Evidence for a deficient pancreatic β-cell response in a rat model of hyperthyroidism

Fukuchi, M; Shimabukuro, Michio; Shimajiri, Yoshinori; Oshiro, Yoshiko; Higa, Moritake; Akamine, Hikaru; Komiya, Ichiro; Takasu, Nobuyuki

doi:10.1016/s0024-3205(02)01791-5

Cited by 36 publications

(36 citation statements)

References 30 publications

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“…Therefore, hyperthyroidism in TRb D337T/D337T mice could explain the increased glucose tolerance and insulin sensitivity that, in this case, would be mediated by the TRa. However, experimental hyperthyroidism has also been associated with insulin resistance and with impaired b-cell responsiveness to the stimulatory action of glucose on insulin secretion (Fukuchi et al 2002, Holness et al 2008). Therefore, it is possible that the phenotype of the mutant mice results from multiple alterations of the homeostasis of glucose utilization and production caused not only by hyperthyroidism but also by resistance to TH action, as seems to be the case in liver glucose metabolism.…”

Section: Tsh In Trbmentioning

confidence: 99%

“…TH effects on growth, body composition, and glucose homeostasis have been described and result from the action of TH on different tissues (Dimitriadis & Raptis 2001, Fukuchi et al 2002, Bassett et al 2007; however, the molecular mechanisms and the subtype of TR predominantly involved are not completely understood. Thus, the aim of this study was to investigate the consequences of the impairment of TR signaling on growth, adiposity, and glucose metabolism of mice carrying the D337T mutation on TRb.…”

Section: Introductionmentioning

confidence: 99%

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The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

Santiago¹,

Santiago²,

Faustino³

et al. 2011

Journal of Endocrinology

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Mice bearing the genomic mutation D337T on the thyroid hormone receptor b (TRb) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRbD337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRbD337T mice exhibited normal glycemia and were more tolerant to an i.p. glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRbD337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration.In addition, hepatic glycogen content was lower in homozygous TRbD337T mice than in wild type. Collectively, the data suggest that TRbD337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-g coactivator 1a, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRb, reproducing a hypothyroid phenotype. In conclusion, mice carrying the D337T-dominant negative mutation on the TRb are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.

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Section: Tsh In Trbmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

Santiago¹,

Santiago²,

Faustino³

et al. 2011

Journal of Endocrinology

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“…16 Several studies evaluating the genomic and nongenomic effects of TH on insulin secretion have been conducted in order to clarify the mechanism(s) behind the IGT observed in hyperthyroidism. 17 For example, in rats treated with high and low doses of T4, fasting blood glucose levels were increased, but serum insulin levels were similar to those of controls. 17 By contrast, in rats treated only with high doses of T4, after an oral glucose load, blood glucose levels were increased, but serum insulin levels were decreased.…”

mentioning

confidence: 94%

Diabetes mellitus in a girl with thyroid hormone resistance syndrome: a little recognized interaction between the two diseases

Stagi¹,

Manoni²,

Cirello³

et al. 2002

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The syndrome of resistance to thyroid hormone (RTH) is characterized by elevated serum free thyroid hormones (FT4 and FT3) in the presence of unsuppressed TSH levels, reflecting resistance to the normal negative feedback mechanisms in the hypothalamus and pituitary. The degree of resistance within peripheral tissues determines whether thyrotoxic clinical features are associated with this condition. Classic features include attention deficit hyperactivity disorder, growth delay, tachycardia, and goiter. However, other features, such as frequent ear, nose and throat infections, hearing deficit, and decreased bone mass have recently been recognized. The phenotype of RTH is variable, with most patients presenting with mild to moderate symptoms. In this report we describe a girl with familiar RTH and diabetes mellitus. This is, to our knowledge, the first report regarding this association. Nearly one year after long-term triiodothyroacetic acid (Triac) therapy, we observed a reduction of thyroid hormone levels with an amelioration of insulin resistance. The possible interactions between these disorders are discussed.

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“…We therefore investigated the impact of hyperthyroidism on the feedback between insulin sensitivity and pancreatic beta cell function in late pregnancy in relation to the suppression by insulin of systemic lipid levels. It is well known that hyperthyroidism modifies lipid dynamics (increased lipolysis and oxidation), impairs insulin action, and can also suppress insulin secretion [20,[23][24][25][26][27][28]. Our aim was to examine whether hyperthyroidism compromises the regulation of insulin secretion and the ability of insulin to modulate fuel homeostasis in late pregnancy, which itself is characterised by a form of insulin resistance that is associated with altered lipid dynamics, but can be countered by enhanced insulin secretion.…”

Section: Introductionmentioning

confidence: 99%

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat

et al. 2005

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Aims/hypothesis: Hyperthyroidism modifies lipid dynamics (increased oxidation), impairs insulin action and can suppress insulin secretion. We therefore examined the impact of hyperthyroidism on the relationship between glucose-stimulated insulin secretion (GSIS) and insulin action, using late pregnancy as a model of physiological insulin resistance that is associated with compensatory insulin hypersecretion to maintain glucose tolerance. Our aim was to examine whether hyperthyroidism compromises the regulation of insulin secretion and the ability of insulin to modulate circulating lipid concentrations in late pregnancy. Materials and methods: Hyperthyroidism was induced by tri-iodothyronine (T 3 ) administration from day 17 to 19 of pregnancy. GSIS was assessed during an IVGTT and during hyperglycaemic clamps in vivo and in vitro, using step-up and -down islet perifusions. Results: Hyperthyroidism in pregnancy elevated the glucose threshold for GSIS and impaired GSIS at low and high glucose concentrations in islet perifusions. In the intact animal, insulin secretion (after bolus glucose) was more rapidly curtailed following removal of the glucose stimulus to secretion. In contrast, GSIS was maintained during protracted hyperglycaemia (hyperglycaemic clamps) in the hyperthyroid pregnant state in vivo. Conclusions/interpretation: Hyperthyroidism in vivo during late pregnancy blunts GSIS in subsequently isolated and perifused islets at low and high glucose concentrations. It also adversely affects GSIS under conditions of an acute glucose challenge in vivo. In contrast, GSIS is maintained during sustained hyperglycaemia in vivo, suggesting that in vivo factors can rescue GSIS. The ability of insulin to suppress systemic lipid levels during hyperglycaemic clamps was impaired. We therefore suggest that higher circulating lipids may preserve GSIS under conditions of sustained hyperglycaemia in the hyperthyroid pregnancy.

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Evidence for a deficient pancreatic β-cell response in a rat model of hyperthyroidism

Cited by 36 publications

References 30 publications

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

Diabetes mellitus in a girl with thyroid hormone resistance syndrome: a little recognized interaction between the two diseases

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat

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