Extreme Insulin Resistance in Association with Abnormally High Binding Affinity of Insulin Receptors from a Patient with Leprechaunism: Evidence for a Defect Intrinsic to the Receptor

Taylor, Simeon I.; Hedo, J A; Underhill, Lisa; Kasuga, Masato; Elders, M. Joycelyn; Roth, Jesse

doi:10.1210/jcem-55-6-1108

Cited by 56 publications

(41 citation statements)

References 20 publications

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“…Both insulin and IGF1 contribute to normal muscle growth, and insulin resistance and diabetes mellitus can be associated with varying degrees of skeletal muscle atrophy and impaired satellite cell proliferation and differentiation (29). Thus, it is possible that alterations in differentiation pattern observed in the mutant lines contribute to the low muscle mass observed in children with Donohue syndrome (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

“…C1 fibroblasts (BJ) were from ATCC; C2, C3, C4, IR-M2 and IR-M3, and IR-M4 fibroblasts were from Coriell. IR-M1 and IR-M3 fibroblasts were previously characterized (11,12). iPS cells were generated from fibroblasts by retroviral transduction of KLF4, SOX2, OCT4, and c-MYC reprogramming factors and tested for pluripotency as previously described (9).…”

Section: Methodsmentioning

confidence: 99%

“…Donohue syndrome (also called leprechaunism) is caused by homozygous or compound heterozygous mutations in the insulin receptor, resulting in a complex clinical phenotype including marked insulin resistance, failure to thrive, and early death (10)(11)(12). iPS cells derived from these patients exhibit severe insulin resistance with defects in insulin signaling, cell proliferation, and gene transcription (9,13).…”

mentioning

confidence: 99%

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Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Iovino

Burkart

Warren

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Iovino

Burkart

Warren

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Some patients with this disorder have a decrease in insulin receptor numbers (17), others have structure alterations of the insulin receptor (18)(19)(20), while others would appear to have a postreceptor defect (3, 6, 7) or a combination of abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…Further, some patients with leprechaunism have been reported to have decreased insulin, epidermal growth factor, multiple stimulating activity, and somatomedin C receptors (17,18,24).…”

Section: Discussionmentioning

confidence: 99%

Decreased Cyclic Guanosine 3´,5´ Monophosphate and Guanylate Cyclase Activity in Leprechaunism: Evidence for a Postreceptor Defect

et al. 1986

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Acanthosis Nigricans and Insulin Resistance Associated With Hypothyroidism

Ober¹

1985

Arch Dermatol

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Extreme Insulin Resistance in Association with Abnormally High Binding Affinity of Insulin Receptors from a Patient with Leprechaunism: Evidence for a Defect Intrinsic to the Receptor

Cited by 56 publications

References 20 publications

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Decreased Cyclic Guanosine 3´,5´ Monophosphate and Guanylate Cyclase Activity in Leprechaunism: Evidence for a Postreceptor Defect

Acanthosis Nigricans and Insulin Resistance Associated With Hypothyroidism

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