Vol. 277, Issue 2, G285-G291, August 1999
Impaired stimulation of intestinal glucose absorption via
hepatoenteral nerves in streptozotocin-diabetic rats
Frank
Stümpel,
Tomas
Kucera, and
Kurt
Jungermann
Institute of Biochemistry and Molecular Cell Biology,
Georg-August-University, 37073 Göttingen, Germany
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ABSTRACT |
In an ex situ organ perfusion system, that of
the isolated nonrecirculating joint perfusion of rat small intestine
and liver, insulin infused into the portal vein increased intestinal
glucose absorption. This insulin action against the bloodstream can be blocked by TTX, indicating a propagation of the insulin signal via
hepatoenteral nerves, which conforms with previous studies with
atropine and carbachol. Insulin action could also be mimicked by
dibutyryl cAMP (DBcAMP) acting directly on the absorptive enterocytes. Because autonomic neuropathy is a common late complication of diabetes
mellitus, the possible impairment of these nerves in the diabetic state
was studied in streptozotocin-diabetic rats. In the isolated joint
intestine-liver perfusion, glucose was applied as a bolus into the
lumen; its absorption was measured in the portal vein. In 5-day
diabetic as well as in control rats, portal insulin, arterial
carbachol, and arterial DBcAMP increased intestinal glucose absorption.
In 3-mo diabetic rats portal insulin and arterial carbachol failed to
stimulate glucose absorption, whereas arterial DBcAMP still did so,
indicating an undisturbed function of the absorptive enterocytes. The
lack of an effect of portal insulin and arterial carbachol and the
unchanged action of DBcAMP in the chronically diabetic rats indicated
that the signaling chain via the hepatoenteral nerves was impaired,
which is in line with a diabetic neuropathy.
diabetic neuropathy; autonomic nervous system; cholinergic
nerves
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INTRODUCTION |
IN THE DEVELOPED WORLD carbohydrates contribute 50% of
the daily intake of calories (4). After digestion of the dietary poly-
and oligosaccharides, monosaccharides are absorbed via different transport systems: glucose is taken up into the enterocyte from the
intestinal lumen via the sodium-dependent glucose transporter 1 (SGLT1)
located in the apical membrane and released from the enterocyte to the
circulation via the sodium-independent glucose transporter 2 (GLUT2) of
the basolateral membrane (7). These transport steps are widely believed
not to be acutely regulated. However, there is growing evidence now for
a short-term regulation of intestinal glucose absorption in several
different experimental systems (5, 6, 16, 18, 19). Recently, an acute
stimulation of intestinal glucose absorption was demonstrated in an ex
situ organ perfusion system, the isolated nonrecirculating joint
perfusion of small intestine and liver of the rat. In this experimental system, insulin, infused into the portal vein (PV), increased intestinal glucose absorption to 250% within 3 min (18). This stimulatory effect of portal insulin on the intestine was inhibited by
atropine and mimicked by carbachol injected into the superior mesenteric artery (SMA; Ref. 18). These findings showed that insulin
was sensed in the hepatoportal area and that a signal was transmitted
against the bloodstream to the enterocytes via hepatoenteral (from
liver to intestine) cholinergic nerves.
Neuropathy, along with microangiopathy and retinopathy, represents one
of the most common late complications of diabetes mellitus (8, 21).
Distal sensory neuropathy is the predominant symptom (15), found in
34% of insulin-dependent diabetic patients (IDDM) and in 26% of
non-insulin-dependent diabetic patients (NIDDM) (10, 22). In addition,
diabetes mellitus also affects the autonomic nervous system. An
autonomic neuropathy was found in 17-22% of patients with IDDM or
NIDDM (23). In functional studies with streptozotocin-diabetic rats, a
loss of
Na+-K+-ATPase
activity in the vagus nerve (12) and an impairment of the stimulation
of hepatic glucose output by sympathetic hepatic nerves (17) were
observed, indicating diabetic neuropathy.
Thus it was the aim of the present investigation to confirm that the
insulin-signaling chain from the liver to the intestine involved
hepatoenteral nerves and to examine a possible functional impairment of
the signaling chain in chronically streptozotocin-diabetic rats in line
with a diabetic neuropathy.
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MATERIALS AND METHODS |
Materials.
All chemicals were of reagent grade and from commercial sources.
Enzymes were purchased from Boehringer (Mannheim, Germany); insulin,
carbachol, and streptozotocin were from Sigma (Munich, Germany); and
TTX was from Roth (Karlsruhe, Germany). BSA, dextran, and DBcAMP were
delivered by AppliChem (Darmstadt, Germany).
Animals.
Male Wistar rats were obtained from Harlan-Winkelmann (Borchen,
Germany). They were kept on a 12-h day-night rhythm with free access to
food (standard diet; Ssniff, Soest, Germany) and water. For the induction of diabetes mellitus, rats (100-120 g body wt) were starved for 24 h, followed by an intraperitoneal injection of
streptozotocin (50 mg/kg body wt, 33 g/l dissolved in 50 mmol/l sodium
citrate at pH 4.5). Animals were then fed the standard diet (Ssniff) ad
libitum. Control rats were weight matched to the body weight of the
chronically diabetic animals following the 3-mo period of diabetes. In
addition, to exclude a possible neurotoxicity of streptozotocin, 5-day
diabetic animals were examined. During the preparation of the joint
perfusion of small intestine and liver, blood and urine samples were
obtained for subsequent determination of the glucose concentration.
Treatment of animals followed the German Law on the Protection of
Animals and was performed with permission from the state animal welfare committee.
Preparation of the isolated joint perfusion of small intestine and
liver.
The joint perfusion of small intestine and liver was performed as
previously described (5, 18). Rats were anesthetized by intraperitoneal
injection of pentobarbital sodium (40 g/l in 0.9% NaCl; 60 mg/kg body
wt). A midline laparatomy was performed, and the SMA and the celiac
trunk (CT) were cannulated. After the immediate incision of the
inferior vena cava (IVC), a nonrecirculating perfusion of
intestine and liver was started at a hydrostatic pressure of 120 cmH2O (i.e., 88 mmHg 
11.77 kPa). Then, spleen and the proximal half of the stomach were removed,
and, for the luminal glucose application, a plastic catheter was
introduced through the pyloric sphincter into the proximal duodenum.
The cecum was incised, and the content of the small intestine was gently washed out with a warmed saline solution. Afterward, a cannula
for the vascular outflow was introduced into the right atrium, and the
tip was positioned at the inflow of the hepatic vein into the IVC and
fixed. Then, intestine and liver were transferred into an organ bath
filled with a warmed saline solution, and two flexible catheters were
introduced into the PV, one for obtaining medium samples and the other
one for infusion of insulin.
Determination of vascular flow.
The flow rate in the SMA was measured with an ultrasound flowmeter T106
(Transonic Systems, Ithaca, NY). Total flow in the IVC was quantified
by fractionated sampling of the effluate into calibrated tubes. The
flow rate in the CT was calculated as the difference between the flow
into the IVC and the SMA.
Perfusion medium, vascular application of effectors, and intestinal
glucose bolus.
The perfusion medium consisted of a Krebs-Henseleit buffer containing
(in mmol/l) 5.0 glucose, 2.0 lactate, 0.2 pyruvate, and 1.0 glutamine,
with 1% wt/vol BSA and 3% wt/vol dextran. The perfusion medium was
equilibrated with a gas mixture of 19 O2:1 CO2. Insulin (final concentration
100 nmol/l), carbachol (final concentration 10 µmol/l), dibutyryl
cAMP (DBcAMP; final concentration 1 µmol/l), or TTX (final
concentration 1 µmol/l) were infused as solutions in perfusion medium
into the vessels as described in the legends of Figs. 1-4. The
luminal glucose bolus (1 g diluted in 1.5 ml 0.9% NaCl) was applied
within 1 min via the catheter placed in the duodenum.
Determination of glucose concentration.
Perfusion samples were taken every 1 min and immediately chilled on
ice. Glucose concentration was measured with the use of a standard
enzymatic technique with glucose dehydrogenase (Merck system; Ref. 1).
Blood and urine concentrations were determined with a glucose analyzer
(model 2; Beckman, Munich, Germany) by the glucose oxidase method.
Statistical analysis.
All results are represented as means ± SE for the indicated number
of experiments. Data were analyzed by Student's
t-test for unpaired data.
P < 0.05 was considered significant.
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RESULTS |
Characterization of acutely and chronically diabetic rats.
Rats were injected with streptozotocin after 24-h starvation to induce
a diabetic state. All treated rats developed clinical signs of
hyperglycemia, e.g., polydypsia or polyuria within 2-3 days. They
were kept for 5 days or 3 mo before they were used for the preparation
of the jointly perfused small intestine and liver. As a simple measure
of the diabetic state, glucosuria was examined from
day 3 onward. At day
5, all streptozotocin-treated rats had developed severe
glucosuria (Table 1). In addition, during
the operative procedure, blood samples were obtained to confirm the
diabetic state. A profound rise in the blood glucose concentration was
observed at 5 days as well as 3 mo after streptozotocin treatment
(Table 1). During the preparation it became obvious that in the
chronically diabetic animals, the weight of the small intestine was
enhanced by 72%, in line with a diabetic enteropathy (Table 1). Most
of the chronically diabetic animals at the end of the 3-mo period
showed another late complication of diabetes, i.e., visual impairment
(detected by inspection of dim lenses).
Inhibition by TTX of the portal insulin-induced but not the
cAMP-induced increase in intestinal glucose absorption.
In all experiments, the first luminal glucose bolus (1 g) was applied
without infusion of any effectors. Under this condition, the basal rate
of glucose absorption reached a maximum of 3.6 ± 0.7 µmol · min
1 · g
organ wt1 (Fig.
1). With an infusion of insulin (100 nmol/l) into the PV, intestinal glucose absorption following the second
glucose bolus after a 25-min interval was increased to a maximal rate
of 14.4 ± 1.7 µmol · min1 · g
organ wt1 (Fig. 1). In the
presence of insulin, glucose absorption following the third glucose
bolus after a 20-min interval (1 g) was elevated again to 13.8 ± 2.1 µmol · min1 · g
organ wt1 (not shown). If
the third glucose bolus (1 g) was applied in the presence of portal
insulin and with an additional infusion of the sodium channel blocker
TTX (1 µmol/l; Ref. 14) into the SMA, peak glucose absorption
amounted to a maximum of 3.7 ± 0.5 µmol · min1 · g
organ wt1 as in the
controls (Fig. 1). In another series of experiments, basal glucose
absorption after the first glucose bolus equaled that of the first
series of experiments, and glucose absorption after the second glucose
bolus was increased by arterial infusion of DBcAMP (1 µmol/l) to 15.3 ± 4.8 µmol · min1 · g
organ wt1 (data not shown).
If the second glucose bolus was applied in the presence of DBcAMP (1 µmol/l) along with arterial infusion of TTX (1 µmol/l), glucose
absorption after the second glucose bolus was not impaired and reached
a maximal rate of 16.2 ± 5.7 µmol · min1 · g
organ wt1 (Fig. 1). The
inhibition of the action of portal insulin but not of arterial DBcAMP
by TTX confirms the conclusion from experiments with atropine and
carbachol (Ref. 18; cf. the introduction) that the signal elicited by
portal insulin in the hepatoportal area was transmitted to the
intestine against the bloodstream via hepatoenteral nerves.
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Fig. 1.
Inhibition by TTX of stimulation by portal insulin of intestinal
glucose absorption in isolated jointly perfused small intestine and
liver of rat. Small intestine and liver were jointly perfused with a
Krebs-Henseleit bicarbonate buffer containing (in mmol/l) 5 glucose, 2 lactate, 0.2 pyruvate, and 1 glutamine, with 1% BSA and 3% dextran. A
glucose bolus (1 g diluted in 1.5 ml 0.9% NaCl) was applied to
intestinal lumen at minutes 6,
31, and
50. Insulin (100 nmol/l) was infused
into portal vein (PV) from minute 21 onward. TTX (1 µmol/l) was infused into superior mesenteric artery
(SMA) from minute 46 onward. In
another series of experiments, dibutyryl cAMP (DBcAMP, 1 µmol/l) was
infused into SMA from minute 21 to
35 and TTX from
minute 26 to
36. Flow in SMA was measured with a
flowmeter, and flow in inferior vena cava (IVC) was measured by
fractionated sampling. Flow in celiac trunk (CT) was calculated from
difference between flow in IVC and SMA. Values are means ± SE of
number of experiments given in parentheses.
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Loss of portal insulin-induced increase in intestinal glucose
absorption in chronically diabetic rats.
After the first glucose bolus without infusion of effectors, the
ensuing basal rate of glucose absorption reached a maximum of 2.6 ± 1.1 µmol · min1 · g
organ wt1 in the control
group (Fig. 2). The total absorption of
glucose (in µmol) during the first 10 min after the glucose bolus was determined as the area under the absorption vs. time curve
(µmol · min1 · g1 × min) multiplied by the organ weight (g). In control animals, total basal glucose absorption amounted to 281 ± 31 µmol. In
chronically diabetic animals, the basal rate of glucose absorption
reached a maximum of 1.7 ± 0.5 µmol · min1 · g
organ wt1 (Fig. 2),
corresponding to a total basal glucose absorption of 228 ± 30 µmol. Total basal glucose absorption was similar in the two groups of
animals because the small intestine weight of the diabetic animals was
72% larger than that of the controls (Table 1). Total basal glucose
absorption in the acutely diabetic animals was not different from that
of control rats (276 ± 22 µmol). For a better comparison, total
basal glucose absorption was taken as 100% in each of the three
experimental groups (Fig. 3).
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Fig. 2.
Impairment of stimulation by portal insulin and arterial carbachol of
intestinal glucose absorption in chronically diabetic rats. Diabetes
mellitus was induced with an intraperitoneal injection of
streptozotocin (50 mg/kg body wt). Experiments were performed as
described in Fig. 1 legend. A glucose bolus (1 g diluted in 1.5 ml
0.9% NaCl) was applied to intestinal lumen at
minutes
6 and 31. Insulin (100 nmol/l) was infused into PV from minute
21, and carbachol (10 µmol/l) was infused into
hepatic artery from minute 21 onward.
Flow in SMA, IVC, and CT was measured as described in Fig. 1 legend.
Values are means ± SE of number of experiments given in
parentheses.
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Fig. 3.
Loss of increase in intestinal glucose absorption by portal insulin in
diabetic rats. Experiments were performed as described in Fig. 1
legend. Glucose (1 g diluted in 1.5 ml 0.9% NaCl) was applied as a
bolus into lumen of small intestine at minute
6 (basal unstimulated absorption) and
minute 31 (stimulated absorption)
after a portal infusion of insulin (100 nmol/l + insulin from
minute 21). Total absorption of
glucose (µmol) during first 10 min after glucose bolus was determined
as area under absorption vs. time curve
(µmol · min1 · g1 × min) multiplied by organ weight (g). Basal absorption following
first glucose bolus was set equal to 100% in control and diabetic
groups of animals. AUC, area under the curve. Values are means ± SE
of 4-5 experiments. * P < 0.05.
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In the control group, insulin (100 nmol/l) infused into the PV
increased the rate of glucose absorption from a maximum of 2.6 ± 1.1 to a maximum of 12.6 ± 4.6 µmol · min1 · g
organ wt1 (Fig. 2); total
insulin-stimulated glucose absorption was raised from basal 281 ± 31 to 737 ± 66 µmol, representing an increase to 262% (Fig. 3).
In chronically diabetic rats, portal insulin did not significantly
raise the rate of intestinal glucose absorption (Fig. 2); the
calculated total glucose absorption was 254 ± 41 µmol with
insulin, compared with 228 ± 30 µmol without insulin (Fig. 3).
Thus the stimulatory effect of portal insulin, which is mediated via
hepatoenteral cholinergic nerves (18), was abrogated in chronically
diabetic rats (Fig. 2). In acutely diabetic rats, the stimulatory
effect of portal insulin on intestinal glucose absorption was
unimpaired (Fig. 3).
The flow rates in the SMA and CT remained essentially constant during
the entire experiments in the three groups of animals, although the
total flow was ~1
ml · min1 · g
organ wt1 lower in the
chronically diabetic rats than in the control rats (Fig. 2,
bottom) and acutely diabetic animals
(not shown). However, because of the higher organ weight (Table 1), the
absolute flow rates were even a little higher in the chronically
diabetic animals, i.e., 29.8 vs. 24.5 ml/min.
Loss of carbachol-induced but not of DBcAMP-induced increase in
intestinal glucose absorption in chronically diabetic rats.
The loss of the portal insulin-induced increase in intestinal glucose
absorption in the 3-mo diabetic animals could be due to an impairment
of the hepatoenteral cholinergic nerves and/or of the absorptive
capacity of the enterocytes. When applied via the SMA, carbachol, a
muscarinic receptor agonist (18), and DBcAMP (6, 16, 19), a
membrane-permeable cAMP analog, have been shown to mimic the
stimulatory effect of portal insulin on glucose absorption in the small
intestine. Therefore, in another series of experiments, the stimulatory
effects of arterial carbachol and DBcAMP were examined to distinguish
between a functional impairment of the hepatoenteral nerves or a
deterioration of the absorptive capacity of the enterocytes.
DBcAMP (10 µmol/l) infused into the SMA caused an increase in total
glucose absorption to 828 ± 48 µmol in control animals. Compared
with the basal glucose absorption of 281 ± 31 µmol, this DBcAMP-elicited elevation amounted to 295% (Fig.
4). In 3-mo diabetic rats, total glucose
absorption was raised by DBcAMP to 547 ± 97 µmol, which
represented a significant increase to 240% compared with the
unstimulated glucose absorption of 228 ± 30 µmol (Fig. 4). In
acutely diabetic rats, DBcAMP stimulated glucose absorption to 262%
(Fig. 4).
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Fig. 4.
Loss of increase in intestinal glucose absorption by arterial carbachol
but not by DBcAMP in diabetic rats. Experiments were performed as
described in Fig. 1 legend. Glucose (1 g diluted in 1.5 ml 0.9% NaCl)
was applied as a bolus into lumen of small intestine at
minute 6 (basal unstimulated
absorption) and at minute 31 (stimulated absorption) after an arterial infusion of carbachol (10 µmol/l + carbachol from minute 29)
or DBcAMP (10 µmol/l + DBcAMP from minute
29 onward), respectively. Total absorption of glucose
(µmol) during first 10 min after glucose bolus was determined as
described in Fig. 2 legend. Values are means ± SE of 4-5
experiments. * P < 0.05.
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Carbachol (10 µmol/l) infused into the SMA induced a rise in total
glucose absorption to 624 ± 51 µmol in the control group. Compared with the basal glucose absorption of 281 ± 31 µmol, this was an increase to 222% (Figs. 2 and 4). However, in 3-mo diabetic rats the stimulatory effect of carbachol was nearly completely abolished; glucose absorption was increased only insignificantly from
228 ± 30 to 294 ± 64 µmol or 128% (Figs. 2 and 4). In the acutely diabetic rats, carbachol significantly increased glucose absorption from 276 ± 22 to 554 ± 63 µmol, equaling 201%
(Fig. 4). These results allow the conclusion that, in the chronically diabetic rats, the absorptive capacity of the enterocytes was essentially intact, whereas the signaling chain "portal
insulin-hepatoenteral nerves-enterocytes-glucose absorption" was impaired.
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DISCUSSION |
Unaltered capacity for intestinal glucose absorption in chronically
streptozotocin-diabetic rats.
Glucose absorption in the small intestine occurs via two translocators:
the sodium-dependent glucose transporter SGLT1 in the apical membrane
and the sodium-independent glucose transporter GLUT2 in the basolateral
membrane (4). In the present investigation, the increase in total
glucose absorption after application of a bolus of 1 g into the lumen
in the jointly perfused small intestine and liver of the rat was in the
same range in control, 5-day acutely diabetic, and 3-mo chronically
diabetic animals, both under basal unstimulated conditions and after
stimulation by DBcAMP. With the experimental system used here, the
isolated jointly perfused small intestine and liver of the rat, the
capacity of the small intestine for glucose absorption was not altered
in the diabetic state under basal and stimulated conditions. The
unchanged basal absorption may be in contrast to data obtained in
isolated segments of the small intestine of streptozotocin-diabetic
rats (3); here the rate of glucose but not of galactose absorption was
slightly increased. However, this isolated increase in glucose
absorption is not easy to understand, because glucose and galactose are
both absorbed via the same transporters, SGLT1 and GLUT2 (4). In autoradiographic examinations, this enhancement was found to be due to
an increase in the number of transporters (3), which was confirmed in
brush-border membrane vesicles of enterocytes (13). In conclusion, the
present and the previous study (3) have shown that the
glucose-absorptive capacity of the small intestine is unaltered or
slightly increased but not impaired in the diabetic state.
Involvement of hepatoenteral nerves in the signaling chain for the
stimulation by portal insulin of intestinal glucose absorption.
In previous examinations with the isolated jointly perfused small
intestine and liver of the rat, the stimulation by portal insulin of
intestinal glucose absorption could be completely blocked by an
infusion of atropine into the SMA and mimicked by arterial carbachol
(18). Therefore, it was concluded that the signal pathway from the PV
to the small intestine involved hepatoenteral cholinergic nerves. To
confirm this conclusion, an additional series of experiments was
performed using the neurotoxin TTX, which blocks sodium channels of
axons and other excitable membranes (14). In the isolated jointly
perfused small intestine and liver of the rat, TTX, infused into the
SMA, entirely prevented the portal insulin-stimulated increase in
intestinal glucose absorption (Fig. 1). Because TTX did not alter the
increased glucose absorption after arterial infusion of DBcAMP, a
direct effect of TTX on the absorptive process can be excluded (Fig.
1). These data support the previous results, which indicated the
involvement of hepatoenteral nerves.
Impaired function of the signaling chain involving hepatoenteral
nerves in chronically streptozotocin-diabetic rats.
The stimulatory effect of portal insulin and arterial carbachol on
glucose absorption was completely abolished in 3-mo chronically diabetic but not in 5-day acutely diabetic rats (Figs. 2-4).
Apparently, the signaling chain from the liver to the intestine
involving hepatoenteral nerves was impaired. The anatomic basis of the
hepatoenteral nerves mediating the enhancement of intestinal glucose
absorption by portal insulin is unknown so far. The signaling chain
must start with the sensing of insulin in the portal vein or liver tissue. Such a sensing of insulin has been described before using electrophysiological methods; in the superfused isolated portal vein of
the rat, the addition of insulin to the superfusate caused an increase
in the discharge rate of the afferent vagus nerve to the central
nervous system (11). Therefore, it is very possible that the
hepatoenteral nerves between liver and small intestine originate in the
hepatoportal area and end in the small intestine, where they would
release ACh to a cell carrying muscarinic receptors. Because cAMP is
the intracellular messenger in the enterocytes stimulating glucose
absorption (6, 16, 19), and because muscarinic receptors are known to
increase inositol 1,4,5-trisphosphate or to decrease cAMP but not to
elevate cAMP (2), ACh cannot act directly on the enterocytes. The
intermediate cells between the hepatoenteral nerve cells and the
enterocytes are not yet known. Because DBcAMP still increased glucose
absorption in the isolated perfused small intestine and liver of
chronically diabetic rats, the absorptive function of the enterocytes
was not impaired. Thus the loss of the stimulatory effect of portal
insulin and arterial carbachol was due to a defect of the intermediate
cells and/or of the hepatoenteral nerve cells.
The hepatoenteral nerves must comprise an insulin sensory function,
which could be a defect due to an insulin resistance. Because an
insulin resistance can be detected very early in the diabetic state,
e.g., within 6-8 h in 3T3-L1 adipocytes (20), the preserved action
of portal insulin in 5-day acutely diabetic rats makes this mechanism
rather unlikely. Thus the signaling chain involving hepatoenteral
nerves and intermediate cells was impaired mainly in its ACh-dependent
effectory branch. This impairment corresponds to a neuropathy. A
diabetic neuropathy is a well-known late complication of diabetes
mellitus in diabetic patients (8, 10, 15, 21, 22, 23). In addition, a
loss of function of autonomic nerves and impairment of
Na+-K+-ATPase
in the vagus (12) and of glucose output from the liver after
sympathetic nerve stimulation (17) have been shown before in 3-mo
streptozotocin diabetic rats.
Possible pathophysiological role of the impairment of the signaling
chain via hepatoenteral nerves in diabetes mellitus.
In diabetes mellitus, postprandial glucose cannot be handled adequately
by the organism, resulting in severe hyperglycemia. This is mainly
because of a decrease in the rate of the insulin-stimulated glucose
disappearance via utilization in skeletal muscle, adipose tissue, and
liver. The loss of function of the hepatoenteral nerves, and thus of
the portal insulin-stimulated glucose absorption, would lower the rate
of glucose appearance and therefore smooth the postprandial increase in
blood glucose concentration. Thus, in the diabetic state, the impaired
signaling via the hepatoenteral nerves mediating the increase in
glucose absorption by portal insulin could constitute an advantage of
diabetic patients: the adjustment of the rate of glucose appearance and
disappearance on a lower level should contribute to reduce postprandial hyperglycemia.
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ACKNOWLEDGEMENTS |
We thank Angela Hunger, Birgit Döring, and Frank Rhode for
excellent technical assistance.
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FOOTNOTES |
This work was supported by the Deutsche Forschungsgemeinschaft through
the Sonderforschungsbereich 402: Molekulare und Zelluläre Hepatogastro-enterologie, Teilprojekt B3.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: F. Stümpel, Institute of Biochemistry and Molecular Cell Biology,
Georg-August-Univ., Humboldtallee 23, 37073 Göttingen,
Germany (E-mail: fstuemp{at}gwdg.de).
Received 25 August 1998; accepted in final form 20 April 1999.
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Am J Physiol Gastroint Liver Physiol 277(2):G285-G291
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