Download Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

The Glucose/Fatty Acid Cycle 1963–2003
Short-chain 3-hydroxyacyl-CoA dehydrogenase
deficiency associated with hyperinsulinism:
a novel glucose–fatty acid cycle?
S. Eaton*†1 , I. Chatziandreou*, S. Krywawych†, S. Pen*, P.T. Clayton† and K. Hussain†
*Department of Paediatric Surgery, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, U.K., and †Department of Biochemistry,
Endocrinology and Metabolism, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, U.K.
Abstract
Hyperinsulinism of infancy is caused by inappropriate insulin secretion in pancreatic β-cells, even when
blood glucose is low. Several molecular defects are known to cause hyperinsulinism of infancy, such as KATP
channelopathies and regulatory defects of glucokinase and glutamate dehydrogenase. Although defects
of fatty acid oxidation have not previously been known to cause hyperinsulinism, patients with deficiency
in SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase; an enzyme of mitochondrial β-oxidation) have
hyperinsulinism. A novel link between fatty acid oxidation and insulin secretion may explain hyperinsulinism
in these patients.
Introduction
SCHAD (short-chain L-3-hydroxyacyl-CoA dehydrogenase; EC 1.1.1.35) catalyses the NAD+ -dependent conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA in mitochondrial fatty acid β-oxidation. The Schad gene is expressed
in most tissues including the pancreas [1] but SCHAD activity
is particularly high in the islets of Langerhans, suggesting
that SCHAD and the regulation of fat oxidation may have an
important function in the β-cell [2,3]. Deficiency of one of
the enzymes of mitochondrial β-oxidation typically produces
hypoglycaemia with elevated plasma concentrations of nonesterified fatty acids and low plasma concentrations of ketone
bodies (high non-esterified fatty acids/D-3-hydroxybutyrate
ratio) [4]. Deficiency of SCHAD activity has been described
but none of these cases has been shown to have mutations
in the Schad gene [5]. Apart from fatty acid oxidation defects,
the main cause of hypoketotic hypoglycaemia in infancy
and childhood is hyperinsulinism. So far mutations in four
different genes have been identified as causing hyperinsulinism. These are gain-of-function mutations of the enzymes
glucokinase and glutamate dehydrogenase and defects in
the genes encoding the SUR1 or KIR6.2 subunits of the
KATP channel in the β-cell membrane [6]. In these disorders,
the pathogenesis of the hyperinsulinism can be explained
using a simple model of β-cell signalling: increased β-cell
glucose metabolism leads to increased ATP production from
acetyl-CoA in the citric acid cycle and a rise in the ATP/
ADP ratio. This leads in turn to opening of potassium
channels, depolarization of the cell membrane and calcium
influx through voltage-gated calcium channels, which finally
triggers insulin secretion (Figure 1). The defects causing
Key words: β-oxidation, carnitine palmitoyltransferase I (CPT I), 3-hydroxyacyl-CoA dehydrogenase, hyperinsulinism.
Abbreviations used: SCHAD, short-chain l-3-hydroxyacyl-CoA dehydrogenase; CPT I, outer
membrane carnitine palmitoyltransferase I; LCFA-CoA, long-chain fatty-acyl-CoA.
To whom correspondence should be addressed (e-mail [email protected]).
1
hyperinsulinism increase ATP production (increased metabolism of glucose or glutamate) or they cause permanent
depolarization.
SCHAD deficiency associated with
mutations in the Schad gene
We recently described a child who presented with non-ketotic
hypoglycaemia with significant plasma insulin at the time
of hypoglycaemia [7]. This child had hydroxybutyrylcarnitine in blood, suggesting that SCHAD enzyme activity
could be defective. This proved to be the case: fibroblast
SCHAD activity was low, there was no SCHAD immunoreactive protein and a homozygous point mutation in the
Schad gene was found [7]. We have subsequently diagnosed
another child with a similar clinical and biochemical
phenotype (K. Hussain, P.T. Clayton, S. Krywawych,
I. Chatziandreou and S. Eaton, unpublished work), and
another family that was originally reported to have glucagon
deficiency has since been found to have hyperinsulinaemic
hypoglycaemia associated with a homozygous point mutation in the Schad gene [8–10]. Hence, it appears that SCHAD
deficiency associated with mutations in the Schad gene
may be a rare but consistent cause of hyperinsulinism.
Fatty acid oxidation disorders are frequently characterized
by non-ketotic hypoglycaemia, associated with a variety
of other symptoms such as cardiomyopathy, myopathy
and retinopathy; however, hyperinsulinism has never been
associated with any known fatty acid oxidation disorder [5],
so it is of importance to determine the biochemical basis for
hyperinsulinism in these patients.
The anaplerotic/lipid signalling pathway
for augmentation of insulin secretion
Fatty acids are a major energy source for unstimulated islets
[11]. An early metabolic event caused by glucose is a shift
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Figure 1 Pancreatic β-cell insulin secretion indicating KATP -channel-dependent insulin secretion (solid arrows) and
augmentation/anaplerosis pathway (dashed arrows)
from fatty acids to glucose as fuel. It has been proposed that,
as in other tissues, this occurs in the β-cell through conversion
of glucose, via pyruvate carboxylase, oxaloacetate, citrate and
acetyl-CoA, to malonyl-CoA which, by inhibiting CPT I
(outer membrane carnitine palmitoyltransferase I), blocks the
entry of long-chain fatty-acyl CoA (LCFA-CoA) into the
mitochondrion (Figure 1). Thus LCFA-CoA is converted
instead into diacylglycerol, triacylglycerols and fatty acids;
it can also be used for protein acylation. LCFA-CoA or
the complex lipids derived from it are potent regulators
of enzymes, ion channels and various signal-transducing
effectors that could thus augment insulin secretion by a KATP independent mechanism [12]. In addition to malonyl-CoA,
other short-chain acyl-CoA esters such as methylmalonylCoA, succinyl-CoA and acetyl-CoA can inhibit CPT
I [13]. We hypothesized that L-3-hydroxybutyryl-CoA
accumulating in the cytosol, originating either from circulating L-β-hydroxybutyrate/L-β-hydroxybutyryl-carnitine
or from export of L-3-hydroxybutyryl-CoA accumulating
within pancreatic β-cell mitochondria, inhibits CPT I and
thereby triggers insulin secretion via the augmentation/lipid
signalling pathway (Figure 2). However, this would require
a cytosolically active carnitine acetyltransferase, which does
not appear to be present [14], or a cytosolic short-chain
acyl-CoA synthase active towards L-3-hydroxybutyrate, and
preliminary evidence suggests that CPT I is not sensitive
to inhibition by L-3-hydroxybutyryl-CoA (S. Pen and S.
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Eaton, unpublished work). In addition, deficiency of L-CPT I
(liver isoform of CPT I) is not known to cause hyperinsulinism [5].
Other hypotheses for insulin secretion in
SCHAD deficiency
There are several other potential mechanisms for insulin
secretion in SCHAD deficiency. They include the following.
(i) The physiological ketone body, D-hydroxybutyrate,
stimulates insulin secretion [15] and it is possible that the
mechanism that causes D-hydroxybutyrate to stimulate insulin secretion is more sensitive to L-hydroxybutyrate compared with D-hydroxybutyrate. However, this explanation
is unlikely because insulin secretion was lower from DLhydroxybutyrate than D-hydroxybutyrate [15]. (ii) The
α-ketoglutarate dehydrogenase/α-ketoglutarate–glutamate
dehydrogenase–glutamate axis is thought to be important
in the control of the anaplerosis/augmentation pathway
[16] and intramitochondrial L-3-hydroxybutyryl-CoA could
interfere with this pathway, e.g. by inhibition of α-ketoglutarate dehydrogenase. (iii) L-Hydroxybutyrate, L-hydroxybutyryl-CoA or L-hydroxybutyryl-carnitine could inhibit
KATP channels, thus triggering insulin secretion. However,
long-chain acyl-CoA esters are activators rather than
inhibitors of KATP channels [17]. (iv) L-Hydroxybutyrate, Lhydroxybutyryl-CoA or L-hydroxybutyryl-carnitine could
The Glucose/Fatty Acid Cycle 1963–2003
Figure 2 Potential pathways by which l-hydroxybutyrate or a metabolite could trigger insulin secretion via inhibition of CPT I
l-β-OHB-carnitine, l-β-hydroxybutyryl-carnitine; l-β-OHB-CoA, l-β-hydroxybutyryl-CoA; CAT, carnitine acetyltransferase.
trigger insulin secretion via the recently described G-proteincoupled receptor GPR40 [18]. (v) SCHAD deficiency causes
modulation of other genes associated with the insulinsecretion apparatus and thus triggers insulin secretion. These
possibilities are difficult to assess, at least in part because there
are no defined inhibitors of SCHAD activity.
Conclusions
SCHAD deficiency associated with mutations in the Schad
gene is a potential cause of hyperinsulinism. The molecular
basis of hyperinsulinism in these patients may provide insight
into a novel glucose–fatty acid cycle.
The Science Development Initiative of Great Ormond Street Hospital/
Institute of Child Health are thanked for support.
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Received 1 July 2003
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