BACKGROUND: Hyperinsulinemia associated with non-ketotic hypoglycemia is observed in patients with mutated β-oxidation enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC). In the present study, we investigated the mechanism underlying HADHSC-mediated regulation of insulin secretion. METHODS: Knockdown of HADHSC expression by RNA interference in INS832/13 β-cells was achieved using short hairpin RNA and short interference RNA. RESULTS: Knockdown of HADHSC increased both fuel- (glucose or leucine plus glutamine) and non-fuel (high KCl)-induced insulin secretion. Enhanced glucose-stimulated insulin secretion (GSIS) induced by HADHSC knockdown was independent of changes in cytosolic Ca(2+) and also occurred in the presence of fatty acids. L-Carnitine, used in the formation of acyl-carnitine compounds, increased GSIS in control cells, but was unable to further increase the augmented GSIS in HADHSC-knockdown cells. The pan transaminase inhibitor amino-oxyacetate reversed HADHSC knockdown-mediated increases in GSIS. Oxidation of [1-(14) C]-palmitate and -octanoate was not reduced in HADHSC-knockdown cells. L-3-Hydroxybutyryl-carnitine (tested using its precursor L-3-hydroxybutyrate) and L-3-hydroxyglutarate, which accumulate in blood and urine, respectively, of HADHSC-deficient patients, did not change insulin secretion. CONCLUSIONS: Insulin secretion promoted by both fuel and non-fuel stimuli is negatively regulated by HADHSC. Enhanced secretion after HADHSC knockdown is not due to inhibition of fatty acid oxidation causing an accumulation of long-chain fatty acids or their CoA derivatives. L-3-Hydroxybutyrate and L-3-hydroxyglutarate do not mediate enhanced secretion caused by reduced HADHSC activity. Transamination reaction(s) and the formation of short-chain acylcarnitines and CoAs may be implicated in the mechanism whereby HADHSC deficiency results in enhanced insulin secretion and hyperinsulinemia.
BACKGROUND:Hyperinsulinemia associated with non-ketotic hypoglycemia is observed in patients with mutated β-oxidation enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC). In the present study, we investigated the mechanism underlying HADHSC-mediated regulation of insulin secretion. METHODS: Knockdown of HADHSC expression by RNA interference in INS832/13 β-cells was achieved using short hairpin RNA and short interference RNA. RESULTS: Knockdown of HADHSC increased both fuel- (glucose or leucine plus glutamine) and non-fuel (high KCl)-induced insulin secretion. Enhanced glucose-stimulated insulin secretion (GSIS) induced by HADHSC knockdown was independent of changes in cytosolic Ca(2+) and also occurred in the presence of fatty acids. L-Carnitine, used in the formation of acyl-carnitine compounds, increased GSIS in control cells, but was unable to further increase the augmented GSIS in HADHSC-knockdown cells. The pan transaminase inhibitor amino-oxyacetate reversed HADHSC knockdown-mediated increases in GSIS. Oxidation of [1-(14) C]-palmitate and -octanoate was not reduced in HADHSC-knockdown cells. L-3-Hydroxybutyryl-carnitine (tested using its precursor L-3-hydroxybutyrate) and L-3-hydroxyglutarate, which accumulate in blood and urine, respectively, of HADHSC-deficientpatients, did not change insulin secretion. CONCLUSIONS:Insulin secretion promoted by both fuel and non-fuel stimuli is negatively regulated by HADHSC. Enhanced secretion after HADHSC knockdown is not due to inhibition of fatty acid oxidation causing an accumulation of long-chain fatty acids or their CoA derivatives. L-3-Hydroxybutyrate and L-3-hydroxyglutarate do not mediate enhanced secretion caused by reduced HADHSC activity. Transamination reaction(s) and the formation of short-chain acylcarnitines and CoAs may be implicated in the mechanism whereby HADHSC deficiency results in enhanced insulin secretion and hyperinsulinemia.
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Authors: Claudiane Guay; Erik Joly; Emilie Pepin; Annie Barbeau; Lisa Hentsch; Marco Pineda; S R Murthy Madiraju; Henri Brunengraber; Marc Prentki Journal: PLoS One Date: 2013-10-10 Impact factor: 3.240
Authors: Mufaddal S Soni; Mary E Rabaglia; Sushant Bhatnagar; Jin Shang; Olga Ilkayeva; Randall Mynatt; Yun-Ping Zhou; Eric E Schadt; Nancy A Thornberry; Deborah M Muoio; Mark P Keller; Alan D Attie Journal: Diabetes Date: 2014-06-26 Impact factor: 9.461