Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4

Smith, T.; Elmendorf, Jeffrey S.; David, Tonya S.; Turinsky, J.

doi:10.1152/ajpendo.1997.272.6.e1071

Cited by 65 publications

(63 citation statements)

References 21 publications

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“…Additionally, resembling our results, the bovine GH transgenic mice have increased basal phosphorylation of IRS-1 in muscle, which may also contribute to the insulin insensitivity seen in those mice. Other studies performed in rats have shown that chronic administration of GH caused impaired insulin signaling, specifically in muscle (31,32).…”

Section: Discussionmentioning

confidence: 91%

Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity

et al. 2001

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Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (ϳ75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LID mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control mice) and abnormal glucose clearance after insulin injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their control littermates. Thus, the high levels of circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID mice. In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues.

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Section: Discussionmentioning

confidence: 91%

Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity

et al. 2001

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“…However, the molecular mechanism of GH-induced insulin resistance has not been clarified. Although decreased IR tyrosine kinase activity was noted in animals after chronic GH administration (33,34), such a change could be secondary to the altered metabolic state associated with insulin resistance. In this study, we attempted to clarify the primary cause of GH-induced insulin resistance.…”

Section: Discussionmentioning

confidence: 98%

“…Nocturnal GH secretion in diabetic patients was suggested to play a role in the hyperglycemia known as dawn phenomenon (32). In vivo studies indicated that chronic administration of GH in rats induced insulin resistance, which was accompanied by decreases in insulin-stimulated autophosphorylation of IR and tyrosine phosphorylation of IRS-1 in skeletal muscle (33,34). GH binds its cognate receptor, which dimerizes and activates a cytosolic tyrosine kinase, Janus kinase 2 (JAK2) (35,36).…”

mentioning

confidence: 99%

Growth Hormone Induces Cellular Insulin Resistance by Uncoupling Phosphatidylinositol 3-Kinase and Its Downstream Signals in 3T3-L1 Adipocytes

et al. 2001

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Growth hormone (GH) is well known to induce in vivo insulin resistance. However, the molecular mechanism of GH-induced cellular insulin resistance is largely unknown. In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-associated PI 3-kinase activity. In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110 CAAX ) or Akt activation stimulated by plateletderived growth factor. Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol. These results indicate that cellular insulin resistance induced by chronic GH treatment in 3T3-L1 adipocytes is caused by uncoupling between activation of PI 3-kinase and its downstream signals, which is specific to the insulin-stimulated PI 3-kinase pathway. This effect of GH might result from the altered subcellular distribution of IRS-1-associated PI 3-kinase.

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“…Treatment with GH in differentiated adipocytes ex vivo, as well as in rat skeletal muscle in vivo, suggest that chronically GH can induce insulin resistance as indicated by reductions in IRS‐1/2 tyrosine and AKT phosphorylation and deoxyglucose transport (Smith et al. 1997; Thirone et al. 1997; Takano et al.…”

Section: Discussionmentioning

confidence: 99%

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle

Cervone

Dyck

2017

Physiol Rep

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Emerging evidence implicates ghrelin, a gut‐derived, orexigenic hormone, as a potential mediator of insulin‐responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin‐stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin‐stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser473 AKT or Thr172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin‐dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle.

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Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4

Cited by 65 publications

References 21 publications

Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity

Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity

Growth Hormone Induces Cellular Insulin Resistance by Uncoupling Phosphatidylinositol 3-Kinase and Its Downstream Signals in 3T3-L1 Adipocytes

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle

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