Commentary

You are what you eat—Do not blame your motherIngo B. Leibiger, Erwin Ilegems, Per-Olof Berggren *

The incidence of diabetes mellitus worldwide is increasing andespecially in case of type 2 diabetes (T2DM) reaching epidemicproportions. According to the Diabetes Atlas recently published bythe International Diabetes Federation, in 2011 more than 360 millionpeople suffered from the disease and this number will increase to morethan 550 million by 2030 [1]. This represents a huge personal burdenfor the people suffering from the disease but also a financial challengefor society to combat all resulting consequences. Genome-wideassociation studies revealed a considerable number of candidate geneshaving a role potentially associated with the development and functionof the pancreatic islet of Langerhans [2], thus placing this micro-organback into the center of attention. However, the outcome of thesestudies made also clear that only a small proportion of T2DM can besolely explained by genetic factors, and underlines the contribution of achanging lifestyle in the development of obesity and insulin resistance.Indeed a decrease in calorie expenditure, due to reduced physicalactivity in combination with an increased calorie intake, resulted overthe last three decades in an increase in obesity especially in theyounger generation, including young parents as well as their children.Obesity is one of the biggest risk factors for developing T2DM, howeverthe underlying mechanism(s) remain unclear. One of the key questionsis how maternal high-calorie consumption during pregnancy and by thechild after birth influences the development of the pancreatic islets ofLangerhans in the offspring.In this issue, Comstock and colleagues [3] address this important questionby studying the impact of early programming (maternal diet) versuspostnatal programming (post-weaning diet) on pancreatic islet develop-ment in non-human primates (NHP). To accomplish this, the authorscompared pancreata from offspring in four different groups up to the ageof 13 months. The first group, named HFD/HFD, was offspring to mothersthat were fed a high-fat diet (HFD) during pregnancy and where theoffspring continued HFD feeding after the weaning period. The secondgroup, CTR/HFD, was offspring to mothers that were fed a control diet(CTR) during pregnancy and where the offspring continued HFD feedingafter the weaning period. The third group, HFD/CTR, was offspring tomothers that were fed HFD during pregnancy and where the offspring wasfed a control diet post-weaning. These three groups were compared to acontrol group, CTR/CTR, i.e. offspring to mothers that were fed a controldiet during pregnancy and where the offspring was fed a control diet post-weaning. While pancreata of the HFD/HFD and CTR/HFD groups showedan increase in islet mass, islet mass in the HFD/CTR group normalized tocontrol levels indicating the high plasticity during islet development.Interestingly, while the islet mass of both HFD/HFD and CTR/HFD groups

http://dx.doi.org/10.1016/j.molmet.2013.01.001

This commentary refers to ‘‘High-fat diet consumption during pregnancy and the early post-natal period

Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-17176 Stockholm, Sweden

*Corresponding author. Tel.: þ46 707295731. Email: per-olof.berggren@ki.se (P.-O. Berggren)

Received December 27, 2012 � Accepted January 3, 2013 � Available online 11 January 2013

MOLECULAR METABOLISM 2 (2013) 1–2 & 2013 Elsevier GmbH. All rights reserved. www.molecula

were increased, this was accomplished by different mechanisms (Fig. 1A).In the HFD/HFD group this increase was gained by an increase in isletdiameter while in the CTR/HFD group the authors observed an increase inislet number and islet density. Another striking difference concerned theratio of insulin-producing b-cells to glucagon-producing a-cells. Islets ofthe CTR/HFD group showed an increased number of both b-cells and a-cells. Islets of the HFD/HFD group, however, showed no increase in a-cellnumber, which resulted in an almost doubling of the b-cell/a-cell ratio.The close to normal serum glucagon levels in the HFD/HFD group werevery likely gained by a hyperactivity of these a-cells. These novelobservations are highly interesting and intensify our desire to get moreinsights into the molecular mechanisms underlying the striking differencesin the development of pancreatic islets in the HFD/HFD versus CTR/HFDgroups. Earlier data published by the same group showed that HFD duringpregnancy in NHP leads to placental insufficiency and placental inflamma-tion, the latter resulting in increased circulating concentration of cytokinesin the fetus which may affect organ development [4]. Other observationsby these authors presented in this issue [3] and earlier [5] demonstratethat maternal HFD leads to the development of early hepatic insulinresistance in the fetus, which is reflected by decreased clearing ofcirculating insulin, increased serum triglyceride levels and increasedhepatic expression of genes involved in gluconeogenesis.A major strength of the present study is the experimental model,namely the use of non-human primates. Although there is a wealth ofdata on pancreatic islet development and function in health and diseasegained from studies on various rodent models, their relevance tohuman pancreatic islet function and dysfunction has to be taken withcaution in the light of novel findings demonstrating that differences inthe islet architecture between rodents and NHP/human have functionalconsequences (see [6] and references therein). With regard to the studyby Comstock and colleagues in this issue [3], a change in the isletcomposition as seen in the HFD/HFD group will certainly have con-sequences in islet function in general and in a-cell and b-cell functionin particular. Data by Rodriguez-Diaz et al. demonstrated that humana-cells in addition to secrete glucagon also secrete the neurotrans-mitter acetylcholine, which primes the secretory response of human b-cell to glucose by paracrine action [7]. A reduction in a-cell numberthus may also lead to reduced paracrine priming of NHP/human b-cellsleading to reduced insulin secretion, as reflected by lower circulatinginsulin C-peptide levels in the HFD/HFD group in the present study [3].Another highly interesting point concerns the plasticity of NHP/humanislets. Pancreatic islets develop until post-puberty in both humans andNHPs. The present study on NHP macaques, which was carried out until

leads to decreased a cell plasticity in the nonhuman primate’’, DOI: 10.1016/j.molmet.2012.11.001.

rmetabolism.com 1

Figure 1: (A) The endocrine cells within the islets of Langerhans in non-human primates, similarly to those in humans, have specific paracrine interactions due a majority of heterotypic cellular contacts. This is in contrast to endocrine cells in the mouse, which

present a majority of homotypic cellular contacts due to the localization of b-cells in the core and of the other endocrine cells in the mantle of their islets. The results obtained by Comstock and colleagues on the quantification of a- and b-cells [3] imply that

the nature of these interactions can be dramatically transformed in the offspring of NHP mothers having followed a HFD during pregnancy. (B) Pancreatic islets transplanted into the anterior chamber of the eye provide longitudinal information on islet function

and plasticity by multicolor in vivo optical imaging [8,9].

Commentary

age 13 months after birth, showed that islet composition in the HFD/CTRgroup, despite maternal HFD diet and potential associated complications inorgan development during pregnancy, normalized to control levels. It is ofgreat interest to learn what time-frame is critical for islet developmentduring infancy/puberty and what is the ‘point-of-no-return’ in isletprogramming by HFD during development. Such a longitudinal studywould ideally be non-invasive and allow monitoring of pancreatic isletmorphology and function in a living NHP under different dietary regimes. Apotential strategy to achieve this would be by applying an in vivo imagingapproach, such as published by Speier and colleagues [8,9]. Followingsurgical capture of a small part of the pancreas and subsequent isolationof pancreatic islets, a few islets will be used for auto-transplantation intothe anterior chamber of the eye (Figure 1B). Following engraftment, theseislets can be readily monitored by fluorescence microscopy through thecornea and will serve as representatives of the in situ pancreatic islets.Such an approach would not only allow to non-invasively monitor isletmorphology and function longitudinally at single-cell resolution, but wouldalso allow evaluating the consequences of changing dietary regimes in thesame NHP.

REFERENCES

[1] /www.idf.org/diabetesatlasS.

[2] Billings, L.K., and Florez, J.C., 2010. The genetics of type 2 diabetes: what have

we learned from GWAS? Annales of the New York Academy of Sciences of the

United States of America 1212:59–77.

2 MOLECULAR MET

[3] Comstock, S.M., Pound, L.D., Bishop, J.M., Takahashi, D.L., Kostrba, A.M.,

Smith, M.S., et al., 2013. High-fat diet consumption during pregnancy and early

post-natal period leads to decreased alpha cell plasticity in the nonhuman

primate. Molecular Metabolism, in this issue, http://dx.doi.org/10.1016/j.mol

met.2012.11.001.

[4] Frias, A.E., Morgan, T.K., Evans, A.E., Rasanen, J., Oh, K.Y., Thornburg, K.L.,

et al., 2011. Maternal high-fat diet disturbs uteroplacental hemodynamics and

increases the frequency of stillbirth in a nonhuman primate model of excess

nutrition. Endocrinology 152:2456–2464.

[5] McCurdy, C.E., Bishop, J.M., Williams, S.M., Grayson, B.E., Smith, M.S., et al.,

2009. Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman

primates. The Journal of Clinical Investigation 119:323–335.

[6] Barker CJ, Leibiger IB, Berggren PO. The pancreatic islet as a signaling hub.

Advances in Biological Regulation, 2012. http://dx.doi.org/10.1016/j.jbior.2012.

09.011.

[7] Rodriguez-Diaz, R., Dando, R., Jaques-Silva, M.C., Fachado, A., Molina, J.,

et al., 2011. Acetylcholine is released by human alpha cells as a paracrine

signal to prime beta cell insulin secretion. Nature Medicine 17:888–892.

[8] Speier, S., Nyqvist, D., Cabrera, O., Yu, J., Molano, R.D., Pileggi, A., et al., 2008.

Noninvasive in vivo imaging of pancreatic islet cell biology. Nature Medicine

14:574–578.

[9] Speier, S., Nyqvist, D., Kohler, M., Caicedo, A., Leibiger, I.B., and Berggren, P.O.,

2008. Noninvasive high-resolution in vivo imaging of cell biology in the anterior

chamber of the mouse eye. Nature Protocols 3:1278–1286.

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