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Department of Biochemistry, School of Biochemistry University of Litoral, Santa Fe and * Endocrinology Research Center, Hospital Ricardo Gutierrez, Buenos Aires, Argentina
3To whom correspondence should be addressed. E-mail: ylombard{at}fbcb.unl.edu.ar
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • dyslipemia • insulin secretion • sucrose-rich diet • skeletal muscle • muscle lipid metabolism
Several experimental studies demonstrated that the macronutrient composition of the diet is an important environmental determinant of the quality of insulin action (1
–4
). However, the mechanisms that underlie nutrient-induced insulin resistance remain unclear. One important variable may be the lipid environment because changes in this environment can influence insulin’s regulation of glucose metabolism (2
,4
,5
). Rats fed a high sucrose diet exhibit impaired insulin action in conjunction with hypertriglyceridemia (1
,6
–8
).
Our laboratory has demonstrated that the abnormal glucose homeostasis and insulin insensitivity that develop in normal rats fed a sucrose-rich diet (SRD)4 depend on both the amount of carbohydrate and the length of time the diet is consumed (6
,9
,10
). Moreover, in the presence of hypertriglyceridemia, plasma glucose and insulin evolve from normoglycemia and hyperinsulinemia after a short time (3–5 wk) to moderate hyperglycemia and normoinsulinemia with long-term (15 up to 40 wk) consumption of a SRD. In addition, a more pronounced increase in the plasma free fatty acid (FFA) level occurs in rats after long-term consumption of a SRD (5
,11
).
On the other hand, the skeletal muscle is the major site of insulin-stimulated glucose disposal. Studies of this tissue in rats have shown that the degree of insulin resistance is strongly correlated with the local accumulation of triglyceride (3
,12
). Although the mechanisms by which sucrose induces skeletal muscle insulin resistance in rats are unclear, it has been suggested that the local or systemic oversupply of lipid may promote the development of insulin insensitivity in this tissue (13
–15
). Recent studies have shown a strong correlation between insulin action and the tissue content of long-chain acyl CoA (LCACoA) in skeletal muscle (16
). LCACoA has been shown to interact with insulin, signaling pathways and glucose metabolism by modulating enzyme activities and gene transcription (17
).
As already mentioned, in rats fed a SRD, a different hormonal and metabolic milieu evolves from the early (3–5 wk) to the late (15–30 wk) stages of dyslipidemia. However, the time courses of the increases in triglyceride and LCACoA levels in skeletal muscle and the development of insulin insensitivity in this tissue have not been carefully studied. In addition, it has been shown that a chronic elevation of plasma FFA levels impairs glucose-stimulated insulin secretion in vitro and in vivo. Fatty acids induce the "lipotoxicity" that contributes to declining ß cell function (18
,19
). A time course study on insulin secretion patterns from isolated ß cells of rats fed a SRD from a few to several weeks has not been conducted.
Therefore, the aims of the present study were to determine the time course of changes in triglyceride and LCACoA concentrations, and the nonoxidative and oxidative fate of glucose both in the basal state and after the euglycemic-hyperinsulinemic clamp in the gastrocnemius muscle of rats fed a sucrose-rich diet for 3, 15 or 30 wk, and to analyze the changes in glucose-stimulated insulin secretion patterns from perifused isolated islets from SRD-fed rats and their correlation with plasma insulin levels and whole-body insulin sensitivity.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Wistar rats initially weighing 175–190 g and purchased from the National Institute of Pharmacology (Buenos Aires, Argentina) were maintained in an animal room under controlled temperature (22 ± 1°C), humidity and airflow conditions, with a fixed 12-h light:dark cycle (light 0700–1900 h). They were initially fed a standard nonpurified diet containing by weight (g/100 g): 63 starch (corn, sorghum, wheat, oats, barley), 22 protein, 3.5 fat, 6 fiber, 1 vitamin mixture and 4 salt mixture (Ralston, Purina, St. Louis, MO). After 1 wk of acclimation, they were randomly divided into two groups of 80 rats (control and experimental). The experimental group received a purified sucrose-rich diet (SRD) containing by weight (g/100 g): 63 sucrose, 17 casein free of vitamins, 5 corn oil, 10 cellulose, 3.5 salt mixture (AIN-93M-MX), 1 vitamin mixture (AIN-93-VX), 0.2 choline chloride, and 0.3 DL-methionine (20
). Details of the methodology used were described elsewhere (11
). The control group received the same purified diet, but with sucrose replaced by cornstarch [high starch diet, (CD)]. The rats had free access to food and water and consumed their respective diets for up to 30 wk. Both diets provided 
15.28 kJ/g of food. The weight of each rat was recorded twice each week during the experimental period. In a separate experiment, the individual energy intakes and weight gains of eight rats in each group were assessed twice each week.
At the end of each experimental period (3, 15 or 30 wk), 24 rats were used from each dietary group. Rats of both the CD and SRD groups were randomly subdivided into 2 groups. In the first subgroup of 12 rats, food was removed at the end of the dark period (0700 h) except as otherwise indicated and experiments were performed between 0800 and 1200 h. In the second subgroup (12 rats used for clamp studies), all of the rats were deprived of food for 5 h. At that time, rats in subgroup 2 were further randomly divided into two groups: 1) those utilized for analytical assays in the gastrocnemius muscle at the beginning of the clamp (6 rats), and 2) those in which the euglycemic clamp was performed (6 rats). The former yielded the values for the start of the clamps (0 min). The experimental protocol was approved by the Human and Animal Research Committee of the School of Biochemistry, University of Litoral, Santa Fe, Argentina.
Analytical methods.
At the end of the dark period, 6 rats from each diet subgroup at each time point were anesthetized with an intraperitoneal injection of pentobarbital (60 mg/kg body). Blood samples obtained from the jugular vein were rapidly centrifuged at 3500 x g, for 15 min at 4°C and the plasma either immediately assayed or stored at -20°C and examined within 3 d. Plasma triglycerides, FFA and glucose levels were determined by spectrophotometric methods and insulin was measured by an immunoreactive assay as previously described (11
). The immunoreactive insulin assays were calibrated against a rat insulin standard (Novo Nordisk, Copenhagen, Denmark). The gastrocnemius muscle was rapidly removed from all of the anesthetized rats, frozen, clamped in liquid nitrogen and stored at -70°C. The homogenates of frozen muscle powder were used for the determination of triglyceride, glycogen, protein, glucose-6-phosphate (G-6-P), LCACoA (21
), and also for the determination of the activities of the glycogen synthase (GSa) (22
), pyruvate dehydrogenase complex (PDHc) (15
), and pyruvate dehydrogenase kinase (PDH-kinase) (15
).
Euglycemic clamp studies.
Whole-body peripheral insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique as previously described (5
). Briefly, after 5 h of food deprivation, 12 rats from each dietary group at each time point were anesthetized, a blood sample was withdrawn, and glucose and insulin levels were assessed. The gastrocnemius muscle of 6 rats from each group was rapidly removed (starting clamp values), frozen, clamped in liquid nitrogen and stored at -70°C for the determination of metabolites and the activities of the enzymes mentioned above. In the other 6 rats, an infusion of highly purified porcine neutral insulin (Actrapid, Novo Nordisk) was administered at 0.8 U/(kg · h) for 2 h. Insulin was infused through one limb of a double lumen cannula connected to the left jugular vein. Blood samples for glucose assays were taken at 5- to 10-min intervals from the right jugular vein. Blood glucose concentration was measured using a Glucomether Analyzer (Boehringer Mannheim, Indianapolis, IN) within 2 min after the samples were obtained. Glycemia was maintained at a euglycemic level by infusing 200 g/L glucose at variable rates through the limb of the double cannula. The glucose infusion began 5 min after the insulin infusion had started. The glucose infusion rate (GIR) during h 2 of the clamp study was taken as the net steady state of the whole-body glucose. In all studies, blood samples (0.3 mL) for insulin determination (11
) were obtained at 60, 90 and 120 min. The hematocrit was measured at the start and at the end of each experiment. At the end of the clamp period, the gastrocnemius muscle was rapidly removed, frozen, clamped in liquid nitrogen and stored at -70°C for the subsequent assays of triglyceride, LCACoA, glycogen, proteins, G-6-P and for those of the activities of GSa, PDHc and PDH-kinase (15
,21
,22
).
GSa activity.
In vitro GSa activity was determined by the method of Golden et al. (22
). The GSa-independent activity was the activity measured at low G-6-P concentration and the total GSa activity was the activity measured at high G-6-P concentration. The fractional velocity of GSa was calculated as the rate of incorporation of labeled uridine-diphospoglucose into glycogen at 0.1 mmol/L G-6-P divided by the rate at 10 mmol/L and expressed as a percentage (23
).
Extraction and assay of PDHc and PDH kinase activities.
The extraction of PDHc from the gastrocnemius muscles was described in detail (15
). PDH activity was expressed as nmol NADH formed per min, per gram of wet tissue, per mg of soluble protein and per unit of citrate synthase (21
).
The isolation and assay of the PDH kinase was done as described by Popov et al. (24
) and D’Alessandro et al. (15
). PDH kinase activity was assayed by determining the ATP-dependent inactivation of PDH activity as a function of time. The apparent first-order rate constant (k, min-1) was calculated from a least-squares linear regression analysis of in (inactivation by ATP) against time of incubation.
Perifusion of isolated islets.
The rats (6 from each dietary group at each time point) were deprived of food for 12 h and decapitated; the islets were isolated by collagenase digestion and collected under a stereoscopic microscope. After the islets were washed twice with Krebs-Ringer bicarbonate (KRB) buffer, groups of 30–40 islets isolated from each rat were loaded in a 13-mm chamber containing a 5-µm nylon membrane filter. Islets were perifused with KRB buffer containing 3 mmol/L glucose, 205 mg/L bovine serum albumin, 40 mg/L dextran-70, pH 7.4, at 37°C (constantly gassed with 5% CO2:95% O2) at a flow rate of 0.9–1.2 mL/min. After a prewash period of 30 min, two basal samples were obtained. Then, the KRB buffer containing a high glucose concentration (16.5 mmol/L) was used until the end of the perifusion period (40 min). Aliquots from the effluent were collected at 1-min intervals until min 15, and then at 5-min intervals until min 40. Samples were stored at -20°C until insulin analysis. The insulin assay sensitivity was 3.56 pmol/L and the intra-assay CV were 8.7, 6.2 and 5.1% for 7.1–35.6, 35.6–71.2 and 71.2–356.0 pmol/L insulin determination ranges, respectively; the interassay CV were 6.6, 5.0 and 5.2% for the given ranges. More details of the methodology used were previously described (5
).
Statistical analysis.
Results are expressed as means ± SEM. The significance of differences between the two groups was determined by Student’s t test. When appropriate, data were subjected to two-way ANOVA with diet and time as the main effects (25
), followed by inspection of all differences between pairs of means by the Newman Keuls’ test (25
). Differences with P-values < 0.05 were considered to be significant.
Reagents.
Enzymes for the assays, substrate and coenzymes were purchased from Sigma Chemical (St. Louis. MO) or from Boehringer Mannheim Biochemical (Indianapolis, IN). Uridine-5'-diphospho [U-14C]glucose was purchased from New England Nuclear (Boston, MA) All other chemicals were reagent grade.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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As previously shown (10
) weight gains and energy intakes did not differ between groups during the first 15 wk of the study. However, significant increases in weight gain (15%) occurred in rats fed the SRD between wk 15 and 30 (Fig. 1
). During this period, energy intake was also higher (P < 0.01) in rats fed the SRD (380 ± 19.6 kJ/d, n = 8) than in those fed the CD (273.0 ± 21.5 kJ/d, n = 8).
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At the end of the dark period (0700 h), in agreement with previous reports from our laboratory (10
), plasma triglycerides and FFA were significantly higher in rats fed the SRD after 3 wk compared with age-matched controls fed the CD (Table 1
). Both triglyceride and FFA levels were greater at 15 and 30 wk compared with wk 3 in rats fed the SRD, whereas no changes in these metabolites occurred in rats fed the CD for the same period of time. Plasma glucose levels were greater after 15 and 30 wk of consuming the SRD compared with rats fed the CD. On the other hand, although plasma insulin levels were higher than controls after short-term (3 wk) consumption of the SRD diet, the groups did not differ at wk 15 and 30.
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To assess the effect of the SRD on whole-body peripheral insulin sensitivity (insulin resistance), euglycemic-hyperinsulinemic clamp studies were performed at the end of each experimental period. Blood glucose was clamped at 5.5–6.0 mmol/L. Postprandial blood glucose concentrations 5 h before the clamp were as follows: (mmol/L, mean ± SEM, n = 6): 5.58 ± 0.25 in SRD and 5.63 ± 0.18 in CD at 3 wk; 7.95 ± 0.29 in SRD and 5.70 ± 0.22 in CD (P < 0.01) at 15 wk, and 8.02 ± 0.21 in SRD and 5.53 ± 0.28 in CD (P < 0.01) at 30 wk. In addition, plasma insulin levels similar to those recorded at the end of the dark period were obtained in both dietary groups at 3, 15 and 30 wk (data not shown). The steady-state blood glucose and insulin concentrations measured over the last 60 min of the clamp did not differ between groups at 3, 15 and 30 wk. The GIR, which measured insulin action in vivo, was lower (P < 0.01) in rats fed the SRD at the end of each experimental period compared with rats fed the CD (Fig. 2
). However, GIR values declined more sharply after 15 and 30 wk in rats fed the SRD (Fig. 2)
. There were no differences in hematocrit from the start to the end of the clamp (data not shown).
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At the start of the clamp studies, the gastrocnemius muscle of the dyslipemic rats fed the SRD for a short time (3 wk) had a greater concentration of LCACoA than the controls (Table 2
). However, triglyceride concentration and glucose oxidation, estimated from the activation state of PDHc, and PDH kinase activities did not differ between the groups (Table 2)
. After 3 wk, triglyceride and LCACoA concentrations in the gastrocnemius muscle of rats consuming the SRD were greater, glucose oxidation was lower (lower PDHc and higher PDH kinase activities) and whole-body insulin resistance (low GIR, Fig. 2
) was more pronounced compared with rats fed the CD. On the other hand, glycogen and G-6-P concentrations and GSa activity did not differ at each time point from those obtained in rats fed the CD (Fig. 3
). The values recorded in Table 2
were similar to those obtained at the end of the dark period (data not shown).
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Compared with the values recorded at the start of the clamp, glycogen and G-6-P concentrations and GSa activity were increased by insulin stimulation in the gastrocnemius muscle of rats fed the CD for 3, 15 or 30 wk (Fig. 3
A, B and C). This occurred also at 3 wk in rats fed the SRD. At wk 15 and 30, insulin stimulation of glycogen and G-6-P concentrations as well as GSa activity were impaired in rats fed the SRD. Muscle triglyceride was increased 130% at the end of the clamp in rats fed the CD at 3, 15 or 30 wk (Fig. 3
D), an increase that also occurred at wk 3 in rats fed the SRD. At wk 15 or 30 wk, the muscle triglyceride concentrations in rats fed the SRD did not differ from those recorded at the start of the euglycemic-hyperinsulinemic clamp (Fig. 3
D). The impaired glucose oxidation (reduced PDHa and increased PDH kinase activities) observed at the start of the clamp (0 min) was still present under conditions of insulin stimulation in rats fed the SRD after 15 and 30 wk (data not shown). In addition, LCACoA levels in both groups did not differ from those recorded at the start of the clamp at wk 3, 15 and 30 (data not shown).
Perifusion of isolated islets.
Insulin secretion (IS) in the perifused islets from control rats demonstrated a classic biphasic pattern in the presence of 16.5 mmol/L glucose stimulation (Fig. 4 A, B and C
). Under our experimental conditions, the first peak occurred after 4 min of perfusion, whereas the second peak rose to its highest value at perifusion time 40 min. Rats fed the SRD for 3 wk (Fig. 4A)
had a greater IS peak in the first phase than rats fed the CD (P < 0.01), whereas IS during the second phase did not differ between groups. The IS patterns of rats fed the SRD for 15 wk (Fig. 4
B) showed a diminished (P < 0.01) and delayed first phase of IS with similar values at 4 and 5 min of perifusion. Moreover, compared with rats fed the CD, SRD-fed rats tended to manifest hypersecretion in the second phase (P = 0.03). Perifused islets from SRD-fed rats at wk 30 (Fig. 4
C) clearly differed from the biphasic pattern of glucose-stimulated hormone secretion. The first peak was not present although IS increased steadily; the values reached were lower than the controls. On the other hand, IS values were higher (P < 0.01) in the second phase than those of the controls.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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An oversupply of lipid deteriorates insulin action in the skeletal muscle and in the whole-body peripheral tissue of rats. This has been reported in rats fed a high fat diet, in which mainly the skeletal muscle triglyceride increased (3
,26
). It has also been reported (1
,8
,11
) in rats fed a high sucrose diet for 3 wk, in which both the circulating plasma triglycerides and FFA increased. The present results expand the above observations showing that a substantial increase of LCACoA concentration within the gastrocnemius muscle of rats fed the SRD for 3 wk seems to be an early indication of the disturbance of lipid metabolism and/or fuel utilization present in the face of hyperinsulinemia and moderate peripheral insulin insensitivity in this dietary group. Interestingly, we previously demonstrated an increase of both LCACoA and triglyceride concentrations and a profound alteration of glucose oxidation in the heart of rats fed a SRD for the same period of time (21
). This may suggest a tissue specificity in the development and worsening of impaired muscle fuel utilization in rats consuming the SRD diet for a short time.
The different metabolic milieu that developed after 15 wk and continued to at least 30 wk in rats fed the SRD could affect the interplay of lipid and glucose metabolism in the skeletal muscle. At these time points, the increase of muscle triglyceride and LCACoA stores occurred concomitant with a significant reduction of PDH activity, a key enzyme in the control of glucose oxidation. A decreased flux through the PDH complex is associated with lower PDHa levels, and the inhibition of this enzyme complex limits the oxidation of pyruvate derived from glycolysis (27
). Our results indicate both a low PDHa and a significant increase of PDH kinase activities in the basal state and after insulin stimulation at the end of both experimental periods.
The mechanisms by which muscle intracellular triglyceride per se may directly modulate glucose metabolism are still unknown. Although a negative correlation between insulin-stimulated glucose uptake and metabolism and triglyceride accumulation can be interpreted within the context of the glucose-fatty acid cycle (27
), an elevated muscle triglyceride store could also result from reduced local lipid oxidation (28
,29
).
On the other hand, LCACoA can also modulate skeletal muscle insulin sensitivity by mechanisms other than the glucose-fatty acid cycle (30
). Accordingly, an increase in the cytosolic pool of this metabolite could alter the effects of insulin on glucose metabolism (e.g., enhancing synthesis of diglycerides, thereby leading to activation of protein kinase C isoforms, which are thought to interfere with insulin signaling) (17
). In the present study, cytosolic LCACoA were not explicitly measured. However, the observation that total LCACoA levels are elevated in the muscle of insulin-resistant 4-d glucose-infused rats (31
) and in insulin-resistant rats fed a high fat diet (16
) provides additional evidence that an increase in this intracellular lipid pool may have a role in the manifestation of muscle insulin insensitivity. Moreover, LCACoA concentration plays a role in the control of malonyl CoA levels in tissues including skeletal muscle. Malonyl CoA seems to be a component of a fuel sensing and signaling mechanism that responds to changes in the fuel milieu and energy expenditure of the muscle cells (32
). At present, we are unaware of any studies examining the level of this metabolite under either basal or insulin stimulation conditions in the skeletal muscle of rats fed a SRD for an extended period of time. Changes in this metabolite could also contribute to the abnormal fuel utilization observed in this tissue.
The present results show a relative impairment of the insulin-stimulated glycogen store and a significant decrease in GSa activity. This indicates that an alteration in the nonoxidative pathway of glucose metabolism is present in rats fed a SRD at either 15 or 30 wk. In these rats, sustained elevations of plasma FFA and triglyceride levels were observed throughout the experimental period. Chalkley et al. (33
) observed a relative impairment of insulin-stimulated glycogen synthesis and reduced GSa activity associated with muscle triglyceride and LCACoA accumulation in rats after 5 h of triglyceride/heparin infusion that elevated plasma FFA during a euglycemic-hyperinsulinemic clamp.
Our data also show a lack of increase in G-6-P levels under conditions of insulin stimulation in the gastrocnemius muscle of rats after long-term consumption of a SRD. Changes in glucose transport rather than glucose phosphorylation may be the major mechanism explaining the absence of an increase in G-6-P in insulin-resistant muscle after insulin stimulation (34
). However, a recent study (35
) suggests an alternative mechanism. An increase of the LCACoA levels may act as an allosteric inhibitor of muscle hexokinase activity and may thus directly affect G-6-P concentration and decrease the flux through this enzyme, resulting in less insulin-stimulated glucose uptake in this tissue (35
).
On the other hand, a significant increase of plasma insulin level helped maintain the normoglycemia in rats fed the SRD for 3 wk. Moreover, a marked rise of the first peak of insulin secretion patterns from in vitro perifused islets was observed at this time point. However, the present results may also suggest that the marked rise of the hormone was unable to maintain whole-body peripheral insulin sensitivity. At 15–30 wk, plasma insulin levels were within a normal range, whereas the altered insulin secretion patterns showed a progressive deterioration that was accompanied by a worsening of the peripheral insulin resistance and by moderate hyperglycemia. Type 2 diabetes is characterized by a progressive loss of ß cell function during the course of the disease. Different independent mechanisms may induce ß cell dysfunction before the development of clinical hyperglycemia (36
). One possibility is that increased fatty acid flux to other tissues and increased triglyceride storage in these tissues promote insulin resistance and other adverse effects referred to as "lipotoxicity" by some authors (37
–39
). An increase in triglyceride content within nonadipocytes, which was associated with the inhibition of ß cell function, was also observed after long-term exposure of rat islets to high levels of fatty acids in vitro (37
–40
). Possible mechanisms underlying this lipotoxicity are beginning to emerge from some recent studies using Zucker diabetic fatty rats (38
). One is that the fatty acid-induced ß cell dysfunction is mediated by upregulation of inducible NO synthase, overproduction of NO and induction of apoptosis (38
). Although some studies seem to implicate glucose toxicity rather than lipotoxicity in the early loss of acute glucose tolerance in humans, they do not rule out the important role of fatty acids as a contributor, or exclude them when the diabetic state is more severe. Moreover, the normalization of the altered patterns of glucose-stimulated insulin secretion, as well as the enhancement of peripheral insulin sensitivity by troglitazone treatment in rats fed a SRD for a long period of time, is largely a consequence of the action of this drug in reducing circulating fatty acids and triglycerides (5
). This suggests that lipotoxicity plays a role in the development of the dyslipemic, insulin-resistant rats fed a SRD.
Finally, the temporal metabolic changes in rats fed a SRD may prove an attractive animal model for studying the role of environmental nutritional factors in the unresolved issue of the relationships among lipid metabolism, insulin resistance and relative insulin deficiency. Although absolute proof is lacking, the findings in rats may be relevant to our understanding of human diseases such as the so-called Plurimetabolic Syndrome.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT), and Universidad Nacional del Litoral by grants: PICT 05-6960/BID 1201/0C-AR and CAI+D 13–1-25. The financial aid from the A. J. Roemmers Foundation for Biochemistry Research, Argentina is also acknowledged.
4 Abbreviations used: CD, control diet; FFA, free fatty acids; G-6-P, glucose-6-phosphate; GIR, glucose infusion rate; GSa, glycogen synthase; IS, insulin secretion, KRB, Krebs-Ringer bicarbonate; LCACoA, long-chain acyl-CoA; PDHc, pyruvate dehydrogenase complex; PDH kinase, pyruvate dehydrogenase kinase; SRD, sucrose-rich diet.
Manuscript received 9 June 2002. Initial review completed 11 July 2002. Revision accepted 8 October 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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