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Effects of Glucagon-Like Peptide-1 on Islet Function and Insulin Sensitivity in Noninsulin-Dependent Diabetes Mellitus¹

Department of Medicine, Lund University (B.A., H.L.), Malmö, Sweden; and Department of Medical Physiology, The Panum Institute (J.J.H.), Copenhagen University, Denmark

Address all correspondence and requests for reprints to: Bo Ahrén, Department of Medicine, Malmö University Hospital, S-205 02 Malmö Sweden.

	Abstract

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Administration of the truncated glucagon-like peptide 1 (GLP-1) has been considered for treatment of noninsulin-dependent diabetes mellitus (NIDDM). We studied its antidiabetogenic mechanism by examining its influences on islet function and peripheral insulin sensitivity in six subjects (aged 56–74 yr) with well-controlled NIDDM. Islet function was evaluated with arginine stimulation at three plasma glucose levels (fasting, 14 mmol/L, and >28 mmol/L). GLP-1 (1.5 pmol/kg per min iv) increased serum insulin levels at fasting glucose (P = 0.028), at 14 mmol/L glucose (P = 0.028), and at 28 mmol/L glucose (P = 0.028). The acute insulin response (AIR) to 5 g iv arginine was increased by GLP-1 at 14 mmol/L glucose (P = 0.028), and the slope_AIR, i.e., the glucose potentiation of insulin secretion, was markedly increased by GLP-1 (P = 0.028). Plasma glucagon levels were reduced by GLP-1 (P = 0.028), and arginine-stimulated glucagon secretion (AGR) was inhibited by GLP-1 at 14 (P = 0.046) and 28 mmol/L glucose (P = 0.028). Glucose-induced inhibition of arginine-stimulated glucagon secretion (slope_AGR) was not significantly affected by GLP-1. In contrast, GLP-1 did not affect the low insulin sensitivity during a hyperinsulinemic, euglycemic clamp. Thus, GLP-1 improves islet dysfunction in diabetes, mainly by increasing the glucose-induced potentiation of insulin secretion. In contrast, the peptide does not seem to improve insulin resistance in NIDDM.

	Introduction

Top Abstract Introduction Subjects, Materials, and Methods Results Discussion References

 
TRUNCATED glucagon-like peptide 1 (GLP-1_{(7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)}amide or GLP-1) is processed from proglucagon in the intestinal L cells and released into the circulation during a meal (1, 2, 3). The peptide has been demonstrated to stimulate insulin secretion both under in vivo and in vitro conditions in experimental animals as well as in healthy human subjects (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13). Therefore, GLP-1 is considered an important incretin hormone (2, 3, 4).

GLP-1 has also been considered as a potential therapeutic agent in noninsulin-dependent diabetes mellitus (NIDDM), because the peptide reduces the circulating glucose levels in this disease (7, 8, 10, 14, 15, 16). In NIDDM, a combination of peripheral insulin insensitivity and reduced B cell function often exists (17, 18, 19, 20, 21, 22, 23). The B cell dysfunction is complex, however, because it comprises both a defective glucose-stimulated insulin secretion as well as an impaired glucose potentiation of non-glucose-stimulated insulin secretion (17). Furthermore, in NIDDM, an inappropriately increased glucagon secretion is also seen (22, 24, 25). If GLP-1 will evolve as a therapeutic agent in NIDDM, it is important to establish the mechanisms of its antidiabetogenic action. However, although it is known that GLP-1 stimulates insulin secretion and inhibits glucagon secretion in NIDDM (7, 8, 10, 14, 15, 16), the detailed influences of GLP-1 on islet function have not been established in diabetics. Furthermore, it is not known whether GLP-1 improves the reduced insulin sensitivity in NIDDM. Therefore, we examined the effects of GLP-1 on the peripheral insulin sensitivity using the euglycemic, hyperinsulinemic clamp (26) and the effects of the peptide on islet function, as evaluated by the glucose-dependent arginine stimulation test, according to Ward et al. (25) in six subjects with NIDDM.

	Subjects, Materials, and Methods

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Study protocol

The study protocol was approved by the ethics committee of the Faculty of Medicine, Lund University before the study. Written informed consent was obtained from all participants.

Patients

Six subjects with NIDDM were studied. Table 1 shows the patient characteristics. All subjects were in good metabolic control, as judged from their fasting levels of blood glucose (7.2 ± 1.5 mmol/L) and hemoglobin A_1c (6.8 ± 1.6%). Except for NIDDM, the patients were healthy, and none were taking any drugs known to affect carbohydrate metabolism, except sulphonylurea in three subjects. Each subject underwent four studies: euglycemic hyperinsulinemic clamp as well as a glucose-dependent arginine stimulation test with infusion of GLP-1 or saline. All studies were undertaken after an overnight fast. The subjects treated with sulphonylurea withheld the medication during the 24 h before the study.

Synthetic human GLP-1 (GLP-1_{(7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)}amide = progluca-gon_(78–107)-amide) was purchased from Peninsula Labs. Europe (Merseyside, U.K.). The same lot number of peptide was used in all studies. The peptide was dissolved in sterile 0.9% saline solution containing 1% human serum albumin and filtered through a 0.22-µm nitrocellulose filter (Millex GV, Millipore, Bedford, MA) and stored at -20 C. Net peptide content (76%) rather than gross weight was used for dose calculations. During the studies, GLP-1 was given as an iv bolus injection of 4.5 pmol/kg body weight followed by a continuous infusion of 1.5 pmol/kg per min.

Insulin sensitivity

Insulin sensitivity was determined with the standardized euglycemic, hyperinsulinemic clamp, performed according to DeFronzo et al. (26). 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, insulin, and C-peptide were taken. Then, a primed-constant infusion of insulin (Actrapid 100 U/mL, Novo Nordisk, Bagsvaerd, Denmark) with a constant infusion rate of 0.28 nmol/m² body surface area/minute 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 achieved insulin, C-peptide, and GLP-1 concentrations were taken at 60 and 120 min. In the GLP-1 study, insulin was given at 30 min after the bolus GLP-1 and following a 30-min iv infusion of GLP-1. GLP-1 was thereafter given throughout the 2-h study period. In the control study, saline was infused at the same rate as GLP-1. The control and GLP-1 studies were undertaken in random order.

Insulin and glucagon secretion

Insulin and glucagon secretion were determined with iv arginine stimulation at three blood glucose levels (fasting, 14 mmol/L, and >28 mmol/L), which is the method introduced by Ward et al. (25). Intravenous catheters were inserted into antecubital veins in both arms. One arm was used for infusion of glucose and the other arm for intermittent sampling. The sampling catheter was kept patent by slow infusion of 0.9% saline. Baseline samples were taken at -5 and -2 min, whereafter the GLP-1 bolus, followed by a 30-min iv infusion of GLP-1, was given. New samples were taken at 25 and 27 min. At 30 min, a maximally stimulating dose of arginine hydrochloride (5 g) was injected iv over 45 sec. Samples were taken at +2, +3, +4, and +5 min after the arginine injection. 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 adjusted to reach the desired blood glucose level of 14 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 taken. The iv infusion of GLP-1 was given throughout. A 2.5-h resting period was then allowed to avoid the well-known priming effect of hyperglycemia (27, 28). After the pause, baseline samples were again obtained, and an iv infusion of GLP-1 was initiated. After 25 and 27 min, new samples were taken. Then a high-speed (900 ml/h) 20% glucose infusion for 25–30 min was used to raise blood glucose to >28 mmol/L, as determined bedside. At this blood glucose level, new baseline samples were taken and arginine (5 g) injected, followed by final +2-, +3-, +4-, and +5-min samples. The iv infusion of GLP-1 was given throughout. In the control study, saline was infused at the same rate as GLP-1. The control and GLP-1-studies were undertaken in random order.

Analyses

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 glucose-dependent arginine stimulation test. Blood samples for analysis of insulin, C-peptide, glucagon, GLP-1, and glucose from the studies were immediately centrifuged at 5 C and serum or plasma frozen at -20 C until analysis in duplicate. Serum insulin and C-peptide concentrations were analyzed with double-antibody RIA techniques. Guinea-pig antihuman insulin antibodies, human insulin standard, and mono-¹²⁵I-tyr-human insulin tracer (Linco Res., St. Louis, MO) were used for insulin assay. For C-peptide assay, guinea pig antihuman C-peptide antibodies, human C-peptide standard, and ¹²⁵I-labeled human C-peptide tracer (Linco) were used. Samples for analysis of glucagon were obtained in prechilled test tubes containing 0.084 ml EDTA (0.34 mol/L) and aprotinin (250 kallikrein inhibiting units/mL blood, Bayer AG, Leverkusen, Germany). Analyses of glucagon concentration were performed with double-antibody RIA using guinea-pig antihuman glucagon antibodies specific for pancreatic glucagon, ¹²⁵I-glucagon as tracer, and glucagon standard (Linco). Plasma concentrations of GLP-1 were measured with a RIA after extraction with ethanol as previously described (29). The antiserum used (code no. 89390) is highly specific for GLP-1 of intestinal origin. Plasma glucose concentrations were analyzed using the glucose oxidase method. All concentrations were taken as means of the duplicate samples.

Calculations

Data are presented as mean ± SEM, 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 DeFronzo et al. (26). Thus, insulin sensitivity (nanomoles glucose per kilogram body weight per minute per picomole insulin per liter) was calculated as the glucose infusion rate during the second hour divided by the mean insulin concentration during the second hour.

In the glucose-dependent arginine stimulation test, the acute insulin response to arginine (AIR) was calculated as the mean of the +2- to +5-min samples minus the prestimulus insulin concentration. Previous studies have shown that arginine-stimulated insulin secretion is maximal when plasma glucose concentration exceeds 25 mmol/L (25). Therefore, AIR at the highest plasma glucose was taken as a measure of the maximal insulin secretory capacity of the B cells (AIR_MAX). It is known that the glucose potentiation of AIR to arginine is linear between plasma glucose 3.5 mmol/L and 18 mmol/L (17). The slope between AIR at fasting plasma glucose and at plasma glucose 14 mmol/L (slope_AIR = AIR/glucose) was calculated as a measure of glucose potentiation of B cell secretion. The PG₅₀ (plasma glucose 50) value was calculated from AIR_MAX and slope_AIR, and defined as the plasma glucose level at which half-maximal insulin secretion is achieved. Acute glucagon responses (AGR) and slope_AGR (representing glucose inhibition of A cells) were calculated in the same manner.

Statistical analyses

Statistical analyses were performed with the SPSS for Windows system (30). Differences between the studies with vs. without infusion of GLP-1 were performed with Wilcoxon’s nonparametric signed rank test for paired observations.

	Results

Top Abstract Introduction Subjects, Materials, and Methods Results Discussion References

 
Insulin sensitivity

In the GLP-1 study, the 30-min infusion of the peptide raised serum insulin levels from 121 ± 20 to 276 ± 63 pmol/L (P = 0.028). The basal serum insulin levels before infusion of insulin in the control study was 148 ± 32 pmol/L. The steady state insulin concentration during the second hour of the clamp study was 808 ± 76 pmol/L in the control study and 1277 ± 186 pmol/L in the GLP-1 study (P = 0.046), and the corresponding figures for plasma glucose were 4.7 ± 0.1 (control study) and 4.8 ± 0.2 mmol/L (GLP-1 study, NS). The amount of glucose infused to maintain the steady state glucose level was 15.5 ± 2.5 µmol/kg per min in the control study vs. 24.1 ± 2.6 µmol/kg per min in the GLP-1 study (P = 0.028). Insulin sensitivity (glucose infusion rate divided by steady state serum insulin) was not different between the two studies (Fig. 1). Serum C-peptide levels were increased by the 30-min GLP-1 infusion, which preceded the insulin infusion, from 1.1 ± 0.1 nmol/L to 2.3 ± 0.3 nmol/L (P = 0.028). During infusion of insulin in the control study, serum C-peptide decreased from 1.2 ± 0.1 to 0.7 ± 0.1 nmol/L (P = 0.028). In contrast, in the GLP-1 study, serum C-peptide further increased to 3.2 ± 0.5 nmol/L (P = 0.028) during the 2-h infusion of insulin.

View larger version (36K): [in this window] [in a new window]   Figure 1. Insulin sensitivity as determined by euglycemic, hyperinsulinemic clamp without or with concomitant infusion of GLP-1 (1.5 pmol/kg per min) in six subjects with NIDDM. Means ± SEM of insulin sensitivity during second hour of clamp are shown. P, Probability level of random difference; NS, not significant.

The 30-min infusion of GLP-1 increased serum insulin levels from 135 ± 27 to 286 ± 64 pmol/L (P = 0.028). At the same time, plasma glucose levels were reduced from 7.8 ± 1.0 to 6.4 ± 0.9 mmol/L (P = 0.028). In the control study, the fasting level of insulin was 137 ± 26 pmol/L and fasting glucose was 8.3 ± 0.8 mmol/L (Fig. 2). The AIR to arginine at this glucose level in the GLP-1 study (337 ± 111 pmol/L) was not significantly different from that in the control study (395 ± 138 pmol/L) (Fig. 3). After raising the glucose level to 14 mmol/L, serum insulin levels in the GLP-1 study were increased to 736 ± 163 pmol/L, whereas serum insulin in the control study remained unaffected at 135 ± 25 pmol/L (P = 0.028) (Fig. 3). The AIR to arginine at this glucose level was 712 ± 204 pmol/L in the presence of GLP-1 compared with 488 ± 141 pmol/L in the control study (P = 0.028). Following the subsequent 2.5-h resting period, plasma glucose (8.3 ± 0.9 mmol/L in the control study vs. 7.9 ± 0.9 mmol/L in the GLP-1-study) and serum insulin (150 ± 20 vs. 129 ± 20 pmol/L, respectively) had returned to fasting levels. Finally, raising the glucose level to 28 mmol/L increased serum insulin in the GLP-1 study to 2020 ± 542 pmol/L compared with only 268 ± 78 pmol/L in the control study (P = 0.028). The AIR to arginine at 28 mmol/L glucose (AIR_MAX) was not affected by GLP-1 (810 ± 182 vs. 887 ± 264 pmol/L, P = NS). The glucose potentiation of arginine-stimulated insulin secretion between fasting levels and 14 mmol/L (slope_AIR) was only 16.7 ± 11.3 pmol insulin/mmol glucose in the control study and markedly increased to 59.1 ± 16.0 pmol insulin/mmol glucose in the GLP-1 study (P = 0.028). PG₅₀ was 12.7 ± 1.5 mmol/L in the control study and 6.9 ± 1.7 mmol/L in the GLP-1-study (P = 0.028).

View larger version (28K): [in this window] [in a new window]   Figure 2. Concentrations of serum insulin (upper) and plasma glucagon (lower) during glucose-dependent arginine stimulation test with saline () or with GLP-1 (•) infusion (1.5 pmol/kg per min) in six subjects with NIDDM. Arginine was injected iv (5 g) at fasting glucose (time = 0 min), after raising glucose to 14 mmol/L (time = 30 min), and after raising glucose to >28 mmol/L (time = 220 min). Means ± SEM are shown.

View larger version (29K): [in this window] [in a new window]   Figure 3. Concentrations of serum insulin (upper left) and plasma glucagon (upper right) before injection of arginine, i.e. at fasting glucose and at glucose levels of 14 mmol/L and >28 mmol/L. Calculated acute insulin (lower left) and glucagon (lower right) responses to arginine injection at three different glucose levels (fasting, 14 mmol/L, and 28 mmol/L) in glucose-dependent arginine stimulation test with saline () or with GLP-1 (•) infusion (1.5 pmol/kg per min) in six subjects with NIDDM are shown. Means ± SEM are shown. P, Probability level of random difference between two groups.

Fasting plasma glucagon was reduced from 54.2 ± 5.9 to 40.9 ± 2.9 ng/L by the 30-min infusion of GLP-1 (P = 0.028) (Fig. 2). Raising the glucose level to 14 mmol/L further reduced glucagon levels to 31.6 ± 2.7 ng/L in the presence of GLP-1, compared with 50.8 ± 8.9 ng/L without GLP-1 (P = 0.028). At the high glucose level of 28 mmol/L, plasma glucagon was 28.2 ± 1.8 ng/mL in the GLP-1 study compared with 37.6 ± 7.5 ng/L in the control study (P = 0.028). Furthermore, the AGRs to arginine were decreased at 14 mmol/L (49.2 ± 4.3 vs 68.7 ± 7.6 ng/L, P = 0.046) and 28 mmol/L glucose levels (37.7 ± 3.7 vs 50.3 ± 1.6 ng/L, P = 0.028; Fig. 3). However, the slope_AGR, i.e. the glucose-induced inhibition of arginine-stimulated glucagon secretion, was not significantly affected by GLP-1, being -3.2 ± 1.2 ng glucagon/mmol glucose in the GLP-1 study vs. -1.7 ± 1.8 ng glucagon/mmol glucose in the control study (P = 0.601) (Fig. 3).

Plasma GLP-1 levels

During the second hour of the euglycemic hyperinsulinemic clamp studies with GLP-1 infusion, GLP-1 levels were 218 ± 84 pmol/L vs. 8.2 ± 1.1 pmol/L in the basal state (P = 0.028). Furthermore, during the glucose-dependent arginine stimulation test, plasma GLP-1 levels were 215 ± 26 after 30 min of GLP-1 infusion compared with 7.7 ± 2.7 pmol/L in the basal state (P = 0.028).

	Discussion

Top Abstract Introduction Subjects, Materials, and Methods Results Discussion References

 
GLP-1 has previously been shown to reduce circulating glucose in subjects with NIDDM (8, 12, 15), and therefore the peptide has been considered for treatment of diabetes (31, 32). However, the mechanisms of the antidiabetogenic action of GLP-1 have not been established. We therefore examined its influences on islet function and insulin sensitivity in NIDDM, because NIDDM is accompanied both by islet dysfunction and insulin resistance (17, 18, 19, 20, 21, 22, 23).

We used the glucose-dependent arginine stimulation test, which provides information on basal insulin, glucagon, and glucose levels, as well as on arginine-stimulated insulin and glucagon secretion and the glucose-induced potentiation of insulin secretion and the glucose-induced inhibition of glucagon secretion (17, 25). Both under basal conditions and after raising the glucose level both to 14 and 28 mmol/L, GLP-1 markedly increased serum insulin levels, which confirms previous studies both in healthy humans and in NIDDM, that glucose-stimulated insulin secretion is increased by GLP-1 (10). We also found that GLP-1 markedly increased the slope_AIR in the subjects with NIDDM without increasing the AIR_MAX. The mean value of slope_AIR was thereby increased from 16 to 59 pmol insulin/mmol glucose. This was mainly because of a marked potentiation of arginine-stimulated insulin secretion at 14 mmol/L glucose. These findings show that a main mechanism of the insulinotropic action of GLP-1 in NIDDM is an increased glucose-induced potentiation of insulin secretion. Also the glucose sensitivity of the B cells was increased by GLP-1, because the PG₅₀ levels were reduced, which could contribute to the insulinotropic action. It should then be emphasized that the PG₅₀ values in the control study were similar to those we previously demonstrated for normal subjects (33), confirming previous studies that PG₅₀ is not altered in NIDDM (25). In contrast, the maximal insulin response to arginine, which occurs at glucose levels >25 mmol/L in NIDDM (25), was not potentiated by GLP-1, inferring that short-term GLP-1 does not augment the maximal secretory capacity of the B cells. Furthermore, GLP-1 did not potentiate arginine-stimulated insulin secretion at fasting glucose in these subjects. This suggests that the glucose threshold for GLP-1 to augment arginine-stimulated insulin secretion in NIDDM is above 7 mmol/L.

Previous studies have shown that GLP-1 inhibits glucagon secretion both under normal conditions and in NIDDM (7, 15). We demonstrated that GLP-1 inhibits both basal plasma glucagon levels, glucagon levels after elevation of glucose, and arginine-stimulated glucagon secretion at high glucose levels. Thus, in NIDDM, GLP-1 is a potent glucagonostatic agent.

It has previously been argued that GLP-1 not only affects islet function but also improves peripheral glucose uptake. For example, in humans who have fasted, GLP-1 potentiated the insulin-independent glucose disposal, as calculated by the Bergman minimal model approach (9). Similarly, GLP-1 has been demonstrated to increase glucose utilization during a hyperinsulinemic clamp in subjects with IDDM (7). In contrast, a study on glucose turnover in [³H]glucose-infused healthy humans has shown that GLP-1 is without effect on the peripheral uptake of glucose (R_d) (34). We found in this study that GLP-1 does not affect insulin sensitivity in the subjects with NIDDM as determined by the euglycemic hyperinsulinemic clamp. Plasma insulin levels were markedly increased during the clamp (>800 pmol/L), which would have totally suppressed hepatic glucose production (35). Hence, any alterations in glucose requirement to maintain the desired blood glucose level of 5.0 mmol/L would be executed by changes in the degree of peripheral glucose uptake. In the GLP-1 study, we found that the amount of glucose infused to maintain euglycemia was significantly increased by the peptide, which would suggest that GLP-1 could improve insulin resistance in NIDDM. However, in spite of infusing the same amount of insulin in the control and GLP-1 studies, the steady state insulin levels were significantly higher in the GLP-1 study than in the control study. Therefore, the correct measure of insulin sensitivity in this clamp study, the amount of glucose infused to maintain euglycemia divided by the steady state insulin levels, was not different between the two studies. The results thus suggest that GLP-1 does not improve the insulin sensitivity in NIDDM. This does not exclude minor effects of GLP-1 on the sensitivity to insulin at other insulin levels. However, compared with the marked islet effect of the peptide, we suggest that the main antidiabetogenic action of the peptide in NIDDM is exerted through islet effects rather than on insulin sensitivity.

To establish the mechanism of the surprisingly higher steady state insulin level in the GLP-1 study than in the control study, we also determined C-peptide during the euglycemic, hyperinsulinemic clamp. It is well known that insulin and C-peptide are released from the B cells in equimolar amounts (36). Therefore, C-peptide levels give an estimate of the endogenous insulin secretion. Serum C-peptide levels were reduced during the hyperinsulinemia in the control study, which supports previous findings that insulin inhibits its own secretion in humans (37). Interestingly, however, serum C-peptide levels increased in the GLP-1 study. Thus, in spite of marked hyperinsulinemia, GLP-1 stimulated insulin secretion. This illustrates the potency of the insulinotropic action of GLP-1 and explains the finding that steady state insulin was higher in the presence of GLP-1.

Based on the results presented in this study, we conclude that in subjects with NIDDM, GLP-1 increases basal insulin levels, potentiates glucose- and arginine-stimulated insulin secretion, and increases the B cell sensitivity to glucose. GLP-1 also inhibits glucagon secretion, but the peptide does not improve insulin resistance. The study therefore supports the conclusion that GLP-1 might be a useful tool for the treatment of NIDDM with a main effect to improve the islet dysfunction of the disease.

	Acknowledgments

 
The authors are grateful to Lilian Bengtsson, Eva Holmström, and Margaretha Persson for expert technical assistance.

	Footnotes

 
¹ The study was supported by the Swedish Medical Research Council (Grant 14X-6834); the Ernhold Lundström, Albert Påhlsson, Crafoord, and Novo Nordic Foundations; the Swedish Diabetes Association; Malmö University Hospital; and the Faculty of Medicine, Lund University.

Received May 21, 1996.

Revised July 3, 1996.

Accepted October 23, 1996.

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