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Influence of exogenous insulin on C-peptide levels in subjects with type 2 diabetes
Diabetes Research and Clinical Practice 68 (2005) 202–206 www.elsevier.com/locate/diabres
Influence of exogenous insulin on C-peptide levels in subjects with type 2 diabetes M. Albaredaa, M. Riglaa, J. Rodrı´guez-Espinosab, A. Caballeroa, A. Chicoa, R. Cabezasa, G. Carrerasa, A. Pe´reza,* a
Department of Endocrinology, Hospital Sant Pau, UAB, Sant Antonio Ma Claret, 167, 08025 Barcelona, Spain Department of Biochemistry, Hospital Sant Pau, UAB, Sant Antonio Ma Claret, 167, 08025 Barcelona, Spain
b
Received 26 May 2004; received in revised form 20 October 2004; accepted 22 October 2004 Available online 8 December 2004
Abstract Aim: The aim of this study was to determine whether the influence of insulin therapy on fasting and stimulated C-peptide levels in type 2 diabetic subjects is due to plasma glucose reduction or a direct effect of exogenous insulin. Methods: Plasma glucose and serum C-peptide levels were determined before and after IV injection of 1 mg glucagon on three separate days in 21 type 2 diabetic subjects. Day 1: without pharmacological treatment and fasting plasma glucose >11.1 mmol/ L; day 2: fasting plasma glucose 4.4–7.8 mmol/L, 1 h after withdrawing intravenous regular insulin infusion; day 3: fasting plasma glucose 4.4–7.8 mmol/L with bed-time NPH insulin. Results: Fasting and glucagon stimulated C-peptide levels were higher on day 1 than days 2 and 3. Fasting, but not stimulated Cpeptide levels, were lower on day 3 than day 2. These differences were not appeared when the percentage of C-peptide increment or the C-peptide/glucose ratio were compared in the three days. Conclusions: Blood glucose reduction instead of exogenous insulin is responsible for the C-peptide decrease during insulin therapy in type 2 diabetic subjects. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: C-peptide; Insulin treatment; Type 2 diabetes mellitus; Glucagon
1. Introduction Our previous decades, interest in the measurement of fasting and glucagon stimulated C-peptide levels has increased, as it may be of clinical benefit. In * Corresponding author. Tel.: +34 93 291 90 30; fax: +34 93 291 92 70. E-mail address: [email protected] (A. Pe´rez).
patients with diabetes, C-peptide concentration can help to differentiate type 1 and type 2 diabetes, to select the best treatment in patients with type 2 diabetes (insulin versus oral agents or insulinsensitizing versus insulin-secretagogue agents) and in the decision to discontinue insulin therapy, especially in obese subjects [1–4]. However, although C-peptide response to glucagon is one of the most reliable insulin secretion
0168-8227/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2004.10.005
M. Albareda et al. / Diabetes Research and Clinical Practice 68 (2005) 202–206
indicators because it is simple, safe and reproducible [5,6], its interpretation is difficult because of the lack of standardization and the influence of factors such as blood glucose levels and treatment with hypoglycemic drugs. Acute and chronic elevations of the prestimulatory blood glucose level potentiate the insulin response to glucagon [7,8], while acute and chronic reduction of blood glucose levels results in a decreased insulin response [7–9] and a blood glucose concentration below 3.5 mmol/L results in an almost total suppression of the stimulating glucagon action [10]. Furthermore, whether or not the decreased serum C-peptide concentration observed with insulin therapy is due to a blood glucose reduction or direct suppressive effect of exogenous insulin is not clear [9,11]. Thus, the aim of the present study was to clarify whether the effect of insulin therapy on fasting and glucagon stimulated C-peptide in type 2 diabetes is due to glycemic improvement or a direct effect of exogenous insulin.
2. Patients and methods Twenty-one subjects with type 2 diabetes with a mean age of 63.3 8.5 years, mean body mass index (BMI) of 26.9 5 kg/m2 and diabetes duration of 7.7 5 years participated in this study. Fifteen had previously been treated with oral anti-diabetic agents, four only with diet and two had been recently diagnosed (Table 1). All had normal values of plasma creatinine. No patient had an intercurrent illness and liver and thyroid function were normal. No subject
Table 1 Clinical characteristics of the 21 type 2 diabetic patients Patients Age (years) Sex (male/female) BMI (kg/m2) Diabetes duration (years) Creatinine concentration (mmol/L) HbA1c (%)
21 63.3 8.5 7/14 26.9 5 7.7 5 82 10 10.7 3
Previous treatment Diet only Oral anti-diabetic agents No treatment
4 15 2
203
was taking any medication, which altered glucose metabolism at the time of study. All patients had stopped oral anti-diabetic agents at least 48 h prior to hospitalization. The study was approved by the Local Ethics Board and informed consent was obtained from all patients. 2.1. Study design After admission to hospital, all patients were studied after a 12-h overnight fast on three separate days. Day 1 (hyperglycemia): patients were studied with a fasting plasma glucose concentration >11.1 mmol/L after at least 48 h without any hypoglycemic treatment except diet. Day 2 (nearnormoglycemia—iv regular insulin): the study was performed with fasting plasma glucose between 4.4 and 7.8 mmol/L, which was obtained with an overnight intravenous infusion of regular insulin. Based on a previous report of Gjessing et al. [12], insulin infusion was stopped 1 h before blood samples were obtained, in order to restore insulin levels. Day 3: (near-normoglycemia—NPH insulin): this study was also performed at levels of fasting plasma glucose between 4.4 and 7.8 mmol/L, which was maintained with bed-time NPH insulin. On each occasion, after placement of a cannula in an ante-cubital vein, blood specimens for plasma glucose and serum C-peptide determinations were obtained before and 6 min after an intravenous bolus of 1 mg of glucagon (Glucagon Gen Hypokit1, Novo Nordisk). Plasma glucose was determined by an oxidase method (Technicon RA-XT analyzer, Technicon Instruments, Tanytown, NT, USA). Serum C-peptide concentrations were measured by radioimmunoassay (RIA-Coat1 C-Peptide, Byk-Sangtec Diagnostica GmbH & Co-KG, RFA) with a limit of detection of 99 pmol/L. Intra- and inter-assay variability were <5 and <10%, respectively and cross-reactivity with proinsulin 25%. 2.2. Statistical analysis Data are shown as mean S.D. Differences in glucose and C-peptide concentrations between study days were assessed by two-way Anova and Student’s paired t-tests. A p-value of <0.05 was considered statistically significant.
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Fig. 1. Fasting and stimulated plasma glucose and C-peptide concentrations on the three studied days (day 1: hyperglycemia; day 2: nearnormoglycemia—iv regular insulin; day 3: near-normoglycemia—NPH insulin).
3. Results Fasting and glucagon stimulated plasma glucose and serum C-peptide concentrations on the three study days are shown in Fig. 1. As expected, mean fasting and stimulated plasma glucose was higher on day 1 (p < 0.001), but there was no difference between day 2 and day 3, while the increment of plasma glucose after glucagon administration was lower on day 1 (5.9%) than day 2 (14.8%) and day 3 (15%) (p < 0.05). Mean fasting C-peptide on day 1 (741.42 324.14 pmol/L) was higher than day 2 (476.86 310.77
pmol/L) and day 3 (343.4 215 pmol/L) (p < 0.001) (Fig. 1), but the ratio fasting C-peptide/fasting glucose was similar between the three days (data not shown). Stimulated C-peptide was higher on day 1 than the other two days (p < 0.001) (Fig. 1). The absolute increment of C-peptide after glucagon stimulation was also higher on day 1 (447.7 347.7 pmol/L) compared with day 2 (322.9 259.3 pmol/L) (p < 0.05), but not day 3 (331.6 251.9 pmol/L). However, no difference was found between the three study tests when the percentage of C-peptide increment was evaluated (76, 76.6 and 106%, respectively).
M. Albareda et al. / Diabetes Research and Clinical Practice 68 (2005) 202–206
4. Discussion In the present study we confirmed that the fasting and C-peptide response to glucagon are related to fasting plasma glucose in type 2 diabetes. However, our main finding is that glycemic control improvement rather than a direct inhibitory effect of exogenous insulin is presumably responsible for the C-peptide decrease during insulin therapy in type 2 diabetic subjects. The present study showed that acute (day 2) and subacute (day 3) improvement of glycemic control significantly decreased fasting C-peptide concentration and the C-peptide response to glucagon in type 2 diabetic subjects. These findings are in agreement with results of previous studies [8–12], and because hyperglycemia was chronic and near-normalisation of glycemia on day 2 was acute, the effect seems to be related to blood glucose reduction rather than to an improvement of insulin sensitivity. Moreover, the lack of differences between fasting C-peptide/plasma glucose ratios supports the determinant effect of glucose concentration on C-peptide levels. Furthermore, the C-peptide increment in response to glucagon or oral glucose tolerance testing does not seem to be influenced by the degree of glycemic control [9,13,14]. Accordingly, in our study, although the absolute increment of C-peptide in response to glucagon stimulation was higher on day 1 compared to day 2, no difference was observed between the three experimental situations when we considered the percentage of C-peptide increment. These data suggest that, for clinical purposes, simultaneous determination of C-peptide and plasma glucose concentrations or measurement of the increment of C-peptide response to glucagon may be advisable to exclude the effect of plasma glucose concentration [13,14]. Fasting Cpeptide determination may be prefered because it is easy to perform, but the C-peptide increment after glucagon stimulation may offer additional information and help to distinguish type 2 patients with different control with oral anti-diabetic agents [14]. In order to clarify whether exogenous insulin plays a role in the decreased C-peptide levels, we compared fasting and post-glucagon C-peptide after improvement of glycemic control with bed-time NPH insulin and intravenous regular insulin infusion, which was stopped 60 min before the glucagon test, in order to
205
restore insulin levels and avoid the direct insulin suppressive effect [9,12]. Under this condition (intravenous regular insulin infusion), taking into account that insulin given intravenously has a half-life of 5 min and a biological effect for about 20 min [15] and that in previous studies plasma insulin levels dropped to basal concentrations 30–60 min after stopping the insulin infusion [9,12,13], a direct effect of intravenous insulin infusion on C-peptide concentration is unlikely. Thus, our findings of similar stimulated C-peptide concentrations and C-peptide/ plasma glucose ratios in both study conditions, support our contention that the observed reduction in the C-peptide levels with insulin therapy are due to blood glucose reduction. In summary, we confirmed that plasma glucose concentration is the most important determinant of fasting and glucagon stimulated C-peptide and this effect is improved by estimation of fasting C-peptide/ plasma glucose ratio and the percentage of C-peptide increment after glucagon stimulation. In addition, our data suggest that insulin therapy does not have a direct effect, independently of plasma glucose reduction, on fasting and stimulated C-peptide concentration. These data could be of clinical relevance in evaluating and interpreting b-cell function in type 2 diabetic patients, although a clamp study and the assessment of insulin resistance in relation to b-cell function would be necessary to corroborate this. Acknowledgment This study was supported by FISC-03/08.
References [1] Diabetes control and complications trial (DCCT), Results of feasibility study, Diabetes Care 10 (1987) 1–19. [2] C. Hendriksen, O.K. Faber, J. Drejer, C. Binder, Treated diabetes evaluated by the plasma C-peptide response to intravenous glucagon, Diabetologia 13 (1977) 615–619. [3] P. Koskinen, J. Viikari, K. Irjala, H.L. Kaihola, P. Seppa¨ la¨ , Cpeptide determination in the choice of treatment in diabetes mellitus, Scand. J. Clin. Lab. Invest. 45 (1985) 589–597. [4] S. Madsbad, T. Krarup, P. McNair, et al. Practical clinical value of the C-peptide response to glucagon stimulation in the choice of treatment in diabetes mellitus, Acta Med. Scand. 210 (1981) 153–156.
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M. Albareda et al. / Diabetes Research and Clinical Practice 68 (2005) 202–206
[5] H.J. Gjessing, E.M. Damsgaard, L.E. Matzen, A. Fr1land, O.K. Faber, Reproducibility of B-cell function estimates in non-insulin-dependent diabetes mellitus, Diabetes Care 10 (1987) 558–562. [6] J.H. Juang, H.S. Huang, M.J. Huang, C-peptide response to glucagon in patients with non-insulin-dependent diabetes mellitus, J. Formosan Med. Assoc. 91 (1992) 491–496. [7] H.J. Gjessing, B. Reinholdt, O. Pedersen, The plasma Cpeptide and insulin responses to stimulation with intravenous glucagon and a mixed meal in well-controlled type 2 (noninsulin-dependent) diabetes mellitus: dependency on acutely established hyperglycemia, Diabetologia 32 (1989) 858– 863. [8] S.W. Park, S.H. Ihm, H.J. Yoo, J.Y. Park, K.U. Lee, Differential effects of ambient blood glucose level and degree of obesity on basal serum C-peptide level and the C-peptide response to glucose and glucagon in non-insulin-dependent diabetes mellitus, Diabetes Res. Clin. Pract. 37 (1997) 165–171. [9] I. Nosari, G. Lepore, M.L. Maglio, F. Cortinovis, G. Pagani, The effect of various blood glucose levels on post-glucagon Cpeptide secretion in type 2 (non-insulin-dependent) diabetes, J. Endocrinol. Invest. 15 (1992) 143–146.
[10] T. Ro¨ nnemaa, Practical aspects in performing the glucagon test in the measurement of C-peptide in diabetic patients, Scand. J. Clin. Lab. Invest. 46 (1986) 345–349. [11] T. Lindstro¨ m, H.J. Arnqvist, J. Ludvigsson, H.H. von Schenck, C-peptide profiles in patients with non-insulin-dependent diabetes mellitus before and during insulin treatment, Acta Endocrinol. 126 (1992) 477–483. [12] H.L. Gjessing, B. Reinhold, O. Pedersen, The effect of chronic hyperglycaemia on the islet b-cell responsiveness in newly diagnosed type 2 diabetes, Diabetic Med. 9 (1992) 601–604. [13] Y. Iwasaki, K. Kondo, H. Hasegawa, Y. Oiso, C-peptide response to glucagon in type 2 diabetes mellitus. A comparison with oral glucose tolerance test, Diabetes Res. 25 (1994) 129– 137. [14] R. Prando, P. Odetti, P. Melga, R. Giusti, E. Ciuchi, V. Cheli, Progressive deterioration of beta-cell function in nonobese type 2 diabetic subjects, Diabetes Metab. 22 (1996) 185–191. [15] P.D. Home, M. Massi-Benedetti, G.A. Shepherd, I. Hanning, K.G. Alberti, D.R. Owens, A comparison of the activity and disposal of semi-synthetic human insulin and porcine insulin in man by the glucose clamp tecnique, Diabetologia 22 (1982) 41–45.
Influence of exogenous insulin on C-peptide levels in subjects with type 2 diabetes M. Albaredaa, M. Riglaa, J. Rodrı´guez-Espinosab, A. Caballeroa, A. Chicoa, R. Cabezasa, G. Carrerasa, A. Pe´reza,* a
Department of Endocrinology, Hospital Sant Pau, UAB, Sant Antonio Ma Claret, 167, 08025 Barcelona, Spain Department of Biochemistry, Hospital Sant Pau, UAB, Sant Antonio Ma Claret, 167, 08025 Barcelona, Spain
b
Received 26 May 2004; received in revised form 20 October 2004; accepted 22 October 2004 Available online 8 December 2004
Abstract Aim: The aim of this study was to determine whether the influence of insulin therapy on fasting and stimulated C-peptide levels in type 2 diabetic subjects is due to plasma glucose reduction or a direct effect of exogenous insulin. Methods: Plasma glucose and serum C-peptide levels were determined before and after IV injection of 1 mg glucagon on three separate days in 21 type 2 diabetic subjects. Day 1: without pharmacological treatment and fasting plasma glucose >11.1 mmol/ L; day 2: fasting plasma glucose 4.4–7.8 mmol/L, 1 h after withdrawing intravenous regular insulin infusion; day 3: fasting plasma glucose 4.4–7.8 mmol/L with bed-time NPH insulin. Results: Fasting and glucagon stimulated C-peptide levels were higher on day 1 than days 2 and 3. Fasting, but not stimulated Cpeptide levels, were lower on day 3 than day 2. These differences were not appeared when the percentage of C-peptide increment or the C-peptide/glucose ratio were compared in the three days. Conclusions: Blood glucose reduction instead of exogenous insulin is responsible for the C-peptide decrease during insulin therapy in type 2 diabetic subjects. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: C-peptide; Insulin treatment; Type 2 diabetes mellitus; Glucagon
1. Introduction Our previous decades, interest in the measurement of fasting and glucagon stimulated C-peptide levels has increased, as it may be of clinical benefit. In * Corresponding author. Tel.: +34 93 291 90 30; fax: +34 93 291 92 70. E-mail address: [email protected] (A. Pe´rez).
patients with diabetes, C-peptide concentration can help to differentiate type 1 and type 2 diabetes, to select the best treatment in patients with type 2 diabetes (insulin versus oral agents or insulinsensitizing versus insulin-secretagogue agents) and in the decision to discontinue insulin therapy, especially in obese subjects [1–4]. However, although C-peptide response to glucagon is one of the most reliable insulin secretion
0168-8227/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2004.10.005
M. Albareda et al. / Diabetes Research and Clinical Practice 68 (2005) 202–206
indicators because it is simple, safe and reproducible [5,6], its interpretation is difficult because of the lack of standardization and the influence of factors such as blood glucose levels and treatment with hypoglycemic drugs. Acute and chronic elevations of the prestimulatory blood glucose level potentiate the insulin response to glucagon [7,8], while acute and chronic reduction of blood glucose levels results in a decreased insulin response [7–9] and a blood glucose concentration below 3.5 mmol/L results in an almost total suppression of the stimulating glucagon action [10]. Furthermore, whether or not the decreased serum C-peptide concentration observed with insulin therapy is due to a blood glucose reduction or direct suppressive effect of exogenous insulin is not clear [9,11]. Thus, the aim of the present study was to clarify whether the effect of insulin therapy on fasting and glucagon stimulated C-peptide in type 2 diabetes is due to glycemic improvement or a direct effect of exogenous insulin.
2. Patients and methods Twenty-one subjects with type 2 diabetes with a mean age of 63.3 8.5 years, mean body mass index (BMI) of 26.9 5 kg/m2 and diabetes duration of 7.7 5 years participated in this study. Fifteen had previously been treated with oral anti-diabetic agents, four only with diet and two had been recently diagnosed (Table 1). All had normal values of plasma creatinine. No patient had an intercurrent illness and liver and thyroid function were normal. No subject
Table 1 Clinical characteristics of the 21 type 2 diabetic patients Patients Age (years) Sex (male/female) BMI (kg/m2) Diabetes duration (years) Creatinine concentration (mmol/L) HbA1c (%)
21 63.3 8.5 7/14 26.9 5 7.7 5 82 10 10.7 3
Previous treatment Diet only Oral anti-diabetic agents No treatment
4 15 2
203
was taking any medication, which altered glucose metabolism at the time of study. All patients had stopped oral anti-diabetic agents at least 48 h prior to hospitalization. The study was approved by the Local Ethics Board and informed consent was obtained from all patients. 2.1. Study design After admission to hospital, all patients were studied after a 12-h overnight fast on three separate days. Day 1 (hyperglycemia): patients were studied with a fasting plasma glucose concentration >11.1 mmol/L after at least 48 h without any hypoglycemic treatment except diet. Day 2 (nearnormoglycemia—iv regular insulin): the study was performed with fasting plasma glucose between 4.4 and 7.8 mmol/L, which was obtained with an overnight intravenous infusion of regular insulin. Based on a previous report of Gjessing et al. [12], insulin infusion was stopped 1 h before blood samples were obtained, in order to restore insulin levels. Day 3: (near-normoglycemia—NPH insulin): this study was also performed at levels of fasting plasma glucose between 4.4 and 7.8 mmol/L, which was maintained with bed-time NPH insulin. On each occasion, after placement of a cannula in an ante-cubital vein, blood specimens for plasma glucose and serum C-peptide determinations were obtained before and 6 min after an intravenous bolus of 1 mg of glucagon (Glucagon Gen Hypokit1, Novo Nordisk). Plasma glucose was determined by an oxidase method (Technicon RA-XT analyzer, Technicon Instruments, Tanytown, NT, USA). Serum C-peptide concentrations were measured by radioimmunoassay (RIA-Coat1 C-Peptide, Byk-Sangtec Diagnostica GmbH & Co-KG, RFA) with a limit of detection of 99 pmol/L. Intra- and inter-assay variability were <5 and <10%, respectively and cross-reactivity with proinsulin 25%. 2.2. Statistical analysis Data are shown as mean S.D. Differences in glucose and C-peptide concentrations between study days were assessed by two-way Anova and Student’s paired t-tests. A p-value of <0.05 was considered statistically significant.
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M. Albareda et al. / Diabetes Research and Clinical Practice 68 (2005) 202–206
Fig. 1. Fasting and stimulated plasma glucose and C-peptide concentrations on the three studied days (day 1: hyperglycemia; day 2: nearnormoglycemia—iv regular insulin; day 3: near-normoglycemia—NPH insulin).
3. Results Fasting and glucagon stimulated plasma glucose and serum C-peptide concentrations on the three study days are shown in Fig. 1. As expected, mean fasting and stimulated plasma glucose was higher on day 1 (p < 0.001), but there was no difference between day 2 and day 3, while the increment of plasma glucose after glucagon administration was lower on day 1 (5.9%) than day 2 (14.8%) and day 3 (15%) (p < 0.05). Mean fasting C-peptide on day 1 (741.42 324.14 pmol/L) was higher than day 2 (476.86 310.77
pmol/L) and day 3 (343.4 215 pmol/L) (p < 0.001) (Fig. 1), but the ratio fasting C-peptide/fasting glucose was similar between the three days (data not shown). Stimulated C-peptide was higher on day 1 than the other two days (p < 0.001) (Fig. 1). The absolute increment of C-peptide after glucagon stimulation was also higher on day 1 (447.7 347.7 pmol/L) compared with day 2 (322.9 259.3 pmol/L) (p < 0.05), but not day 3 (331.6 251.9 pmol/L). However, no difference was found between the three study tests when the percentage of C-peptide increment was evaluated (76, 76.6 and 106%, respectively).
M. Albareda et al. / Diabetes Research and Clinical Practice 68 (2005) 202–206
4. Discussion In the present study we confirmed that the fasting and C-peptide response to glucagon are related to fasting plasma glucose in type 2 diabetes. However, our main finding is that glycemic control improvement rather than a direct inhibitory effect of exogenous insulin is presumably responsible for the C-peptide decrease during insulin therapy in type 2 diabetic subjects. The present study showed that acute (day 2) and subacute (day 3) improvement of glycemic control significantly decreased fasting C-peptide concentration and the C-peptide response to glucagon in type 2 diabetic subjects. These findings are in agreement with results of previous studies [8–12], and because hyperglycemia was chronic and near-normalisation of glycemia on day 2 was acute, the effect seems to be related to blood glucose reduction rather than to an improvement of insulin sensitivity. Moreover, the lack of differences between fasting C-peptide/plasma glucose ratios supports the determinant effect of glucose concentration on C-peptide levels. Furthermore, the C-peptide increment in response to glucagon or oral glucose tolerance testing does not seem to be influenced by the degree of glycemic control [9,13,14]. Accordingly, in our study, although the absolute increment of C-peptide in response to glucagon stimulation was higher on day 1 compared to day 2, no difference was observed between the three experimental situations when we considered the percentage of C-peptide increment. These data suggest that, for clinical purposes, simultaneous determination of C-peptide and plasma glucose concentrations or measurement of the increment of C-peptide response to glucagon may be advisable to exclude the effect of plasma glucose concentration [13,14]. Fasting Cpeptide determination may be prefered because it is easy to perform, but the C-peptide increment after glucagon stimulation may offer additional information and help to distinguish type 2 patients with different control with oral anti-diabetic agents [14]. In order to clarify whether exogenous insulin plays a role in the decreased C-peptide levels, we compared fasting and post-glucagon C-peptide after improvement of glycemic control with bed-time NPH insulin and intravenous regular insulin infusion, which was stopped 60 min before the glucagon test, in order to
205
restore insulin levels and avoid the direct insulin suppressive effect [9,12]. Under this condition (intravenous regular insulin infusion), taking into account that insulin given intravenously has a half-life of 5 min and a biological effect for about 20 min [15] and that in previous studies plasma insulin levels dropped to basal concentrations 30–60 min after stopping the insulin infusion [9,12,13], a direct effect of intravenous insulin infusion on C-peptide concentration is unlikely. Thus, our findings of similar stimulated C-peptide concentrations and C-peptide/ plasma glucose ratios in both study conditions, support our contention that the observed reduction in the C-peptide levels with insulin therapy are due to blood glucose reduction. In summary, we confirmed that plasma glucose concentration is the most important determinant of fasting and glucagon stimulated C-peptide and this effect is improved by estimation of fasting C-peptide/ plasma glucose ratio and the percentage of C-peptide increment after glucagon stimulation. In addition, our data suggest that insulin therapy does not have a direct effect, independently of plasma glucose reduction, on fasting and stimulated C-peptide concentration. These data could be of clinical relevance in evaluating and interpreting b-cell function in type 2 diabetic patients, although a clamp study and the assessment of insulin resistance in relation to b-cell function would be necessary to corroborate this. Acknowledgment This study was supported by FISC-03/08.
References [1] Diabetes control and complications trial (DCCT), Results of feasibility study, Diabetes Care 10 (1987) 1–19. [2] C. Hendriksen, O.K. Faber, J. Drejer, C. Binder, Treated diabetes evaluated by the plasma C-peptide response to intravenous glucagon, Diabetologia 13 (1977) 615–619. [3] P. Koskinen, J. Viikari, K. Irjala, H.L. Kaihola, P. Seppa¨ la¨ , Cpeptide determination in the choice of treatment in diabetes mellitus, Scand. J. Clin. Lab. Invest. 45 (1985) 589–597. [4] S. Madsbad, T. Krarup, P. McNair, et al. Practical clinical value of the C-peptide response to glucagon stimulation in the choice of treatment in diabetes mellitus, Acta Med. Scand. 210 (1981) 153–156.
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M. Albareda et al. / Diabetes Research and Clinical Practice 68 (2005) 202–206
[5] H.J. Gjessing, E.M. Damsgaard, L.E. Matzen, A. Fr1land, O.K. Faber, Reproducibility of B-cell function estimates in non-insulin-dependent diabetes mellitus, Diabetes Care 10 (1987) 558–562. [6] J.H. Juang, H.S. Huang, M.J. Huang, C-peptide response to glucagon in patients with non-insulin-dependent diabetes mellitus, J. Formosan Med. Assoc. 91 (1992) 491–496. [7] H.J. Gjessing, B. Reinholdt, O. Pedersen, The plasma Cpeptide and insulin responses to stimulation with intravenous glucagon and a mixed meal in well-controlled type 2 (noninsulin-dependent) diabetes mellitus: dependency on acutely established hyperglycemia, Diabetologia 32 (1989) 858– 863. [8] S.W. Park, S.H. Ihm, H.J. Yoo, J.Y. Park, K.U. Lee, Differential effects of ambient blood glucose level and degree of obesity on basal serum C-peptide level and the C-peptide response to glucose and glucagon in non-insulin-dependent diabetes mellitus, Diabetes Res. Clin. Pract. 37 (1997) 165–171. [9] I. Nosari, G. Lepore, M.L. Maglio, F. Cortinovis, G. Pagani, The effect of various blood glucose levels on post-glucagon Cpeptide secretion in type 2 (non-insulin-dependent) diabetes, J. Endocrinol. Invest. 15 (1992) 143–146.
[10] T. Ro¨ nnemaa, Practical aspects in performing the glucagon test in the measurement of C-peptide in diabetic patients, Scand. J. Clin. Lab. Invest. 46 (1986) 345–349. [11] T. Lindstro¨ m, H.J. Arnqvist, J. Ludvigsson, H.H. von Schenck, C-peptide profiles in patients with non-insulin-dependent diabetes mellitus before and during insulin treatment, Acta Endocrinol. 126 (1992) 477–483. [12] H.L. Gjessing, B. Reinhold, O. Pedersen, The effect of chronic hyperglycaemia on the islet b-cell responsiveness in newly diagnosed type 2 diabetes, Diabetic Med. 9 (1992) 601–604. [13] Y. Iwasaki, K. Kondo, H. Hasegawa, Y. Oiso, C-peptide response to glucagon in type 2 diabetes mellitus. A comparison with oral glucose tolerance test, Diabetes Res. 25 (1994) 129– 137. [14] R. Prando, P. Odetti, P. Melga, R. Giusti, E. Ciuchi, V. Cheli, Progressive deterioration of beta-cell function in nonobese type 2 diabetic subjects, Diabetes Metab. 22 (1996) 185–191. [15] P.D. Home, M. Massi-Benedetti, G.A. Shepherd, I. Hanning, K.G. Alberti, D.R. Owens, A comparison of the activity and disposal of semi-synthetic human insulin and porcine insulin in man by the glucose clamp tecnique, Diabetologia 22 (1982) 41–45.