Copeptin and Estimated Insulin Sensitivity in Adults With and Without Type 1 Diabetes: The CACTI Study

doi:10.1016/j.jcjd.2018.03.006

Canadian Journal of Diabetes

Volume 43, Issue 1, February 2019, Pages 34-39

https://doi.org/10.1016/j.jcjd.2018.03.006 Get rights and content

Abstract

Objectives

Copeptin, a surrogate marker for vasopressin, is elevated in participants with insulin resistance (IR) and type 2 diabetes. Whereas adults with type 1 diabetes also demonstrate elevated copeptin concentrations and IR compared to controls without diabetes, the relationship between copeptin and IR in type 1 diabetes is unclear.

Methods

Participants with (n=209) and without (n=244) type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, vitals, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, glycated hemoglobin and lipid panels. Estimated insulin sensitivity (eIS) was calculated by validated equations in participants with and without type 1 diabetes. The relationships among copeptin, IR, waist circumference (WC) and body mass index (BMI) were examined with unadjusted and adjusted linear regression models.

Results

Copeptin was correlated with eIS (R=–0.17, R²=0.029), WC (R=0.16, R²=0.026) and BMI (R=0.22, R²=0.048) for type 1 diabetes and with eIS (R=–0.37, R²=0.14), WC (R=0.40, R²=0.16) and BMI (R=0.25, R²=0.063) in non-type 1 diabetes. In multivariable analysis, copeptin correlated with total cholesterol (beta±SE: −0.12±0.04, p=0.008) and low-density lipoprotein (beta±SE: −0.11±0.04, p=0.01) in type 1 diabetes. In non-type 1 diabetes, copeptin was associated with WC (beta±SE: 0.14±0.04, p=0.0024), BMI (beta±SE: 0.13±0.04, p=0.007) and eIS (beta±SE: −0.14±0.04, p=0.0013).

Conclusions

Copeptin does not correlate with markers of IR in type 1 diabetes but strongly correlates in non-type 1 diabetes. Thus, elevated vasopressin activity and IR appear to be independent risk factors for vascular complications in type 1 diabetes.

Résumé

Objectifs

La copeptine, un marqueur de substitution de la vasopressine, est élevée chez les individus présentant une insulino-résistance (IR) et un diabète de type 2. Alors que les adultes atteints de diabète de type 1 présentent également des concentrations élevées de copeptine et une IR par rapport aux témoins non diabétiques, la relation entre la copeptine et l'IR dans le diabète de type 1 n'est pas claire.

Méthodes

Les individus avec (n=209) et sans (n=244) diabète de type 1 dans l'étude Calcification de l'artère coronaire dans le diabète de type 1 (CACTI) ont été évalués pour la copeptine sérique, les signes vitaux, le taux de filtration glomérulaire estimé, le rapport urinaire albumine-creatinine, l'hémoglobine glyquée et le profil lipidique. L'estimation de la sensibilité à l'insuline (eIS) a été calculée à l'aide d'équations validées chez les individus avec ou sans diabète de type 1. Les relations entre la copeptine, l'IR, le tour de taille (WC) et l'indice de masse corporelle (BMI) ont été examinées avec des modèles de régression linéaire non ajustés et ajustés.

Résultats

La copeptine s'est trouvée corrélée avec l'eIS (R=−0.17, R²=0.029), le WC (R=0.16, R²=0.026) et le BMI (R=0.22, R²=0.048) pour le diabète de type 1 et avec l'eIS (R=- 0,37, R²=0,14), le WC (R=0,40, R²=0,16) et leBMI (R=0,25, R²=0,063) pour le diabète non associé au type 1. En analyse multivariée, la copeptine s'est trouvée corrélée avec le cholestérol total (beta±SE: −0.12±0.04, p=0.008) et la lipoprotéine de basse densité (beta±SE: −0.11±0.04, p=0.01) dans le diabète de type 1. Dans le diabète non associé au type 1, la copeptine était associée au WC (beta±SE: 0.14±0.04, p=0.0024), le BMI (beta±SE: 0.13±0.04, p=0.007) et l'eIS (beta±SE: −0.14±0,04, p=0,0013).

Conclusions

La copeptine n'est pas corrélée aux marqueurs d'IR dans le diabète de type 1, mais elle y est fortement corrélée dans le diabète non associé au type 1. Ainsi, une activité élevée de la vasopressine et l'IR semblent être des facteurs de risque indépendants de complications vasculaires dans le diabète de type 1.

Introduction

Vasopressin is elevated in people with type 1 and type 2 diabetes mellitus (1). Serum carboxyterminal provasopressin, or copeptin, is a reliable surrogate marker for vasopressin that has a longer half-life (2) and has been shown to be associated with insulin resistance (IR) and vascular complications in adults with obesity and type 2 diabetes 3, 4. Elevated serum copeptin can also predict the development of type 2 diabetes (5) and is elevated in subjects with type 2 diabetes, where its presence confers increased risk for both cardiovascular disease (CVD) and diabetic kidney disease (DKD) and for mortality 6, 7. Similarly, in type 1 diabetes, we, along with others, have demonstrated that elevated copeptin is associated with CVD and DKD 8, 9. People with type 1 diabetes have an increasing prevalence of obesity and IR, which mirrors the recent trends in the general population over the past several decades (10). This alarming development of obesity in people with type 1 diabetes translates to additional risk factors for DKD and CVD (11).

Yet it remains unclear whether elevated copeptin (and, thus, vasopressin) correlates with IR and measures of central adiposity in type 1 diabetes as observed in those with obesity and type 2 diabetes. Given that elevated copeptin and IR both predict vascular complications in type 1 diabetes, it is possible that vasopressin may promote CVD and DKD through the development of IR. Accordingly, we hypothesized that copeptin would correlate with estimated insulin sensitivity (eIS), body mass index (BMI) and waist circumference (WC) in adults with type 1 diabetes.

Section snippets

Participants

The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (Clinical Trials NCT00005754) enrolled subjects 19 to 56 years of age, with type 1 diabetes (209) and without type 1 diabetes (244), who were asymptomatic for CVD at the baseline visit between 2000 and 2002 and then were re-examined 3, 6 and 14 years later. The study was approved by the Colorado Multiple Institutional Review Board, and all participants provided informed consent. This particular analysis involves data obtained at

Characteristics stratified by type 1 diabetes status

Table 1 describes the characteristics of participants with and without type 1 diabetes. The most prominent differences between the 2 groups were the higher copeptin concentrations and the lower eIS in those with type 1 diabetes compared to their peers without diabetes. As expected, participants with type 1 diabetes also had higher UACR, fasting glucose and A1C levels but similar eGFRs. Despite being more insulin resistant, participants with type 1 diabetes had better lipid profiles, lower DBPs

Discussion

Our study is the first to define the relationships between copeptin, a marker of vasopressin, and IR in adults with type 1 diabetes in comparison to those without type 1 diabetes. The major finding of our study is that unlike in non-type 1 diabetes, copeptin did not correlate with eIS, BMI or WC. Furthermore, fasting blood glucose, A1C and adiponectin levels did associate with copeptin after age, sex, ACEi use and eGFR adjustments were made in adults without type 1 diabetes, but they did not

Conclusions

Our study is the first to define the relationship between copeptin, a surrogate for vasopressin, and markers of IR in adults with and without type 1 diabetes. In adults without type 1 diabetes, we found strong associations with traditional metabolic measures, such as BMI, WC, FBG and eIS. Despite having significantly higher concentrations of copeptin and lower eIS compared to patients without diabetes, copeptin was not associated with eIS in patients with type 1 diabetes. Therefore, it appears

Acknowledgments

Support for this study was provided by National Institutes of Health grants T32-DK063687, R01HL113029, HL61753, HL79611 and HL113029 and the Denver Eating Recovery Center Clinical Investigation Core P30 DK57516 and JDRF grant 17-2013-313. The study was performed at the Adult Colorado Clinical Translational Research at University of Colorado, Denver, supported by NIH-M01-RR00051 and Clinical and Translational Science Awards grant UL1 TR001082, at the Barbara Davis Center for Childhood Diabetes

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Arginine Vasopressin (AVP) is one of the key hormones in the human body. AVP is clinically important because it maintains body fluid balance and vascular tone. Unfortunately, AVP laboratory measurements are always difficult and with low accuracy. Copeptin, the C-terminal of the AVP precursor, is released in equal amounts with AVP, making it a sensitive marker of AVP release. Despite being a non-specific biomarker, copeptin earned a lot of attention as a novel biomarker due to easy and quick laboratory measurements. Recent studies have reported the critical role of copeptin as a clinical indicator, especially in the diagnosis and prognosis of many diseases. Besides, it was reported that the combination between copeptin and gold standard biomarkers improved the prognostic values of those biomarkers. In this review, the role of copeptin as a new predictive diagnostic and prognostic biomarker of various diseases is highlighted according to the most recent studies. In addition, the importance of using copeptin as a marker in different medical departments and the impact of this on improving healthcare service was discussed.
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Plasma copeptin level is higher not only in patients with type 2 diabetes mellitus but also in patients with type 1 diabetes mellitus [119]. A recent study has revealed that copeptin did not correlate with markers of insulin resistance in type 1 diabetes mellitus but strongly correlates in non-type 1 diabetes mellitus [120]. Plasma copeptin levels were lower in individuals with bipolar disorders in comparison to healthy controls.
From its identification and isolation in 1954, arginine vasopressin (AVP) has attracted attention, not only for its peripheral functions such as vasoconstriction and reabsorption of water from kidney, but also for its central effects. As there is now considerable evidence that AVP plays a crucial role in feeding behavior and energy balance, it has become a promising therapeutic target for treating obesity or other obesity-related metabolic disorders. However, the underlying mechanisms for AVP regulation of these central processes still remain largely unknown. In this review, we will provide a brief overview of the current knowledge concerning how AVP controls energy balance and feeding behavior, focusing on physiological aspects including the relationship between AVP, circadian rhythmicity, and glucocorticoids.
The potential value of Copeptin and Pentraxin3 for evaluating the severity of coronary stenosis in patients with coronary artery disease
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Therefore, these results encourage us to explore the potential predicting capacities of CPP and PTX3 for MACEs in future prospective studies. Moreover, recent studies showed that CPP positively correlated with total cholesterol and low-density lipoprotein in patients with type 1 diabetes and reduced PTX3 was associated with improved blood lipid levels under rosuvastatin administration in elderly patients with AMI indicating the potential roles of CPP and PTX3 underlying molecular mechanisms of lipid dysregulation in atherosclerosis [17,18]. Additionally, in light of successful clinical applications of PCSK9 inhibitors for lipid management [19,20], plasma CPP and PTX3 may also be considered as novel targets for future therapeutic strategy for CAD patients.
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The extent of coronary atherosclerosis was accessed by the angiography-based quantitative measurement Gensini score (GS). Blood levels of Brain natriuretic peptide, Copeptin (CPP), Phosphodiesterase 9A, and Pentraxin3 (PTX3) were measured in 56 patients divided into three levels as low GS (n = 17), intermediate GS (n = 19) and high GS (n = 20) based on GS tertiles.
We found that plasma concentrations of CPP and PTX3 were significantly elevated in patients with high GS compared with the low GS group. In addition, Pearson correlation analysis showed that CPP and PTX3 were positively correlated with the GS. Furthermore, Receiver operating characteristics analysis demonstrated that both CPP and PTX3 exhibited discriminative capacities for evaluating the extent of coronary stenosis.
Laboratory tests of CPP and PTX3 via non-invasive means may provide novel information for risk stratification and disease management in CAD patients before invasive angiographic approaches. This study opens the door for enormous opportunities to explore new biomarkers with better efficiency, sensitivity and specificity as alternative/additional methods for evaluating the severity of coronary atherosclerosis in CAD patients in future research.
The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?
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Both experimental and observational studies report glomerular hyperfiltration in response to hyperglycemia as an early clinical entity of diabetes.15–17 In addition to an increased sodium reabsorption due to SGLT upregulation and hyperfiltration, the renin-angiotensin-aldosterone system can be activated in diabetes, which stimulates sodium reabsorption through the epithelial sodium channel,18,19 as well as the elevation of vasopressin levels induces antinatriuretic effects20–25 by increasing the mRNA expression and subsequent protein abundance of NKA.26,27 Taking all these diabetes-induced alterations into account, mathematical modeling of the rat nephron has predicted an increase in sodium transport and sodium transport–dependent QO2 by ∼50% and 100%, respectively.16
Diabetic kidney disease is the most common cause of end-stage kidney disease and poses a major global health problem. Finding new, safe, and effective strategies to halt this disease has proven to be challenging. In part that is because the underlying mechanisms are complex and not fully understood. However, in recent years, evidence has accumulated suggesting that chronic hypoxia may be the primary pathophysiological pathway driving diabetic kidney disease and chronic kidney disease of other etiologies and was called the chronic hypoxia hypothesis. Hypoxia is the result of a mismatch between oxygen delivery and oxygen demand. The primary determinant of oxygen delivery is renal perfusion (blood flow per tissue mass), whereas the main driver of oxygen demand is active sodium reabsorption. Diabetes mellitus is thought to compromise the oxygen balance by impairing oxygen delivery owing to hyperglycemia-associated microvascular damage and exacerbate oxygen demand owing to increased sodium reabsorption as a result of sodium–glucose cotransporter upregulation and glomerular hyperfiltration. The resultant hypoxic injury creates a vicious cycle of capillary damage, inflammation, deposition of the extracellular matrix, and, ultimately, fibrosis and nephron loss. This review will frame the role of chronic hypoxia in the pathogenesis of diabetic kidney disease and its prospect as a promising therapeutic target. We will outline the cellular mechanisms of hypoxia and evidence for renal hypoxia in animal and human studies. In addition, we will highlight the promise of newer imaging modalities including blood oxygenation level–dependent magnetic resonance imaging and discuss salutary interventions such as sodium–glucose cotransporter 2 inhibition that (may) protect the kidney through amelioration of renal hypoxia.
SGLT2 inhibition increases serum copeptin in young adults with type 1 diabetes
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During hyperglycaemia, the change in copeptin in response to SGLT2i inversely correlated with the change in plasma aldosterone concentration (r = −0.33, P = 0.037, Table 3). Previous studies have reported elevated concentrations of copeptin even in people with well controlled T1D compared to healthy controls [17]. Although diuresis secondary to glycosuria is thought to partially explain such observations, the mechanisms are not clear.
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In this post-hoc, exploratory analysis, serum copeptin, glomerular filtration rate (GFR_Inulin), effective renal plasma flow (ERPF_PAH), plasma renin angiotensin aldosterone system markers, HbA_1c, 24-hour urine volume and sodium excretion were measured in 40 participants with T1D (24.3 ± 5.1 years) during eu- and hyperglycaemia before and after 8 weeks of 25 mg of daily empagliflozin.
Higher baseline copeptin correlated with higher HbA_1c, lower 24-hour urine volume and sodium excretion, after correcting for age, sex, systolic blood pressure, and HbA_1c. Copeptin concentrations increased in response to empagliflozin under euglycaemia (4.1 ± 2.1 to 5.1 ± 2.8 pmol/L, P = 0.0053) and hyperglycaemia (3.3 ± 1.4 to 5.6 ± 2.8 pmol/L, P < 0.0001). The rise in copeptin in response to empagliflozin correlated with change in 24-hour urine volume, but was independent of changes in fractional excretion of sodium and haematocrit.
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Original ResearchCopeptin and Estimated Insulin Sensitivity in Adults With and Without Type 1 Diabetes: The CACTI Study

Abstract

Objectives

Methods

Results

Conclusions

Résumé

Objectifs

Méthodes

Résultats

Conclusions

Introduction

Section snippets

Participants

Characteristics stratified by type 1 diabetes status

Discussion

Conclusions

Acknowledgments

J Diabetes Complicat

Eur J Pharmacol

Diabetes Res Clin Pract

Eur J Obstet Gynecol Reprod Biol

J Diabetes Complicat

Vasopressin and diabetes mellitus

Nephron

Copeptin, a marker of vasopressin, in abdominal obesity, diabetes and microalbuminuria: The prospective Malmo Diet and Cancer Study cardiovascular cohort

Int J Obes (Lond)

Copeptin predicts coronary artery disease, cardiovascular and total mortality

Heart

Plasma copeptin, a unifying factor behind the metabolic syndrome

J Clin Endocrinol Metab

Plasma copeptin and the risk of diabetes mellitus

Circulation

Copeptin, a surrogate marker for arginine vasopressin, is associated with cardiovascular and all-cause mortality in patients with type 2 diabetes (ZODIAC-31)

Diabetes Care

Copeptin, a surrogate marker for arginine vasopressin, is associated with declining glomerular filtration in patients with diabetes mellitus (ZODIAC-33)

Diabetologia

Plasma copeptin, kidney outcomes, ischemic heart disease, and all-cause mortality in people with long-standing type 1 diabetes

Diabetes Care

Obesity, insulin resistance, and type 1 diabetes mellitus

Curr Opin Endocrinol Diabetes Obes

Metabolic syndrome, insulin resistance and cardiovascular disease in type-1 diabetes mellitus

Arq Bras Cardiol

Original Research
Copeptin and Estimated Insulin Sensitivity in Adults With and Without Type 1 Diabetes: The CACTI Study