Thyroid Function and Insulin Secretion from the Perfused Pancreas in the Rat

Lenzen, Sigurd; Joost, H. G.; Hasselblatt, A.

doi:10.1210/endo-99-1-125

Cited by 45 publications

(23 citation statements)

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“…Experimental hyperthyroidism induced by thyroid hormone treatment leads to a reduction in glucoseinduced insulin secretion from the isolated pancreas (31), and this is not due to impairment of the insulin-secreting capacity of individual ␤-cells (32). It was also reported that stimulated insulin secretion is significantly increased in patients with hyperthyroidism, possibly reflecting increased ␤-cell sensitivity to glucose (33).…”

Section: Discussionmentioning

confidence: 99%

Liganded Thyroid Hormone Receptor-α Enhances Proliferation of Pancreatic β-Cells

Furuya

Shimura

Yamashita

et al. 2010

Journal of Biological Chemistry

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Failure of the functional pancreatic ␤-cell mass to expand in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing ␤-cells is important for ␤-cell proliferation in adult animals. In rat pancreatic ␤-cell lines (RIN5F), treatment with 100 nM thyroid hormone (triiodothyronine, T 3 ) enhances cell proliferation. This result suggests that T 3 is required for ␤-cell proliferation or replication. To identify the role of thyroid hormone receptor ␣ (TR␣) in the processes of ␤-cell growth and cell cycle regulation, we constructed a recombinant adenovirus vector, AdTR␣. Infection with AdTR␣ to RIN5F cells increased the expression of cyclin D1 mRNA and protein. Overexpression of the cyclin D1 protein in AdTR␣-infected cells led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway, along with cell cycle progression and cell proliferation following treatment with 100 nM T 3 . Conversely, lowering cellular cyclin D1 by small interfering RNA knockdown in AdTR␣-infected cells led to down-regulation of the cyclin D1/CDK/Rb/E2F pathway and inhibited cell proliferation. Furthermore, in immunodeficient mice with streptozotocin-induced diabetes, intrapancreatic injection of AdTR␣ led to the restoration of islet function and to an increase in the ␤-cell mass. These results support the hypothesis that liganded TR␣ plays a critical role in ␤-cell replication and in expansion of the ␤-cell mass during postnatal development. Thus, liganded TR␣ may be a target for therapeutic strategies that can induce the expansion and regeneration of ␤-cells.The pancreatic ␤-cell mass plays an essential role in determining the amount of insulin that is secreted to maintain blood glucose levels within a narrow range. Elucidation of the mechanisms that control the size of the ␤-cell mass is essential to allow development of regenerative therapy for both type 1 and type 2 diabetes, which are diseases characterized by an insufficient ␤-cell mass (1). Several mechanisms have been proposed to explain the process of adult ␤-cell mass expansion, including neogenesis from pancreatic duct cells or hematopoietic tissues, replication of highly active ␤-cell progenitors within the islets, and simple ␤-cell proliferation. The size of the ␤-cell mass is governed by the balance between the growth (differentiation and replication) and death (apoptosis) of these cells, but the mechanisms that sense the ␤-cell mass and maintain its homeostasis are largely unknown (2). Several recent reports have indicated that proliferation or replication of existing ␤-cells rather than differentiation of new ␤-cells from stem cells, is one mechanism involved in maintenance of the ␤-cell mass in adults (3, 4).To clarify the mechanisms involved in the replication of ␤-cells, we focused on molecular regulation of the cell cycle in mature pancreatic ␤-cells. Terminally differentiated cells often make the decision to replicate at the interface of the G 0 /G 1 phase of the cel...

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Section: Discussionmentioning

confidence: 99%

Liganded Thyroid Hormone Receptor-α Enhances Proliferation of Pancreatic β-Cells

Furuya

Shimura

Yamashita

et al. 2010

Journal of Biological Chemistry

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“…In particularly prone individuals, hyperthyroidism can induce a so-called "thyroid diabetes" [2]. Thyroxine treatment causes a state of experimental hyperthyroidism and reduces the pancreatic insulin content and glucose-induced insulin secretion [4,5]. This is accompanied by a reduction in the beta-cell volume of the pancreas [5].…”

Section: Methodsmentioning

confidence: 99%

“…given i.p. for 5 consecutive days) (Sigma, St. Louis, Mo., USA) dissolved in 0.9% NaCl solution [4,9]. Alternatively, in time course studies, L-thyroxine (20 mg/kg b.wt.)…”

Section: Methodsmentioning

confidence: 99%

Thyroxine induces pancreatic beta-cell apoptosis in rats

2002

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Aims/hypothesis. Thyroid hormones reduce glucose tolerance in animals and humans. This effect is accompanied by a reduction in the beta-cell volume of the pancreas. Methods. We studied the underlying mechanism using terminal UTP nick end labelling (TUNEL) and caspase-3 to analyse apoptosis and BrdU labelling of betacell proliferation. Results. The reason for the reduction of the beta-cell volume of the pancreas after thyroxine treatment is apparently an increased rate of beta-cell apoptosis by an increase of TUNEL and caspase-3 positive rat beta cells. In parallel, thyroxine treatment increased the rate of apoptosis in rat pancreatic ductal cells which are considered to contribute to the pool of stem cells from which insulin-producing beta cells originate. The effects of thyroid hormone treatment are reversible through an increase of the beta-cell replication rate when thyroxine is withdrawn as documented by an increase of the BrdU labelling index. Conclusion/interpretation. An increased rate of betacell death due to apoptosis causes a decrease of insulin content and glucose-induced insulin secretion from the pancreas in hyperthyroidism. The resulting reduction of beta cells in the pancreas can provide an explanation for the decrease of glucose tolerance in hyperthyroidism. [Diabetologia (2002) underlying pancreatic beta-cell loss is not known [2]. The prohormone thyroxine is deiodinated to triiodothyronine in many tissues [6] including pancreatic islets [7]. Triiodothyronine mediates its effects through binding to thyroid hormone nuclear receptors [6]. As thyroid hormones play a major role in apoptotic tissue remodelling [8] we studied whether the effects of thyroxine on the endocrine pancreas might be caused by an increased rate of apoptosis of the beta cells in the islets of Langerhans. Materials and methodsExperimental design. Experimental hyperthyroidism accompanied by mild hyperglycaemia (5.5 ± 0.1 vs 4.7 ± 0.1 mmol/l in control rats; p < 0.05, Student's t test) and mild hyperinsulinaemia (0.59 ± 0.11 vs. 0.40 ± 0.04 ng/ml in control rats; p < 0.05, Student's t test) was induced in Lewis rats (190-230 g) through treatment with L-thyroxine (600 µg/kg Thyroid hormones have a multitude of metabolic effects [1] and act as insulin antagonists [2]. Hyperthyroidism induces glucose intolerance in animals and humans [2,3]. In particularly prone individuals, hyperthyroidism can induce a so-called "thyroid diabetes" [2]. Thyroxine treatment causes a state of experimental hyperthyroidism and reduces the pancreatic insulin content and glucose-induced insulin secretion [4,5]. This is accompanied by a reduction in the beta-cell volume of the pancreas [5]. However, the mechanism

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“…The findings in the present work suggest that glucose possesses the highest capacity to stimulate insulin secretion from the pancreas of hypothyroid animals whereas this capacity is minimum in the hyperthyroid rats. Charles et al (1975) showed that glucose elevates the cyclic AMP level in the beta cells which acts as a feed forward modulator of glucose induced insulin release in euthyroid animals, while Lenzen et al (1976) suggested that hyperthyroidism results in decreased glucose induced insulin release, whereas experimental hypothyroidism induces increased secretion of insulin from the pancreas. On the contrary, Balabokin (1971) and Jolin (1974) found that in hypothyroidism glucose-induced insulin secretion decreases but thyroxine treatment reverses the effect.…”

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confidence: 99%