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Division of Diabetes (B.B., M.R.B., C.D., K.C., R.A.D.), Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Novartis Institutes for Biomedical Research (C.W., Y.-L.H.), Cambridge, Massachusetts 02139; PharmaWrite, L.L.C. (B.E.D.), Princeton, New Jersey 08540; Novartis Pharmaceuticals Corp. (M.L.-S., Y.W., J.E.F.), East Hanover, New Jersey 07054; Panum Institute (J.J.H., C.F.D.), University of Copenhagen, DK-2400 Copenhagen, Denmark; and Institute of Biomedical Engineering (A.M.), National Research Council, 35127 Padova, Italy
Address all correspondence and requests for reprints to: Bogdan Balas, M.D., Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Drive, MC 7886, San Antonio, Texas 78229. E-mail: balas{at}uthscsa.edu.
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Abstract |
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Methods: Sixteen patients with type 2 diabetes (age, 48 ± 3 yr; body mass index, 34.4 ± 1.7 kg/m2; hemoglobin A1c, 9.0 ± 0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-3H-glucose iv and 1-14C-glucose orally).
Results: After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02 ± 0.06 vs. 0.74 ± 0.06 mg·kg–1·min–1; P = 0.004), and insulin secretion rate increased by 21% (P = 0.003) despite significant reduction in mean plasma glucose (213 ± 4 vs. 230 ± 4 mg/dl; P = 0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P = 0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P < 0.02). The decline in EGP was positively correlated (r = 0.55; P < 0.03) with the decrease in fasting plasma glucose (change = –14 mg/dl).
Conclusions: During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.
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Introduction |
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Whether DPP-4 inhibitors promote glycemic control solely by increasing plasma GLP-1 levels remain controversial because previous studies demonstrated that the rise in endogenous GLP-1 concentration after DPP-4 inhibition is modest, and these drugs have a delayed effect (weeks) to improve glucose homeostasis (7, 8). Variable effects of vildagliptin on plasma insulin levels also have been reported. After a meal tolerance test, DPP-4 inhibitors (including vildagliptin) have been shown to either have no effect or increase insulin levels in the face of a decrease in plasma glucose concentration (3, 9). However, other studies have observed a reduction in plasma insulin concentration, as well as insulin secretory rate, after short-term treatment with vildagliptin (10). During long-term vildagliptin administration, improved insulin sensitivity has been demonstrated in both animals (11) and humans (9, 10) with type 2 diabetes.
Clinical studies have shown not only the expected reduction in postprandial glucose levels but an unexpected decrease in the fasting glucose concentration as well (4). The latter might be expected in chronic studies in which the improved metabolic state may contribute to the reduction in fasting plasma glucose. However, in an acute study with vildagliptin, there was a clear suggestion that fasting glucose levels already were reduced after first day of treatment (10). This suggests that the effect of vildagliptin to increase GLP-1 and glucose-dependent insulinotropic peptide (GIP) levels may extend into the postmeal period, thereby increasing the insulin to glucagon ratio and thus inhibiting postmeal hepatic glucose production.
In the present study we investigated the mechanisms by which the DPP-4 inhibitor vildagliptin reduces postmeal plasma glucose concentrations in type 2 diabetic patients using a double-tracer technique. We chose to examine the response to a single dose of vildagliptin in diabetic patients not previously exposed to a DPP-4 inhibitor to avoid the confounding effects of metabolic changes associated with chronic drug administration.
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Subjects and Methods |
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Sixteen patients with T2DM were studied: 10 males and six nonfertile females, aged 48 ± 3 yr, body mass index 34.4 ± 1.7 kg/m2, hemoglobin A1c 9.0 ± 0.3%, diabetes duration 3.5 ± 0.6 yr with no detectable antiglutamate decarboxylase antibodies or diabetes complications. All subjects were in good health as determined by medical history, physical examination, screening blood tests, urinalysis, and electrocardiogram. Diabetes was controlled by diet and exercise alone (n = 4) or a stable dosage (
6 months) of metformin (n = 3), sulfonylurea (n = 4), or both (n = 5). No subject was taking any other medication known to affect glucose or lipid metabolism. Body weight was stable (± 3 pounds) in all participants for 6 months before study. No subject participated in a heavy exercise program.
All studies were carried out at the Clinical Research Center of the University of Texas Health Science Center at San Antonio. The study was approved by the Institutional Review Board of the University of Texas Health Science Center at San Antonio, and informed written consent was obtained from each patient before participation.
Study design
The study used a double-blind, randomized, placebo-controlled, two-period crossover design. At screening all subjects received dietary guidance and remained on a weight-maintaining diet (50% carbohydrates, 20% protein, and 30% fat) from screening to the end of study. Patients continued to take their regular antidiabetic medication throughout the studies.
Meal tolerance test with double tracer
The first meal tolerance test was done 7–21 d after the screening visit. Subjects were admitted to the General Clinical Research Center at 0700 h on the morning of the day of study after a 10-h overnight fast. At 0800 h, they were fed a standardized breakfast (one fifth of daily caloric allotment) and at 1200 h, they were fed a standardized lunch (two fifths of daily caloric allotment). At 1430 h, a catheter was inserted into an antecubital vein and a prime [20 µCi x fasting plasma glucose (FPG)/100]-continuous (0.20 µCi/min) infusion of [3-3H]glucose was started and maintained until 0800 h on the next day. A second catheter was placed in the antecubital vein of the opposite arm for blood withdrawal. At 1730 h subjects ingested 100 mg vildagliptin or placebo (assigned in random fashion) with 200 ml water. At 1800 h (time 0), subjects ingested a standardized mixed meal (75 g of glucose, 19 g of protein, and 22 g of lipid in a total of 535 calories). The glucose in the meal was labeled with 75 µCi of [1-14C]glucose. Patients consumed their dinner within 30 min and were not allowed to eat or drink anything else except water until 0800 h on the following morning.
Plasma samples for 3-3H-glucose activity were drawn at –30, –20, –15, –10, – 5, and 0 min before ingestion of the meal, every 15 min from 1800 to 2400 h and every 30 min thereafter until 0800 h. Plasma 1-14C-glucose-specific activity was obtained at time 0, every 15 min from 1800 to 2400 h, and every 30 min thereafter. Samples for plasma insulin, C-peptide, glucagon, GLP-1, and free fatty acids (FFAs) concentrations and DPP-4 activity were obtained at –30, –15, and 0 min before the meal and every 15–30 min thereafter until 0800 h on the following morning. Urine was collected from 1800 to 2200 h (period 1) and 2200 to 0800 h (period 2) for determination of urinary glucose concentration. Approximately 14 d later, all subjects returned to the General Clinical Research Center for a repeat procedure that was identical with first study. Whether subjects received vildagliptin or placebo during the first or second study was randomly determined.
Analytical determinations
The plasma glucose concentration was determined by the glucose oxidase method with a Beckman Glucose Analyzer II (Beckman Instruments Inc., Fullerton, CA). Plasma insulin, C-peptide, and glucagon concentrations were determined by RIA (Diagnostics Products, Los Angeles, CA). Plasma FFA concentration was measured by standard colorimetric methods (Wako Diagnostics, Neuss, Germany). Plasma 3H-glucose and 14C-glucose radioactivity was determined on barium hydroxide/zinc sulfate precipitated plasma extracts as previously described (12). Plasma DPP-4 activity was measured by an enzymatic assay (1). Plasma intact GLP-1 concentration was measured by ELISA using an N-terminal-specific antibody (Linco Research, St. Charles, MO) in the laboratory of Novartis. Plasma intact GIP concentration was measured by RIA with an antibody specific for the N terminus in the laboratory of Carolyn Deacon (13).
Calculations
Basal rates of appearance in the systemic circulation were measured as the ratio of the [3-3H]glucose infusion rate to the steady-state plasma [3-3H]glucose-specific activity. After glucose ingestion, total rates of glucose appearance and glucose disappearance from the peripheral circulation were computed from the [3-3H]glucose data using a two-compartment model for the glucose system. Calculations were based on a total glucose distribution volume of 250 ml/kg, an initial glucose distribution volume of 65 ml/kg, and a clearance rate of glucose from the first compartment of 29 ml/kg·min. Urinary glucose loss was subtracted from the rate of total glucose disappearance that was integrated over the two time periods (0–480 and 480–840 min) to obtain total tissue glucose disposal during the entire test. The [1-14C]glucose data were used to calculate the appearance of oral glucose. The [1-14C]glucose plasma radioactivity was divided by the specific activity of the glucose drink to calculate the plasma oral glucose concentrations, i.e. the levels that glucose would attain in the systemic circulation if the sole source of glucose were the oral load. These calculated oral glucose concentration and the [3-3H]glucose data were then used to compute the appearance of oral glucose in peripheral plasma. The rate of appearance of endogenous glucose was subsequently obtained as the difference between total and oral rates of glucose appearance (14, 15).
Insulin secretory rate (ISR) was estimated from plasma C-peptide levels (16) using ISEC, a program that uses a regularized method of deconvolution constrained to nonnegative values to carry out the calculations (17). An index of ß-cell function was calculated as the ratio of the ISR [area under the curve (AUC)] to the plasma glucose (AUC) levels for specified time intervals.
We also examined the effect of vildagliptin on ß-cell function using the Mari model (18, 19), which provides four indices of insulin secretion: 1) insulin secretion at a fixed, near basal plasma glucose concentration of approximately 140 mg/dl, which provides an index of basal secretory tone; (2) a dynamic component that represents the dependence of insulin secretion on the plasma glucose concentration and represents ß-cell sensitivity to glucose; 3) the rate sensitivity or ability of the ß-cell to respond to the rate of change in plasma glucose concentration; and 4) a time-dependent potentiation factor that accounts for a number of modulators of insulin secretion.
The absolute and incremental/decremental AUCs for specified time intervals were calculated for each parameter using the trapezoidal method.
Statistical methods
Each of the derived pharmacodynamic end points was summarized by treatment. ANOVA was performed for treatment comparisons. The sources of variation in the ANOVA model were sequence, period, and treatment as fixed effects and subject (sequence) as a random effect. The least squares mean treatment difference and associated P value were derived from the comparison between vildagliptin and placebo within the ANOVA. Correlation coefficients (r) were derived and used as a measure of association.
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Results |
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After the administration of 100 mg of vildagliptin at 1730 h, there was a prompt and virtually complete suppression of plasma DPP-4 activity, which persisted until 0800 h on the following morning (Fig. 1
). DPP-4 inhibition was associated with significant postmeal increases in both plasma GLP-1 and GIP concentrations, which did not return to basal levels until 0800 (Fig. 1). After vildagliptin, meal-stimulated plasma insulin and C-peptide concentrations increased significantly, whereas plasma glucagon decreased significantly (Figs. 1 and 2 and Table 1). These changes in plasma insulin and glucagon concentrations were associated with a significant reduction in postmeal plasma glucose concentration (Fig. 1 and Table 1), which persisted throughout the overnight period, and there was a 14 mg/dl decrease in the FPG on the morning after the administration of vildagliptin, although the decrease in FPG did not reach statistical significance. After vildagliptin there was a tendency for the postmeal plasma FFA concentration to decrease and remain decreased throughout the sleeping hours, but the decline did not reach statistical significance when compared with placebo (data not shown).
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) and remained elevated during the postmeal period and throughout the sleeping hours (Fig. 3). Because the primary stimulus for insulin secretion is the rise in plasma glucose concentration, the ISR (AUC)/glucose (AUC) represents an index of ß-cell function. During all time periods after vildagliptin, ISR (AUC)/glucose (AUC) was increased (Fig. 3). Using the Mari model (18, 19), after a single dose of vildagliptin, the ß-cell dose-response curve was shifted upward so that insulin secretion at 150 mg/dl glucose (approximate basal glucose concentration) was significantly increased (5.2 ± 0.7 vs. 4.4 ± 0.7 pmol·kg–1·min–1, P < 0.04). The slope of the curve relating insulin secretion rate to the plasma glucose concentration, i.e. glucose sensitivity, tended to increase (0.050 ± 0.007 vs. 0.039 ± 0.006 pmol·kg–1·min–1·mg–1·dl, P = 0.28), but the difference did not reach statistical significance (Fig. 4). The change in insulin secretion at 150 mg/dl glucose was inversely related to the change in mean plasma glucose concentration during the mixed meal (r = –0.66, P < 0.002). Vildagliptin did not significantly change the potentiation factor.
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During the 6-h period after ingestion of the meal (1800–2400 h), the rate of appearance of oral glucose was similar in the vildagliptin and placebo studies (1.72 ± 0.14 vs. 1.61 ± 0.14 mg·kg–1·min–1) and it would be calculated that 66.6 ± 0.9 and 67 ± 0.9 grams of the ingested glucose load was absorbed. The total rate of glucose appearance (oral plus endogenous) in the systemic circulation during the 6 h after ingestion of the meal was similar in both groups (2.84 ± 0.25 vs. 2.77 ± 0.21 mg·kg–1·min–1, P = 0.78). The difference the rate of total systemic glucose appearance and oral glucose appearance provides the rate of endogenous glucose production (EGP), which primarily reflects the liver, with a small contribution from the kidney. The time course of change in EGP is displayed in Fig. 5. In both the vildagliptin and placebo groups, there was a prompt suppression of EGP after the meal. However, within 60 min after ingestion of the meal, suppression of EGP was greater with vildagliptin and the inhibition of EGP was significantly greater during all time periods from 2000 to 0800 h on the following morning (Fig. 5). From 0 to 240, 0 to 480, and 0 to 840 min, the suppression of EGP was 25, 34, and 59% greater (all P 
0.01) after vildagliptin vs. placebo. The decrement in overnight EGP after vildagliptin was correlated with the decrement in fasting plasma glucose concentration (r = 0.55, P < 0.03). Both the increments in plasma insulin concentration (C-peptide, ISR) and the decrement in plasma glucagon concentration were correlated with decrement in EGP (r = 0.51, P < 0.05 and r = –0.49, P < 0.05, respectively). The increment in insulin to glucagon ratio correlated with the enhanced suppression of EGP (r = 0.79, P < 0.001). No significant differences were noticed in the glucose disappearance rate or the glucose metabolic clearance rate (Fig. 6) during the vildagliptin vs. placebo studies. Urinary excretion of glucose was significantly reduced by vildagliptin during the first 4 h after the ingestion of the mixed meal (757 ± 207 vs. 1617 ± 381 mg/dl, P < 0.02).
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Discussion |
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-cell function). A single dose of 100 mg vildagliptin at +1730 h caused a greater than 90% suppression of DPP-4 activity that was maintained until 0800 h on the following morning. This inhibition of DPP-4 activity was associated with significant increases on both meal-stimulated plasma active GLP-1 and GIP levels, which remained elevated throughout the evening and sleeping hours and did not return toward basal levels until 0800 h on the following morning. These results suggest that DPP-4 inhibitors can exert effects that persist well beyond the postmeal period.
Consistent with previous publications (3, 9), our results demonstrate that even a single dose of vildagliptin can augment insulin secretion in T2DM patients (Fig. 3
). However, unlike most previous studies, our results demonstrate that both plasma insulin and C-peptide concentrations were increased in absolute terms, whereas previous studies demonstrated reduced or unchanged plasma insulin C-peptide levels which, in the essence of a reduction in plasma glucose concentration, led to an increase in ISR (AUC)/glucose (AUC). This difference between our present and prior studies may be explained by the fact that we measured the plasma insulin response after the evening meal, whereas previous studies evaluated insulin secretion in the morning after an overnight fast. Because the plasma insulin concentration provides only an indirect measure of insulin secretion, we also measured the plasma C-peptide concentration and, by deconvolution analysis (16, 17), calculated the ISR. In each subject we observe an increase in ISR (AUC)/glucose (AUC) (Fig. 3), which did not return to values observed in the placebo-treated group until 0600 h on the following morning, i.e. approximately 12 h after the vildagliptin was ingested. We also examined the effect of vildagliptin on ß-cell function using the Mari model (18, 19). Consistent with previous results in which vildagliptin was administered to T2DM subjects for 28 d, there was an upward shift of the ß-cell dose-response curve such that insulin secretion at 150 mg/dl glucose, i.e. about the plasma glucose concentration at the start of the mixed meal, increased significantly. There also was a modest increase in the slope of the dose-response curve relating the insulin secretory rate of the plasma glucose concentration (Fig. 4). Collectively, these results demonstrate that a single dose of vildagliptin is capable of improving ß-cell function. Neither the rate sensitivity nor the potentiation factor changed significantly after vildagliptin.
No previous study has examined the effect of DPP-4 inhibition on glucose kinetic after ingestion of a mixed meal in T2DM individuals. Vildagliptin administration 30 min before meal ingestion significantly reduced the postprandial plasma glucose excursion. This could not be explained by an alteration in glucose appearance or enhanced splanchnic glucose uptake because the rate of appearance of ingested 14C-glucose was virtually identical in the vildagliptin and placebo studies. Rather, the rate of endogenous (primarily reflecting hepatic) glucose production was significantly reduced after vildagliptin. Although a small amount of EGP has been shown to be derived from the kidney, we believe that the enhanced suppression of EGP after vildagliptin primarily reflects an effect on the liver because previous studies (20) have shown that ingestion of a mixed meal has no effect on renal glucose production in type 2 diabetic patients. This reduction in EGP is most likely explained by two factors: 1) an increase in insulin secretion, leading to enhanced portal delivery of insulin to the liver, and 2) enhanced suppression of plasma glucagon concentration (Fig. 2). However, an effect on the liver independent of insulin and glucagon, possibly mediated by GLP-1 (21), cannot be excluded. During the 6-h period after meal ingestion, vildagliptin caused a 1.3-fold greater reduction in EGP than placebo. Both the increments (increases) in plasma insulin concentration (C-peptide, ISR) and the decrement (decrease) in plasma glucagon concentration were correlated with decrement (decrease) in EGP. Not surprisingly, the increment (increase) in insulin to glucagon ratio, which is the primary determinant of hepatic glucose production, was strongly correlated with the enhanced suppression of EGP (r = 0.79). It is noteworthy that the reduction in fasting plasma glucose concentration and EGP, after vildagliptin persisted long after the meal was completely absorbed and persisted until 0800 h on the following morning. During this overnight period, the reduction in EGP was correlated with the decrease in FPG concentration (r = 0.55). The observation is consistent with previous studies that have demonstrated that the rate of basal EGP is the primary determinant of the fasting plasma glucose concentration (22).
Two previous studies (9, 10) demonstrated an improvement in insulin sensitivity in T2DM subjects after chronic vildagliptin administration. In the present study, we failed to observe any increase in either the rate of glucose disappearance or the metabolic clearance rate of glucose after the mixed meal in vildagliptin-treated subjects. The difference between the present and previous studies may reflect the duration of treatment: one dose vs. 28 d (10) and 1 yr (9). It is noteworthy that there was a tendency for the plasma FFA concentration to decline in the present study. It is possible that more chronic DPP-4 inhibition would have resulted in a more substantial decline in plasma FFA and increase in insulin-stimulated glucose disposal. The most likely explanation for the downward trend in plasma FFAs after meal ingestion is the increase in plasma insulin level with resultant inhibition of lipolysis.
Lastly, vildagliptin therapy was associated with a significant reduction in urinary glucose excretion after meal ingestion. This simply could be explained by the reduction in postprandial plasma glucose excursion. However, it remains to be determined whether the increases in GLP-1 and/or GIP either directly or indirectly influence renal glucose handling. With respect to this possibility, acute GLP-1 administration has been shown to reduce glomerular hyperfiltration in T2DM patients (23).
In summary, a single dose of 100 mg of vildagliptin administered before the evening meal: 1) causes a sustained inhibition of plasma DPP-4 activity and increase meal/post meal levels of GLP-1 and GIP; 2) improves ß-cell function as manifested by an increase in ISR(AUC)/glucose(AUC) and by modeling; 3) augments meal/postprandial plasma insulin levels and reduces plasma glucagon concentration; 4) improves meal glucose tolerance primarily related to enhanced suppression of EGP; and 5) decreases overnight plasma glucose levels, which are correlated with a significant reduction in endogenous glucose production.
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Footnotes |
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First Published Online January 23, 2007
Abbreviations: AUC, Area under the curve; DPP-4, dipeptidyl peptidase IV; EGP, endogenous glucose production; FFA, free fatty acid; FPG, fasting plasma glucose; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; ISR, insulin secretory rate; T2DM, type 2 diabetes mellitus.
Received August 28, 2006.
Accepted January 17, 2007.
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