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Original Studies |
Department of Medicine, Lund University, S-205 02 Malmö, Sweden
Address all correspondence and requests for reprints to: Dr. Hillevi Larsson, Department of Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: hillevi.larsson{at}medforsk.mas.lu.se
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Abstract |
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Introduction |
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Previous studies in subjects with impaired glucose tolerance (IGT) have shown an increased P/I ratio in the fasting state (5, 19, 20, 21, 22), although this has not been confirmed in other studies (6, 23, 24, 25, 26). However, as the half-lives of proinsulin and insulin differ (27), studies on the P/I ratio also have to be undertaken after acute stimulation of insulin secretion, which until now has not been performed in subjects with IGT.
We have previously demonstrated that when matched for degree of insulin sensitivity, postmenopausal women with IGT have reduced insulin secretory responses to both glucose and arginine compared to those of women with normal glucose tolerance (NGT) (28, 29). The purpose of the present study was to examine whether there also is a defective proinsulin processing, manifested as an increased P/I ratio, in IGT. Therefore, we measured the P/I ratios after acute arginine stimulation at three different glucose levels in women with normal or impaired glucose tolerance.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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C Peptide, insulin, and proinsulin secretion were assessed in 23 women selected from a larger cohort of postmenopausal women enrolled in a study of insulin secretion and insulin sensitivity (28). The 23 women (aged 61–62 yr; mean ± SD, 61 yr 9 ± 6 months) were all healthy (except for IGT in 13 subjects), and none was taking any medication known to affect carbohydrate metabolism. The ethics committee of Lund University approved of the study, and written informed consent was obtained from all participants before entry in the study. It is known that islet secretory capacity must be evaluated in relation to the subject’s insulin sensitivity, as the islet ß-cell secretory capacity adapts to the ambient insulin sensitivity (28, 30). Therefore, the 23 women were selected so that a group with NGT (n = 10) was matched for insulin sensitivity and glucose levels during the arginine stimulation test to a randomly selected group of IGT (n = 13). The studies of glucose tolerance, insulin sensitivity and insulin secretion were all performed on separate days, in the morning after an overnight fast, with at least 1 week in between visits.
Anthropometric measurements
All measurements were performed with the subjects in light clothing without shoes. Body weight was measured to the nearest 0.1 kg in the morning before breakfast. Height was measured to the nearest centimeter. Body mass index (BMI) was calculated as the weight (kilograms) divided by height (meters) squared. Waist and hip circumferences were measured with the subjects standing. The waist circumference was measured at the level of the umbilicus, hip circumference was measured at the level of the greater trochanters, and the waist to hip ratio was calculated as a measure of central adiposity.
Glucose tolerance
Oral glucose tolerance was determined with a standard WHO 75-g glucose load (31), with capillary blood glucose samples taken before and 2 h after the glucose load. The subjects spent the 2 h in a semirecumbent position and were not allowed to smoke during the test. According to WHO criteria, NGT was defined as a 2 h capillary blood glucose value less than 7.8 mmol/L, and IGT was defined as a 2 h capillary blood glucose value of 7.8–11.1 mmol/L (31).
Insulin sensitivity
Insulin sensitivity was determined with the euglycemic, hyperinsulinemic clamp, performed according to the method of DeFronzo et al. (32). Intravenous catheters were inserted into antecubital veins in both arms. One arm was used for infusion of glucose and insulin. The contralateral arm was used for intermittent sampling, and the catheter was kept patent with slow infusion of 0.9% saline. Baseline samples of glucose and insulin were taken. A primed constant infusion of insulin (100 U/mL; Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark) at a rate of 0.28 nmol/m2 body surface area·min was started. After 4 min, a variable rate 20% glucose infusion was added, and its infusion rate was adjusted manually throughout the clamp procedure to maintain the blood glucose level at 5.0 mmol/L. Blood glucose was determined bedside every 5 min. Samples for analysis of the insulin concentration achieved were taken at 60 and 120 min.
Islet function
C Peptide, insulin, and proinsulin secretion were determined with iv arginine stimulation at three glucose levels [fasting plasma glucose (FPG), 14 mmol/L (PG14), and >25 mmol/L (PG>25)], as previously described (33, 34). Intravenous catheters were inserted into antecubital veins in both arms. One arm was used for infusion of glucose, and the other arm was used for intermittent sampling. The sampling catheter was kept patent by slow infusion of 0.9% saline when not used. Baseline samples were taken at -5 and -2 min. A maximally stimulating dose of arginine hydrochloride (5 g) was then injected iv over 45 s. Samples were taken at 2, 3, 4, and 5 min. A variable rate 20% glucose infusion was then initiated to raise and maintain blood glucose at 13–15 mmol/L. Blood glucose was determined every 5 min bedside, and the glucose infusion was adjusted to reach the desired blood glucose level of 13–15 mmol/L in 20–25 min. New baseline samples were taken, then arginine (5 g) was again injected, and 2, 3, 4, and 5 min samples were taken. A 2.5-h resting period was allowed to avoid the well known priming effect of hyperglycemia (35, 36). After the pause, baseline samples were again obtained. Then, a high speed (900 mL/h) 20% glucose infusion during 25–30 min was used to raise blood glucose to more than 25 mmol/L, as determined bedside. At this blood glucose level, new baseline samples were taken, and arginine (5 g) was injected, followed by final 2, 3, 4, and 5 min samples. The plasma glucose levels achieved during the glucose clamps did not differ between NGT and IGT groups [mean ± SD level with PG14, 13.4 ± 1.6 vs. 13.7 ± 1.6 mmol/L (P = 0.68); mean level with PG>25, 26.5 ± 3.2 vs. 27.9 ± 4.9 mmol/L (P = 0.44)].
Analyses
The blood glucose concentration was determined bedside by the glucose dehydrogenase technique with a Hemocue (Hemocue AB, Ängelholm, Sweden) during the hyperinsulinemic, euglycemic clamp and with an Accutrend (Boehringer Mannheim Scandinavia AB, Bromma, Sweden) during the arginine test. Blood samples for analysis of C peptide, insulin, proinsulin, and glucose from the arginine and clamp studies and of glucose from the oral glucose tolerance test were immediately centrifuged at 5 C, and serum or plasma was frozen at -20 C until analysis in duplicate. Serum C peptide, insulin, and proinsulin concentrations were analyzed using a double antibody RIA technique. The C peptide assay (Linco Research, Inc., St. Charles, MO) uses guinea pig antihuman C peptide antibody, human C peptide standard, and [125I]human C peptide as tracer. The assay cross-reacts slightly with proinsulin (<4.0% on a molar basis). For the insulin assay, guinea pig antihuman insulin antibodies, human insulin standard and mono-[125I]Tyr-human insulin (Linco Research, Inc.) were used. The assay is specific for insulin, with no cross-reactivity (<0.2%) with intact proinsulin or des-31,32-proinsulin. The intra- and interassay coefficients of variation of the insulin assay are less than 3%. Total proinsulin was measured using goat antibodies raised against human proinsulin, human proinsulin standard, and [125I]human proinsulin as tracer (Linco Research, Inc.). This assay detects intact proinsulin (100%) and des-31,32-proinsulin (95%), but does not cross-react with insulin, C peptide, or des-64,65-proinsulin (<0.1%). Plasma glucose concentrations were analyzed using the glucose oxidase method. Concentrations of C peptide, insulin, proinsulin and glucose from the arginine and clamp studies were taken as means of the duplicate samples.
Calculations and statistics
Data are presented as the mean ± SE unless otherwise noted. For calculation of insulin sensitivity, a steady state condition was assumed during the second hour of the clamp. Calculations were performed according to the method of DeFronzo et al. (32). Thus, insulin sensitivity (nanomoles of glucose per kg BW-1·min-1/pmol·L-1) was taken as the glucose infusion rate during the second hour of the clamp divided by the measured mean insulin concentration during the second hour of the clamp.
The acute C peptide (ACRarg), insulin (AIRarg), and proinsulin (APIRarg) responses to arginine were calculated as the mean of the 2–5 min samples minus the mean prestimulus hormone concentration. P/I ratios were calculated for each prestimulatory glucose level (P/Iglu). Furthermore, ratios were calculated between the acute proinsulin to acute insulin responses (APIRarg/AIRarg) at the three glucose levels.
Statistical analyses were performed with the SPSS for Windows system (SPSS, Inc., Chicago, IL) (37). The Kolmogorov-Smirnov test was used to ensure that the studied variables did not significantly differ from a normal distribution (P > 0.05 for all variables). Differences between IGT and NGT groups were tested with Student’s t test for unrelated samples. Differences in APIRarg/AIRarg among the three glucose levels within each group were tested with Student’s t test for related samples (adjustment for multiple comparisons was made according to Bonferroni). Two-sided tests were used, and P < 0.05 was considered statistically significant. Pearson’s product-moment correlation coefficients were obtained to estimate linear correlation between variables. Linear regressions were calculated with the Sigmaplot 4.0 for Windows program (SPSS, Inc.).
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Results |
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Of the 23 women, 10 had NGT, and 13 had IGT. Characteristics of
the study groups are shown in Table 1
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The subjects were selected so the groups were matched for insulin
sensitivity, because the insulin sensitivity has to be taken into
consideration when comparing measures of insulin secretion (28, 30).
The two groups did not differ in body weight, BMI, or waist to hip
ratio, whereas the IGT group had increased fasting and 2 h glucose
levels.
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The time course for the glucose-dependent arginine stimulation
test is shown in Fig. 1. After each
arginine injection at FPG, PG14, or PG>25, the C peptide (Fig. 1A),
insulin (Fig. 1B), and proinsulin (Fig. 1C) levels were rapidly
increased. The serum insulin levels were significantly lower in the IGT
group than in the NGT group at both the PG14 and PG>25
(P < 0.05). Similarly, the serum C peptide levels were
reduced in the IGT subjects at the PG14 (P < 0.005).
In contrast, serum proinsulin levels did not differ between NGT and IGT
women at any time point during the glucose-dependent arginine
stimulation test.
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Table 2 shows the mean C peptide,
insulin, and proinsulin levels at fasting glucose and after
raising plasma glucose to 14 and more than 25 mmol/L (i.e.
before each arginine injection) during the glucose-dependent arginine
stimulation. The fasting levels of C peptide or insulin did not differ
between the IGT and NGT groups. The women with IGT had reduced C
peptide and insulin levels compared to women with NGT at PG14 and a
tendency for reduced levels also at PG>25. At all three glucose
levels, the total proinsulin levels showed no significant difference
between IGT and NGT women.
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The women with IGT had reduced ACRarg both at FPG and
PG14, whereas the ACRarg at PG>25 was not significantly
reduced in the IGT group compared to that in the women with NGT (Fig. 2A). The AIRarg was markedly
decreased in the IGT women at all three glucose levels (Fig. 2B). In
contrast, the APIRarg did not differ between IGT and NGT
subjects at FPG, PG14, or PG>25 (Fig. 2C).
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The P/I ratio at fasting glucose (P/Iglu) did not
differ between IGT and NGT groups (mean ± SD,
13.6 ± 5.0% vs. 11.1 ± 2.7%; P
= 0.18; Fig. 3A). In contrast, the IGT
women had significantly increased P/Iglu ratio after
raising the plasma glucose to PG14 (10.7 ± 4.4% vs.
6.4 ± 1.8%, P = 0.006) and PG>25 (11.4 ±
5.2% vs. 6.7 ± 2.1%, P = 0.007). The
APIRarg/AIRarg (Fig. 3B) was increased in the
IGT group compared to that in the NGT group at FPG and PG>25 [FPG,
2.2 ± 1.4% vs. 1.3 ± 0.6% (P =
0.047); PG>25, 3.5 ± 1.6% vs. 2.3 ± 0.7%
(P = 0.037)]. In contrast, the difference between the
groups was not significant at PG14 (2.4 ± 1.2% vs.
1.8 ± 0.6%; P = 0.19).
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The APIRarg/AIRarg increased significantly from FPG to PG14 and from PG14 to PG>25 in the NGT group [FPG vs. PG14, 1.25 ± 0.63% vs. 1.80 ± 0.64% (P = 0.002); PG14 vs. PG>25, 1.80 ± 0.64% vs. 2.29 ± 0.70% (P < 0.001)]. In the IGT group the APIRarg/AIRarg was similar between FPG and PG14 (FPG vs. PG14, 2.24 ± 1.35% vs. 2.37 ± 1.20%; P = 0.34), but increased markedly from PG14 to PG>25 (PG14 vs. PG>25, 2.37 ± 1.20% vs. 3.49 ± 1.59%; P < 0.001). Although the relative proinsulin levels overall were higher in IGT, the increase between FPG and PG>25 did not differ between NGT and IGT subgroups in either relative or absolute terms (data not shown).
Correlations between fasting and stimulated P/I ratios
The fasting P/I ratio was highly correlated to the
stimulated APIRarg/AIRarg at all three
glucose levels (FPG, r = 0.84; PG14, r = 0.77; PG>25, r
= 0.82; P < 0.001 for all). Figure 4 shows the relation between P/I and
APIRarg/AIRarg at fasting.
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In the IGT group, insulin sensitivity was negatively correlated to
the APIRarg/AIRarg at PG14 (r = -0.56;
P = 0.045; Fig. 5B) as
well as to the P/Iglu at FPG (r = -0.58;
P = 0.036). In the NGT women, none of these
correlations was significant. If anything, the r values were positive,
but nonsignificant (P/Iglu at FPG: r = 0.50;
P = 0.14; APIRarg/AIRarg at
PG14: r = 0.10; P = 0.78; Fig. 5A). Therefore, it
seems that in IGT, but not in NGT, a reduced insulin sensitivity is
associated with an increased release of proinsulin relative to insulin.
There were no correlations between FPG and P/I ratios either during
fasting or after glucose or arginine stimulation (r < 0.21;
P > 0.35). In contrast, across all 23 subjects, the
2 h glucose was positively correlated to the glucose-stimulated
P/I ratios at PG14 and PG>25 (PG14: r = 0.51; P =
0.012; PG>25: r = 0.47; P = 0.023) and the
APIRarg/AIRarg at FPG (r = 0.42;
P = 0.05; Fig. 6). Thus,
the worse the glucose tolerance, the greater the proportion of
proinsulin released after acute stimulation.
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Discussion |
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Earlier studies have been inconclusive regarding the relative proinsulin levels in the fasting state in IGT, mainly because they have analyzed proinsulin and insulin only in baseline, i.e. nonstimulated, samples. Several studies have shown an increase of the P/I ratio in IGT (5, 19, 20, 21, 22), whereas others have found normal levels compared to those in groups with NGT (6, 23, 24, 25, 26). From the present study it can be concluded that there is a trend toward an increased P/I ratio in the fasting state in IGT compared to NGT, but this increase does not reach statistical significance. In contrast with this, we show that the P/I ratio is significantly increased after acute stimulation of insulin secretion. As there are differences in the half-lives of insulin and proinsulin (27), the circulating concentrations during the fasting state do not reflect what is actually released from the ß-cell granules. Instead, measuring directly after acute stimulation of insulin secretion gives a better estimate of the granule content of insulin and proinsulin. The finding of our study that there is an increased proinsulin to insulin ratio after acute stimulation in IGT therefore indicates a defective proinsulin processing in the granules in IGT. Quantitatively, despite the increased proinsulin secretion in IGT, the total secretion of proinsulin-derived molecules is decreased in IGT. Thus, the reduced specific insulin responses in IGT that we previously observed (28, 29, 38) are due to a defect in proinsulin processing combined with a reduced total insulin secretion. In type 2 diabetes it has been demonstrated unequivocally that there is an increased P/I ratio both in the fasting state (4, 5, 6, 7, 8, 9) and after acute stimulation (8). It seems, therefore, that IGT is indeed a prediabetic stage also in the sense that several aspects of the multifaceted ß-cell dysfunction seen in diabetes are present already in IGT.
Our present findings support the idea that relative hyperproinsulinemia is a sign of primary ß-cell dysfunction and is not secondary to hyperglycemia, as the subjects in the present study showed only a slight increase in fasting glucose compared to normal subjects. This conclusion is supported by a study showing that long term hyperglycemia does not alter the P/I ratio in healthy subjects (39). Furthermore, studies by Kahn et al. showed that increasing the P/I ratio by corticosteroid or GH treatment is not dependent on hyperglycemia (40). We therefore conclude that defects in proinsulin processing precede the onset of overt hyperglycemia in prediabetic subjects.
The P/I ratios measured after acute stimulation were highly correlated to the P/I ratio in fasting. Thereby, it seems that the fasting P/I ratio could be a good and easily obtained approximate of the proinsulin and insulin actually secreted from the ß-cells. However, the finding that there was a significantly higher P/I ratio after acute stimulation but not under fasting conditions in the IGT subjects suggests that measuring the P/I ratio after stimulation is advantageous. The failure to detect any difference between IGT and NGT in the baseline P/I ratio may indicate that the two groups differ in the clearance rates of the two peptides. The reason for the discrepancy could, however, also be that the groups were too small to detect a significant difference in the fasting state due to individual differences in peptide clearance, which increases the variance of the P/I ratio in the fasting state compared to that after acute stimulation.
Our measure of proinsulin included determination of both intact and des-31,32-split proinsulin, which are the dominating proinsulin forms in the circulation, as recently reviewed by Hales and colleagues (41). This raises the question of whether the increased proinsulin release in IGT is composed of the intact or the split form. In this context it is of interest that it has previously been shown in subjects with type 2 diabetes that the relative amounts of intact and split proinsulin do not differ from those found in healthy subjects, indicating that the further cleavage of proinsulin is not disturbed in diabetes (8, 42). Also, in a small sample of IGT subjects, the proportions of intact and split proinsulin did not differ from those in controls (43). Therefore, to determine the P/I ratio after acute stimulation in IGT, it seems sufficient to measure total proinsulin.
We found that in the IGT group, insulin sensitivity correlated negatively with the P/I ratio after arginine stimulation. Thus, the more insulin resistant the subjects, and, therefore, the greater the demand on insulin production, the higher the relative proinsulin content released into the circulation. In IGT, ß-cells thus react with reduced proinsulin processing when stressed to produce more insulin. This failure of subjects with IGT to compensate for an increased insulin demand by enhancing the proinsulin processing is another sign of islet dysfunction in IGT and may be of pathophysiological importance for their glucose intolerance. In the women with NGT, on the contrary, there was no such negative relation. If anything, there was a weak positive association between insulin sensitivity and the relative proinsulin content. This is similar to the study of Mykkänen et al. (44) where reduced insulin sensitivity was seen to be compensated with increased proinsulin processing in subjects with normal glucose tolerance. Also, in obese insulin-resistant Pima Indians, a reduced P/I ratio was seen compared to that in nonobese, less insulin-resistant controls (6). This adaptation may enable healthy subjects faced with insulin resistance to increase their insulin release. However, the magnitude of the reduction in the relative proinsulin content is not large enough to fully compensate for the increased insulin demand caused by insulin resistance, implying that an absolute increase in the insulin production to balance the reduced insulin sensitivity is also required. In contrast with these findings (6, 44), a recent study by Wang et al. (25) suggested that P/I ratios are not altered in insulin-resistant compared to insulin-sensitive subjects. Whether these differences may be explained by varying methods remains to be determined.
Furthermore, we found that the 2 h glucose level during the oral glucose tolerance test correlated positively with the P/I ratio after acute stimulation in the entire study group. Thus, there seems to be a gradual worsening of the proinsulin processing as the glucose tolerance deteriorates. This is in line with the previously reported higher P/I ratios in frankly diabetic subjects (4, 5, 6, 7, 8, 9).
An interesting finding was that the P/I ratio after arginine stimulation increased from the fasting to the higher glucose levels in women with normal and those with impaired glucose tolerance. When measuring at the higher glucose levels, the increased plasma glucose potentiates the insulin responses to arginine, and thus increases the demand on the ß-cell. The increased release of proinsulin at the highest glucose level could be a physiological sign of increased granule turnover in the ß-cell when the insulin release is maximally stimulated or could illustrate that when the ß-cell is acutely stressed, proinsulin processing is reduced. As it has been shown previously that a prolonged, mild hyperglycemia did not alter the P/I ratio (39), we suggest that our finding is due to the very high glucose level combined with the repeated arginine injection that give a maximal stimulation of ß-cell secretion. Another type of increased ß-cell demand, in the form of hemipancreatectomy, has been shown to increase the relative proinsulin concentrations (45). In contrast with these findings, Nauck et al. (46) showed in healthy subjects that a 3-h stimulation (at 11 mmol/L glucose with addition of tolbutamide and glucagon) that caused the release of a large proportion of the pancreatic content, did not alter the relative proinsulin release. This discrepancy may be due to the age of the subjects, as it has been suggested that the relative proinsulin content increases with age (7).
In the present study, insulin and proinsulin secretion were measured after iv arginine stimulation at different glucose levels. It may be argued that measurements of serum insulin concentrations do not reflect the actual secretion from the ß-cells, as a large part of insulin is extracted in the liver (47, 48, 49). We therefore also measured C peptide, which is known not to be subjected to any significant degree of hepatic extraction (50) and therefore gives a better estimation of the true insulin secretion. Our results clearly show a reduced insulin secretion in the group with IGT when studying both C peptide and insulin levels compared to that in subjects with NGT. Furthermore, the AIRs and ACRs to arginine were highly correlated (r = 0.94; P < 0.001) across the entire range of responses (i.e. at all three glucose levels). This suggests that measurement of the acute insulin responses to arginine really reflects the actual islet secretory function. Thus, our previous findings of a reduced insulin secretion in IGT based on arginine-stimulated serum insulin levels (28, 29) have now been validated by measuring C peptide. The reduction in insulin secretion in the present study was most marked after raising plasma glucose to 14 mmol/L (significant reductions of both AIR and ACR), which is in accordance with our previous finding of a reduced glucose potentiation of insulin secretion as the major defect in subjects with IGT (38).
In conclusion, we have demonstrated that women with IGT have an increased P/I ratio after acute stimulation of insulin secretion compared to women with NGT. This indicates a reduced proinsulin processing in IGT. Thus, there seems to be a combined islet dysfunction in subjects with IGT consisting of both decreased insulin secretion and defective processing of proinsulin, leading to increased relative proinsulin release.
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Acknowledgments |
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Footnotes |
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Received December 10, 1998.
Revised February 17, 1999.
Accepted February 23, 1999.
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References |
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