1550-7289/13/$http://dx.doi.org

*CorrespondSao Paulo, Braz

E-mail: ricar

Surgery for Obesity and Related Diseases 9 (2013) 1022–1024

Controversies in Bariatric Surgery

Low levels of C-peptide may not be a sign of pancreatic β-celldeath or apoptosis: New insight into pancreatic endocrine

function and indications for metabolic surgeryRicardo V. Cohen, M.D., F.A.C.S.*, Tarissa Z. Petry M.D., Pedro Paulo Caravatto, M.D.

The Center of Excellence for Metabolic and Bariatric Surgery, Hospital Oswaldo Cruz, Sao Paulo, Brazil

Received June 3, 2013; accepted August 19, 2013

Type 2 diabetes mellitus (T2 DM) is characterized by adecline in insulin secretion and increased hepatic and per-ipheral insulin resistance, resulting in poor glycemic controland several long-term complications [1]. C-peptide fulfillsan important function in the synthesis of insulin. Aftercleavage of proinsulin in pancreatic β-cells, the 31-amino-acid protein C-peptide is secreted into the portal circula-tion in equimolar concentrations with insulin. C-peptide hasbeen used as a surrogate marker for β-cell function in pati-ents with type 1 and 2 diabetes mellitus [2]. Indeed, recentstudies aimed at the development of new T2 DM treatmentmodalities have monitored the levels of C-peptide and othermarkers [3] with the goal of identifying severe β-celldysfunction. In addition, fasting C-peptide levels have beenused as a criterion for determining inclusion or exclusion inseveral T2 DM treatment protocols [4–6].Several clinical trials have arbitrarily adopted a C-peptide

level of 1 ng/dL as the threshold for protocol inclusion[6–9]. Levels below this threshold were predicted to lead topoor outcomes in patients selected for surgical treatment. Inclinical practice, fasting C-peptide levels have been used asa marker of β-cell function before bariatric/metabolic pro-cedures in T2 DM patients, and also as a prognostic factorfor predicting success after metabolic surgery. Higher levelsof C-peptide have been shown to indicate better outcomes,leading to the suggestion that the selection of surgical tech-nique should be based on fasting C-peptide levels [8,10].Unlike latent autoimmune diabetes of adulthood, in which

the diabetes results from a cellular-mediated autoimmune

– see front matter r 2013 American Society for Metabolic and/10.1016/j.soard.2013.08.004

ence: Ricardo Cohen, Rua Padre João Manuel, 222 #131,il 01411-000.do.cohen@haoc.com.br

destruction of pancreatic β-cells leading to low fastingC-peptide levels, it is generally accepted that β-cells un-dergo apoptosis in T2 DM as a consequence of intensemetabolic stress [11–13]. In the early stages of T2 DM, pan-creatic β-cells adapt to insulin resistance by increasing theirmass and function [14]. Under the condition of severeinsulin resistance and subsequent glucotoxicity, a hormone,betatrophin, was recently identified as a factor correlatedwith β-cell proliferation and mass expansion and, thus, withimproved glucose tolerance [15]. Furthermore, injection ofbetatrophin into animals improved insulin resistance, henceproviding better glycemic control [16]. However, whetherand to what level this peptide is expressed in white fat cellsand liver remain unknown. Moreover, the lack of betatro-phin expression in T2 DM patients has been suggestedto be associated with obesity and decreased incretin secre-tion [17–19].There is now compelling evidence that, regardless of a

patient’s body mass index, gastrointestinal (GI) surgery is agood option for uncontrolled T2 DM. This evidence is pro-vided by the results of a large long-term longitudinal trialand its sub-studies [20–23], prospective controlled caseseries [24,25], and randomized controlled studies [26–28].At present, metabolic surgery is a rescue option for uncon-trolled disease [29]. Consequently, the β-cell according toclassic concepts may be overstressed and susceptible toenter into apoptosis and death, and sometimes, the inter-ventions may be ineffective because they are applied toolate. In such patients, fasting C-peptide levels may be low,reflecting decreased insulin secretion; therefore, usingC-peptide levels to select patients may be flawed.Recently, Talchai et al. [30] presented an interesting

and provocative hypothesis for the mechanisms underlying

Bariatric Surgery. All rights reserved.

Fasting Levels of C-peptide and Metabolic Surgery / Surgery for Obesity and Related Diseases 9 (2013) 1022–1024 1023

β-cell failure and decreased insulin secretion. Forkhead boxproteins are transcription factors that play important roles inregulating the expression of genes involved in the differ-entiation and longevity of several cell types, including pan-creatic β-cells. Investigations of forkhead box expressionhave shown that, under conditions of glucotoxicity or lipo-toxicity, cellular apoptosis may be absent. They proposedthat the reduction in β-cell function and mass is secondaryto contextual pancreatic cell dedifferentiation whereby cellslose their identity as β-cells and adopt an α-cell fate, result-ing in glucagon secretion. Glucagon plays an essential rolein the regulation of hepatic glucose production as well aselevated fasting and postprandial plasma glucagon concen-trations in patients with T2 DM, all of which contribute tohyperglycemia [31]. Although the cause of hyperglucago-nemia in some patients is unclear, recent studies haveshown a lack of suppression after oral ingestion but pre-served suppression after administration of isoglycemicintravenous glucose, pointing to a role for factors in thegut in the control of glucagon secretion. In addition, theeffects of glucagon are counterbalanced by the effects ofintestinal incretins and possibly betatrophin [32,33]. Inter-estingly, after a reduction in metabolic stress, these repur-posed α-cells may redifferentiate into α-cells and resumetheir normal role in insulin secretion. Thus, low fastinglevels of C-peptide may not reflect complete destruction ofpancreatic β-cells, a possibility with important consequen-ces for the selection of patients for metabolic surgery andother forms of T2 DM treatment.To better assess β-cell function, postprandial C-peptide

levels, considered together with fasting levels, may betterpredict β-cell reserve than fasting levels alone. Several animaland human trials have shown an immediate decrease ininsulin resistance after GI interventions, leading to rapid reliefof glucotoxicity and lipotoxicity, occurring via weight loss-independent mechanisms [34–36]. This positive metaboliceffect may contribute to the positive outcomes after metabolicsurgery, as well as to the restoration of cellular identity. Thisphenomenon of “pancreatic plasticity” will be an importantconsideration in decisions about early gastrointestinal inter-ventions, surgical or endoscopic, in T2 DM patients.This new insight into the pathophysiology of T2 DM is

important for both surgeons and others in the medicalcommunity [37]. Endocrinologists will endeavor to developdrugs that can prevent β-cell dedifferentiation or restoretheir cellular identity [38] and eventually promote β-cellregeneration [39]. Better criteria for the selection of patientsfor surgery, including better measures of β-cell mass andfunction, are required. Fasting C-peptide levels may not beas predictive of treatment success as previously thought, es-pecially in patients with uncontrolled disease, limiting theiruse in the selection of one surgical technique over another.Redirecting food through the proximal GI tract has gainednew mechanistic perspectives in reducing insulin resistancewithout any link to weight loss [35,36,40].

Fasting levels of C-peptide alone should not be used asthe only tool for assessment of β-cell function and reserve.Postprandial levels of C-peptide and mathematical modelssuch as the C-peptide deconvolution curve may be betterparameters for assessing β-cell function, although their mea-surement and construction may be impractical.In summary, the limitations of using fasting levels of

C-peptide as a marker of β-cell function should be reco-gnized. At present, using only low fasting levels of C-pep-tide are not adequate to contraindicate surgery, or to be usedas an exclusion criterion for clinical trials. Patients present-ing with poor glycemic and metabolic control should per-haps undergo a short period of preoperative intensivemedical treatment to control their glycemia before levelsof C-peptide (fasting and/or postprandial) are measured atbaseline and postoperatively. It may also be helpful to ob-tain several blood samples for fasting C-peptide measure-ment after diet and lifestyle modifications. These could addsome predictive value to fasting C-peptide levels, increasingtheir validity and reliability and avoiding any influence ofglucotoxicity and lipotoxicity.

Disclosures

The authors have no commercial associations that mightbe a conflict of interest in relation to this article.

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