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
43 drug discovery papers about Rabson-Mendenhall syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
43 drug discovery papers about Rabson-Mendenhall syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-13 | Case Report: Tirzepatide improves glycemic control in Rabson-Mendenhall syndrome.
Rabson-Mendenhall syndrome (RMS) is an extremely rare autosomal recessive disorder caused by variants in the INSR gene, which encodes the insulin receptor. The condition is characterized by profound insulin resistance, resulting in diabetes that is exceptionally difficult to control and carrying a poor prognosis, typically in the second to third decade of life. Death most commonly occurs due to ketoacidosis and severe infections. There is no established consensus on optimal treatment; initial therapy usually includes metformin and pioglitazone, often combined with SGLT2 inhibitors, followed by maintenance with high doses of insulin. Two patients with genetically confirmed RMS were treated with subcutaneous tirzepatide for 3 months (2.5-3.3 mg weekly), followed by a 3-month washout period. Clinical, biochemical, and body composition parameters were assessed at baseline, after treatment, and after withdrawal. After 3 months of treatment, HbA1c decreased from 8.9% to 6.3% in one patient and from 10.3% to 8.1% in the other. Insulin resistance improved in one case, whereas insulinemia decreased markedly in the other. Glycemic control deteriorated after treatment withdrawal. Tirzepatide was generally well tolerated, although both patients experienced a reduction in fat mass, and one developed proliferative retinopathy, probably related to the rapid fall in HbA1c. Low-dose tirzepatide improved glycemic control in RMS and may represent a potential adjunctive therapy, warranting careful monitoring.
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.
small molecules
2026-09-01 | Exploring the therapeutic response to sodium-glucose cotransporter-2 inhibition in INSR-related insulin resistance monogenic diabetes: case-based analysis and narrative review.
INSR-related insulin resistance is a form of monogenic diabetes caused by pathogenic variants in the INSR gene, resulting in impaired insulin receptor signalling and a spectrum of insulin resistance. Conventional diabetes management strategies relying on insulin sensitisation or augmentation are often less effective and evidence to guide treatment in those with heterozygous INSR mutations remains limited. A 63-year-old male diagnosed with type 2 diabetes aged 40 presented with a relatively stable fasting glucose and disproportionate postprandial hyperglycaemia despite prandial insulin. He had bilateral asymmetric mixed hearing loss (conductive/sensorineural) and early cardiovascular disease. C-peptide was preserved at 1.3 nmol/L with serum glucose at 7.1 mmol/L. Monogenic diabetes genetic testing identified a heterozygous likely pathogenic variant (i.e. mutation) in INSR (c.3473G > A, (p.Arg1158Gln)). Treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2 inhibitor) achieved 78% time-in-range (TIR). Subsequent SGLT2 inhibitor withdrawal for four months due to pyelonephritis led to TIR deterioration to 2% despite intensified basal insulin. Berberine initiation produced modest improvement (TIR 24%). Following re-introduction of the SGLT2 inhibitor, TIR rapidly improved to 85%, with restoration of a stable overnight profile. A narrative review identified eight cases with INSR-related insulin resistance (Donohue/Rabson-Mendenhall/type A insulin resistance) treated with a SGLT2 inhibitor. All reports documented clinically meaningful HbA1c reductions (1.4-3.6%) and, where available, improved CGM metrics. SGLT2 inhibitors provide insulin-independent glycaemic benefit in INSR-related insulin resistance. AMPK-activating strategies, including metformin, berberine, and exercise, may provide adjunctive benefit via cellular glucose uptake, although evidence remains limited. We propose a two-factor therapeutic framework targeting (1) insulin-independent glucosuria and (2) AMPK-mediated glucose uptake as a rational management approach for this rare form of diabetes.
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.
proteins
2026-09-13 | Case Report: Tirzepatide improves glycemic control in Rabson-Mendenhall syndrome.
Rabson-Mendenhall syndrome (RMS) is an extremely rare autosomal recessive disorder caused by variants in the INSR gene, which encodes the insulin receptor. The condition is characterized by profound insulin resistance, resulting in diabetes that is exceptionally difficult to control and carrying a poor prognosis, typically in the second to third decade of life. Death most commonly occurs due to ketoacidosis and severe infections. There is no established consensus on optimal treatment; initial therapy usually includes metformin and pioglitazone, often combined with SGLT2 inhibitors, followed by maintenance with high doses of insulin. Two patients with genetically confirmed RMS were treated with subcutaneous tirzepatide for 3 months (2.5-3.3 mg weekly), followed by a 3-month washout period. Clinical, biochemical, and body composition parameters were assessed at baseline, after treatment, and after withdrawal. After 3 months of treatment, HbA1c decreased from 8.9% to 6.3% in one patient and from 10.3% to 8.1% in the other. Insulin resistance improved in one case, whereas insulinemia decreased markedly in the other. Glycemic control deteriorated after treatment withdrawal. Tirzepatide was generally well tolerated, although both patients experienced a reduction in fat mass, and one developed proliferative retinopathy, probably related to the rapid fall in HbA1c. Low-dose tirzepatide improved glycemic control in RMS and may represent a potential adjunctive therapy, warranting careful monitoring.
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.
small molecules
2026-09-01 | Exploring the therapeutic response to sodium-glucose cotransporter-2 inhibition in INSR-related insulin resistance monogenic diabetes: case-based analysis and narrative review.
INSR-related insulin resistance is a form of monogenic diabetes caused by pathogenic variants in the INSR gene, resulting in impaired insulin receptor signalling and a spectrum of insulin resistance. Conventional diabetes management strategies relying on insulin sensitisation or augmentation are often less effective and evidence to guide treatment in those with heterozygous INSR mutations remains limited. A 63-year-old male diagnosed with type 2 diabetes aged 40 presented with a relatively stable fasting glucose and disproportionate postprandial hyperglycaemia despite prandial insulin. He had bilateral asymmetric mixed hearing loss (conductive/sensorineural) and early cardiovascular disease. C-peptide was preserved at 1.3 nmol/L with serum glucose at 7.1 mmol/L. Monogenic diabetes genetic testing identified a heterozygous likely pathogenic variant (i.e. mutation) in INSR (c.3473G > A, (p.Arg1158Gln)). Treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2 inhibitor) achieved 78% time-in-range (TIR). Subsequent SGLT2 inhibitor withdrawal for four months due to pyelonephritis led to TIR deterioration to 2% despite intensified basal insulin. Berberine initiation produced modest improvement (TIR 24%). Following re-introduction of the SGLT2 inhibitor, TIR rapidly improved to 85%, with restoration of a stable overnight profile. A narrative review identified eight cases with INSR-related insulin resistance (Donohue/Rabson-Mendenhall/type A insulin resistance) treated with a SGLT2 inhibitor. All reports documented clinically meaningful HbA1c reductions (1.4-3.6%) and, where available, improved CGM metrics. SGLT2 inhibitors provide insulin-independent glycaemic benefit in INSR-related insulin resistance. AMPK-activating strategies, including metformin, berberine, and exercise, may provide adjunctive benefit via cellular glucose uptake, although evidence remains limited. We propose a two-factor therapeutic framework targeting (1) insulin-independent glucosuria and (2) AMPK-mediated glucose uptake as a rational management approach for this rare form of diabetes.
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.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Mecasermin rinfabate [Iplex] | proteins | EMA | — | [INACTIVE] Insmed Europe Limited |
rhIGF-I/rhIGFBP-3 | proteins | FDA | — | Insmed, Inc. |
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