Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment.

Ogawa, Atsushi; Harris, V.; McCorkle, Sara Kay; Unger, Roger H; Luskey, Kenneth L.

doi:10.1172/jci114528

Cited by 201 publications

(97 citation statements)

References 19 publications

(12 reference statements)

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“…Amylin, a 37-aa peptide hormone cosecreted with insulin from pancreatic ␤-cells (11), binds specific receptors in the hindbrain area postrema (AP) that activate multiple central nervous system (CNS) regions to regulate both glucose and energy homeostasis (12). In obese humans, the amylin analog pramlintide elicited sustained reductions in food intake and body weight (13,14).…”

mentioning

confidence: 99%

Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

Roth¹,

Roland²,

Cole³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

392

383

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Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.pramlintide ͉ metreleptin ͉ adiposity ͉ synergy ͉ leptin resistance T he discovery of leptin in 1994 (1) revolutionized our understanding of the biological basis of body-weight regulation and raised hopes that this adipokine could be a breakthrough treatment for obesity. Although leptin plays a pivotal role in regulating energy homeostasis in rodents and humans, its pharmaceutical development as a stand-alone antiobesity agent has proven unsuccessful (2). Although leptin replacement elicits profound weight loss in leptindeficient (Lep ob /Lep ob ) mice and humans (3, 4), even high pharmacological doses elicit only marginal weight loss in non-leptindeficient, diet-induced obese (DIO) rodents and humans (2, 5). The obese state is thus thought to be associated with ''leptin resistance,'' wherein overweight/obese individuals become insensitive to high circulating leptin concentrations (6). The mechanistic basis for leptin resistance is poorly understood, but rodent data implicate leptin transport saturation (7), leptin receptor down-regulation (8), and reduced hypothalamic postreceptor signaling (9, 10).Amylin, a 37-aa peptide hormone cosecreted with insulin from pancreatic ␤-cells (11), binds specific receptors in the hindbrain area postrema (AP) that activate multiple central nervous system (CNS) regions to regulate both glucose and energy homeostasis (12). In obese humans, the amylin analog pramlintide elicited sustained reductions in food intake and body weight (13,14). Amylin-induced weight loss in DIO rats that was observed to be fat-specific with relative...

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mentioning

confidence: 99%

Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

Roth¹,

Roland²,

Cole³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

392

383

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“…1A). We have further evaluated the effect of amylin over the glycemia of streptozotocin-induced diabetic mice (Da et al 2010, Wu and Huan 2008, Xu et al 2006, Ogawa et al 1990). Amylin was administrated through subcutaneous route and glycemia was monitored from whole blood.…”

Section: Resultsmentioning

confidence: 99%

“…Type 1 diabetes was induced by one intraperitoneal (ip.) injection of STZ (200 mg/kg) dissolved in fresh citrate buffer (100 mM, pH 4.5) (Da et al 2010, Wu and Huan 2008, Xu et al 2006, Ogawa et al 1990). Normal (non-diabetic) group received just the vehicle (0.1mL).…”

Section: Pharmacological Evaluation Of Amylinmentioning

confidence: 99%

Amylin induces hypoglycemia in mice

Guerreiro

Silva

Sola‐Penna

et al. 2013

An. Acad. Bras. Ciênc.

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Amylin is a 37-aminoacid pancreatic protein that exerts control over several metabolic events such as glycemia and lacticemia. Amylin has long been shown to induce increases in arterial plasma glucose. We decided to investigate whether amylin plays additional roles in the glucose metabolism. We evaluated glucose homeostasis using whole blood from the tail tip of fasting, conscious, unrestrained normal and streptozotocyn-induced diabetic mice following subcutaneous administration of mouse amylin. Subcutaneous injection of 1 μg mouse amylin caused a transient decrease in whole blood glucose in both normal and diabetic mice in the absence of insulin. The blood glucose levels were lowest approximately 2 hours after amylin administration, after that they gradually recovered to the levels of the control group. The hypoglycemic effect followed a dose-dependent response ranging from 0.1 to 50 µg / mouse. These results reveal the ability for amylin in the direct control of glycemia at low doses in the absence of insulin.

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“…One of these signals is the peptide hormone amylin, which is co-secreted with insulin from pancreatic beta-cells in response to food intake (Butler et al, 1990;Ogawa et al, 1990) and is considered a physiological satiation signal (Lutz et al, 1995;Lutz, 2005). Chronic amylin administration leads to a sustained reduction in food intake due to a decrease in average meal size and subsequently to a reduction in body weight gain in rats .…”

Section: -Introductionmentioning

confidence: 99%

Identification of central projections from amylin-activated neurons to the lateral hypothalamus

2010

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The ability of the pancreatic hormone amylin to inhibit food intake relies on a direct activation of the area postrema (AP). This activation is synaptically transmitted to the nucleus of the solitary tract (NTS), the lateral parabrachial nucleus (LPB), the central amygdaloid nucleus (Ce) and the lateral bed nucleus of stria terminalis (BSTL). Interestingly, neurons of the rostro-dorsal lateral hypothalamic area (dLHA), which are activated during fasting, are inhibited by peripheral amylin, although they lack amylin receptors. Using the retrograde tracer cholera toxin-B (Ctb) we analyzed whether the dLHA receives neuronal projections from amylin-activated brain areas. The anterograde tracer biotinylated dextran-amine (BDA) was used to confirm the projections and to identify further neuronal pathways potentially involved in amylin signaling. We identified dense projections from the amylin activated neurons in the LPB and sparse projections from the NTS to the dLHA. LPB fiber efferents were found in close proximity to dLHA nuclei activated by 24h of fasting. The AP and the Ce showed no projections to the dLHA. Dense efferents were also observed from the LPB to other hypothalamic areas, namely to the ventromedial, dorsomedial, paraventricular and arcuate nuclei. This study provides neuroanatomical evidence that among the amylin activated areas, the LPB provides the strongest input to the dLHA, thus it may mediate the amylin-induced inhibition of the dLHA. ABSTRACTThe ability of the pancreatic hormone amylin to inhibit food intake relies on a direct

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Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment.

Abstract: Amylin, a peptide copackaged with insulin in j-cell granules, was measured in the effluent of the perfused rat pancreas by means of a newly developed specific radioimmunoassay. Its secretion parallels that of insulin in response to 20 mM glucose, 10 mM arginine, or the combination thereof.

Cited by 201 publications

References 19 publications

Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

Amylin induces hypoglycemia in mice

Identification of central projections from amylin-activated neurons to the lateral hypothalamus

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