The plasma C-peptide and insulin responses to stimulation with intravenous glucagon and a mixed meal in well-controlled Type 2 (non-insulin-dependent) diabetes mellitus: dependency on acutely established hyperglycaemia

Diabetologia, Dec 1989

Summary The dose-response relationships between acutely established hyperglycaemia and the plasma C-peptide and insulin responses to i. v. stimulation with 1 mg of glucagon and a standard mixed meal were investigated in 10 patients with well-controlled Type 2 (non-insulin dependent) diabetes mellitus. Hyperglycaemia was maintained for 90 min before stimulation using a hyperglycaemic clamp technique. Each test was performed on different steady state blood glucose levels of ∼6 mmol/l, ∼12 mmol/l, and ∼20 mmol/l, respectively. The plasma C-peptide and insulin responses after glucagon and the meal were potentiated markedly at each level of prestimulatory hyperglycaemia. After glucagon injection, the relative glucose potentiation of the insulin response was significantly higher than the relative glucose potentiation of the C-peptide response at each level of hyperglycaemia (p<0.01). This difference may be explained by a higher fractional hepatic removal of insulin at normoglycaemia, since the molar ratio between the incremental C-peptide and insulin responses after glucagon stimulation was higher at prestimulatory normoglycaemia (4.85 (3.65–12.05)) than at the prestimulatory blood glucose concentrations ∼12 mmol/l (2.41 (2.05–4.09)) (p< 0.01) and ∼20 mmol/l (2.24 (1.37–3.62)) (p<0.01). In conclusion, the islet B-cell responses to glucagon and a standard mixed meal are potentiated to a high degree by acutely established prestirnulatory hyperglycaemia in patients with well-controlled Type 2 diabetes. Acute prestirnulatory hyperglycaemia is also associated with a markedly reduced incremental C-peptide/insulin ratio after glucagon stimulation in such patients. Measurement of the insulin response after i. v. glucagon injection at acute hyperglycaemia compared with the response at normoglycaemia therefore seriously overestimates the relative glucose potentiation of pancreatic B-cell responsiveness in patients with well-controlled Type 2 diabetes.

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The plasma C-peptide and insulin responses to stimulation with intravenous glucagon and a mixed meal in well-controlled Type 2 (non-insulin-dependent) diabetes mellitus: dependency on acutely established hyperglycaemia

Diabetologia The plasma C-peptide and insulin responses to stimulation with intravenous glucagon and a mixed meal in well-controlled Type 2 (non-insulin-dependent) diabetes mellitus: dependency on acutely established hyperglycaemia H.J. Gjessing 0 B. Reinholdt 0 O. Pedersen 0 0 1Divisionof Endocrinologyand Metabolism,UniversityClinic of Internal Medicine , Aarhus Arntssygehus,Arhus, and 2Central Laboratory , Fredericia Hospital , Fredericia , Denmark Summary. The dose-response relationships between acutely established hyperglycaemia and the plasma C-peptide and insulin responses to i.v. stimulation witfi 1 mg of glucagon and a standard mixed meal were investigated in 10 patients with well-controlled Type 2 (non-insulin dependent) diabetes mellitus. Hyperglycaemia was maintained for 90min before stimulation using a hyperglycaemic clamp technique. Each test was performed on different steady state blood glucose levels of - 6 mmol/1, -12 mmol/1, and ~20 mmol/1, respectively. The plasma C-peptide and insulin responses after glucagon and the meal were potentiated markedly at each level of prestirnulatory hyperglycaemia. After glucagon injection, the relative glucose potentiation of the insulin response was significantly higher than the relative glucose potentiation of the C-peptide response at each level of hyperglycaemia (p < 0.01). This difference may be explained by a higher fractional hepatic removal of insulin at normoglycaemia, since the molar ratio between the incremental C-peptide and insulin responses after glucagon stimulation was higher at prestimulatory normoglycaemia (4.85 (3.65-12.05)) than at the prestimulatory blood glucose concentrations ~12 mmol/1 (2.41 (2.05-4.09)) (p < 0.01) and -20 mmol/1 (2.24 (1.37-3.62)) (t7< 0.01). In conclusion, the islet B-cell responses to glucagon and a standard mixed meal are potentiated to a high degree by acutely established prestimulatory hyperglycaemia in patients with well-controlled Type 2 diabetes. Acute prestimulatory hyperglycaemiais also associated with a markedly reduced incremental C-peptide/insulin ratio after glucagon stimulation in such patients. Measurement of the insulin response after i.v. glucagon injection at acute hyperglycaemia compared with the response at normoglycaemia therefore seriously overestimates the relative glucose potentiation of pancreatic B-cell responsiveness in patients with well-controlled Type2 diabetes. Plasma C-peptide; plasma insulin; islet B-cell function; Type 2 (non-insulin-dependent) diabetes mellitus; glucose potentiation; insulin clearance - 9 Springer-Verlag1989 T h r o u g h o u t recent years, it has been established, that the pancreatic B-cell response to different non-glucose secretagogues is potentiated by acute elevations in the prestimulatory blood glucose concentration in normal subjects [ 1, 2 ] as well as in patients with Type 2 (non-insulin-dependent) diabetes mellitus [ 1, 3 ]. In several studies, insulin measurements in serum have been used in the estimation o f glucose potentiation o f B-cell responsiveness [1, 21. However, acute hyperglycaemia is associated with hyperinsulinaemia in normal subjects and in most patients with Type 2 diabetes mellitus. I f hyperinsulinaemia is p r o n o u n c e d , hepatic insulin receptors m a y become saturated and this m a y result in a reduced fractional hepatic insulin removal [ 4-11 ]. M e a s u r e m e n t o f peripheral plasma insulin concentrations may, therefore, introduce a systematic error in the assessment o f glucose potentiation o f islet B-cell responsiveness. The magnitude o f such an error has not been evaluated in Type,' 2 diabetes mellitus, but can be quantitated by relating the plasma insulin response to the plasma C-peptide response at each level o f prestimulatory hyperglycaemia. Measurement o f plasma C-peptide after stimulation with i.v. glucagon was introduced as islet B-cell estimate in Type I (insulin-dependent) diabetes mellitus as the response was closely correlated to the response after a standard mixed meal [ 12 ]. In Type 2 diabetes, this correlation is only modest [ 13 ]. It seems possible that the increase in blood glucose concentration during a meal potentiates the B-cells maximally and renders elevations in prestimulatory blood glucose concentration unimportant to the islet B-cell responsiveness. Hence, the aim o f the present study was to evaluate the dose response relationship between different levels o f steady state acute hyperglycaemia and the simultaneous plasma C-peptide and insulin responses after stimulation with i.v. glucagon and a standard mixed meal in patients with well-controlled Type 2 diabetes mellitus. S u b j e c t s and m e t h o d s Ten patients with well-controlled Type 2 diabetes were studied in the outpatient clinic at the Division of Endocrinology and Metabolism, Aarhus amtssygehus. All patients fulfilled the WHO criteria of diabetes mellitus [ 14 ] at diagnosis but had during treatment shown fasting blood glucose levels below 8 mmol/1 in the outpatient clinic during the preceding year. None of the patients had intercurrent diseases or late complications of diabetes. Five patients were treated with diet only and five with diet and tolbutamide. Pertinent clinical data as well as plasma C-peptide in the fasting state and 6 min after the i.v. glucagon challenge at normoglycaemia are shown in Table 1. No significant differences were found in clinical data, C-peptide levels, or in the degree of glucose potentiation between patients treated with diet only and patients also treated with tolbutamide. We, therefore, studied all the patients as one group. Informed consent was obtained from all patients. The study was approved by the ethical committee of Aarhus County. Each patient was examined after an overnight fast on 6 occasions with an interval from 1 day to 6 weeks between each test. All tests were performed within 8 weeks in each individual patient. Glucagon or meal stimulation was performed at steady state blood glucose levels of - 6 mmol/1, ~12 mmol/1, and ~20 mmol/1. The order of the tests were planned to comply with patient wishes as much as possible. The study protocol is outlined in Figure 1. The patients were rested supine and a cannula was placed in a cubital vein in the left as well as F 120 in the right arm. Blood glucose was raised with a bolus injection of 50% (weight/volume) glucose. Hyperglycaemia was maintained with a variable infusion of 20% or 50% glucose with a volumetric precision pump (IMED922, I M E D Scandinavia, Stockholm, Sweden) [ 15 ]. Through the contralateral cannula, blood samples were continuously taken. If 50% glucose was used to maintain hyperglycaemia, the infusion cannula and the blood sampling cannula were exchanged every hour and the cannula previously used for glucose infusion thoroughly washed with isotonic saline before being used for blood sampling. After 90 min of stable hyperglycaemia 1 mg of glucagon was given i.v. or ingestion of the meal was started. During the tests glucose infusion was maintained at the prestimulatory rate. Blood samples for determination of plasma C-peptide and insulin were taken before the induction of hyperglycaemia and - 9 0 , - 6 0 , - 3 0 , 0, 3, 6, 9, 15, and 20 min after the glucagon injection and - 9 0 , - 6 0 , - 3 0 , 0, 30, 60, and 120 min after the beginning of the meal. Plasma proinsulin concentrations were measured before induction of hyperglycaemia, immediately before stimulation with glucagon and the meal, and 6 min after stimulation with glucagon and 120 min after the beginning of the meal. The meal consisted of one boiled egg, half a slice of rye bread with butter, two slices of white bread with butter, and 15 g 30% cheese, 20 g jam, 0.21 skimmed milk, and tea or coffee ad libitum. The meal contained 17 g fat, 50 g carbohydrate, and 23 g protein. Insulin and Cpeptide responses to glucagon and the meal were calculated as the incremental area under plasma curve corrected for the prestimulatory level. Relative glucose potentiation was calculated as the plasma Cpeptide and insulin responses to glucagon and the meal at prestimulatory hyperglycaemia in percent of the responses at prestimulatory normoglycaemia. Blood glucose concentration was measured by a glucose oxidase method (Glucose analyser, Yellow Springs Instruments Co., Yellow Springs, Ohio, USA). Plasma C-peptide concentration was measured by RIA using the method of Heding [ 16 ] with antibody M1221 from Novo Research Institute (Bagsvaerd, Denmark). The cross-reactivity with proinsulin is approximately 80%. In our laboratory the within and between coefficient of variation was 0.04 and 0.05. Plasma insulin concentration was also measured by RIA [171. Proinsulin in plasma was quantitated by a two-site, two-step, time-resolved immunofluorometric assay (DELFIA). The principle of this technique is published elsewhere [ 18 ]. The assay for proinsulin uses a monoclonal antibody with specificity for human C-peptide as catching antibody and a monoclonal antibody with specificity for human insulin as detecting antibody. The assay is calibrated by means of the WHO International Reference Reagent for Human Proinsulin for Immunoassay (code 84/611) appropriately diluted in proinsulin-free human serum. The dose-response curve for undiluted specimens is linear in the range t.6 to 1600 pmol/1 (r = 0.999). The total impression was estimated by assaying 3 different serum specimens with low, moderate, and high proinsulin concentrations. Each specimen was assayed 36 times over several different assay days. Total coefficient of variation was 12.4%, 7.3%, and 6.4%, at 4.37 pmol/1, 18.2 pmol/1, and 72.7 pmol/1, respectively. The cross-reactivity with human C-peptide was less than 0.4% and with human insulin less than 0.1%. The coefficient of correlation between results obtained with the present fluorescence immunoassay and results obtained with a previously published RIA [19] for proinsulin was 0.999. Statistical analysis Data are expressed as median values with 25% and 75% ranges. Mann-Whitney's non-parametric ranked-sum test was used for unpaired data and Wilcoxon's non-parametric ranked-sum test for paired data. Significance of correlation was tested by Spearman's non-parametric ranked-correlations test. Results Median blood glucose, plasma insulin, and plasma Cpeptide values and 25% and 75% percentiles before and after stimulation with glucagon and the meal are given in Figure 1. Overnight fasting values of blood glucose, plasma insulin, and plasma C-peptide were similar on the six study days. Fasting blood glucose values were within the normal range (median 6.1 mmol/1, 25% and 75% percentiles 5.7-6.6mmol/1). During hyperglycaemia at - 1 2 mmol/1 and at - 2 0 mmol/1 plasma insulin increased from the fasting value 0.16nmol/1 (0.13-0.22 nmol/1) to the prestimulus levels 0.21 nmol/1 (0.17-0.35 nmol/1) (p < 0.05), and 0.23 nmol/1 (0.16-0.53 nmol/1) (p <0.01), respectively, while plasma C-peptide values increased from 0.78nmol/1 (0.65-0.92 nmol/1) to 1.27 nmol/1 (0.84-1.94 nmol/1) (p < 0.01) and 1.53 nmol/1 (0.76-2.50 nmol/1) (p < 0.01). The increases in plasma insulin and plasma Cpeptide values tended to level off during the last 30 min of hyperglycaemia prior to stimulation. rainx nmolll 50 A-IRI A-EP l 12 20 12 Preshmulafory b[ood gtucose (mmoffl) 20 The median blood glucose concentration increased significantly during the meal (p<0.01), when the prestimulatory blood glucose concentration was - 6 mmol/1 (Fig. 1, left panel). In contrast, the median blood glucose concentration showed a significant decrease during the meal (p < 0.01), when the prestimulatory blood glucose concentration was ~20 mmol/1 (Fig. 1, fight panel), despite a continuous i.v. glucose infusion during the meal at a rate which had been sufficient to keep the blood glucose concentration at ~20 mmol/1 prior to stimulation. A similar but insignificant trend was found in median blood glucose concentration during the meal, when prestimulatory blood glucose concentration ,was - 1 2 mmol/1 (Fig. 1, middle panel). Figure 2 shows the dose-response relationship between increasing prestimulatory'blood glucose concentrations and the insulin and C-peptide responses to stimulation with glucag,on and the meal. The responses after both glucagon injection and food intake continued to increase throughout: the investigated range of prestimulatory blood gluct)se levels. Table 2 shows the prestimulatory values of plasma insulin and C-peptide at the two levels of hyperglycaemia in percent of the prestimulatory values at normoglycaemia together with the insulin and C-peptide responses at hyperglycaemia in percent of the responses at normoglycaemia. The relative glucose potentiation of the prestimulatory plasma insulin and C-peptide values as well as the relative potentiation of the C-peptide response to glucagon were of a similar magnitude. Moreover, the meal-induced insulin and C-peptide responses exhibited a similar pattern. However, the relative glucose potentiation of the insulin response to glucagon was significantly higher (p < 0.01) than the relative potentiation of the other estimates of islet B-cell function. Table 3 shows median prestimulatory molar ratios of plasma C-peptide to plasma insulin as well as the median ratio of incremental amount of C-peptide to insulin after stimulation with glucagon. The molar ratio before stimulation was approximately 5:1 at all prestimulatory blood glucose levels. The molar ratio of the responses after glucagon was also approximately 5:1 at prestimulatory normoglycaemia, but only about 2.5:1 at both levels of prestimulatory hyperglycaemia (p < 0.01). The correlation between the incremental plasma Cpeptide response after stimulation with glucagon and the meal was only modest at all three prestimulatory blood glucose levels ( ~ 6 m m o l / l : r=0.58, p < 0 . 1 0 , - 1 2 m m o l / l : r=0.60, p < 0 . 1 0 , and - 2 0 m m o l / l : r = 0.68, p < 0.05). No significant correlations were found between body mass index (BMI) and absolute values of islet Bcell estimates at the different prestimulatory blood glucose values or between BMI and the values obtained at prestimulatory hyperglycaemia in percent of the values obtained at prestimulatory normoglycaemia. No difference was found in overnight fasting values of plasma proinsulin on the six study days. The overall value was 17 pmol/1 (11-31 pmol/1). At prestimulatory normoglycaemia, plasma proinsulin increased to 31 p m o l / l (14-52 pmol/l) (p <0.01) 6 min post glucagon and to 68 pmol/1 (35-90 pmol/1) (p < 0.01) 120 min after the start of the meal. After 90 min of stable hyperglycaemia at - 1 2 mmol/1, plasma proinsulin values increased to 35 pmol/1 (16-49 pmol/1) (p < 0.01) with a further increase to 57 pmol/1 (32-118 pmol/1) (p < 0.01) 6 min post glucagon and to 137 pmol/1 (63-166 pmol/1) (p<0.01) 120min after the start of the meal. After 90 min of stable hyperglycaemia at ~20 mmol/1, plasma proinsulin values increased to 47pmol/1 (15-67pmol/1) (p<0.01) with a further increase to 93 pmol/1 (31-157 praol/1) (p < 0.01) 6 min post glucagon and to 178pmol/1 (41-304pmol/1) (p<0.01) 120 min after the start of the meal. The overall ratio between plasma proinsulin and plasma C-peptide after an overnight fast was 2.4% (1.8-3.6%). This ratio was unchanged after 90 min of stable hyperglycaemia at - 1 2 retool/1 (2.8% (1.7-3.7%)) and at - 2 0 mmol/1 I(3.1%(1.8-3.6%)). It was also unchanged 6 min post glucagon stimulation at prestimulatory normoglycaemia (2.2% (0.9-3.0%)), at prestimulatory blood glucose ~-12 mmol/! (2.5% (1.6-3.6%)) and at prestimulatory blood glucose ~20 mmol/1 (2.4% (1.5-3.3%)). In contrast, a significant increase was found in the ratio 120 rain after the start of the meal at prestimulatory nonnoglycaemia (3.2% (2.5-4.3%)) (p < 0.02), at prestimulatory blood glucose - 1 2 mmol/1 (4.1% (2.7-6.1%)) (p <0.01) and at prestimulatory blood glucose - 2 0 mmol/1 (4.7% (2.7-6.6%)) (p < 0.01). There was no significant difference between the ratio at prestimulatory normoglycaemia and the ratio at prestimulatory hyperglycaemia 120 min after the start of the meal. > Discussion In this study we have shown, that pancreatic B-cell responsiveness is considerably enhanced by an acute elevation in prestimulatory blood glucose concentration in patients with Type 2 diabetes mellitus [ 1, 3 ]. However, after stimulation with i.v. glucagon the relative potentiation (incremental response at hyperglycaemia in percent of imcremental response at normoglycaemia) was considerably higher using measurement of insulin in plasma instead of C-peptide. In studies on glucose potentiation of islet B-cell responsiveness in Type 2 diabetes plasma insulin measurements have been used in the estimation of pancreatic insulin secretion [1]. Our findings show that such a procedure introduces a serious overestimation of relative glucose potentiation of islet B-cell responsiveness. The explanation for this overestimation of relative glucose potentiation using measurements of peripheral plasma insulin probably is saturation of hepatic insulin receptors after glucagon stimulation at prestimulatory hyperglycaemia. Thus, the hepatic clearance of insulin after glucagon stimulation seemed to be considerably reduced at hyperglycaemia than at normoglycaemia as reflected by a lower molar ratio between C-peptide and insulin during the test at prestimulatory hyperglycaemia than at prestimulatory normoglycaemia. In other studies a reduced hepatic insulin clearance during hyperinsulinaemia has also been reported in normal subjects and in Type2 diabetes [ 4-11 ]. Mikines et al. suggested that insulin receptors in the liver are saturated at a peripheral plasma insulin concentration of -0.70nmol/1 in normal subjects when hyperinsulinaemia is produced by endogenous secretion [11]. In our study, plasma insulin concentrations were considerably above this level after glucagon stimulation during each level of prestimulatory hyperglycaemia. These conclusions assume that changes in the ratio between incremental plasma C-peptide and plasma insulin areas under the curve reflect changes in hepatic insulin clearance. The procedure assumes, however, that insulin and C-peptide are secreted in equimolar amounts to the portal bloodstream, that the hepatic degradation of C-peptide is negligible, and that the nonhepatic clearance and the volume of distribution of the peptides are independent of the metabolic status and the concomitant plasma C-peptide and insulin levels. Not all of these assumptions have been fully validated [ 20, 21 ]. However, concerning the high plasma C-peptide values measured during hyperglycaemia in our study, it is especially of interest that the metabolic clearance of C-peptide seems to be independent of the concomitant plasma C-peptide level in humans [22]. Due to the differences in half-life of insulin and C-peptide, it is also a prerequisite that steady-state conditions are present or, alternatively, that both peptides are followed after stimulation until reaching the prestimulatory level [ 20, 21 ]. Thus, we did not calculate the ratio between the incremental plasma C-peptide and insulin areas after meal stimulation, since peripheral plasma C-peptide and insulin values had not reached baseline values 2 h after the beginning of the meal. A further potential pitfall is co-determination of proinsulin in the C-peptide assay. In our study, the median ratio between plasma proinsulin and plasma C-peptide was always below 5% and independent of prestimulatory hyperglycaemia. Co-determination of proinsulin cannot, therefore, explain our results. In several studies plasma C-peptide 6 min after injection of I mg of glucagon, has been used in attempts to distinguish between patients with and without insulin requirement [ 23-27 ] or between patients with Type 1 and Type 2 diabetes discriminated according to clinical criteria [ 28 ]. In most of these studies, large overlaps in glucagon stimulated plasma C-peptide values have been reported between such patient groups [ 24-28 ], although in one study the glucagon stimulated plasma C-peptide value of 0.60 nmol/1 provided a sharp cut-off between patients with fasting blood glucose values above and below 8 retool/1 during treatment with diet in combination with tolbutamide [ 23 ]. Relative glucose potentiation of plasma C-peptide 6 min after glucagon injection was, in the present study, as large as 202% (151-232%) at prestimulatory blood glucose ~12 mmol/l and 232% (178-337%) at ~20 mmol/1. We also measured glucose potentiation of the B-cell response to a standard mixed meal. Blood sampling was stopped 2 h after the start of the meal. This was done as in a previous study we have shown that peak plasma C-peptide on average is seen 2 h after the start of a standard mixed meal in Type 2 diabetes [ 29 ]. Furthermore, in that same study, the incremental plasma Cpeptide area under the curve until 2 h after the start of the meal correlated closely to the area obtained until 31/2h after the meal (r=0.97, p<0.01). It therefore seems to be an acceptable assumption that the incremental plasma C-peptide area under the curve until 2 h after the start of the meal closely reflects the total area under the curve to the meal. Blood glucose concentration was actually decreasing during the meal at prestimulatory hyperglycaemia despite a continuous i.v. glucose infusion at a rate which had been sufficient to keep blood glucose concentrations at prestimulatory levels. The explanation for the decrease in blood glucose concentration was probably the enhanced production of insulin in combination with an increased sensitivity to insulin during hyperglycaemia [ 15 ]. A further explanation could be an elevated urinary excretion of glucose during the meal at hyperglycaemia. This variable was not assessed during the study. Despite the decrease in blood glucose concentration during the meal at hyperglycaemia, glucose potentiation of the islet Bcell response to stimulation with the meal was evident using measurements of either plasma insulin or C-peptide. We conclude, that the B-cell response to both i.v. glucagon and a mixed meal are markedly potentiated by acutely established hyperglycaemia in well-controlled Type 2 diabetes mellitus. Acute prestimulatory hyperglycaemia is associated with a markedly decreased incremental C-peptide/insulin ratio after glucagon stimulation. Measurement of the insulin response after i.v. glucagon injection at hyperglycaemia compared with the response at normoglycaemia, therefore, seriously overestimates the relative glucose potentiation of pancreatic B-cell responsiveness in patients with well-controlled Type 2 diabetes mellitus. Acknowledgements. The study was supported by grants from Carlo Erba Pharmitalia, Milano, Italy, Novo-Nordisk A/S, Bagsv~erd,Denmark, and the Danish Diabetes Association. Measurements of plasma insulin were performed by Dr. Hans Orskov, Institute of Experimental Clinical Investigation, Arhus University, ~rhus Kommunehospital, Arhus, Denmark. Measurements of plasma proinsulin were performed by Dr. Rent Djurup, NIT Pilot Plant, Novo-Nordisk A/S, Bagsv~erd, Denmark. 1. Ward KW , Bolgiano DC , Mcknight B , Halter JB , Porte Jr D ( 1984 ) Diminished B-cell secretory capacity in patients with noninsulindependent diabetes mellitus . J Clin Invest 74 : 1318 - 1328 2. 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H. J. Gjessing, B. Reinholdt, O. Pedersen. The plasma C-peptide and insulin responses to stimulation with intravenous glucagon and a mixed meal in well-controlled Type 2 (non-insulin-dependent) diabetes mellitus: dependency on acutely established hyperglycaemia, Diabetologia, 1989, 858-863, DOI: 10.1007/BF00297450