Diabetologia

, Volume 55, Issue 12, pp 3392–3395

Acarbose treatment enhances mid-regional pro-atrial natriuretic peptide concentrations in non-diabetic individuals: further evidence for a common cardiometabolic pathway?

Authors

    • Department of Clinical NutritionGerman Institute of Human Nutrition Potsdam
    • Department of Endocrinology, Diabetes and NutritionCharité Universitätsmedizin Berlin
  • O. Pivovarova
    • Department of Clinical NutritionGerman Institute of Human Nutrition Potsdam
    • Department of Endocrinology, Diabetes and NutritionCharité Universitätsmedizin Berlin
  • A. Traberth
    • Department of Clinical NutritionGerman Institute of Human Nutrition Potsdam
    • Department of Endocrinology, Diabetes and NutritionCharité Universitätsmedizin Berlin
  • A. Sparwasser
    • Thermo Fisher Scientific, BRAHMS (part of Thermo Fisher Scientific), Biotechnology Centre Hennigsdorf
  • M. O. Weickert
    • Department of Clinical NutritionGerman Institute of Human Nutrition Potsdam
    • Department of Endocrinology, Diabetes and NutritionCharité Universitätsmedizin Berlin
    • Warwickshire Institute for the Study of Diabetes, Endocrinology and MetabolismUniversity Hospitals Coventry and Warwickshire
    • Division of Metabolic & Vascular Health, Warwick Medical SchoolUniversity of Warwick
  • W. Bernigau
    • Department of EpidemiologyGerman Institute of Human Nutrition Potsdam
  • A. L. Birkenfeld
    • Department of Endocrinology, Diabetes and NutritionCharité Universitätsmedizin Berlin
  • A. M. Arafat
    • Department of Endocrinology, Diabetes and NutritionCharité Universitätsmedizin Berlin
  • A. Bergmann
    • Thermo Fisher Scientific, BRAHMS (part of Thermo Fisher Scientific), Biotechnology Centre Hennigsdorf
  • A. F. H. Pfeiffer
    • Department of Clinical NutritionGerman Institute of Human Nutrition Potsdam
    • Department of Endocrinology, Diabetes and NutritionCharité Universitätsmedizin Berlin
Research Letter

DOI: 10.1007/s00125-012-2724-9

Cite this article as:
Rudovich, N., Pivovarova, O., Traberth, A. et al. Diabetologia (2012) 55: 3392. doi:10.1007/s00125-012-2724-9

Keywords

Acarbose Mid-regional pro-atrial natriuretic peptide Type 2 diabetes

Abbreviations

CVD

Cardiovascular disease

MR-proANP

Mid-regional pro-atrial NP

NP

Natriuretic peptide

proANP

Pro-atrial natriuretic peptide

STOP-NIDDM

Study to Prevent NIDDM

To the Editor: Heinisch et al reported that acute infusion of B-type natriuretic peptide (NP) enhances the initial glucose distribution, resulting in a decrease of postload glucose concentrations by beta cell-independent mechanisms in healthy individuals [1]. This study added to growing evidence regarding a close pathophysiological link between NPs and metabolic traits in obesity, type 2 diabetes and associated diseases [2]. The mechanisms by which NP regulates glucose metabolism are not fully understood, but a reciprocal relationship between glucose regulation and NP has been suggested in type 2 diabetes and cardiovascular diseases (CVDs) [1, 2]. In addition, we and others observed the same type of relations between insulin and NP in obesity [3, 4]. Previous large-cohort observations such as the Study to Prevent NIDDM (STOP-NIDDM) [5, 6] indicate that reduction of postprandial glucose load may be involved in the prevention of both type 2 diabetes and incident hypertension, pointing to a potential ‘bi-directional relationship’ between metabolic and cardiovascular pathways. Unfortunately, STOP-NIDDM was not designed to characterise the mechanisms of acarbose action.

We here investigated whether acarbose-induced modulation of postprandial glucose levels affects mid-regional pro-atrial NP (MR-proANP), which is a stable fragment of N-terminal pro-atrial NP (proANP). This was a single-centre double-blind randomised placebo-controlled crossover study in individuals with different stages of glucose tolerance (Fig. 1; registered trial number ISRCTN40281673; the complete information regarding participants' allocation, primary outcome and side effects has previously been published in Rudovich et al [7]). Following a wash-out period of glucose-lowering medication for at least 3 weeks, the participants were randomised to one of two interventions: placebo–acarbose (n = 32) and acarbose–placebo (n = 31). Four individuals discontinued the study because of dissatisfaction with the allocated intervention or lack of time to participate. Three individuals were excluded because of adverse events (gastrointestinal discomfort, all receiving acarbose treatment), and one was excluded because of a drug-unrelated serious adverse event (ischaemic insult). Thus, 55 participants (n = 20 individuals with type 2 diabetes; n = 35 individuals without diabetes) were eligible for the final analyses.
https://static-content.springer.com/image/art%3A10.1007%2Fs00125-012-2724-9/MediaObjects/125_2012_2724_Fig1_HTML.gif
Fig. 1

Study design and participants' disposition. This was a single-centre double-blind randomised placebo-controlled crossover study in individuals with different stages of glucose tolerance. Placebo and acarbose were administered in the same manner. (S)AE, (serious) adverse effect; TID, three times daily

The study protocol was approved by the ethical committees of Potsdam University and Brandenburg, Germany. All study participants gave informed consent. Details of recruitment and phenotyping (individuals with type 2 diabetes/individuals without diabetes: age 60.7 ± 9.4/57.0 ± 5.4 years, 47.4/44.4% female and 52.6/55.6% male, BMI 31.9 ± 5.5/31.4 ± 3.1 kg/m2, waist circumference 105.1 ± 13.7/102.4 ± 7.8 cm and HbA1c 6.2 ± 0.8/5.7 ± 0.5%) of study participants were published recently [7]. Eligible patients were randomised to receive either acarbose (300 mg/day in three divided doses; Glucobay, BayerVital, Leverkusen, Germany) followed by placebo or vice versa, with each administered for 12 weeks, with a 12 week wash-out between interventions. Liquid-meal challenge tests were performed for 240 min using a commercial preparation (Biosorb Energie; Pfrimmer Nutricia, Erlangen, Germany; 77.6 g carbohydrate, 22.3 g fat, 24 g protein, 2,510 kJ per 400 ml) after a 12 h overnight fast. In accordance with the treatment period, either 100 mg acarbose or placebo was given immediately at the start of the meal challenges. Pre-treatment experiments were conducted without drug exposition. Further venous blood samples for the analysis of hormones and blood glucose were taken at −20, −10, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210 and 240 min, timed from ingestion of the meal. Changes in fasting MR-proANP were measured using an immunoassay (MR-proANP immunoluminometric assay (LIA); BRAHMS, Hennigsdorf, Germany).

Individuals with type 2 diabetes had higher HbA1c levels and postprandial glycaemic responses, but the anthropometric data and lipid profiles were not different between the groups (data not shown). During the 12 weeks of treatment, no significant changes in body weight were observed with exposure to placebo or acarbose (Table 1). Nevertheless, all analyses of acarbose effects were adjusted for changes in body weight. Fasting blood glucose and insulin levels remained unchanged during acarbose treatment in both groups (data not shown). As expected, a moderate but significant reduction of postprandial glycaemia by acarbose was observed during the liquid-meal tests (Table 1). The effect on postprandial blood glucose levels was accompanied by a decrease in postprandial insulin concentrations during acarbose treatment (Table 1). In individuals without diabetes, fasting levels of MR-proANP increased after 12 weeks of acarbose treatment (median [range] 23.6% of baseline [from +37.1 to +12.7%], p = 0.001; Table 1). Moreover, changes in fasting MR-proANP levels (week 0–week 12) correlated negatively with changes in the incremental AUC ΔAUCinsulin(week 0–week 12) (r =−0.53, p < 0.0001) and with changes in ΔAUCglucose(week 0–week 12) was observed (r =−0.32, p = 0.02). In individuals with type 2 diabetes, changes in fasting MR-proANP levels failed to reach significance. This was probably related to reduced power in this smaller subgroup, though a potential influence of treatment e.g. with metformin on MR-proANP levels cannot be finally excluded (Table 1).
Table 1

Effects of acarbose treatment on body weight, postprandial glycaemic and insulinogenic response and fasting MR-proANP levels in non-diabetic participants (n = 35) and participants with type 2 diabetes (n = 20)

Variable/marker

Placebo

Acarbose

p valuea

Baseline (week 0)

End of treatment (week 12)

Baseline (week 0)

End of treatment (week 12)

Non-diabetic participants (n = 35)

     

  Body weight (kg)b

88.5 ± 14.3

88.6 ± 14.5

90.0 ± 13.3

88.4 ± 14.3

0.054

  AUCglucose (0–240 min) (mmol/l × min)

230.3 ± 168.1

197.4 ± 133.3

208.4 ± 187.2

124.6 ± 152.8

0.014

  AUCinsulin (0–240 min) (pmol/l × min [×103])

63.5 ± 43.1

65.8 ± 37.2

68.0 ± 37.3

41.6 ± 25.2

<0.001

  Fasting MR-proANP (pmol/l)

60.8 ± 30.1

53.8 ± 29.0

54.9 ± 28.8

63.9 ± 29.3

0.001

Participants with type 2 diabetes (n = 20)

     

  Body weight (kg)b

91.6 ± 16.5

91.3 ± 15.7

92.4 ± 15.8

91.5 ± 15.9

0.421

  AUCglucose (0–240 min) (mmol/l × min)

372.3 ± 213.8

363.9 ± 273.6

409.6 ± 227.9

251.4 ± 211.3

0.034

  AUCinsulin (0–240 min) (pmol/l × min [×103])

80.0 ± 55.5

90.0 ± 120.4

76.8 ± 52.1

61.8 ± 40.5

0.307

  Fasting MR-proANP (pmol/l)

75.7 ± 30.5

70.2 ± 23.4

67.0 ± 24.4

73.9 ± 29.2

0.095

Values are mean ± SD

Mixed linear models include participant as random factor, treatment type (acarbose or placebo), treatment sequence (acarbose followed by placebo or vice versa), the period effect, the baseline levels of each treatment period and changes in the body weight (t 12t 0) as covariates

aLevel of significance based on differences in treatment effects between interventions, evaluated by comparisons of end-of-treatment levels from both treatment periods with that of the first-period baseline

bMixed linear models include participant as random factor, treatment as fixed factor and values at week 0 as covariates

Treatment with acarbose led to an increase in MR-proANP levels in individuals without diabetes that was strongly correlated with a reduction of postprandial insulin and glucose levels. Thus, although the observed acarbose-induced increase in circulating MR-proANP levels was relatively small, it still may contribute to assumed cardioprotective and antihypertensive effects of this drug, as indicated by results from the STOP-NIDDM study, and may provide further evidence for the existence of a ‘common cardiometabolic pathway’ [1, 2].

We observed no significant changes in body weight, insulin sensitivity or markers of systemic inflammation in the present study during the 3 month acarbose treatment [7], supporting that treatment with acarbose might have influenced the observed upregulation of MR-proANP via changes in postprandial insulin responses, and further indicating a potential direct role of insulin in the regulation of ANP-secretion and/or clearance [3].

Given the careful selection of our study participants, all participants had comparable insulin sensitivity and seemed to be in good glycaemic control [7]; we were, however, unable to demonstrate a significant increase in MR-proANP in the individuals with type 2 diabetes, possibly because of the short treatment time, issues related to reduced power in this subgroup, and potential effects of pre-treatment with other drugs such as metformin. Another explanation may be loss of insulin-dependent regulation of ANP in individuals with diabetes. Further studies are needed to investigate the potential relation between glucose and insulin-modulating effects of glucose-lowering drugs and their consequences regarding the NP system and potential prevention of CVD.

Trial registration International Standard Randomised Controlled Trial Number Register ISRCTN40281673

Acknowledgements

We thank all study participants for their cooperation. We gratefully acknowledge the technical assistance of A. Wagner, M. Hannemann, K. Sprengel, S. Baeker, J. Bogusch, A. Herzberg, U. Zingler and J. Inderthal.

Funding

The study was supported in part by grants from the Bundesministerium für Bildung und Forschung (MGP 0313042C/ NR, MOW, AFHP), from Bayer Vital, Leverkusen, Germany and from BRAHMS, Berlin-Hennigsdorf, Germany.

Duality of interest

A. Sparwasser and A. Bergmann are employees of BRAHMS (part of Thermo Fisher Scientific), Biotechnology Centre, Hennigsdorf, Berlin, Germany, a company that manufactures and holds patent rights on the MR-proANP assay.

Contribution statement

NR and AFHP were responsible for the conception and design of study. NR, OP and AT conducted the study. NR, OP, AT, AS, AB, WB, MOW, ALB, AMA and AFHP contributed to the acquisition, review, analysis and discussion of data. NR was responsible for drafting the manuscript. OP, AT, AS, WB, MOW, AB, ALB, AMA and AFHP contributed to the critical revision of the manuscript for important intellectual content. All authors approved the final version.

Copyright information

© Springer-Verlag 2012