1 Laboratoire Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique Enseignement Supérieur Associé 7059, Université Paris, 75251 Paris, France; and 2 Instituto de Bioquimica-Centro Mixto Universite Complutense y Consejo Superior Investigaciones Científicas, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
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ABSTRACT |
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The availability of the Goto-Kakisaki (GK) rat model of non-insulin-dependent diabetes mellitus prompted us to test the effect of a limited period of undernutrition in previously diabetic young rats on their insulin secretion and insulin action during adult age. Four-week-old female GK rats were either food restricted (35% restriction, 15% protein diet) or protein and energy restricted (35% restriction, 5% protein diet) for 4 wk. Food restriction in the young GK rat lowered weight gain but did not aggravate basal hyperglycemia or glucose intolerance, despite a decrease in basal plasma insulin level. Furthermore, the insulin-mediated glucose uptake by peripheral tissues in the GK rat was clearly improved. We also found that food restriction, when it is coupled to overt protein deficiency in the young GK rat, altered weight gain more severely and slightly decreased basal hyperglycemia but conversely aggravated glucose tolerance. Improvement of basal hyperglycemia was related to repression of basal hepatic glucose hyperproduction, despite profound attenuation of basal plasma insulin level. Deterioration of tolerance to glucose was related to severe blunting of the residual glucose-induced insulin secretion. It is, however, likely that the important enhancement of the insulin-mediated glucose uptake helped to limit the deterioration of glucose tolerance.
Goto-Kakisaki rat; non-insulin-dependent diabetes mellitus; malnutrition; energy restriction; protein-energy restriction; insulin secretion
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INTRODUCTION |
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BASED ON EPIDEMIOLOGICAL EVIDENCE,
malnutrition has been envisaged as an etiological factor
and/or a precipitating factor for diabetes in malnourished individuals
from developing countries (4, 20, 26) as well as in elderly patients
who are often undernourished (1). Numerous studies in humans and
laboratory animals have also clearly stated that malnutrition exerts a
significant deleterious impact on a previously normal pancreatic
-cell function (reviewed in Ref. 20).
However, some confusion still exists in the literature concerning the
relationship between malnutrition and insulin action; a high tissue
sensitivity to insulin has been suggested (7, 17, 18), because
malnutrition in general and dietary protein deprivation in particular
are characterized by low fasting blood glucose levels despite low
insulin levels in both humans and rodents (3, 7, 10, 17, 18). As a
matter of fact, we have reported that the protein- and
energy-restricted rats present an increased utilization of glucose in
the basal postabsorptive state and in euglycemic-hyperinsulinemic
conditions (18). A similar conclusion was reported in rats subjected to
food restriction from the fetal stage (11). On the contrary, insulin
resistance has also been reported in undernourished rats (22), and it
was found to be aggravated in undernourished rats with mild
streptozotocin diabetes (22). Moreover, it has been shown that the
deleterious effect of chronic malnutrition on -cell function
amplifies the overall
-cell deficit in mild streptozotocin diabetes,
and refeeding reverses this effect (21).
Against this background, we propose to reevaluate the interaction
between chronic malnutrition and diabetes using the Goto-Kakisaki (GK) rat, a model of hereditary non-insulin-dependent diabetes (NIDDM)
that is not overweight (19). The overall objective of the present study
was to identify the way chronic malnutrition influences the severity of
the -cell secretory deficit and the glucose production and glucose
utilization defects in the diabetic GK rat. Our experiments were also
designed to attempt to dissociate an energy restriction effect from a
protein restriction effect on glucose metabolism. For this purpose,
weaned GK rats were restricted to 65% of their normal ad libitum daily
food intake; one group received a standard diet (15% protein) and the
other received an isocaloric but low-protein (5%) diet. Glucose
tolerance, in vivo and in vitro glucose-induced insulin release, and
basal and insulin-stimulated glucose production and glucose utilization in vivo were evaluated over a 4-wk period.
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MATERIALS AND METHODS |
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Diets. The powdered semisynthetic standard diet contained by weight (g/100 g) 68% starch, 4% cellulose, 5% lipid (maize oil), and 15% protein (casein) (remaining 8% moisture) and by calories 72% carbohydrate, 12% lipid, and 15% protein. The powdered semisynthetic low-protein diet contained by weight (g/100 g) 78% starch, 4% cellulose, 5% lipid (maize oil), and 5% protein (casein) and by calories 83% carbohydrate, 12% lipid, and 5% protein. The two diets were isoenergetic, and the energy content per 100-g diet was 375 calories. Both diets contained 2 g/100 g yeast, a salt mixture (3.5 g/100 g), and a vitamin mixture (2.2 g/100 g), as described previously (18).
Animals. Female GK rats issued from our GK colony (19) were weaned 28 days after birth and from this age were fed either a standard or a protein-restricted diet for 4 wk onward. One member of each pair of littermates was fed ad libitum (standard diet), with daily food intake being measured, and the intake of the other member of the pair was restricted for the next 4 wk to 65% of the ad libitum intake (standard diet or low-protein diet), with the food being placed in the cage each evening (1 hour before dark cycle onset). GK rats fed the standard diet ad libitum were used as controls.
It is important to mention that no major alteration of the feeding pattern took place in the restricted groups, because we have verified that rats had an excess of food available most of the time during the nocturnal feeding period, and the restricted rats never consumed in one short meal their daily food ration (in contrast to the findings usually reported in more severe food restriction protocols). Because in the glucose tolerance and clamp experiments performed at 1400, food was withdrawn in the three groups of rats in the morning of the study shortly after the light cycle onset, one may therefore consider that the duration of subsequent fasting was comparable in the three groups. After following the diet for 3 wk, animals from each group underwent a glucose tolerance test. After following the diet for 4 wk, randomly selected animals from each group were used for in vitro perfusion of the pancreas. The remaining animals in each group underwent measurement of in vivo insulin action with the glucose-insulin clamp technique.Isolated pancreas perfusion technique.
Rats were anesthetized with pentobarbital sodium (4 mg/100 g body wt
ip). Isolation and perfusion of the pancreas were performed as
previously described (12). The perfusate was a Krebs-Ringer bicarbonate
buffer with the following components: 2.8 mmol/l D-glucose (Merck, Darmstadt, Germany), 118 mmol/l NaCl, 4 mmol/l KCl, 2.5 mmol/l
CaCl2, 1.2 mmol/l MgSO4, 1.2 mmol/l
KH2PO4, 25 mmol/l NaHCO3, 1.25 g/l
fatty acid-free BSA (Sigma, St. Louis, MO), and 40 g/l dextran T-70
(Pharmacia, Uppsala, Sweden). When needed, D-glucose or
L-arginine (Sigma) was administered through a side-arm
syringe. In all protocols, the complete effluent (3 ml/min) was
collected from the cannula in the portal vein at 1-min intervals in
chilled tubes and was frozen for storage at 20°C until assay.
Glucose tolerance tests.
Intravenous glucose tolerance tests (0.5 g glucose/kg body wt) were
performed under pentobarbital sodium anesthesia (4 mg/100 g body wt ip)
at 1400 in rats fasted from 0900. Blood was withdrawn from the tail
vein, and samples (250 µl) were immediately centrifuged at 4°C;
plasma was stored at 20°C until assayed.
Euglycemic-hyperinsulinemic clamp studies. Studies were performed at 1400 in rats fasted from 0900 according to a previously detailed procedure (6, 13). The rats were considered to be in the postabsorptive period, and the rate of glucose production was a measure of endogenous glucose production. Rats were anesthetized with pentobarbital sodium. Body temperature was maintained at 37-38°C with heating lamps. One carotid artery was catheterized for blood sampling, and a tracheotomy was systematically performed to avoid respiratory problems during anesthesia.
Blood samples of 150 µl were collected 20 min after the end of the surgery for the determination of basal blood glucose and plasma insulin concentrations. Next, insulin was infused at a constant rate of 20 µl/min (3.0 mmol · hEndogenous glucose production and whole body glucose utilization.
Endogenous glucose production in the basal state and during the
hyperinsulinemic clamp studies was assessed by a primed continuous infusion of [3-3H]glucose (New England Nuclear, Dreiech,
Germany). The labeled glucose was administered as an initial
intravenous priming dose (4 µCi) followed immediately by a continuous
intravenous infusion at a rate of 0.2 µCi/min. Steady-state glucose
specific activity was established by 40 min both in the basal state and
the clamp studies. The rate of glucose appearance (Ra)
was then equal to the rate of glucose disappearance (Rd),
and these two parameters were calculated by dividing the
[3-3H]glucose infusion rate
[disintegrations · min1
(dpm) · min
1] by the steady-state value
of glucose specific activity (dpm/g). In the basal state, the rate of
endogenous glucose production is equal to Ra. In the clamp
studies, the rate of endogenous glucose production was calculated by
substracting the exogenous steady-state glucose infusion rate (SSGIR)
from Ra. The rate of glucose utilization by the whole body
mass (GUR) was calculated as GUR = Rd, and the glucose
production rate (GPR) in the liver was calculated as GPR = Ra-SSGIR.
Samples, analytical techniques, and calculations. Plasma glucose was determined with a glucose analyzer (Beckman, Palo Alto, CA). Blood samples for measuring glucose specific activity were deproteinized with Ba(OH)2-ZnSO4 and immediately centrifuged. An aliquot of the supernatant was used for the determination of glucose using a glucose oxidase method. Another aliquot of the supernatant was evaporated to dryness at 60°C to remove tritiated water. The dry residue was dissolved in 0.1 ml distilled water and was counted with 3 ml of ReadySolv-MP scintillation solution (Beckman). Plasma immunoreactive insulin was estimated using purified rat (studies in the basal state) or porcine (clamp studies) insulin as standards (Novo), antibody to mixed (porcine + bovine) insulin cross-reacting similarly with porcine and rat insulin standards, and porcine monoiodinated 125I-labeled insulin (6, 18). Charcoal was used to separate free from bound hormone. The method allows the determination of 2 µU/ml (0.08 ng/ml or 14 pmol/I) with a coefficient of variation within and between assays of 10%.
The insulin and glucose responses during the glucose tolerance test were calculated as the incremental plasma insulin values integrated over the 30-min period after the glucose injection (Statistical analysis. Results are given as means ± SE. Statistical analysis was performed using ANOVA (Scheffé's F-test) or Student's t-test for unpaired data.
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RESULTS |
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Characteristics of the GK rats.
After weaning (4 wk), female GK rats fed ad libitum gained weight and
continued to grow throughout the observation period (Fig.
1). Food-restricted GK rats gained weight
at a considerably lower rate during the same observation period (Fig.
1). The deficiency state in this group could be regarded as one of
combined protein-energy malnutrition. Calculation of the daily protein
intake per gram body weight at the end of the 4-wk period of
restriction indicated that it was not significantly different in the
restricted rats from that in the unrestricted rats (1.7 ± 0.2 g
protein/100 g body wt, n = 9, and 1.4 ± 0.2,
n = 6, respectively), thus suggesting that the protein
deficiency remains mild under these experimental conditions.
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Glucose tolerance and in vivo insulin secretory response to glucose.
The mean incremental glucose area (G) in the food-restricted group
tended to increase in response to an intravenous glucose load, whereas
in the protein- and energy-restricted group it was clearly increased
(P < 0.001) compared with the unrestricted group.
In vitro insulin secretory response.
The in vitro insulin release in response to glucose and arginine was
studied with the isolated perfused pancreas preparation. Basal insulin
secretion in the presence of 2.8 mmol/l glucose in the perfusion medium
was not significantly different in the food-restricted rats compared
with the controls but was decreased (P < 0.05) in the
protein- and energy-restricted GK rats (Table 2). Exposure for 20 min to a 16 mmol/l
glucose concentration that induces the pattern of impaired insulin
release typical of the control GK pancreases elicited a similar
increase of insulin output in the food-restricted GK pancreases. Also,
the incremental insulin response to 19 mmol/l arginine remained
unchanged in the food-restricted group compared with that in the
control group. By contrast, the insulin response elicited in the
protein- and energy-restricted GK rats by 16 mmol/l glucose was
severely blunted (P < 0.01; Fig.
2), because the incremental insulin
response was only 30% of the control response (Table 2). A similar
blunted pattern (P < 0.001) was observed during 19 mmol/l
arginine stimulation (Table 2).
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In vivo glucose metabolism and insulin action.
The basal rate of glucose production (reflective of hepatic glucose
production in the postabsorptive state) was depressed (P < 0.001) in the food-restricted and protein- and
energy-restricted GK rats relative to controls when expressed per
animal. However, when expressed per kilogram body weight, it was
enhanced (P < 0.001) in the protein- and energy-restricted
group. Paradoxically, the endogenous glucose production in the
food-restricted rats, whether expressed per rat or per kilogram body
weight, was enhanced fourfold above the basal state after a submaximal
hyperinsulinemia (2.4 nmol/l as a mean; Table
3). Under similar hyperinsulinemia, endogenous glucose production in the protein- and calorie-restricted GK
rats was severely depressed (P < 0.01) relative to the
control GK rats.
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DISCUSSION |
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This study extends to young diabetic GK rats previous observations in young normal rats (7, 9, 11, 17, 24) that food restriction (30-50% restriction) does not support normal growth. The moderate growth retardation in rats exposed to food restriction contrasts with the drastic growth arrest observed in the protein- and energy-restricted group. Of course, at the beginning of the restriction protocol, the rats have to cope not only with energy restriction but also with an insufficient protein intake. However, the preservation of a daily protein intake (when expressed per unit body weight) that we found in the food-restricted GK rats at the end of the 4-wk protocol suggests that these rats did not experience irreversible and major protein restriction. We previously came to the same conclusion in normal Wistar rats using the same dietary manipulation (18). Note that, using diet compositions close to the present diets and using normal rats, Wade et al. (25) have reported that serum albumin level was not significantly affected by a reduction in caloric consumption as severe as 50% after 6 wk (18% protein diet), whereas a 50% food restriction combined with 4% protein in the food significantly decreased the serum concentration of albumin. Given these data, one may hold as important for the significance of our study that the food-restricted group exhibits mainly energy deficiency with limited associated protein malnutrition whereas the protein- and energy-restricted group is clearly protein deficient. This is an issue of importance, because it helps to delineate the respective effects of two parameters that are intimately associated in most animal studies of malnutrition (7, 9, 11, 17, 24).
The food-restricted GK rats were able to maintain their in vivo insulin
response to glucose, and their insulin secretory response to glucose or
to arginine in vitro (isolated perfused pancreas) was found to be
similar to that in control GK rats. This indicates that food
restriction, as used in our present experimental protocol, did not
exert any major detrimental structural or functional damage to the
-cells of the GK rats.
By contrast, in the protein- and energy-restricted rats, the basal
plasma insulin level was drastically decreased, and the in vivo insulin
response to glucose was very poor. This is in agreement with previous
reports using similar protein-energy manipulation in nondiabetic rats
(9, 16, 24, 27). Such impairment of insulin release in vivo is dramatic
and is related to intrinsic abnormality(ies) of the pancreatic
-cells, because low responsiveness of
-cells in the protein- and
energy-deficient GK rats could be evidenced in vitro in the perfused
pancreas experiments. In fact, there is no doubt that protein-energy
malnutrition causes a generalized insensitivity of the remaining
-cells, because in vitro responses to arginine and glucose were
found to be blunted. It is interesting to note that protein-energy
malnutrition in normal rats has been reported to cause a diminution of
-cell mass (23), and such
-cell atrophy has been considered a
rather typical feature of protein shortage (2, 5, 8, 23). Moreover, we
cannot presently eliminate the possibility in the GK rats that the
blunting of basal plasma insulin levels as well as that of the insulin
response as observed in vivo during a glucose challenge are also
related to an impaired environment of the pancreatic
-cells. The
determinants of such an altered environment for
-cell function in
the protein- and energy-restricted GK rats are presently unknown.
However, as long as the comparison with the situation in the normal rat
submitted to the same dietary restriction is valid (14, 15), a tenable
possibility is that increased plasma catecholamines and enhanced
sympathetic nerve activity exert a deleterious effect on
-cell function.
Under basal conditions, food-restricted GK rats maintained a plasma
glucose level that was not significantly different from that in control
GK rats (still in the diabetic range); however, this was obtained in
the face of a significantly decreased basal plasma insulin level (and
accordingly, a return of insulin level toward the value found in normal
nondiabetic Wistar rats). By contrast, their tolerance to intravenous
glucose was lower than in control rats, as shown by a significantly
increased incremental plasma glucose area (G value).
The total body glucose metabolism in the food-restricted GK rats, as measured by the rate of exogenous glucose infusion required to maintain the blood glucose level at euglycemia and at steady-state plasma insulin, was significantly higher than that in the control GK rats at submaximal insulin levels. This indicates that the total body glucose metabolism was more responsive to insulin in the food-restricted GK rats compared with the control GK rats. The basal glucose utilization rate as estimated by the glucose turnover value was significantly higher in the food-restricted GK rats. During the clamp studies, the glucose utilization induced by submaximal insulin levels was significantly greater (4.6-fold increase when related to body mass) in the food-restricted GK rats than in the control GK rats. These data suggest that insulin-mediated glucose uptake is enhanced in the food-restricted GK rats.
Under basal postabsorptive conditions and in the face of drastically lowered plasma insulin levels, the protein- and energy-restricted GK rats experienced a significant decrease in plasma glucose, but it remained in the diabetic range. Tolerance to intravenous glucose was aggravated, as shown by an increased incremental plasma glucose area value. Such a glucose intolerance is obviously related to the decreased glucose-induced insulin release in vivo. Alternatively, it could also be related to a decreased sensitivity to insulin. In fact, the total body glucose metabolism (rate of exogenous glucose infusion at submaximal insulin levels) in the protein- and energy-restricted GK rats was significantly higher than that in the control GK rats. Their basal glucose utilization rate (glucose turnover) was significantly higher (1.6-fold increase), and, during the clamp studies, the glucose utilization induced by submaximal insulin levels was significantly greater (1.8-fold increase) in the protein- and energy-restricted GK rats than in the control GK rats. Therefore, one may conclude that insulin-mediated glucose uptake was indeed enhanced in the protein- and energy-restricted GK rats.
Furthermore, the comparison of insulin action between the two protocols of restriction investigated here suggests that glucose utilization was more efficiently increased by insulin in the food-restricted GK rats than in the protein- and energy-restricted GK rats.
One of the aims of our study was also to evaluate the effect of insulin on endogenous glucose production in the food-restricted GK rats. In the basal state (postabsorptive state), the hepatic glucose production value (when expressed per body mass and when compared with the value in control GK rats) was increased in the protein- and energy-restricted GK rats, whereas it remained unchanged in the food-restricted GK rats. Without knowing at the present time the circulating levels of the counterregulatory hormones, we cannot conclude that insulin action in the liver of both restricted groups was impaired in the basal state. In the presence of submaximal insulin levels (euglycemic clamp studies), the glucose production in the food-restricted GK rats, instead of being suppressed, was paradoxically enhanced. We are presently without any satisfactory explanation for such a pattern. However, it is consistent with our previous proposal that food restriction from weaning (18) or from the fetal stage (11) promotes hepatic insulin resistance. In the protein- and energy-restricted GK rats, the pattern was clearly different; although the hepatic glucose production in control GK rats remained elevated in the presence of submaximal insulin levels, it was almost blocked in the protein- and energy-restricted GK rats.
In conclusion, we have found that a 35% food restriction in the young GK rat does not aggravate basal hyperglycemia or glucose intolerance, despite a decrease of the basal plasma insulin level. Furthermore, our data provide direct evidence that food restriction determines changes in the effect of insulin on some target tissues, because the insulin-mediated glucose uptake by peripheral tissues in the GK rat was indeed improved. We also found that the 35% food restriction, when coupled to overt protein deficiency, slightly decreases basal hyperglycemia but conversely aggravates glucose tolerance. Improvement of basal hyperglycemia was related to repression of basal hepatic glucose hyperproduction, despite profound attenuation of the basal plasma insulin level. Deterioration of tolerance to glucose was related to severe blunting of the residual glucose-induced insulin secretion. It is, however, likely that the important enhancement of the insulin-mediated glucose uptake helps to limit the deterioration of glucose tolerance.
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ACKNOWLEDGEMENTS |
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This work was supported by a grant from the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche (no. 95-G-0103; program interministériel "Aliment Demain") and by the France/Spain program for Science (Coopération Franco-Espagnole Centre National de la Recherche Scientifique/Consejo Superior Investigaciones Científicas; projets 1986 et 5249).
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FOOTNOTES |
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C. Alvarez was the recipient of a fellowship from the Université Paris 7/D. Diderot (Maître de Conférence invité, emploi no. 234MA0202).
Address for reprint requests and other correspondence: B. Portha, Lab. Physiopathology of Nutrition, CNRS ESA 7059, Université Paris 7/D. Diderot, 2 place Jussieu, Tour 33, 75251 Paris Cedex 05, France (E-mail: portha{at}paris7.jussieu.fr).
Received 17 June 1999; accepted in final form 14 January 2000.
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