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Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review.
Masunaga, Y, Fujisawa, Y, Muramatsu, M, Ono, H, Inoue, T, Fukami, M, Kagami, M, Saitsu, H, Ogata, T
Endocrine journal. 2021;(1):111-117
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Abstract
SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.
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Clinical Features of Type B Insulin Resistance in Japanese Patients: Case Report and Survey-Based Case Series Study.
Hirota, Y, Suwanai, H, Yamauchi, T, Kadowaki, T
Journal of diabetes research. 2020;:4359787
Abstract
Type B insulin resistance (TBIR) is an extremely rare disease characterized by marked hyperglycemia and insulin resistance and often coexists with autoimmune diseases. The characteristics, symptoms, blood glucose patterns, comorbidities, and treatments of TBIR all vary and are not defined. In this study, we described a case of TBIR that developed 6 months after DPP-4 inhibitor administration and immediately after the patient caught a cold. Treatment using prednisolone and insulin-like growth factor-1 was effective. We also conducted an observational survey-based case series study in a Japanese cohort comprising 21 cases. The average age of onset of TBIR was 62.3 ± 14.8 (17-84) years, and 61.9% of subjects were male. The majority of patients (90.4%) were 50 years old and over. During the study period, there was a high percentage (85.7%) of episodes of hypoglycemia, which was the trigger for diagnosis in more than 50% of cases. Glycemic patterns included 7 cases of hyperglycemia (33.3%), 10 cases of hypoglycemia (47.6%), and 4 cases of both hyperglycemia and hypoglycemia (19.1%). In the hypoglycemic group, 90.0% of patients were male. Furthermore, 71.4% of cases were antinuclear antibody positive, and 81.0% of cases were complicated with autoimmune disease. Systemic lupus erythematosus (38.1%) and Sjögren's syndrome (23.8%) were relatively common as coexisting autoimmune diseases. Treatment was based on prednisolone use, which was used in 88.9% of patients. On the other hand, the effect of IGF-1 was limited. Overall, the prognosis of TBIR was good.
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[Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].
Ros, P, Colino-Alcol, E, Grasso, V, Barbetti, F, Argente, J
Anales de pediatria (Barcelona, Spain : 2003). 2015;(1):e30-4
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Abstract
Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory.
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Normal-weight 14-year-old girl with acanthosis nigricans and markedly increased hepatic steatosis: evidence for the important role of ectopic fat deposition in the pathogenesis of insulin resistance in childhood and adolescence.
Springer, F, Nguyen, HP, Machann, J, Schweizer, R, Ranke, MB, Binder, G, Schick, F, Ehehalt, S, ,
Hormone research in paediatrics. 2010;(5):376-80
Abstract
BACKGROUND A major factor in the development of insulin resistance is obesity. While the contribution of intrahepatic lipids to insulin resistance is well established in adults, there are only few reports in childhood and adolescence. AIM: To investigate the correlation between ectopic fat deposition and insulin sensitivity in a normal-weight girl with acanthosis nigricans before and after lifestyle intervention. METHODS Variations in body fat composition and intrahepatic lipids were monitored by means of anthropometric measures and by means of methods based on magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS We present the case of a normal-weight 14-year-old Caucasian girl with pronounced hepatic steatosis together with acanthosis nigricans, increased waist-circumference and increased visceral fat. During a 7-month period of lifestyle intervention, the girl lost 7.1 kg in weight. Acanthosis nigricans, whole-body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA) improved significantly (before intervention: WBISI 0.42, HOMA 22.2; after intervention: WBISI 1.35, HOMA 6.9). Even though all lipid compartments were decreased in size, the intrahepatic lipids showed an extraordinarily great reduction. CONCLUSION This case presentation of a normal-weight girl with acanthosis nigricans and markedly increased hepatic steatosis provides support for the association between intrahepatic fat deposition and insulin resistance in adolescence.
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A clinical approach to severe insulin resistance.
Savage, DB, Semple, RK, Chatterjee, VKK, Wales, JKH, Ross, RJM, O'Rahilly, S
Endocrine development. 2007;:122-132
Abstract
Extreme forms of insulin resistance are a rare cause of type 2 diabetes. However, individuals with severe insulin resistance pose unique diagnostic and therapeutic challenges, and have often acted as 'experiments of nature' providing important novel information regarding endocrine physiology and mechanistic insights relevant to the study of more common disorders. Progress in understanding the molecular pathogenesis of such syndromes is also beginning to yield novel therapeutic options. Severe insulin resistance typically presents in 1 of 3 ways: (1) disordered glucose metabolism including both diabetes and/or paradoxical hypoglycaemia; (2) acanthosis nigricans, a velvety hyperpigmentation of axilliary and flexural skin often associated with skin tags; or (3) hyperandrogenism in girls (hirsutism, oligo-/amenorrhoea and polycystic ovaries). Lipodystrophy is a major cause of severe insulin resistance and needs to be looked for very carefully, particularly in the patients with significant dyslipidaemia and fatty liver. Specific treatments are now available for some forms of severe insulin resistance; for example, leptin replacement in patients with generalized lipodystrophy. In the absence of a specific diagnosis and therapy, metformin is a useful insulin sensitizer and should be used in conjunction with aggressive diet and exercise interventions.
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Extreme subcutaneous insulin resistance: a misunderstood syndrome.
Soudan, B, Girardot, C, Fermon, C, Verlet, E, Pattou, F, Vantyghem, MC
Diabetes & metabolism. 2003;(5):539-46
Abstract
Extreme subcutaneous insulin resistance (SIR) is a rare syndrome characterized by severe resistance to subcutaneous insulin with normal intravenous insulin sensitivity. Its pathophysiology is unknown, though an increased insulin degrading activity has been suggested. We report the case of a 35 year-old female patient with type I diabetes since the age of 3. Despite five shots of insulin/day, the patient progressively developed permanent ketosis related to severe acquired SIR with insulin doses as high as 500 U/day. Subcutaneous infusion of insulin and lispro insulin through an external pump did not improve resistance: HbA(1c) levels remained between 14 and 18% (N<6.5%). After numerous ketoacidotic episodes, continuous ambulatory intravenous insulin infusion was attempted through a central port due to a lack of peripheral venous access. HbAlc improved (8.5%) and daily insulin needs decreased to below 40U. However, the treatment had to be discontinued because of thrombosis and infection at different times. Intraperitoneal insulin infusion with an external pump was then proposed. HbAlc improved to 8% during 18 months but several episodes of catheter infection and encapsulation led to its removal. An intraperitoneal pump was surgically implanted, leading to the stabilization of HbA(1c) to around 8%. An insulin degradation assay did not demonstrate any excess of insulin degrading activity in the patient's or controls' subcutaneous tissue; nevertheless, excessive amounts of insulin were found in the patient's derm compared to controls. This case report of acquired SIR raises the question of its treatment and mechanisms. Regarding treatment, intraperitoneal delivery of insulin appears to be the best solution, but the mechanisms underlying SIR still remain unclear.
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[Leprechaunism caused by mutations in the insulin receptor gene].
Murashita, M, Tajima, T, Nakae, J, Fujieda, K
Nihon rinsho. Japanese journal of clinical medicine. 2002;(2):344-9
Abstract
Leprechaunism represents the most severe form of insulin resistance syndrome, manifesting abnormal glucose metabolism and intrauterine, postnatal growth retardation. Mutations in both alleles of the insulin receptor gene have been identified. Recombinant human IGF-I treatment could prevent postnatal growth retardation and normalize glucose metabolism, however there are few reports of long-term treatment with IGF-I. We have a case of compound heterozygous mutations of the insulin receptor gene, who has been treated with IGF-I more than 11 years. Relatively higher dose of IGF-I is necessary for maintaining sufficient serum IGF-I levels. After 10 years' treatment with IGF-I, polycystic ovary, kidney enlargement, albuminuria and retinopathy are complicated in this patient. In this review, we summarized basic actions of insulin and insulin receptor, classification of mutations in the insulin receptor gene, clinical feature and our results of long-term treatment with IGF-I in leprechaunism.
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8.
The clinical implications of insulin resistance.
Peters, AL
The American journal of managed care. 2000;(13 Suppl):S668-74; discussion S675-81
Abstract
Insulin resistance is a prime risk factor associated with atherosclerosis and thrombosis. Other risk factors include dyslipidemia, obesity, and hypertension. The constellation of those factors, which is known as the cardiovascular dysmetabolic syndrome, increases the risk of macrovascular disease. Insulin resistance may contribute directly to cardiovascular disease and may also act as a precursor of diabetes, which is also associated with an increased risk of macrovascular disease. Insulin resistance can be difficult to assess clinically, but it is invariably present in patients with type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Treatment of insulin resistance includes diet, exercise, smoking cessation, strict control of hypertension, aggressive treatment of lipid abnormalities, and keeping the hemoglobin A1c level below 7%. New oral agents improve glycemic control for those with diabetes or insulin resistance, but their role in reducing the risk of macrovascular disease is undetermined.