Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons.

D’Alessio, David A.; Vogel, Robin E.; Prigeon, R L; Laschansky, Ellen C.; Koerker, Donna J.; Eng, John; Ensinck, John W.

doi:10.1172/jci118380

Cited by 111 publications

(25 citation statements)

References 47 publications

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“…Elimination of GLP1 activity with GLP1-immunoneutralizing antisera or the GLP1R antagonist exendin , which is a truncated form of the lizard GLP1-related peptide exendin-4, results in impaired glucose tolerance, and diminished glucose-stimulated insulin levels in both animals and humans (17,(42)(43)(44). Furthermore, basal GLP1 signaling in the fasting state is essential for regulation of glucose homeostasis, because infusion of exendin increases levels of fasting glucose and glucagon in human subjects, demonstrating that even low basal levels of GLP1 exert a tonic inhibitory effect on glucagon-secreting α cells (45).…”

Section: The Proglucagon-derived Peptidesmentioning

confidence: 99%

The role of gut hormones in glucose homeostasis

Drucker¹

2007

J. Clin. Invest.

544

409

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The gastrointestinal tract has a crucial role in the control of energy homeostasis through its role in the digestion, absorption, and assimilation of ingested nutrients. Furthermore, signals from the gastrointestinal tract are important regulators of gut motility and satiety, both of which have implications for the long-term control of body weight. Among the specialized cell types in the gastrointestinal mucosa, enteroendocrine cells have important roles in regulating energy intake and glucose homeostasis through their actions on peripheral target organs, including the endocrine pancreas. This article reviews the biological actions of gut hormones regulating glucose homeostasis, with an emphasis on mechanisms of action and the emerging therapeutic roles of gut hormones for the treatment of type 2 diabetes mellitus.

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Section: The Proglucagon-derived Peptidesmentioning

confidence: 99%

The role of gut hormones in glucose homeostasis

Drucker¹

2007

J. Clin. Invest.

544

409

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“…AAM, amino acid mixture. observed in baboons (19) and healthy human subjects (24). Although SUR-1 Ϫ/Ϫ mice are relatively normoglycemic in the fed state (6, 7), they develop hypoglycemia with fasting, which allowed us to test the potential for exendin-(9 -39) to normalize fasting blood glucose in the absence of functional K ATP channels.…”

Section: Tablementioning

confidence: 99%

Exendin-(9–39) Corrects Fasting Hypoglycemia in SUR-1–/– Mice by Lowering cAMP in Pancreatic β-Cells and Inhibiting Insulin Secretion

León

Delson

et al. 2008

Journal of Biological Chemistry

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Congenital hyperinsulinism is a disorder of pancreatic ␤-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in brain damage or death if untreated. Loss-of-function mutations in the K ATP channel (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of congenital hyperinsulinism. Most patients are unresponsive to available medical therapy and require palliative pancreatectomy. Similar to the human condition, the SUR-1 ؊/؊ mouse is hypoglycemic when fasted and hyperglycemic when glucose-loaded. We have previously reported that the glucagon-like peptide-1 receptor antagonist exendin-(9 -39) raises fasting blood glucose in normal mice. Here we examine the effect of exendin-(9 -39) on fasting blood glucose in SUR-1 ؊/؊ mice. Mice were randomized to receive exendin-(9 -39) or vehicle. Fasting blood glucose levels in SUR-1 ؊/؊ mice treated with exendin-(9 -39) were significantly higher than in vehicle-treated mice and not different from wild-type littermates. Exendin-(9 -39) did not further worsen glucose tolerance and had no effect on body weight and insulin sensitivity. Isolated islet perifusion studies demonstrated that exendin-(9 -39) blocked amino acid-stimulated insulin secretion, which is abnormally increased in SUR-1 ؊/؊ islets. Furthermore, cAMP content in SUR-1 ؊/؊ islets was reduced by exendin-(9 -39) both basally and when stimulated by amino acids, whereas cytosolic calcium levels were not affected. These findings suggest that cAMP plays a key role in K ATP -independent insulin secretion and that the GLP-1 receptor is constitutively active in SUR-1 ؊/؊ ␤-cells. Our findings indicate that exendin-(9 -39) normalizes fasting hypoglycemia in SUR-1mice via a direct effect on insulin secretion, thereby raising exendin-(9 -39) as a potential therapeutic agent for K ATP hyperinsulinism.Congenital hyperinsulinism is a genetic disorder of pancreatic ␤-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in brain damage or death if inadequately treated. Loss-of-function mutations in the K ATP -sensitive channel (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of hyperinsulinism (K ATP HI). K ATP -sensitive channels couple the metabolic state of the ␤-cell to membrane potential by sensing changes in intracellular ATP concentration. In pancreatic ␤-cells, closure of the channel in response to elevation of the ATP/ADP ratio following stimulation with glucose leads to depolarization of the membrane and activation of voltage-dependent calcium channels with resultant exocytosis of insulin-containing granules (1). Thus, K ATP -sensitive channels play a critical role in the triggering pathway of glucosestimulated insulin secretion (2). In contrast, the amplifying pathway of insulin release operates independently of K ATP -sensitive channels and functions to augment fuel-stimulated insulin secretion (3). Electrophysiologi...

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“…Based on current evidence, the actions of circulating GLP-1 are best understood as a set of coordinated processes that promotes glucose tolerance ( Figure 1). Indeed, the most consistent finding across disparate studies in which GLP-1 signaling was blocked or reduced in vivo has been the development of abnormally high blood glucose levels following enteral or parenteral glucose administration (3)(4)(5)(6).…”

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confidence: 99%

New ways in which GLP-1 can regulate glucose homeostasis

D’Alessio

Sandoval

Seeley

2005

Journal of Clinical Investigation

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Glucagon-like peptide-1 (GLP-1) has a diverse set of peripheral actions which all serve to promote enhanced glucose tolerance, and for this reason it has become the basis for new treatments for type 2 diabetes. In this issue of the JCI, Knauf et al. provide clear evidence that GLP-1 signaling in the CNS is also linked to the control of peripheral glucose homeostasis by inhibiting non-insulin-mediated glucose uptake by muscle and increasing insulin secretion from the pancreas (see the related article beginning on page 3554). The authors' work points to an important need to integrate diverse GLP-1 signaling actions and peripheral GLP-1 function in order to better understand both normal and abnormal glucose homeostasis.

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Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons.

Cited by 111 publications

References 47 publications

The role of gut hormones in glucose homeostasis

The role of gut hormones in glucose homeostasis

Exendin-(9–39) Corrects Fasting Hypoglycemia in SUR-1–/– Mice by Lowering cAMP in Pancreatic β-Cells and Inhibiting Insulin Secretion

New ways in which GLP-1 can regulate glucose homeostasis

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