Tissue-Specific and Glucose-Dependent Expression of Receptor Genes for Glucagon and Glucagon-Like Peptide-1 (GLP-1)

Yamato, Eiji; Ikegami, Hiroshi; Takekawa, K.; Fujisawa, T; Nakagawa, Y.; Hamada, Yoji; Ueda, Hiroo; Ogihara, Toshio

doi:10.1055/s-2007-978985

Cited by 50 publications

(30 citation statements)

References 7 publications

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“…In agreement with these previous studies, we were unable to convincingly detect GLP-1 receptor protein or mRNA in neonatal liver (data not shown). To date, only one GLP-1 receptor has been identified (6,11,14,15,25,36,63,64). However, there are studies in which some actions of GLP-1 are not blocked by the antagonist Exendin-(9 -39) (13,38), suggesting that Ex-4 may mediate some of its actions through a different receptor.…”

Section: Discussionmentioning

confidence: 99%

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Raab

Vuguin

Stoffers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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(IUGR) has been linked to the development of Type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagonlike-peptide-1 agonist, Exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of Exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given Exendin-4 on days 1-6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to Exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance. intrauterine growth retardation; diabetes; liver; insulin resistance UTEROPLACENTAL INSUFFICIENCY limits availability of substrates to the fetus and retards growth during gestation (40, 47). We have previously shown in a rat model of uteroplacental insufficiency and intrauterine growth retardation (IUGR) that this abnormal metabolic intrauterine milieu affects the development of the fetus by inducing mitochondrial dysfunction and oxidative stress which, in turn, modifies gene expression and function of susceptible cells in the pancreas, muscle, and liver (43,46,48). The end result is the later development of diabetes in adulthood with the salient features of most forms of Type 2 diabetes (T2DM) in the human: defects in insulin action and insulin secretion (49). IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin (62). Basal HGP is also mildly elevated in IUGR rats (62). These defects in hepatic glucose metabolism are secondary to oxidative stress, which impairs insulin signaling (43,62).We have also demonstrated that short-term administration of the long-acting incretin hormone glucagon-like peptide-1 (GLP-1) receptor agonist, Exendin-4 (Ex-4), during the neonatal period, improves glucose tolerance, prevents the progressive reduction in ␤-cell mass tha...

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Section: Discussionmentioning

confidence: 99%

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Raab

Vuguin

Stoffers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Only one cloned GLP-1 receptor has been found (7,10,15,18,39,52,72), but there is one previous case in which receptors have distinctly different pharmacology, i.e., insensitivity to the antagonist exendin-(9O39), as previously described (54).…”

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confidence: 84%

“…When the action of GLP-1 is inhibited, glucose tolerance is impaired (11). Receptors for GLP-1 are present in the periphery as well as the central nervous system, in which it may act to modulate fluid and food intake (7,10,15,18,19,39,48,52,72). GLP-1 receptors are also present on afferent nerves, and several of its actions are postulated to involve activation of vagal afferents or those from the dorsal roots (45,54,70).…”

mentioning

confidence: 99%

Local, exendin-(9—39)-insensitive, site of action of GLP-1 in canine ileum

Daniel¹,

Anvari²,

Fox-Threlkeld

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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Glucagon-like peptide-1 (GLP-1) modulates glucose levels following a meal, including by inhibition of gastric emptying and intestinal transport. Intra-arterial injection of GLP-1 into the gastric corpus, antrum, or pylorus of anesthetized dogs had no effect on the contractile activity of the resting or neurally activated stomach. GLP-1 injected intra-arterially inhibited intestinal segments when activated by enteric nerve stimulation but not by acetylcholine. Isolated ileum segments were perfused intra-arterially, instrumented with strain gauges to record circular muscle activity and with subserosal electrodes to stimulate enteric nerves. GLP-1 caused concentration-dependent inhibition of nerve-stimulated phasic but not tonic activity. This was absent during TTX-induced activity and partly prevented by N G-nitro-l-arginine. Exendin-(9—39), the GLP-1 antagonist, had no intrinsic activity and did not affect the actions of GLP-1. Capsaicin mimicked the effects of GLP-1 and may have reduced the effect of subsequent GLP-1. GLP-1 may mediate paracrine action on afferent nerves in the canine ileal mucosa using an unusual receptor.

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“…GLP-1 exerts its effect at the GLP-1R to stimulate adenylyl cyclase activity and cAMP production [94]. GLP-1R expression is widely distributed particularly in the brain, GI tract and pancreas [94,95]. Circulating GLP-1 levels rise after a meal and fall in the fasted state.…”

Section: Ghrelinmentioning

confidence: 99%

The role of gut hormones and the hypothalamus in appetite regulation

et al. 2010

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Abstract. The World Health Organisation has estimated that by 2015 approximately 2.3 billion adults will be overweight and more than 700 million obese. Obesity is associated with an increased risk of diabetes, cardiovascular events, stroke and cancer. The hypothalamus is a crucial region for integrating signals from central and peripheral pathways and plays a major role in appetite regulation. In addition, there are reciprocal connections with the brainstem and higher cortical centres. In the arcuate nucleus of the hypothalamus, there are two major neuronal populations which stimulate or inhibit food intake and influence energy homeostasis. Within the brainstem, the dorsal vagal complex plays a role in the interpretation and relaying of peripheral signals. Gut hormones act peripherally to modulate digestion and absorption of nutrients. However, they also act as neurotransmitters within the central nervous system to control food intake. Peptide YY, pancreatic polypeptide, glucagon-like peptide-1 and oxyntomodulin suppress appetite, whilst ghrelin increases appetite through afferent vagal fibres to the caudal brainstem or directly to the hypothalamus. A better understanding of the role of these gut hormones may offer the opportunity to develop successful treatments for obesity. Here we review the current understanding of the role of gut hormones and the hypothalamus on food intake and body weight control.

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Tissue-Specific and Glucose-Dependent Expression of Receptor Genes for Glucagon and Glucagon-Like Peptide-1 (GLP-1)

Cited by 50 publications

References 7 publications

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Local, exendin-(9—39)-insensitive, site of action of GLP-1 in canine ileum

The role of gut hormones and the hypothalamus in appetite regulation

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