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Diabetes Volume 65, November 2016
Ravi Retnakaran
The Insulin-Like Growth Factor Axis:
A New Player in Gestational Diabetes
Mellitus?
COMMENTARY
Diabetes 2016;65:3246–3248 | DOI: 10.2337/dbi16-0048
Gestational diabetes mellitus (GDM), defined as glucose
intolerance of varying severity with first onset and recognition in pregnancy, is a diagnosis that holds relevance for
the diabetes epidemic across two generations—that of the
mother and her child (1,2). Indeed, despite typically regaining normal glucose tolerance in the immediate postpartum,
women with previous GDM have a very high risk of future
progression to type 2 diabetes (T2D) (3). Similarly, their
offspring have an elevated risk of accruing metabolic abnormalities in childhood that may be partly attributable
to the intrauterine environment of the GDM pregnancy (4).
As such, enhanced understanding of the pathophysiology
of GDM could yield strategies for early identification of
at-risk mothers and ideally mitigation of their metabolic
risk, to the benefit of both mother and child (2).
Current understanding of the pathophysiology of GDM
holds that affected women have a defect in pancreatic
b-cell function that first manifests clinically as an inability
to fully compensate for the marked insulin resistance of
the latter half of pregnancy, resulting in characteristic hyperglycemia in late second or third trimester (1,2). Importantly, although this clinical presentation arises in response
to the physiologic stress test posed by pregnancy, affected
women have chronic b-cell dysfunction and insulin resistance that is readily apparent in the years thereafter and
that contributes to their elevated lifetime risk of T2D (5,6).
Moreover, it is now recognized that metabolic dysfunction
actually long precedes the development of GDM, leading to
the recent emergence of a host of markers that may enable
the early identification of at-risk women in first trimester
and even prior to pregnancy (7–11) (Fig. 1).
Against this backdrop, in this issue of Diabetes, Zhu
et al. (12) report a detailed longitudinal characterization
across pregnancy of circulating components of the insulinlike growth factor (IGF) axis in women with and without GDM. The IGF axis is a signal transduction complex
consisting of 1) the growth factors IGF-I and IGF-II, 2) a
series of IGF binding proteins (IGFBPs) that may regulate
their bioavailable fraction, and 3) membrane receptors
through which they act (13). Although traditionally linked
to the regulation of cellular growth and differentiation, a
growing body of evidence has recently implicated components of the IGF axis as potential factors in glucose homeostasis (14,15). For example, in a nested case-control
analysis from the Nurses’ Health Study, baseline IGFBP-2
and IGFBP-1 levels were inversely associated with incident diabetes over median 9 years follow-up, whereas
IGFBP-3 (which binds .90% of circulating IGF-I) showed
a positive association (16). Total circulating IGF-I has
yielded conflicting relationships with diabetic risk in a
series of studies (16–19), possibly reflecting the necessity
of focusing on its bioactive fraction (reflected by unbound
free IGF-I or the total IGF-I/IGFBP-3 molar ratio). Taken
together, this evolving literature is currently suggestive of
a complex physiology between the IGF axis and glucose
homeostasis that remains to be fully elucidated at this time.
In this context, the impact of the IGF axis in GDM is of
interest, given the pathophysiologic and clinical relationship
between GDM and T2D. Zhu et al. (12) thus report a timely
case-control study of total IGF-I, IGFBP-2, IGFBP-3, and
IGF-I/IGFBP-3 ratio measured at multiple time points
in pregnancy in 107 women who developed GDM and
214 non-GDM control subjects. They showed that plasma
IGF-I, IGFBP-3, and IGF-I/IGFBP-3 ratio increased across
pregnancy, whereas circulating levels of IGFBP-2 decreased. Of note, IGF-I and IGFBP-3 concentrations at
10–14 weeks’ gestation were positively associated with
the risk of developing GDM later in the pregnancy. An
even more robust association was shown for IGFBP-2,
higher levels of which at 10–14 weeks predicted a significantly lower risk of subsequent GDM. Collectively,
these findings suggest that components of the IGF axis,
Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada;
Division of Endocrinology, University of Toronto, Toronto, Canada; and LunenfeldTanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
© 2016 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit, and the
work is not altered. More information is available at http://www.diabetesjournals
.org/content/license.
Corresponding author: Ravi Retnakaran, [email protected].
See accompanying article, p. 3495.
diabetes.diabetesjournals.org
Retnakaran
3247
Figure 1—Circulating factors measured before pregnancy and in the first trimester that have been associated with the subsequent
diagnosis of GDM in late second/third trimester. GGT, g-glutamyl transferase; HOMA-IR, HOMA of insulin resistance; TPA, tissue plasminogen activator.
particularly IGFBP-2, may be relevant to the development
of GDM.
An invaluable feature of this study is the serial measurement of multiple elements of the IGF axis across all
three trimesters, providing insight into their temporal
patterns over time before and after the development
of GDM. In addition, the clinical characterization of the
study population has allowed for matching and/or adjustment of relevant covariates, including diabetes risk
factors. However, these data also raise important new
questions.
A critical unresolved question is whether or not the
IGF axis contributes to the pathophysiology of GDM. As
women with GDM have chronic insulin resistance, they
exhibit many associated features (e.g., dyslipidemia, adipokine dysregulation, inflammation) that differ from their
peers but that are not necessarily related to the b-cell
dysfunction that underlies the development of GDM
(2,5). Indeed, although IGF-I, IGFBP-2, and IGF-I/IGFBP-3
at 10–14 weeks’ gestation correlated with HOMA of insulin
resistance at 15–26 weeks, their relationships with b-cell
function are not known. In this regard, it is notable that the
only correlation between these IGF axis components and
glucose values on the oral glucose tolerance test on which
GDM was diagnosed was the inverse association between
IGFBP-2 and fasting glucose. From a pathophysiologic perspective, this is mildly disconcerting insofar as postchallenge
glycemia is characteristic of GDM (i.e., hence the need for the
oral glucose tolerance test for its diagnosis). It is currently
unclear whether decreased IGFBP-2 is contributing to the
pathophysiology of GDM or whether it is another reflection
of the chronic insulin resistance of this patient population.
Irrespective of its potential role in the etiology of
GDM, IGFBP-2 could still serve as a predictor for the
early identification of at-risk women. Notably, IGFBP-2 at
10–14 weeks’ gestation yields a modest incremental improvement in the prediction of GDM beyond conventional
factors (12). Given current focus on pregravid predictors of
GDM that might enable risk modification prior to conception, future studies should evaluate the predictive capacity of
IGFBP-2 measurement prior to pregnancy, ideally with comprehensive adjustment for the factors shown in Fig. 1. The
implications of the IGF axis for postpartum progression to
T2D following GDM require similar investigation (20). Thus,
though its etiologic and clinical role remains to be fully established, it is currently clear that the IGF axis (and particularly
IGFBP-2) warrants further study as an emerging player in
the natural history of both GDM and T2D.
Funding. R.R. is supported by a Heart and Stroke Foundation of Ontario MidCareer Investigator Award.
Duality of Interest. No potential conflicts of interest relevant to this article
were reported.
References
1. Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest 2005;
115:485–491
2. Retnakaran R. Glucose tolerance status in pregnancy: a window to the
future risk of diabetes and cardiovascular disease in young women. Curr Diabetes Rev 2009;5:239–244
3. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus
after gestational diabetes: a systematic review and meta-analysis. Lancet 2009;
373:1773–1779
4. Hiersch L, Yogev Y. Impact of gestational hyperglycemia on maternal and
child health. Curr Opin Clin Nutr Metab Care 2014;17:255–260
5. Kramer CK, Swaminathan B, Hanley AJ, et al. Each degree of glucose intolerance in pregnancy predicts distinct trajectories of b-cell function, insulin
sensitivity, and glycemia in the first 3 years postpartum. Diabetes Care 2014;37:
3262–3269
6. Xiang AH, Kjos SL, Takayanagi M, Trigo E, Buchanan TA. Detailed physiological characterization of the development of type 2 diabetes in Hispanic
women with prior GDM. Diabetes 2010;59:2625–2630
7. Savvidou M, Nelson SM, Makgoba M, Messow CM, Sattar N, Nicolaides K.
First-trimester prediction of gestational diabetes mellitus: examining the potential
of combining maternal characteristics and laboratory measures. Diabetes 2010;
59:3017–3022
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Commentary
8. Wen SW, Xie RH, Tan H, Walker MC, Smith GN, Retnakaran R. Preeclampsia
and gestational diabetes mellitus: pre-conception origins? Med Hypotheses
2012;79:120–125
9. Hedderson MM, Darbinian J, Havel PJ, et al. Low prepregnancy adiponectin
concentrations are associated with a marked increase in risk for development of
gestational diabetes mellitus. Diabetes Care 2013;36:3930–3937
10. Sridhar SB, Xu F, Darbinian J, Quesenberry CP, Ferrara A, Hedderson MM.
Pregravid liver enzyme levels and risk of gestational diabetes mellitus during a
subsequent pregnancy. Diabetes Care 2014;37:1878–1884
11. Ryckman KK, Spracklen CN, Smith CJ, Robinson JG, Saftlas AF. Maternal
lipid levels during pregnancy and gestational diabetes: a systematic review and
meta-analysis. BJOG 2015;122:643–651
12. Zhu Y, Mendola P, Albert PS, et al. Insulin-like growth factor axis and gestational
diabetes mellitus: a longitudinal study in a multiracial cohort. Diabetes 2016;65:
3495–3504
13. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding
proteins. Endocr Rev 2002;23:824–854
14. Rajpathak SN, Gunter MJ, Wylie-Rosett J, et al. The role of insulin-like
growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes Metab Res Rev 2009;25:3–12
Diabetes Volume 65, November 2016
15. Kim MS, Lee DY. Insulin-like growth factor (IGF)-I and IGF binding proteins
axis in diabetes mellitus. Ann Pediatr Endocrinol Metab 2015;20:69–73
16. Rajpathak SN, He M, Sun Q, et al. Insulin-like growth factor axis and risk
of type 2 diabetes in women. Diabetes 2012;61:2248–2254
17. Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham
NJ. Circulating concentrations of insulin-like growth factor-I and development of
glucose intolerance: a prospective observational study. Lancet 2002;359:1740–
1745
18. Wallander M, Brismar K, Ohrvik J, Rydén L, Norhammar A. Insulin-like
growth factor I: a predictor of long-term glucose abnormalities in patients with
acute myocardial infarction. Diabetologia 2006;49:2247–2255
19. Drogan D, Schulze MB, Boeing H, Pischon T. Insulin-like growth factor 1
and insulin-like growth factor-binding protein 3 in relation to the risk of type 2
diabetes mellitus: results from the EPIC-Potsdam Study. Am J Epidemiol 2016;
183:553–560
20. Lappas M, Jinks D, Shub A, Willcox JC, Georgiou HM, Permezel M. Postpartum IGF-I and IGFBP-2 levels are prospectively associated with the development of type 2 diabetes in women with previous gestational diabetes mellitus.
Diabetes Metab. 4 July 2016 [Epub ahead of print] DOI: 10.1016/j.diabet
.2016.06.004