Download Autoregulation of endogenous glucose production in man

New Insights into the Molecular and Cellular Regulation of Glycogen Storage and Degradation
Autoregulation of endogenous glucose production in man
L. Tappy, P. Tounian and N. Paquot
Institute of Physiology, Faculty of Medicine, University of Lausanne, Switzerland
II
Introduction
Blood glucose is maintained within tight limits in
healthy humans, thus avoiding the deleterious
effects of hyper- or hypo-glycaemia. For this purpose, the endogenous production of glucose has
to be finely regulated to adapt to the whole body
glucose utilization on one hand and to the
absorption of exogenous dietary carbohydrate on
the other. In pathological conditions (diabetes
mellitus, hyperglycaemia secondary to critical illness) blood glucose levels are increased as the
result of a combination of increased endogenous
glucose production and decreased glucose utilization by insulin-sensitive tissues (predominantly
skeletal muscle) [1,2].
In postabsorptive conditions, glucose is
released into the systemic circulation predominantly by liver and, to a lesser extent, by kidney
cells. Hepatic glycogen breakdown and intrahepatic conversion of gluconeogenic substrates
(lactate, amino acids, glycerol) both contribute to
the synthesis of glucose 6-phosphate (G6P)
which is subsequently converted into glucose by
the enzyme glucose-6-phosphatase. In addition,
it has recently been observed, in both animals
[3] and man [4],that 13C-labelled hepatic glycogen content increased during infusions of
['3C]glucose. When ['3C]glucose was acutely
replaced by unlabelled glucose infused at the
same rate, [13C]glycogencontent decreased even
though net glycogen deposition was known to
occur under such conditions. These experiments
indicate that simultaneous hepatic glycogen synthesis and breakdown occur in liver cells. In
other terms, hepatic G6P synthesis exceeds
hepatic glucose release, with the excess of G6P
being reconverted, at least in part, to glycogen.
To what extent other intrahepatic pathways of
G6P disposal (de nova lipogenesis, oxidation)
exist remains undetermined. As a consequence,
endogenous glucose production cannot be
assumed to be merely the sum of the glycogenolytic and gluconeogenic rates. Instead, it is best
represented by the difference between the rate of
intrahepatic G6P synthesis (glycogenolysis and
gluconeogenesis) and disposal (glycogen synthesis, oxidation, de n o w lipogenesis) [ S ] .
Administration in healthy humans of exogenous gluconeogenic precursors stimulates
gluconeogenesis. Several observations, however,
indicate that overall endogenous glucose production does not increase when gluconeogenesis is
increased by administration of glycerol [6,7], lactate [8], amino acids [9] or fructose [lo]. In two
of these experiments, plasma glucose and insulin
concentrations were clamped by infusions of exogenous somatostatin, insulin and glucagon, indicating that failure to increase overall hepatic
glucose production when gluconeogenesis is
stimulated does not depend on alterations in glucoregulatory hormones [8,10] (Figure 1). These
observations indicate that resting postabsorptive
endogenous glucose production has its own
Figure I
Overall endogenous glucose production (EGP) and
plasma insulin and glucose concentrations in healthy
volunteers infused with exogenous fructose at a rate of
22 pmol/min per kg
Each subject was studied on t w o occasions, during infusion of
fructose alone (SRIF-) or during concomitant infusions of somatostatin, insulin and glucagon to maintain constant concentrations
after fructose infusion.
of these hormones (SRIF+). H, Basal; 0,
*P <0.05 compared with basal. Data are taken from ref. [ 101.
Abbreviation used: NIDDM, non-insulin-dependent
diabetes mellitus.
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regulation, independent of changes in the relative
rates of gluconeogenesis and glycogenolysis.
The mechanisms by which overall glucose
output is maintained constant when gluconeogenesis is acutely stimulated by exogenous substrates remain incompletely elucidated. A mirror
suppression of glycogenolysis has been suggested. Two observations, however, contradict
this hypothesis. In one study, [13C]fructo~e
was
infused, and monitoring of I3CO2production and
of respiratory gas exchanges allowed quantification of oxidation of exogenous carbohydrate (i.e.
fructose and neoformed glucose) from oxidation
of endogenous carbohydrate (i.e. glycogen); it
was observed that oxidation of endogenous carbohydarate (and hence net glycogen utilization)
was not significantly suppressed during fructose
administration [10,11]. In the second study,
endogenous glycogen pools were preliminarily
labelled by adding ['3C]glucose to the food consumed during the 2 days preceding the experiment. Plasma ['3C]glucose in these conditions
can be used as an index of glycogenolysis [12].
Acute administration of lactate did not suppress
plasma ['3C]glucose levels, indicating no acute
inhibition of glycogenolysis [ 131. It is therefore
likely that suppression of gluconeogenesis from
endogenous precursors [7,13] or stimulation of
glycogen, synthesis [lo] are responsible for the
maintenance of a constant overall glucose output
when gluconeogenesis is acutely stimulated at
the substrate level.
Two studies indicated that overall endogenous glucose production was not dependent on
the variations in gluconeogenesis from glucose
precursors from an endogenous source. In one
study, administration of long-chain triacylglycerol
emulsions in healthy humans enhanced plasma
non-esterified fatty acid concentrations and lipid
oxidation. Conversion of endogenous lactate into
glucose was increased, presumably as a result of
a stimulatory effect of non-esterified fatty acids
on liver cells, but overall glucose output was not
altered 1141. In another study, postabsorptive
glucose production and substrate oxidation rates
were assessed in lean and obese non-diabetic
subjects. [ ' 3 C ] G l u c ~ ~had
e been added to their
meals during the 2 days preceding this measurement, and endogenous [13C]glyc~gen
enrichment
was calculated from breath 13C02and respiratory
gas exchanges, and measurement of plasma
['3C]glu~oseenrichment allowed estimation of
the relative rates of gluconeogenesis and glycogenolysics [12]. It was observd that total glucose
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Figure 2
Postabsorptive endogenous glucose production, glycogenolysis and gluconeogenesis in lean and obese nondiabetic subjects
Overall endogenous glucose production was measured with
[6,6-*H]glucose, and fractional glycogenolysis and gluconeogenesis were assessed as described by Gay et al. [ 121. Gluconeogenesis (W; pnol/min) and glycogenolysis (0;pmol/min) showed
large interindividual variations, whereas overall endogenous
glucose production was very similar between the subjects. This
observation indicates the presence of mechanisms that regulate
overall endogenous glucose production irrespective of relative
changes in gluconeogenesis from endogenous precursors (unpublished work). BMI, body mass index.
BMI (Kg/m2)
25 20 47 25 25 28 27 35 44 33 33
production did not differ markedly between the
subjects, whereas gluconeogenesis showed wide
variations (Figure 2). In addition, the gluconeogenic rate was positively correlated with net lipid
oxidation, suggesting that it was a major factor
regulating gluconeogenesis. It was also apparent
that during a chronic stimulation of gluconeogenesis from endogenous gluconeogenic precursors, overall hepatic glucose production was
maintained by a suppression of glycogenolysis
[15]. These observations contrast with the previous reports indicating that acute administration
of gluconeogenic substrate did not inhibit glycogenolysis. Changes in plasma insulin and glucose
concentrations or in hepatic glycogen constant
over time may possibly explain this difference.
An increased fasting endogenous glucose production is present in patients with non-insulindependent diabetes mellitus (NIDDM), and is
thought to be a major determinant of fasting
hyperglycaemia [ 16,171. An enhanced gluconeogenesis is thought to account for the major portion of the increase in hepatic glucose output in
these patients [18-201. The question therefore is
whether the stimulation of gluconeogenesis
(which is presumably due to an increased release
of gluconeogenic precursors secondary to insulin
resistance) is directly responsible for a rise in
New Insights into the Molecular and Cellular Regulation of Glycogen Storage and Degradation
endogenous glucose output. This would indicate
a defective autoregulation of hepatic glucose production. Two observations, however, indicate that
this is not the case. In one study, gluconeogenesis was acutely inhibited by administration
of ethanol in a group of patients with NIDDM.
This manoeuvre, however, failed to decrease
glucose output or glycaemia [21]. In another
study, gluconeogenesis was stimulated by
repeated oral administration of fructose in obese
patients with NIDDM. Here again, fructose
increased gluconeogenesis, but did not alter
overall endogenous glucose production [22]. This
indicates that hepatic glucose production is
increased in NIDDM, but remains autoregulated.
In conclusion, there is ample evidence that
overall endogenous glucose production remains
constant when gluconeogenesis is acutely
increased at the substrate level both in healthy
subjects and in patients with NIDDM. In healthy
subjects, this also occurs when changes in
plasma insulin and glucagon concentrations are
prevented, suggesting autoregulation. Several
questions, however, await further investigations.
It remains to be determined whether this constancy of endogenous glucose production when
gluconeogenesis varies is also observed in conditions where glucose fluxes are increased (such as
during exercise) or decreased (such as during a
prolonged fast). In addition, the mechanisms
responsible for this control of glucose production
remain unelucidated. The effects of a chronically
increased flux of gluconeogenic substrate, as in
insulin-resistant patients, on the metabolic pathways involved in glucose production and on
plasma hormone and substrate concentrations is
still incompletely known. Finally, the hypothesis
of an autoregulation of endogenous glucose production supposes that some signals are sensed by
the liver causing it to adapt its production to
whole body glucose utilization. Such signals still
have to be delineated.
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Received 15 July 1996
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