Rabson-Mendenhall syndrome: a rare case of severe insulin resistance

Insulin resistance syndromes are a heterogeneous group of disorders with variable clinical phenotypes, associated with increased blood glucose and insulin levels. A 20-year-old female, diabetic for 12 years, reported with hyperglycemia not responding to high dose of insulin; therefore, insulin dosage was increased but did not lead to appropriate glycemic control. Investigations revealed hyperglycemia (random blood glucose 23 mmol/L) glycosylated hemoglobin (HbA1c) 9.2%. Ultrasonogram of the abdomen showed prominent ovaries with fatty liver. Echocardiography revealed mild mitral, pulmonary and tricuspid regurgitation and pulmonary hypertension. Based on the clinical features, skin changes and the onset of type 2 diabetes mellitus, Rabson-Mendenhall syndrome (RMS) was considered. In last admission, she was admitted for hyperglycemic control and treated with intravenous fluids, insulin infusion, metformin, pioglitazone, linagliptin, hydroxychloroquine, sulphonylurea, antibiotics. There is no complete cure for the condition and the current treatments are difficult and not very promising. BIRDEM Med J 2022; 12(1): 83-87

Severe insulin resistance in long-term acute leukaemia survivors: lesson learned from a clinical case and review of the literature

With the improvement of haematopoietic stem cell transplantation (HSCT) and radiotherapy, the population of cancer survivors is increasing and therefore increasing the number of patients living with late metabolic complications. We describe a case of a childhood acute lymphoblastic leukaemia survivor who developed insulin resistance 10 years after HSCT and total body radiation requiring a high dose of insulin (>1,500 IU). Using insulin-sensitising agents metformin and thiazolidinediones improved the control and reduced the insulin requirement – eventually stopping insulin. We describe for the first time the phenomenon of reverse diurnal variation in insulin sensitivity based on the clinical picture alone, which has not previously been described in the literature. We have reviewed the plausible mechanisms of developing insulin resistance, reverse diurnal variation and the role of thiazolidinediones in reducing lipotoxicity and adipocyte differentiation resulting in improved insulin sensitivity in such cases.

Insulin receptor autoantibody-mediated hypoglycemia in a woman with mixed connective tissue disease

Autoantibodies to the insulin receptor are rare and typically cause severe insulin resistance and hyperglycemia, a condition termed type B insulin resistance. Uncommonly, antibodies to the insulin receptor can cause hypoglycemia. We present the case of a woman who developed recurrent severe hypoglycemia and myopathy, was found to have insulin receptor autoantibodies and mixed connective tissue disease, and had resolution of hypoglycemia with immunosuppression. A 55-year-old woman with a history of obesity, hypertension, and prior hemorrhagic stroke presented with recurrent severe hypoglycemia. A diagnostic fast resulted in hypoinsulinemic hypoketotic hypoglycemia. Adrenal function was intact. Progressive myopathy had developed simultaneously with her hypoglycemia, and rheumatologic evaluation revealed mixed connective tissue disease. The plasma acylcarnitine profile was normal, extensive oncologic evaluation including IGF-2 measurement was unrevealing, and anti-insulin antibody testing was negative. Ultimately, anti-insulin receptor antibodies were found to be present. The patient was treated with glucocorticoids and rituximab. Eight weeks after initiation of immunosuppression, the insulin receptor antibody titer had decreased and hypoglycemia had resolved. Eight months after diagnosis, the patient remained free of severe hypoglycemia despite tapering of glucocorticoids to a near-physiologic dose. Though antibodies to the insulin receptor typically cause severe insulin resistance, this patient had no evidence of insulin resistance and instead presented with recurrent severe hypoglycemia, which responded to glucocorticoids and rituximab. The diagnosis of insulin receptor antibody-mediated hypoglycemia is rare but should be considered in patients with systemic autoimmune disease, including mixed connective tissue disease, in the appropriate clinical context.

Maternal High-Fat Feeding Affects the Liver and Thymus Metabolic Axis in the Offspring and Some Effects Are Attenuated by Maternal Diet Normalization in a Minipig Model

Maternal high-fat diet (HFD) affects metabolic and immune development. We aimed to characterize the effects of maternal HFD, and the subsequent diet-normalization of the mothers during a second pregnancy, on the liver and thymus metabolism in their offspring, in minipigs. Offspring born to high-fat (HFD) and normal diet (ND) fed mothers were studied at week 1 and months 1, 6, 12 of life. Liver and thymus glucose uptake (GU) was measured with positron emission tomography during hyperinsulinemic-isoglycemia. Histological analyses were performed to quantify liver steatosis, inflammation, and hepatic hematopoietic niches (HHN), and thymocyte size and density in a subset. The protocol was repeated after maternal-diet-normalization in the HFD group. At one week, HFDoff were characterized by hyperglycemia, hyperinsulinemia, severe insulin resistance (IR), and high liver and thymus GU, associating with thymocyte size and density, with elevated weight-gain, liver IR, and steatosis in the first 6 months of life. Maternal diet normalization reversed thymus and liver hypermetabolism, and increased HHN at one week. It also normalized systemic insulin-sensitivity and liver fat content at all ages. Instead, weight-gain excess, hyperglycemia, and hepatic IR were still observed at 1 month, i.e., end-lactation. We conclude that intra-uterine HFD exposure leads to time-changing metabolic and immune-correlated abnormalities. Maternal diet-normalization reversed most of the effects in the offspring.

Congenital insulin resistance in the practice of the pediatrician and pediatric endocrinologist -path to diagnosis

Introduction. Hyperinsulinemic hypoglycemia in children is most commonly due to congenital hyperinsulinism. When hyperinsu-linemia is accompanied by fasting hypoglycemia and postprandial hyperglycemia, rare syndromes of severe insulin resistance, which include Rabson - Mendenhall syndrome, should be suspected. This article provides an analytical review of current data on this rare genetic pathology and presents a clinical case of a previously undescribed combination of Rabson-Mendenhall syndrome with mutations in the insulin receptor gene INSR in the compound heterozygous state with multiple congenital anomalies of other organs.Clinical case. Patient N, 5.5 months old boy, with suspected congenital hyperinsulinism due to episodes of frequent severe hypoglycemia from the first day of life. At the age of 5 months, an episode of hypoglycemia up to 2.2 mmol/L was registered at an appointment with a pediatric endocrinologist. An examination was ordered, which found that against a background decrease in blood glucose to 1.9 mmol/L, C-Peptide level >5000 ng/mL, insulin level >300 lU/mL, cortisol - 971 nmol/L, TSH -3.88 mlU/L, free T4 - 10.53 pmol/L (10-23.2).The importance of early diagnosis of severe insulin resistance to prevent developmental disorders in children is emphasized. The issue of organizing multiple effective monitoring of a patient’s glycemia required special attention in this clinical case. Due to the features of metabolism in young children, we abandoned flash glucose monitoring systems and used a modern glucose meter with an integration program with a mobile application and the ability to generate reports for subsequent analysis as a reliable means of glycemic control.Summary. Based on the results of the genetic study in association with the clinical phenotype, age of debut, the patient was clinically diagnosed with Rabson-Mendenhall syndrome.Discussion. The paradoxical nature of glycemic fluctuations (severe fasting hypoglycemia and postprandial diabetic hyperglycemia) is quite typical for syndromes of severe insulin resistance and should draw the attention of an informed primary care physician.Conclusion. Careful attention to the symptoms of hypoglycemia, especially with a debut in the neonatal period, recurrent episodes, and the severity of the decrease in blood glycemia. If normal or elevated levels of insulin and C-peptide are detected against the background of hypoglycemia, the first thing to think about is congenital hyperinsulinism.

Human Insulin (Entuzity KwikPen)

CADTH recommends that Entuzity KwikPen should be reimbursed by public drug plans to improve glycemic control in adults and children with diabetes mellitus, if certain conditions are met. Entuzity KwikPen should only be reimbursed if it is initiated by a specialist with experience in treating severe insulin resistance and if the cost of Entuzity KwikPen does not exceed the least expensive basal or bolus combination insulin pens or cartridges. Entuzity KwikPen should only be covered to treat patients with diabetes mellitus with unacceptable glycemic control who require more than 200 units of insulin per day, with or without other therapies.

Approach to diagnosing a pediatric patient with severe insulin resistance in low- or middle-income countries

Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli-Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and therefore, our approach is especially applicable to low- or middle-income countries.

Estimating Enhanced Endogenous Glucose Production in Intensive Care Unit Patients with Severe Insulin Resistance

Background: Critically ill ICU patients frequently experience acute insulin resistance and increased endogenous glucose production, manifesting as stress-induced hyperglycemia and hyperinsulinemia. STAR (Stochastic TARgeted) is a glycemic control protocol, which directly manages inter- and intra- patient variability using model-based insulin sensitivity (SI). The model behind STAR assumes a population constant for endogenous glucose production (EGP), which is not otherwise identifiable. Objective: This study analyses the effect of estimating EGP for ICU patients with very low SI (severe insulin resistance) and its impact on identified, model-based insulin sensitivity identification, modeling accuracy, and model-based glycemic clinical control. Methods: Using clinical data from 717 STAR patients in 3 independent cohorts (Hungary, New Zealand, and Malaysia), insulin sensitivity, time of insulin resistance, and EGP values are analyzed. A method is presented to estimate EGP in the presence of non-physiologically low SI. Performance is assessed via model accuracy. Results: Results show 22%-62% of patients experience 1+ episodes of severe insulin resistance, representing 0.87%-9.00% of hours. Episodes primarily occur in the first 24 h, matching clinical expectations. The Malaysian cohort is most affected. In this subset of hours, constant model-based EGP values can bias identified SI and increase blood glucose (BG) fitting error. Using the EGP estimation method presented in these constrained hours significantly reduced BG fitting errors. Conclusions: Patients early in ICU stay may have significantly increased EGP. Increasing modeled EGP in model-based glycemic control can improve control accuracy in these hours. The results provide new insight into the frequency and level of significantly increased EGP in critical illness.

Genotype-Structure-Phenotype Correlations in Disease-Associated IGF1R Variants and Similarities to Those in INSR Variants

We previously reported that genotype-phenotype correlations in 12 missense variants causing severe insulin resistance, located in the second and third fibronectin type III (FnIII) domains of the insulin receptor (INSR), containing the α-β cleavage and part of insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently reported crystal structures of IGF1R. A structural bioinformatics analysis of five previously reported disease-associated heterozygous missense variants and a likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core formation and stability of the FnIII domains or affect the α-β cleavage site, while the likely benign variant would not affect the folding of the domains. A functional analysis of these variants in CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated variants, but not in those expressing the wild-type form or the likely benign variant. These results demonstrated genotype-phenotype correlations in the FnIII domain variants of <i>IGF1R</i>, which are presumably consistent with<i> </i>those of <i>INSR</i> and would help in the early diagnosis of patients with disease-associated <i>IGF1R</i> variants.

Genotype-Structure-Phenotype Correlations in Disease-Associated IGF1R Variants and Similarities to Those in INSR Variants

We previously reported that genotype-phenotype correlations in 12 missense variants causing severe insulin resistance, located in the second and third fibronectin type III (FnIII) domains of the insulin receptor (INSR), containing the α-β cleavage and part of insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently reported crystal structures of IGF1R. A structural bioinformatics analysis of five previously reported disease-associated heterozygous missense variants and a likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core formation and stability of the FnIII domains or affect the α-β cleavage site, while the likely benign variant would not affect the folding of the domains. A functional analysis of these variants in CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated variants, but not in those expressing the wild-type form or the likely benign variant. These results demonstrated genotype-phenotype correlations in the FnIII domain variants of <i>IGF1R</i>, which are presumably consistent with<i> </i>those of <i>INSR</i> and would help in the early diagnosis of patients with disease-associated <i>IGF1R</i> variants.