Effect of β-hydroxybutyrate and acetoacetate on insulin and glucagon secretion from perfused rat pancreas

Ikeda, Tadasu; Yoshida, Tazue; Ito, Yasuo; Murakami, Isao; Mokuda, O; Tominaga, Masato; Mashiba, Hiroto

doi:10.1016/0003-9861(87)90552-2

Cited by 32 publications

(17 citation statements)

References 22 publications

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“…NEFA and ketones also influence glucagon secretion. Although a physiological role of lipids is not established, NEFA and ketones have been reported to suppress glucagon secretion in vitro [7] and administration of lipid has been shown to decrease plasma glucagon levels in man [8].…”

Section: Normal Alpha Cell Functionmentioning

confidence: 99%

“…Although other non-glucose secretagogues, such as isoproterenol, are also used in provocative tests of beta cell function [26], bolus administration of isoproterenol is less effective than arginine in stimulation of acute glucagon release in humans [27]. Acute insulin-induced hypoglycaemia has also been used to assess alpha cell [9] NEFA [8] Parasympathetic nerves [10] Ketones [7] Adrenaline (epinephrine) [112] Insulin [113] Oxytocin [114] Somatostatin [115] Vasopressin [116] Secretin [117] GIP [118] GLP-1 [54] PACAP [119] Carbohydrate meal [18] GRP [120] CCK [121] VIP [122] Protein meal [18] Stress [20] Hypoglycaemia [3] GRP gastrin-releasing peptide; PACAP pituitary adenylate cyclaseactivating polypeptide; VIP vasoactive intestinal polypeptide function in humans [28], although arginine stimulation tests clearly pose less risk and are more routinely employed.…”

Section: Clinical Measures Of Alpha Cell Functionmentioning

confidence: 99%

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Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

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Section: Normal Alpha Cell Functionmentioning

confidence: 99%

Section: Clinical Measures Of Alpha Cell Functionmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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“…In the present study, chronic exposure to Ͼ2 mM HB affected insulin secretion, this concentration of HB augmenting glucose-induced insulin acutely in vitro (4,10,15,28,29,31) and being frequently observed in serum in various pathophysiological states (18). Acute exposure to the L-isomer was ineffective on insulin release, presumably due to no capacity to oxidize the isomer in islets (4,28).…”

Section: Discussionmentioning

confidence: 43%

“…The function of these substrates in regulating insulin output from pancreatic ␤-cells is less well understood. In short-term exposure of Ͻ60 min, ketone bodies such as D-␤-hydroxybutyrate (HB) are oxidized by islet cells and enhance insulin secretion in the presence of stimulatory levels of glucose (4,10,15,28,29,31). However, little is known of the effect of prolonged exposure to ketone bodies on pancreatic ␤-cells and insulin secretion.…”

mentioning

confidence: 99%

Chronic exposure to β-hydroxybutyrate inhibits glucose-induced insulin release from pancreatic islets by decreasing NADH contents

Takehiro

Fujimoto²,

Shimodahira³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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Yamada. Chronic exposure to ␤-hydroxybutyrate inhibits glucoseinduced insulin release from pancreatic islets by decreasing NADH contents. Am J Physiol Endocrinol Metab 288: E372-E380, 2005. First published October 12, 2004 doi:10.1152/ajpendo.00157.2004.-To investigate the effects of chronic exposure to ketone bodies on glucose-induced insulin secretion, we evaluated insulin release, intracellular Ca 2ϩ and metabolism, and Ca 2ϩ efficacy of the exocytotic system in rat pancreatic islets. Fifteen-hour exposure to 5 mM D-␤-hydroxybutyrate (HB) reduced high glucose-induced insulin secretion and augmented basal insulin secretion. Augmentation of basal release was derived from promoting the Ca 2ϩ -independent and ATP-independent component of insulin release, which was suppressed by the GDP analog. Chronic exposure to HB affected mostly the second phase of glucose-induced biphasic secretion. Dynamic experiments showed that insulin release and NAD(P)H fluorescence were lower, although the intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) was not affected 10 min after exposure to high glucose. Additionally, [Ca 2ϩ ]i efficacy in exocytotic system at clamped concentrations of ATP was not affected. NADH content, ATP content, and ATP-to-ADP ratio in the HB-cultured islets in the presence of high glucose were lower, whereas glucose utilization and oxidation were not affected. Mitochondrial ATP production shows that the respiratory chain downstream of complex II is not affected by chronic exposure to HB, and that the decrease in ATP production is due to decreased NADH content in the mitochondrial matrix. Chronic exposure to HB suppresses glucose-induced insulin secretion by lowering the ATP level, at least partly by inhibiting ATP production by reducing the supply of NADH to the respiratory chain. Glucose-induced insulin release in the presence of aminooxyacetate was not reduced, which implies that chronic exposure to HB affects the malate/aspartate shuttle and thus reduces NADH supply to mitochondria. islet; reduced nicotinamide adenine dinucleotide; adenosine 5Ј-triphosphate

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“…In addition, leucine alone, as well as hydroxybutyrate or ␣-ketoisocaproic acid, which each can be metabolized to acetoacetate, and acetoacetate itself, in combination with other metabolites, stimulate insulin release in INS-1 832/13 cells (27,28). ␤-Hydroxybutyrate also potentiates insulin release in the presence of a physiological concentration of glucose in human islets (Table 6) and in rat pancreatic islets as well (27,66,67). PC is not directly involved in the metabolism of ␤-hydroxybutyrate (Fig.…”

Section: Low Pyruvate Carboxylation and Atp Citrate Lyase And A More mentioning

confidence: 99%

Differences between Human and Rodent Pancreatic Islets

MacDonald

Longacre

Stoker

et al. 2011

Journal of Biological Chemistry

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Anaplerosis, the net synthesis in mitochondria of citric acid cycle intermediates, and cataplerosis, their export to the cytosol, have been shown to be important for insulin secretion in rodent beta cells. However, human islets may be different. We observed that the enzyme activity, protein level, and relative mRNA level of the key anaplerotic enzyme pyruvate carboxylase (PC) were 80 -90% lower in human pancreatic islets compared with islets of rats and mice and the rat insulinoma cell line INS-1 832/13. Activity and protein of ATP citrate lyase, which uses anaplerotic products in the cytosol, were 60 -75% lower in human islets than in rodent islets or the cell line. In line with the lower PC, the percentage of glucose-derived pyruvate that entered mitochondrial metabolism via carboxylation in human islets was only 20 -30% that in rat islets. This suggests human islets depend less on pyruvate carboxylation than rodent models that were used to establish the role of PC in insulin secretion. Human islets possessed high levels of succinyl-CoA:3-ketoacid-CoA transferase, an enzyme that forms acetoacetate in the mitochondria, and acetoacetyl-CoA synthetase, which uses acetoacetate to form acyl-CoAs in the cytosol. Glucose-stimulated human islets released insulin similarly to rat islets but formed much more acetoacetate. ␤-Hydroxybutyrate augmented insulin secretion in human islets. This information supports previous data that indicate beta cells can use a pathway involving succinyl-CoA:3-ketoacid-CoA transferase and acetoacetyl-CoA synthetase to synthesize and use acetoacetate and suggests human islets may use this pathway more than PC and citrate to form cytosolic acyl-CoAs.Understanding the enzymatic makeup of human pancreatic islets is fundamental to developing strategies for designing artificial beta cells and beta cells differentiated from stem cells as treatments for type 1 diabetes, as well as modulating beta cell metabolism for the treatment of type 2 diabetes. Until recently, most of the information about normal insulin secretion came from studies of rodent islets or clonal cell lines. Although a recent study showed human pancreatic islets respond to insulin secretagogues similarly to rodent islets (1), what is still unknown is whether the use of intracellular pathways of secretagogue metabolism is the same in human islets as in rodent islets and cell lines. During the last few years, human islet preparations from human donors have become more readily available to researchers. By studying the levels of enzymes, the functional units of metabolism, the recent abundant supply of human islets has enabled our laboratory to discover clues suggesting differences in metabolic pathways between pancreatic islets of humans and rodents that have implications for better understanding normal human beta cell physiology.Anaplerosis, the biosynthesis of citric acid cycle intermediates (2), is widely believed to be important for insulin secretion (3). Pyruvate carboxylase (PC) 2 is the key anaplerotic enzyme in this process ...

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Effect of β-hydroxybutyrate and acetoacetate on insulin and glucagon secretion from perfused rat pancreas

Cited by 32 publications

References 22 publications

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Chronic exposure to β-hydroxybutyrate inhibits glucose-induced insulin release from pancreatic islets by decreasing NADH contents

Differences between Human and Rodent Pancreatic Islets

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