Studies on the role of β-cell metabolism in the insulinotropic effect of α-ketoisocaproic acid

Holze, Susanne; Panten, U.

doi:10.1016/0304-4165(79)90204-6

Cited by 8 publications

(3 citation statements)

References 14 publications

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“…It has been suggested that insulin-releasing fuels may initiate the secretory process by changing the B-cell metabolism (Grodsky et al, 1963;Coore & Randle, 1964;Ashcroft et al, 1973;Malaisse et al, 1979b). At least the non-metabolizable leucine analogue (-)-BCH and 4-methyl-2-oxopentanoate do not act by producing specific trigger metabolites (Christensen et al, 1971;Lenzen et al, 1982), but may operate by enhancing production of hydrogen (reducing equivalents) in the B-cell mitochondria (Holze & Panten, 1979;Hutton et al, 1979;Panten et al, 1980;Sener et al, 1981;Malaisse-Lagae etal., 1982). Two main routes exist along which intramitochondrial hydrogen production could elicit insulin secretion (Panten et al, 1980).…”

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confidence: 99%

Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue

Panten¹,

Zielmann²,

Langer³

et al. 1984

Biochemical Journal

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In mouse pancreatic islets the kinetics of insulin secretion and O2 uptake in response to the non-metabolizable leucine analogue (+/-)-BCH (2-endo- aminonorbornane −2-carboxylic acid) were compared. In addition, the fuel-mobilizing effect of (+/-)-BCH was studied with a mitochondrial fraction from islets. (1) Within 2 min 20 mM-(+/-)-BCH markedly enhanced insulin release or O2 consumption by islets respiring in the absence of exogenous fuels. During prolonged exposure to 20 mM-(+/-)-BCH secretion declined more rapidly than O2 uptake. (2) L-Glutamine (10 mM) prevented the decrease of both insulin release and O2 uptake of islets exposed to 20mM-(+/-)-BCH. During the second phase of insulin release in response to 20 mM-(+/-)-BCH + 10 mM-L-glutamine, kinetics of secretion and respiration correlated closely. (3) Initial peaks were consistently seen in the (+/-)-BCH-induced secretory profiles, but never in the respiratory profiles. (4) In contrast with L-glycerol 3-phosphate, L-malate or pyruvate, L-glutamine or L-glutamate maintained low rates of oxidative phosphorylation in B-cell mitochondria. The effects of L-glutamine or L-glutamate were potentiated severalfold by (+/-)-BCH. (5) The effects of other branched-chain amino acids on oxidative phosphorylation resembled their effects on insulin release, redox state of nicotinamide nucleotides and glutamate dehydrogenase activity. (6) The results support the view that (+/-)-BCH stimulates insulin secretion via a primary enhancement of hydrogen supply to the respiratory chain of B-cell mitochondria.

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confidence: 99%

Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue

Panten¹,

Zielmann²,

Langer³

et al. 1984

Biochemical Journal

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“…14 C-Labeled KIC was prepared and analyzed as described previously (13). All other reagents were analytical grade and were obtained from Merck (Darmstadt, 1596 PANTEN AND KLEIN Endo • 1982 Vol Vll • No 5 West Germany).…”

Section: Chemicals and Mediamentioning

confidence: 99%

“…2, which reflect the mean rates of O2 uptake during the Concentration-dependent metabolism of KIC by mouse islets. Forty islets were incubated in basal medium for 30 min and then for 60 min in the same medium but containing in addition[1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]KIC (1.8-0.2 Ci/mol), [2-14 C]KIC (2.4-0.3 Ci/mol), or [U-14 C]KIC (2.2-0.3 Ci/mol). Degradation of [1-14 C]KIC or [2-14 C]KICis expressed as nanomoles of 14 CO 2 formed per h/jug DNA.…”

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O₂Consumption by Isolated Pancreatic Islets, as Measured in a Microincubation System with a Clark-Type Electrode*

Panten

Klein

1982

Endocrinology

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The role of B-cell respiration in fuel-induced insulin secretion has not been clarified. Therefore, a new method for the measurement of O2 uptake in islets of Langerhans was developed. An all-glass microincubation chamber was equipped with a Clark-type electrode, a stirring bar, and a special channel for loading the chamber with islets, media, and test compounds. The sensitivity of the system was sufficient for convenient determination of O2 consumption by less than 100 islets. Using DNA as reference value, the exactness of the method was scaled up considerably. Basal O2 uptake in mouse islets amounted to 5.6 +/- 0.2 nmol/h/micrograms DNA. alpha-Ketoisocaproic acid (2.5-20 mM) enhanced O2 consumption by 63-207%. The rate of O2 uptake as well as those of insulin secretion and oxidation of alpha-ketoisocaproic acid in incubated mouse islets were maximal at about 10 mM alpha-ketoisocaproic acid. 14CO2 production from U-14C-labeled alpha-ketoisocaproic acid was up to 36% lower than the corresponding increase in O2 uptake. However, the differences were partly caused by insufficient mixing of media in the oxidation studies. D-Glucose (20 mM) released more than twice the amount of insulin than 5 mM alpha-ketoisocaproic acid, although O2 uptake in the islets did not differ. The results are consistent with the view that an increase in the production of metabolic energy is necessary for recognizing insulin-releasing fuels by B-cells.

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Glucose both inhibits and stimulates insulin secretion from isolated pancreatic islets exposed to maximally effective concentrations of sulfonylureas

Panten

Schwanstecher

Wallasch

et al. 1988

Naunyn-Schmiedeberg's Arch Pharmacol

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Isolated pancreatic islets from mice were perifused with media containing maximally effective concentrations of glibenclamide (0.1-10 mumol/l) or glipizide (1 mumol/l). In these islets an increase of the glucose concentration from 10 mmol/l to 40 mmol/l or addition of D-glyceraldehyde (20 mmol/l) caused a temporary decrease in insulin release which was followed by a sustained enhancement of release. alpha-Ketoisocaproate (3 or 20 mmol/l) did not inhibit insulin release; at high concentration it was an even stronger secretagogue than D-glucose or D-glyceraldehyde. It is concluded that high energy phosphates couple B-cell fuel metabolism and insulin release by acting both on the ATP-dependent K+ channel and on other targets not yet identified.

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Studies on the role of β-cell metabolism in the insulinotropic effect of α-ketoisocaproic acid

Cited by 8 publications

References 14 publications

Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue

Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue

O₂Consumption by Isolated Pancreatic Islets, as Measured in a Microincubation System with a Clark-Type Electrode*

Glucose both inhibits and stimulates insulin secretion from isolated pancreatic islets exposed to maximally effective concentrations of sulfonylureas

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Studies on the role of β-cell metabolism in the insulinotropic effect of α-ketoisocaproic acid

Cited by 8 publications

References 14 publications

Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue

Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue

O2Consumption by Isolated Pancreatic Islets, as Measured in a Microincubation System with a Clark-Type Electrode*

Glucose both inhibits and stimulates insulin secretion from isolated pancreatic islets exposed to maximally effective concentrations of sulfonylureas

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O₂Consumption by Isolated Pancreatic Islets, as Measured in a Microincubation System with a Clark-Type Electrode*