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Department of Molecular Medicine, Endocrine and Diabetes Unit, Rolf Luft Center for Diabetes Research, Karolinska Hospital, S-171 76 Stockholm; and the Department of Clinical Chemistry, Huddinge University Hospital, S-141 86 Huddinge, Sweden; and the Departments of Medicine and Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106
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Introduction |
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The mechanisms behind the coupling of glucose stimulus to the insulin secretory process in NIDDM are not clear. Whether the impaired insulin release is due to impaired secretory capacity, altered stimulus-secretion coupling, or both is unknown. Also unknown is to what extent this deficient insulin response reflects changes in islet glucose metabolism. Islets from the GK rat have been reported to have either normal or markedly increased utilization of glucose (5, 6, 7, 8, 9, 10, 11). The amount of glucose converted to CO2 by the GK islet has been reported to be reduced from normal relative to glucose utilization (5, 8, 9, 10, 11). If glucose utilization is normal or increased, then relatively more of the carbon of the glucose used in the GK than in the normal islet must be converted to a product other than CO2. As the glycerophosphate dehydrogenase shuttle, a means of transferring NADH generated in glycolysis into the mitochondrion, has been reported to be reduced in the GK rat (12), we examined the possibility that the product might be lactate.
Pyruvate’s role, as a sink for that NADH, could then also result in a loss of that energy source and, hence, in a relative decrease in CO2 production. As most of the oxidation of glucose to CO2 occurs in the Krebs cycle, another possibility to explain the decreased oxidation to utilization ratio in the GK rat islets could be an increased exit of carbon entering the cycle to other than CO2. Therefore, another purpose of the study was to assess the fate of the carbons of acetate and leucine, compounds oxidized in the cycle. The capacity of mitochondria to produce ATP was also examined.
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Materials and Methods |
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Animals and isolation of islets
Male GK rats between 2–3 months of age were from our colony at
the Karolinska Hospital. As control, Wistar rats, matched in age and
weight, were purchased from a local breeder (B&K Universal, Sollentuna,
Sweden). The GK rat originated by selective inbreeding of Wistar rats
(3). There is no prediabetic GK rat available because the rat is
hyperglycemic by 1 week of age (13). All rats had free access to food
and water. The animals were killed at 0900 h, and blood was
collected for the determination of glucose. The pancreata of the
animals were removed, cleaned from the fat tissue, and washed in
Hanks’ solution. Each pancreas was then cut into small pieces and
placed in a scintillation glass bottle with 8 ml Hanks’ solution
containing 25 mg collagenase (Boehringer Mannheim, Mannheim, Germany).
The tissue was digested at 37 C for 20 min under continuous shaking
(150 strokes/min). The suspension was diluted with cold solution and
allowed to settle. The sediment was washed twice with cold solution.
Islets from the sediment were collected using a glass pipette under
stereomicroscopy.
Substrate metabolism
In the first series of experiments, the islets from each of 8
rats from the group of control and GK rats were divided into 5 or 6
batches (25 islets in each batch). Four batches were randomly selected
to be incubated with the [3H/14C]glucose, and
a fifth batch was used to determine DNA. A sixth batch was also
allocated randomly from the islets from 4 of the 8 rats, and the islets
in that batch were used to measure insulin release (see below). For the
determinations of glucose oxidation and utilization, 25 islets were
placed in an incubation vial with either 5.5 or 16.7 mM
glucose (in duplicate, hence the use of 4 batches of islets), 0.5% BSA
(fraction V), 1 µCi [5-3H]glucose, and 1 µCi
[U-14C]glucose in 100 µl Krebs-bicarbonate buffer (pH
7.4). Each vial with its content was placed in a scintillation bottle,
sealed, and gassed with O2-CO2 (19:1, vol/vol)
for 3 min. After 90-min incubation at 37 C, 100 µl 10% perchloric
acid were injected into the vial, and 250 µl hyamine (Packard
Instrument Co., Meriden, CT) and 250 µl water were injected into the
bottle to absorb 14CO2 and
3H2O. Parallel incubations were performed, but
without islets.
14CO2 and 3H2O were collected overnight. The vial with its acidified contents was removed, and scintillation fluid (Ultima Gold, Packard Instrument Co.) was added to the bottle, which was then assayed for the radioactivity in a liquid scintillation spectrophotometer (Packard Tri-Carb 1900 TR liquid scintillation analyzer).
One milligram of sodium L-lactate was added as a carrier to the acidified incubate, which was then centrifuged (3000 x g, 10 min). The supernatant was neutralized with KOH. The precipitated potassium perchlorate was removed by centrifugation. The supernatant was passed through anion exchange resin AG1-X8 (100–200 mesh) in the formate form (Bio-Rad Laboratories). The column was washed until there was no radioactivity in the eluent. Lactic acid was then eluted from the column with 5 ml 0.4 M sodium formate (BDH, Poole, UK) and evaporated to dryness. The residue was dissolved in water and evaporated twice. A water solution of the resulting residue was chromatographed twice using an HPX-87H system. The fraction eluting with the mobility of lactate was assayed for 14C and lactate content using lactate oxidase (model 23A glucose/lactic acid analyzer, Yellow Springs Instrument Co., Yellow Springs, OH).
In the second series of experiments, batches of 20 islets from 5 rats from the group of control Wistar and GK rats were placed in 4 different vials with 5.5 mM glucose, 1 mM acetate, 1 mM leucine, and 0.5% BSA in 100 µl Krebs-bicarbonate buffer. Sodium acetate and L-leucine were purchased from Merck (Darmstadt, Germany). The first vial contained [1-14C]acetate, the second contained [2-14C]acetate, the third contained [1-14C]leucine, and the fourth contained [2-14C]leucine, each 1 µCi. Parallel incubations were identically prepared, except without islets. Each vial with its content was placed in a scintillation bottle, sealed, gassed with the O2-CO2 for 3 min, and then also incubated at 37 C for 90 min. One tenth of a milliliter of 10% perchloric acid was injected into each vial, and 1.5 ml CO2-free 1 N NaHCO3 was placed by injection at the bottom of the vial. The vials with their contents were kept at 37 C for 2 h to absorb into the NaOH the CO2 evolved.
The vials were removed, and 2 ml 5% BaCl2 were added to each bottle. The barium carbonate that precipitated was collected by filtration, washed with CO2-free water, dried, and weighed. Weights were about the theoretical yield from 0.5 mmol NaHCO3. The barium carbonate was placed at the bottom of a wide-mouth bottle containing 5 ml water and closed with a rubber stopper from which a scintillation vial containing 2 ml Hyamine was suspended. After evacuating air from the bottle through the stopper, 2 ml 1 N H2SO4 was injected through the stopper into the water. The bottle with its contents was kept at 37 C for 2 h to allow the CO2 evolved from the barium carbonate to be absorbed into the hyamine. Scintillation fluid was then added, and 14C activity was assayed in a scintillation counter.
Thus, in the experiments with [14C]acetate and [14C]leucine, 14CO2 was not collected in hyamine directly as was done for [14C]glucose in this study. This is due to the fact that acetate is volatile and produces large blank values for 14CO2 (14). We eliminated high blanks by collecting CO2 in NaOH and then precipitating it as BaCO3. As sodium acetate and barium acetate are water soluble, [14C]acetate absorbed in the NaOH was removed when the BaCO3 was collected (15).
Insulin release
Groups of three islets (from a batch of 25 islets) were
incubated in triplicate for 1 h at 37 C in 300 µl Krebs-Ringer
bicarbonate buffer containing 2 mg BSA and 5.5 or 16.7 mM
glucose. After incubation, an aliquot of the medium was stored at -70
C for insulin assay. Insulin was measured by RIA with the addition of
charcoal to separate free and bound insulin (16).
Mitochondrial ATP production
Mitochondria was prepared from approximately 400 islets of
control rats and 300 islets of GK rats using the procedure of Idahl and
Lembert (17). They were suspended in 100 µl of a medium containing
250 mM sucrose and 1 mM EDTA, pH 7.5, measured
by luminescence using a reagent based on firefly luciferase, and the
rate of ATP production was determined in the mitochondrial suspension
at a final dilution of 1:1000 (18). ATP production was continuously
monitored at 25 C in the presence of ADP, inorganic phosphate, and one
of the following substrate combinations: 1) glutamate and malate, 2)
N,N,N1,N1-tetramethyl-1,4-phenyldiamine
and ascorbate, 3) palmitoyl-L-carnitine and malate, 4)
pyruvate and malate, and 5) succinate and rotenone. Rotenone was added
to block complex I, i.e. NADH oxidase-ubiquinone reductase
complex, and also to prevent the accumulation of oxaloacetate, which
inhibits succinate dehydrogenase. As a reference base for the
determinations of mitochondrial ATP production rate, mitochondrial
enzyme citrate synthase activity was determined (19, 20) in the
mitochondrial suspensions and in islet homogenates.
Assay of glucose and DNA
The blood glucose concentration was measured by a glucose
oxidase method using the model 23A glucose analyzer. Islet DNA content
was assayed using a fluorometric method modified by Hinegardner
(21).
Calculations
The 14CO2 and
3H2O formed by the islets was taken as the
difference in the 14C in CO2 and the
3H in H2O incubated in the presence and absence
of islets. The amounts of 14CO2 and
3H2O formed (picomoles of glucose equivalent)
were calculated by dividing the radioactivity (disintegrations per min)
in the CO2 and H2O by the specific activity
(disintegrations per min/pmol) of [U-14C]glucose and
[5-3H]glucose in the medium. The yield of
3H2O was corrected for the recovery of
3H by incubating 3H2O under
identical conditions. The specific activity of lactate in
disintegrations per min/mg was calculated from the 14C
radioactivity and the lactate content in the fraction collected using
HPLC. 14C incorporated into lactate was taken as the
difference in the presence and absence of islets. The amounts of
lactate formed (picomoles) as glucose equivalent were calculated by
multiplying the disintegrations per min of 14C in the
lactate fraction isolated by HPLC by 1 mg lactate, the amount of
lactate that had been added as carrier, and dividing by the amount of
lactate in milligrams in the HPLC fraction and the specific
radioactivity (disintegrations per min/pmol) of the
[U-14C]glucose in the incubate. Yields of
14CO2 from [14C]acetate and
[14C]leucine in disintegrations per min were calculated
by subtracting the disintegrations per min in CO2 collected
in the absence of islets from the disintegrations per min in their
presence. Yields of 14CO2 expressed in
nanomoles of 14CO2 per ng islet DNA/h of
incubation were calculated by multiplying the nanomoles incubated by
the yields of 14CO2 in disintegrations per
min/h and dividing by the disintegrations per min/h of labeled compound
incubated.
ATP production by mitochondria was calculated 1) per nanograms of DNA in the islet homogenate from which the mitochondria were collected, and 2) per unit of citrate synthase activity measured in the same mitochondrial preparation in which ATP production was measured.
A simplified model of Krebs cycle metabolism was used to calculate the
fate of acetate carbon in the cycle (22). In the model, acetyl coenzyme
A (CoA) condenses with oxaloacetate to form citrate, and then the
citrate is oxidized to oxaloacetate via 
-ketoglutarate. The only
carbon entering the cycle is from acetate, via acetyl CoA, and from
pyruvate, the pyruvate fixing CO2 to form oxaloacetate and
the pyruvate being decarboxylated to acetyl CoA. The only products of
the cycle, i.e. those exiting the cycle, are CO2
and oxaloacetate or its equivalent, i.e. a dicarboxylic acid
of the cycle. Then, (14CO2 from
[1-14C]acetate)/(14CO2 from
[2-14C]acetate) = (1 - f2)/(1 -
f)2, where f is the rate the
oxaloacetate equivalents leave the cycle as a fraction of the rate of
formation of oxaloacetate in the cycle from citrate and from the
fixation of CO2 by pyruvate.
Statistical analyses
Results are expressed as the mean ± SEM. The
significance of differences was assessed by Student’s t
test for unpaired observations.
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Results |
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).
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). At
16.7 mM glucose, both control and GK rat islets used about
twice as much glucose as at 5.5 mM glucose.
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). A
16.7-mM glucose concentration stimulated glucose oxidation
3.1-fold in control islets and 2.3-fold in GK rat islets above that at
5.5 mM glucose. Thus, at both the low or high
concentrations of glucose, the paired ratios between
[U-14C]glucose oxidation and [5-3H]glucose
utilization were similar in islets from GK and control rats.
Lactic acid
The conversion of [14C]glucose to
[14C]lactate was significantly less in control islets
than in GK rat islets at 5.5 mM glucose (Table 2). At 16.7
mM glucose, more 14C from
[14C]glucose was incorporated into lactate in both
control and GK rat islets, but the incorporation into lactate was
significantly greater in GK then in control rat islets. The paired
ratios between [14C]lactate production and
[5-3H]glucose utilization were similar in control and GK
rats at both 5.5 and 16.7 mM glucose. The ratio between the
sum of glucose oxidation and lactate production and glucose utilization
was not different in control and GK rat islets regardless of the
glucose concentration in the incubation medium. Recovery of
14C in CO2 and lactate of 14C in
glucose used by the islets ranged from 87–93% in control and GK
rat islets at both low and high glucose concentrations.
Insulin release
In control rat islets, glucose-stimulated insulin release was
3.7-fold higher at 16.7 than at 5.5 mM glucose, whereas in
GK rat islets the increase was only 1.6-fold (Table 3). Compared with control rat islets, in
GK rat islets, glucose-induced insulin release was significantly lower
at both 5.5 and 16.7 mM glucose.
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) was the same in control and GK
rat islets (mean, 2.94 and 2.83). The ratios of the yield from
[1-14C]leucine and [2-14C]leucine were also
the same in control and GK rat islets, also about 3.0. However, yields
from both acetate and leucine were 40–50% more from the GK than from
the control islets.
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). ATP production from
GK rat islets was then significantly less than that from control islets
(P < 0.05).
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Discussion |
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Compared with islets from control rats of the Wistar strain, glucose utilization by islets from GK rats, measured by 3HOH production from [5-3H]glucose, has been reported to be about the same expressed per protein content (5, 6, 7, 8) or to be increased almost 2- to 3-fold or more (9, 10, 11), as in the present study.2 The increase in glucose utilization was observed in GK rats from the colony in London (10) and our colony (9, 11), whereas little if any change was observed using rats from a colony in Paris (5, 6, 7, 8). Thus, in the London colony, glucose utilization was 0.09 pmol/ng protein·h in control islets and 0.18 pmol/ng protein·h in GK rat islets at 16.7 mM glucose (10). In our recent studies, glucose utilization was 0.14 pmol/ng protein·h in control islets and 0.64 pmol/ng protein·h in GK rat islets at 16.7 mM glucose (11). In contrast, GK rat islets from the Paris colony used 0.27 pmol/ng protein·h glucose, and control islets used 0.33 pmol/ng protein·h glucose at 16.7 mM (8). The reason for these discrepancies is not known. Although all GK rat colonies originated in Japan, our colony differs from Paris colonies also in terms of ß-cell mass and islet insulin content (8, 23, 24). The ratio of the oxidation of 14C-labeled glucose to 14CO2 to glucose utilization has been reported to be about half as much in islets from GK rats as in those from control rats (5, 8, 9, 10), except the decrease in the ratio was less in one study and was not observed when islets were incubated at a low glucose concentration (7). In our study, the ratios of glucose oxidation/glucose utilization, lactate production/glucose utilization, and glucose oxidation and lactate production/glucose utilization were similar in islets from GK and control rats. Thus, utilization, oxidation, and lactate production were about 3-fold increased in the GK islets incubated at 5.5 mM and were 2.5-fold increased at 16.7 mM glucose.
The ratio of the yields of the 14CO2 from
[1-14C]acetate and [2-14C]acetate and of
that from [1-14C]leucine and [2-14C]leucine
were also similar in control and GK rat islets. Both oxidations measure
mitochondrial metabolism. A ratio of 3.0 from the labeled acetates
using the simplified model of Krebs cycle activity (15, 25), calculates
to half the 14C of the [1-14C]acetate
and one sixth of the 14C of
[2-14C]acetate entering the cycle, exiting the cycle as
CO2 and the remaining 14C exiting as a
dicarboxylic acid, presumably
malate.3 The yield of
14CO2 from [1-14C]leucine
measures the decarboxylation of -ketoisocaproic acid formed by
transamination of the leucine. About one third of carbon 1 of the
isovaleryl CoA formed from the -ketoisocaproic acid is then oxidized
to CO2 via acetyl CoA, as evidenced by the
[1-14C]leucine/[2-14C]leucine ratio of 3.0.
Ratios of yields of 14CO2 from specifically
14C-labeled glucose can also provide a measure of the
oxidation in the Krebs cycle of acetyl units derived from glucose.
Those ratios, with a minor exception (5), have also been similar in
incubations of islets from control and GK rats.
14CO2 yields from the labeled leucine and
acetates were about one and one half times more in GK than in control
rat islets.
Oxidation of endogenous glutamine and palmitate, especially at low glucose concentrations, was previously reported to be greater in islets from our colony of GK than in those from control rats (26). The islets of GK and Wistar rats that were used contained similar numbers of cells, as evidenced by DNA content. Our studies have also suggested similar percentages and volumes of ß-cells in islets from control and GK rats (23), so differences between them in utilization and oxidation cannot be ascribed to differences in those islet characteristics. Proinsulin biosynthesis is also similar in control and GK rat islets from our colony (27). Interestingly the expression of glucose transporter (GLUT-2) was shown to be decreased in GK rat islets (28), although glucokinase activity was unchanged (29).
The contribution of non-ß-cells to glucose metabolism in islets is yet to be firmly established. It cannot be excluded that functional alterations in non-ß-cells significantly contributed to increased glucose utilization and lactate production in GK islets. In this context, it is of interest that ß-cells have been found to have several times less lactic dehydrogenase activity than non-ß-cells isolated from islets (30). Also, ßHC-9 cells, cultured cells derived from ß-cells, do not accumulate lactate (31). Glucose utilization in the ß-cell is also severalfold less than that in non-ß-cells (30). In the present study, about 90% of glucose used could be accounted for in the products CO2 and lactate. If utilization (2.5- to 3.0-fold more in the GK than control islets) were coupled to normal processes in energy production, proportionally more ATP would be expected to have been generated in the GK than control islets and in the face of impaired insulin secretion. Due to markedly increased glucose utilization and oxidation, the amount of ATP generated would be expected to far exceed the amount consumed by the increase in glucose cycling we find in GK rat islets (9). Thus, the present findings do not support a relationship between that consumption and the impaired secretion. However, as the cycling is a cytoplasmic process, it could be speculated that cycling decreases the ATP/ADP ratio in that region of the cell that plays an exquisite role in control of the ATP regulated K+ channels and consequently insulin responses. Evidence has been presented that insulin secretion from islets of GK rats is not impaired after the energy-generating steps of metabolism (32), although the effect of glucose on exocytosis is impaired (11).
The present findings might then suggest that the defect in metabolism in the GK rat lies within the process that couples the metabolism of glucose to the production of energy. However, there has been 1) a failure to find deletions or point mutations in mtDNA that directs the synthesis of components of the electron transport system (24), and 2) normal activities of quinone reductase and cytochrome c oxidase in islets from GK rats (33).
Furthermore, we found no significant differences in the capacity of GK
mitochondria to generate ATP from substrates entering the electron
transport system at complex I. There was a small, but significant,
decrease in the capacity to generate ATP from substrates entering via
complex II, i.e. succinate and rotenone. It is via complex
II that FADH2 is generated in the glycerophosphate dehydrogenase
shuttle. This finding is compatible with the previous observation of
decreased activity of FAD-linked -glycerophosphate dehydrogenase in
the GK islets (12), which was normalized by insulin treatment (33).
In conclusion, this has been an effort to elucidate the biochemical site(s) responsible for impaired insulin secretion in the GK rat islets. The main findings is that glucose utilization, oxidation, and lactate production were markedly increased in islets from GK rats. In view of nearly normal function of mitochondria in the GK rat islets, it is difficult to explain these findings. The possibility of an increased turnover of ATP due to altered activity of adenosine triphosphatase and phosphatases remains to be investigated.
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Footnotes |
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1 This work was supported by grants from the Swedish Medical Research
Council (0034), Eli Lilly Co. (Indianapolis, IN), the Swedish Diabetic
Association, Karolinska Institutes Research Funds, NIH Grant DK-14507,
and Fogarty International Center Senior Fellowship Award TWO1986. 
2 Islets of GK rats have been reported to have a
protein content from as low as 0.59 µg/islet (5 ), 70% the content of
islets from control Wistar rats, to as high as 2.1–2.4 µg/islet (7 26 ), 125–140% the content of islets from control Wistar islets.
3 When f = 0.5 (see calculations), the ratio
of 14CO2 yields is 3.0. Then at steady state,
half the amount of oxaloacetate formed experiences a second turn of the
cycle. All of the 14C from [1-14C]acetate
that condenses via acetyl CoA to form citrate is oxidized to
14CO2 in that second turn. Therefore, 50% of
the 14C from [1-14C]acetate entering the
cycle is oxidized to 14CO2, and the remainder
leaves the cycle as oxaloacetate equivalent. Then, 16.6% of the
14C from [2-14C]entering the cycle is
oxidized to 14CO2 (50/16.6 = 3.0), and
83.3% leaves the cycle as oxaloacetate equivalent.
Received December 17, 1997.
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