Histologic distribution of insulin and glucagon receptors

Watanabe, Masaru; Hayasaki, Hana; Tamayama, Takumi; Shimada, M.

doi:10.1590/s0100-879x1998000200008

Cited by 35 publications

(24 citation statements)

References 96 publications

(86 reference statements)

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“…1 A , left panel). Consistent with previous studies (34–36), IR was expressed at the highest level in the duodenum followed by the jejunum, with 50% lower levels in the ileum. The colon had levels similar to those in the duodenum.…”

Section: Resultssupporting

confidence: 92%

Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

et al. 2017

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Insulin receptors (IRs) and IGF-I receptors (IGF-IR) are major regulators of metabolism and cell growth throughout the body; however, their roles in the intestine remain controversial. Here we show that genetic ablation of the IR or IGF-IR in intestinal epithelial cells of mice does not impair intestinal growth or development or the composition of the gut microbiome. However, the loss of IRs alters intestinal epithelial gene expression, especially in pathways related to glucose uptake and metabolism. More importantly, the loss of IRs reduces intestinal glucose uptake. As a result, mice lacking the IR in intestinal epithelium retain normal glucose tolerance during aging compared with controls, which show an age-dependent decline in glucose tolerance. Loss of the IR also results in a reduction of glucose-dependent insulinotropic polypeptide (GIP) expression from enteroendocrine K-cells and decreased GIP release in vivo after glucose ingestion but has no effect on glucagon-like peptide 1 expression or secretion. Thus, the IR in the intestinal epithelium plays important roles in intestinal gene expression, glucose uptake, and GIP production, which may contribute to pathophysiological changes in individuals with diabetes, metabolic syndrome, and other insulin-resistant states.

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Section: Resultssupporting

confidence: 92%

Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

et al. 2017

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“…Glucagon stimulated FGF-21 secretion, expression and protein production in vitro in rodent adipocytes; however, no increase inFgf-21 mRNA expression was detectable in white adipose tissue in glucagon-treated animals. Highest density of glucagon receptors are found in hepatocytes [31,32], but much less abundant in adipocytes [31,33]. We therefore hypothesise that glucagon primarily stimulates FGF-21 secretion in the liver leading to high circulating FGF-21 which, in turn, may concomitantly suppress endogenous FGF-21 production in adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

et al. 2012

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Aims/hypothesis Glucagon reduces body weight by modifying food intake, glucose/lipid metabolism and energy expenditure. All these physiological processes are also controlled by fibroblast growth factor 21 (FGF-21), a circulating hepatokine that improves the metabolic profile in obesity and type 2 diabetes. Animal experiments have suggested a possible interaction between glucagon and FGF-21 however, the metabolic consequences of this crosstalk are not understood. Methods The effects of exogenous glucagon on plasma FGF-21 levels and lipolysis were evaluated in healthy volunteers and humans with type 1 diabetes, as well as in rodents with streptozotocin (STZ)-induced insulinopenic diabetes. In vitro, the role of glucagon on FGF-21 secretion and lipolysis was studied using isolated primary rat hepatocytes and adipocytes. Fgf-21 expression in differentiated rat pre-adipocytes was suppressed by small interfering RNA and released FGF-21 was immunoneutralised by polyclonal antibodies. Results Glucagon induced lipolysis in healthy human volunteers, patients with type 1 diabetes, mice and rats with STZ-induced insulinopenic diabetes, and in adipocytes isolated from diabetic and non-diabetic animals. In addition, glucagon increased circulating FGF-21 in healthy humans and rodents, as well as in patients with type 1 diabetes, and insulinopenic rodents. Glucagon stimulated FGF-21 secretion from isolated primary hepatocytes and adipocytes derived from animals with insulinopenic diabetes. Furthermore, FGF-21 stimulated lipolysis in primary adipocytes isolated from non-diabetic and diabetic rats. Reduction of Fgf-21 expression (by approximately 66%) or immunoneutralisation of released FGF-21 markedly attenuated glucagon-stimulated lipolysis in adipocytes. Conclusions/interpretation These results indicate that glucagon increases circulating FGF-21 independently of endogenous insulin levels. FGF-21 participates in glucagon-induced stimulation of lipolysis.

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“…These studies provide evidence of the role of GDNF signaling in pancreatic neoplasia but at a far later stage in the neoplastic process than the changes observed in the current study. The coupling of GDNF to HIRmAb may have facilitated the accumulation of the compound in the pancreas, because numerous insulin receptors are present in the duct cells [40], [41]. This may have also contributed to overactivation of tyrosine kinase signaling pathways that are stimulated by both GDNF and insulin, affecting duct cells normal metabolic function.…”

Section: Discussionmentioning

confidence: 99%

A Monoclonal Antibody-GDNF Fusion Protein Is Not Neuroprotective and Is Associated with Proliferative Pancreatic Lesions in Parkinsonian Monkeys

et al. 2012

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Glial cell line derived neurotrophic factor (GDNF) is a neurotrophic factor that has neuroprotective effects in animal models of Parkinson’s disease (PD) and has been proposed as a PD therapy. GDNF does not cross the blood brain barrier (BBB), and requires direct intracerebral delivery to be effective. Trojan horse technology, in which GDNF is coupled to a monoclonal antibody (mAb) against the human insulin receptor (HIR), has been proposed to allow GDNF BBB transport (ArmaGen Technologies Inc.). In this study we tested the feasibility of HIRMAb-GDNF to induce neuroprotection in parkinsonian monkeys, as well as its tolerability and safety. Adult rhesus macaques were assessed throughout the study with a clinical rating scale, a computerized fine motor skills task and general health evaluations. Following baseline measurements, the animals received a unilateral intracarotid artery MPTP injection. Seven days later the animals were evaluated, matched according to disability and blindly assigned to receive twice a week iv. treatments (vehicle, 1 or 5 mg/kg HIRmAb-GDNF) for a period of three months. HIRmAb-GDNF did not improve parkinsonian motor symptoms and induced a dose-dependent hypersensitivity reaction. Quantification of dopaminergic striatal optical density and stereological nigral cell counts did not demonstrate differences between treatment groups. Focal pancreatic acinar to ductular metaplasia (ADM) was noted in four of seven animals treated with 1 mg/kg HIRmAb-GDNF; two of four with ADM also had focal pancreatic intraepithelial neoplasia 1B (PanIN-1B) lesions. Minimal to mild, focal to multifocal, nonsuppurative myocarditis was noted in all animals in the 5 mg/kg treatment group. Our results demonstrate that HIRmAb-GDNF dosing in a monkey model of PD is not an effective neuroprotective strategy and may present serious health risks that should be considered when planning future use of the IR antibody as a carrier, or of any systemic treatment of a GDNF-containing molecule.

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Histologic distribution of insulin and glucagon receptors

Cited by 35 publications

References 96 publications

Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

A Monoclonal Antibody-GDNF Fusion Protein Is Not Neuroprotective and Is Associated with Proliferative Pancreatic Lesions in Parkinsonian Monkeys

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