with severe insulin resistance may be warranted to mitigate this risk. Presentation: Thursday, June 15, 2023
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Drug Discovery Landscape
2 orphan drug designations for Rabson-Mendenhall syndrome.
2 orphan drug designations for Rabson-Mendenhall syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Mecasermin rinfabate [Iplex] | proteins | EMA | 2004-10-21 | — | [INACTIVE] Insmed Europe Limited |
rhIGF-I/rhIGFBP-3 | proteins | FDA | 2003-12-09 | — | Insmed, Inc. |
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