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Departments of Internal Medicine F (T.V., T.K.), Gentofte Hospital; Medical Physiology (T.V., J.J.H.), The Panum Institute; Clinical Pharmacology (J.S.), Gentofte Hospital; Endocrinology (S.M.), Hvidovre Hospital, DK-2650 Copenhagen; Biostatistics (A.V.), Novo Nordisk A/S; and Assay and Cell Technology (A.G.J.), Novo Nordisk A/S, DK-2880 Bagsværd, Denmark
Address all correspondence and requests for reprints to: Tina Vilsbøll, M.D., Department of Internal Medicine F, Gentofte Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: tivi{at}gentoftehosp.kbhamt.dk.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-glucosidase inhibitors or accelerated gastric emptying, increases GLP-1 secretion (7, 8). However, the gastric emptying rate does not seem to exhibit consistent changes in type 2 diabetes mellitus and obesity and is more often reported as delayed (9, 10). Therefore, increased proximal absorption could hypothetically explain a decreased GLP-1 secretion in the patients. This suggestion is supported by a study showing that obese subjects may have increased proximal absorption rates (11), which could provide an explanation for the decreased GLP-1 secretion in obesity reported by several groups (12, 13, 14). In extension of this theory, ingestion of a small meal, compared with a larger meal, might result in decreased or absent incretin hormone secretion. First, the aim of the present investigation was to evaluate postprandial concentrations of intact and total GIP and GLP-1 in type 1 and type 2 diabetic patients and in two groups of matched healthy subjects, in response to ingestion of a small and a large breakfast meal (260 and 520 kcal, respectively). Second, the aim was to evaluate whether the ß-cell sensitivity to glucose was changed in response to the degree of stimulation of the ß-cell. |
Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects were studied. Type 1 diabetic patients/lean healthy subjects and type 2 diabetic patients/obese healthy subjects were matched, with respect to sex, age, and body mass index (BMI). None of the participants had a history of gastrointestinal disease. Demographic and descriptive characteristics of the study participants are presented in Table 1
. All type 1 and type 2 diabetic patients were diagnosed according to the World Health Organization criteria (15, 16). The type 1 diabetic patients were all treated with multiple injections (two or three times a day) of sc insulin (between 16 and 72 IU/d). Six of the type 1 diabetic patients had no measurable plasma concentrations of C-peptide (nonsecretors), and two patients had fasting plasma C-peptide levels of 60 and 180 pM, respectively. Four of the type 2 diabetic patients were treated with diet alone, whereas four were treated with diet plus biguanides and/or sulfonylureas. One of the type 1 diabetic patients and four of the type 2 diabetic patients had a history of hypertension and were treated with angiotensin converting enzyme (ACE)-inhibitors and/or calcium antagonists. None of the healthy subjects had a family history of diabetes, and they all had a normal 75-g oral glucose tolerance test, according to the World Health Organization criteria (16), which was carried out immediately before inclusion in the study. All participants were without anemia, had normal serum creatinine levels (<130 µM), and no macroalbuminuria, proliferative retinopathy, or impaired liver function. All participants agreed to participate after oral and written information. The study was approved by the Copenhagen County Ethical Committee, dated 10 February 2000 (No: KA 99151m), and the study was conducted according to the principles of the Helsinki Declaration.
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All oral antidiabetic treatment was discontinued before the study (sulfonylureas, 3 d before the study; biguanides, 7 d before the study). After an overnight fast (2200 h), the subjects were studied in a seated position, with one cannula inserted into the cubital vein for blood sampling. In randomized order, within 1 wk, two meal tests were performed. The meals (small and large, respectively) comprised 260 kcal (1090 kJ) and 520 kcal (2180 kJ) and consisted of 25 and 50 g white bread, 25 and 50 g black bread, 10 and 20 g low-fat margarine, 15 and 30 g cheese, 20 and 40 g jam, and 100 and 200 ml milk (33% fat, 48% carbohydrate, and 19% protein). Thirty minutes before ingestion of the test meal, the type 1 diabetic patients injected their normal insulin dose. The insulin dose was the same on the 2 experimental days, except for one patient who experienced hypoglycemia after ingestion of the large meal. Therefore, for this patient, the insulin dose was reduced by 60% on the day of ingestion of the small meal. Half the meal was ingested during the first 5 min; thereafter, 1.5 g paracetamol, dissolved in 50 ml water, was taken orally by the participants. Finally, the rest of the meal was ingested during the next 5 min; thus, the whole meal was consumed within 10 min. Venous blood was drawn 15, 10, and 0 min before and 15, 30, 45, 60, 75, 90, 120, 150, and 180 min after ingestion of the breakfast meal. Blood was distributed into fluoride tubes for plasma glucose analysis and into chilled tubes containing heparin or EDTA (6 mM) plus aprotinin (500 KIU/ml blood; Trasylol; Bayer Corp., Leverkusen, Germany) for hormone analyses. Tubes were immediately cooled on ice and centrifuged at 4 C within 20 min. Plasma was stored at -20 C until analysis (plasma for insulin and C-peptide analysis was stored at -80 C).
Analysis
Plasma glucose concentrations were measured, during the experiments, by a glucose oxidase method using a glucose analyzer (Yellow Springs Instrument Model YSI 2300 STAT plus analyzer; YSI, Inc.,Yellow Springs, OH). Plasma insulin and C-peptide concentrations were measured by auto-DELPHIA automatic fluoroimmunoassay (Wallac, Inc., Turku, Finland). The detection limit is approximately 3 pM for insulin and 17 pM for C-peptide. Intra- and interassay coefficients of variation for insulin are 4–10% at 39–1.240 pM. Intra- and interassay coefficients of variation for C-peptide are 3–6% at 380-2700 pM. The cross-reactivity with intact and split proinsulin in the C-peptide assay is 63–87%. Incretin hormones were measured using RIA. Total GIP was measured using the C-terminally directed antiserum R65 (17, 18), which reacts fully with intact GIP and the N-terminally truncated metabolite, GIP(3–42). The assay has a detection limit of 2 pM and an intra-assay variation of approximately 6%. Intact, biologically active GIP was measured using a newly developed assay as described (5). The assay is specific for the intact N terminus of GIP, and it cross-reacts less than 0.1% with GIP(3–42) or with the structurally related peptides GLP-1(7–36)amide, GLP-1(9–36)amide, GLP-2(1–33), GLP-2(3–33), or glucagon at concentrations of up to 100 nM. Intra-assay variation was less than 6%, and interassay variation was approximately 8 and 12% for 20 and 80 pM standards, respectively. C-terminal GLP-1 (total) immunoreactivity was measured as described previously (19), using standards of synthetic GLP-1(7–36)amide (= proglucagon 78–107amide) and antiserum no. 89390. The assay cross-reacts less than 0.01% with C-terminally truncated fragments and 83% with GLP-1(9–36)amide and has a detection limit of 1 pM. Intra-assay and interassay coefficients of variation were less than 6% and 15%, respectively, at 40 pM. The N-terminal GLP-1 assay, measuring the concentration of intact GLP-1, was measured using a two-site sandwich immunoassay (20) based on two monoclonal antibodies: the near C-terminally directed GLP1F5 as catching antibody and the strictly N-terminal Mab26.1 as detecting antibody. Standards were GLP-1(7–36)amide. The assay showed less than 0.1% cross-reactivity with N-terminally truncated or extended forms of GLP-1, GLP-1(1–37), GLP-1(8–37), or GLP-1(9–37). Detection limit was 1 pM, and intra-assay coefficient of variation was better than 5%. The glucagon assay is directed against the C-terminus of the glucagon molecule (antibody code no. 4305) and, therefore, measures glucagon of mainly pancreatic origin. The sensitivity is approximately 1 pM, and the intra-assay coefficient of variation is less than 6% in the range between 10 and 25 pM (21). Plasma concentrations of acetaminophen (paracetamol) were determined by means of HPLC (22). The calibration curve was linear up to 30 µg/ml (198.1 µM), with a limit of detection of 1 µg/ml (7 µM). Intra-assay variations were 0.7% for concentrations of 2.3 µg/ml and 0.7% for concentrations of 12 µg/ml. Interassay variations were 6% and 2.5% for concentrations of 1 µg/ml (7 µM) and 10 µg/ml (66 µM), respectively.
Assessment of insulin secretion rates (ISRs)
ISRs for each individual, during the two experiments, were derived by deconvolution of peripheral C-peptide concentrations using a two-compartment model of C-peptide kinetics (23, 24) and population-based C-peptide kinetic parameters (25). The population-based parameters are derived from analysis of a large number of individual kinetic parameters, allowing calculation of values adjusted for clinical status (normal, obese, or type 2 diabetes and age and gender) (25). ISR is expressed as pmol·kg-1·min-1.
Relationship between glucose concentration and insulin secretion
The calculated ISR values were plotted against plasma glucose, to establish the relationship for each individual after the small and the large meal. The slopes of these approximately linear relations were evaluated by cross-correlation analysis, as previously described (26), and expressed as pmol·kg-1·min-1·mM-1 and regarded as measures of ß-cell responsiveness to glucose. The individual slopes were calculated by linear regression analysis of the relation between ISR and plasma glucose measured at the same time points. The slopes express the simultaneous increase in ISR per unit increase in glucose concentrations. This calculation was only done for the type 2 diabetic patients and obese healthy subjects, because six of the type 1 diabetic patients were nonsecretors. The data from the lean healthy subjects were not subjected to this analysis, because their variation in plasma glucose was small and of a short duration, making it impossible, in most subjects, to obtain reliable linear relations by cross-correlations.
Statistical analysis and calculations
All results are presented as the mean ± SEM. Statistical analysis was carried out as a two-factor ANOVA for repeated measurements, with post hoc contrasting of patient results vs. healthy subjects, using the software Statistica (Statsoft, Tulsa, OK). Areas under the curve (AUCs) were calculated using the trapezoidal rule, and t tests for paired data were used for comparing the large and the small meal.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Fasting plasma glucose concentrations are shown in Table 1
; and the postprandial plasma glucose profiles, in Fig. 1. In the type 1 and type 2 diabetic patients, the plasma glucose concentrations tended to be higher, although not statistically significant, after ingestion of the large meal, compared with the small meal. The glucose profile was similar in the two groups of healthy subjects, regardless of the size of the meal (Fig. 1). Time courses of insulin and C-peptide concentrations are shown in Fig. 2, and AUCs for C-peptide and incretin hormone responses are shown in Table 2. Further, the hormone profiles were divided into an early response, defined as the AUC during the first 30 min of the meal test [AUC (0–30 min)], and a late response, defined as the AUC between 30–180 min of the experiment [AUC (30–180 min)]. Early C-peptide responses to the small and the large meal were similar in type 2 diabetic patients and lean and obese healthy subjects, whereas a significantly increased late C-peptide response (P < 0.003) was seen in these three groups during the large meal test (Table 2). Out of the eight type 1 diabetic patients, only two patients showed an increase in C-peptide during the meal tests.
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Basal ISRs are shown in Table 3. The incremental amount of insulin secreted was increased by a factor of two during the large meal, compared with the small meal, in type 2 diabetic patients and in lean and obese healthy subjects (Table 3) (no calculation was made in type 1 diabetic patients, see above). The slopes of ISR vs. plasma glucose concentrations were calculated for type 2 diabetic patients and in obese healthy subjects to investigate the ß-cell sensitivity to glucose for each individual after the small and the large meal. A tendency toward increased sensitivity was seen in both type 2 diabetic patients and obese healthy subjects, with an increase of 29% from 0.70 to 0.99 pmol·kg-1·min-1·mM-1 in the diabetic patients (P = 0.19) and of 22% from 2.66 to 3.43 pmol·kg-1·min-1·mM-1 in the obese healthy subjects (P = 0.04).
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In type 2 diabetic patients and obese healthy subjects, fasting glucagon responses were 12 ± 1 and 11 ± 2 pM, respectively (not statistically significant, NS). Corresponding results were 8 ± 1 pM in both type 1 diabetic patients and lean healthy subjects (NS). An increase in glucagon concentrations (data not shown) was seen in all four groups, with peak concentrations after 30 min, during both the small and the large meal test. Peak glucagon concentrations were 22 ± 3 pM (small meal) and 24 ± 3 pM (large meal) in type 2 diabetic patients. Corresponding results were 21 ± 4 and 19 ± 3 pM in obese healthy subjects, 13 ± 1 and 16 ± 1 pM in type 1 diabetic patients, and 12 ± 1 and 12 ± 1 pM in lean healthy subjects, respectively. Type 2 diabetic patients and obese healthy subjects showed increased glucagon responses in the first hour of the study, compared with type 1 diabetic patients and lean healthy subjects, respectively (ANOVA, P < 0.01–0.05).
GLP-1 and GIP
Time courses of incretin hormone concentrations during the investigation are shown in Fig. 3. Early total GLP-1 (intact peptide plus primary metabolite) responses [AUC (0–30 min)] were the same in all four groups, during both meals; whereas the late responses [AUC (30–180 min)] were significantly higher during the large meal, compared with the small meal test (Table 2). A comparison of total GLP-1 concentrations in the type 2 diabetic patients and in obese healthy subjects showed that both total and incremental AUCs were significantly lower, during both the small and the large meal, in the patients (P < 0.02). Correspondingly, the plasma concentrations of total GLP-1 were significantly lower in the type 2 diabetic patients, compared with the healthy subjects, during the late phase of the small meal [ANOVA, P < 0.02 (90 min)]. Early intact GLP-1 responses increased in the two patient groups during the large meal, compared with the small meal, whereas the early intact GLP-1 responses were the same during both meal tests in the two groups of healthy subjects (Table 2). The late intact GLP-1 responses tended to increase in all four groups during the large meal, but significantly so only in the two groups of diabetic subjects (Table 2). The incremental intact GLP-1 response to the small meal [AUC (0–30 min)] was lower in the type 2 diabetic patients, compared with the healthy subjects (P = 0.04).
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and Table 2). Late total and intact GIP responses [AUC (30–180 min)] were highly significantly increased in all four groups during the day of the large meal test (P < 0.001). Increased fasting concentrations of total GIP were found in obese (compared with lean) healthy subjects on the day of the large meal test (P < 0.05). Intact GIP responses were the same when comparing the four groups, except when ANOVAs were made between obese and lean healthy subjects, where an increased GIP concentration was found in the obese healthy subjects, both at fasting level (both meal tests) (P < 0.01) and early phase (P < 0.02, up to 30 min) postprandial levels during the small meal test. Paracetamol
Peak concentrations and time-to-peak in the four groups (mean ± SEM) amounted to 119 ± 3 µM (small meal, 30 min) and 103 ± 13 µM (large meal, 30 min) in type 2 diabetic patients. Corresponding results were 133 ± 13 µM (30 min) and 113 ± 15 µM (30 min) in obese healthy subjects, 150 ± 16 (45 min) and 136 ± 17 µM (30 min) in type 1 diabetic patients, and 189 ± 10 (30 min) and 136 ± 12 µM (30 min) in lean healthy subjects, respectively. Peak concentrations were lower in the type 1 diabetic patients and in lean healthy subjects, compared with the type 2 diabetic patients and obese healthy subjects (probably because of the fact that the dose was not adjusted for body weight), but the shape of the curves was the same in all four groups during both meals. AUCs for subjects with comparable weights were not statistically different; and no differences, with respect to time-to-peak or ascending or descending slopes, were apparent.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Previous studies concerning the incretin responses during normal physiological conditions, i.e. meal ingestion, have given conflicting results regarding the influence of obesity and/or diabetes of either type (6, 12, 29, 30), and one of the aims of the present investigation was to further evaluate meal-stimulated incretin secretion and both type 1 and 2 diabetes, compared with appropriate control groups, and to investigate whether differences in meal sizes, as employed by previous investigators, could explain some of the discrepancies. For this study, we used validated RIAs for the determination of total + intact GIP and total GLP-1 (5, 17, 19, 31). Intact GLP-1 was measured with a newly developed sandwich ELISA assay, which has been validated against the commonly used RIAs and was chosen for this investigation because of its superior sensitivity (20). Lugari et al. (29) reported that a GLP-1 response, as observed in healthy subjects after ingestion of a small meal (230 kcal), was absent in type 2 diabetic patients. We previously found that type 2 diabetic patients have a preserved (but significantly reduced) GLP-1 response to a meal test (566 kcal), compared with healthy subjects (6). A smaller meal could, theoretically, result in a reduced exposure of the GLP-1-producing cells (L cells) of the intestine to stimulatory nutrients and/or an increased proximal absorption of nutrients in obese subjects and thereby explain an absent response. In the present investigation, however, we found a significant GLP-1 response to the small meal in all groups of subjects. Our previous finding of a decreased response in type 2 diabetic patients, compared with healthy controls (6, 12), was confirmed for both meals, suggesting that type 2 diabetic patients generally have an attenuated GLP-1 secretion. Indeed, the intact GLP-1 plasma profile that was obtained here was very similar to that observed in our earlier investigation, in spite of the use of an entirely different assay. After the present study was initiated, Lugari et al. (30) reported that, even after ingestion of 700 kcal, a GLP-1 response could not be detected in type 2 diabetic patients. Their results are in contrast to the present study, and the difference can only be explained by differences in methodology or by unexpected differences regarding the type 2 diabetic patients. At least, differences in meal size do not seem to explain the discrepancies. Lugari et al. (29) also reported lack of a GLP-1 response to meal ingestion in patients with type 1 diabetes. Our type 1 diabetic patients had a normal incremental total and intact GLP-1 response, compared with healthy subjects with similar body weight. Fasting intact GLP-1 concentrations tended to be lower in the type 1 diabetic patients, compared with the lean healthy subjects. As suggested for GIP (32), this could be attributable to negative feedback on endogenous GLP-1 secretion in the fasting state, caused by exogenous insulin administered 30 min before ingestion of the meal (15 min before the first blood sample). However, to our knowledge, effects of insulin on GLP-1 secretion have not as yet been reported.
In the present study, we also wanted to evaluate to what extent abnormalities regarding gastric emptying and/or proximal absorption rates, previously demonstrated to characterize at least some obese subjects (12, 13, 14), might influence incretin secretion. As mentioned above, no difference in gastric emptying between lean and obese healthy subjects was found. The normal values found in our obese subjects might be explained by the fact that only moderately overweight subjects, with BMIs up to 36 kg/m2, were included. On the other hand, a significantly increased fasting GIP concentration and an increased early-phase GIP response were seen in obese healthy subjects, compared with lean healthy subjects. In 1988, Marks (33) hypothesized that GIP might function as an obesity-promoting hormone; and, in a recent paper, Miyawaki et al. (34) showed that GIP-receptor knock-out mice gained less weight than normal mice when treated with a high-fat diet. Together, these observations suggest that GIP may be an important factor for increased nutrient uptake and triglyceride accumulation in the adipose tissue; and therefore, high GIP levels may predispose to the development of obesity. No previous studies have measured intact GIP responses in type 1 diabetic patients; but, in these patients, as for type 2 diabetic patients, as previously shown (6), normal responses were seen when compared with healthy subjects.
As previously discussed, the lower GLP-1 response seen in diabetic patients is probably a consequence of type 2 diabetes rather than a primary defect (12, 35). Thus, normal 24-h plasma concentration profiles were observed in first-degree relatives of patients with type 2 diabetes (36); and, in a study of identical twins discordant for type 2 diabetes, only the diabetic twin had decreased GLP-1 levels (35). Finally, in a recent study, it was shown that GLP-1 is eliminated at similar rates in type 2 diabetic patients and healthy subjects, indicating that the decreased GLP-1 concentrations in type 2 diabetic patients are not attributable to differences in the elimination of GLP-1 (37).
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the curve; BMI, body mass index; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide; ISR, insulin secretion rate.
Received November 27, 2002.
Accepted March 3, 2003.
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M. R. Druce, C. J. Small, and S. R. Bloom Minireview: Gut Peptides Regulating Satiety Endocrinology, June 1, 2004; 145(6): 2660 - 2665. [Abstract] [Full Text] [PDF]
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G. M. Steil, C.-m. Hwu, R. Janowski, F. Hariri, S. Jinagouda, C. Darwin, S. Tadros, K. Rebrin, and M. F. Saad Evaluation of Insulin Sensitivity and {beta}-Cell Function Indexes Obtained From Minimal Model Analysis of a Meal Tolerance Test Diabetes, May 1, 2004; 53(5): 1201 - 1207. [Abstract] [Full Text] [PDF]
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