PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of diacareAmerican Diabetes AssociationSubscribeSearchDiabetes Care Journal
 
Diabetes Care. 2013 April; 36(4): 928–934.
Published online 2013 March 14. doi:  10.2337/dc12-0239
PMCID: PMC3609527

Glycemia, Insulin Resistance, Insulin Secretion, and Risk of Depressive Symptoms in Middle Age

Tasnime N. Akbaraly, PHD,1,2,3 Meena Kumari, PHD,1 Jenny Head, MSC,1 Karen Ritchie, PHD,2,3,4 Marie-Laure Ancelin, PHD,2,3 Adam G. Tabák, MD, PHD,1,5 Eric Brunner, PHD,1 Isabelle Chaudieu, PHD,2,3 Michael G. Marmot, MD, PHD,1 Jane E. Ferrie, PHD,1 Martin J. Shipley, MSC,1 and Mika Kivimäki, PHD1

Abstract

OBJECTIVE

The extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS).

RESEARCH DESIGN AND METHODS

In this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up.

RESULTS

Over the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25–3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex.

CONCLUSIONS

Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.

Type 2 diabetes (T2D) is associated with depression (1,2). Plausible mechanisms underlying this association include the depressogenic effect of the treatment and management of T2D (36) and of the influence of the T2D diagnosis itself because it can be viewed as a stressful life event (7,8). Recently, the hypothesis that the link between diabetes and depression results from a direct biological impact of diabetes-related biological changes has raised particular interest. More specifically, it has been proposed that hyperglycemia and hyperinsulinemia may alter hypothalamic-pituitary-adrenal (HPA) axis function, which, in turn, increases the risk of depressive symptoms (DepS) (9,10).

To date, the results from observational studies investigating the association between fasting glucose level and depression are mixed. Some investigations found that impaired fasting glucose (11) and high glycated hemoglobin (12) are associated with increased DepS, but others failed to observe this association (4,1315) or suggested that the association varies by sex (16,17). Similarly, associations between hyperinsulinemia, insulin resistance, and depression showed conflicting results with findings from six studies showing a positive association between insulin resistance and DepS (1723), two reporting a null effect (24,25), and one suggesting that insulin resistance is inversely associated with DepS (26). Methodological limitations, such as cross-sectional study design and small sample size, may have contributed to these inconsistencies. Furthermore, the possibility of a nonlinear relationship between levels of fasting glucose (7) or insulin and DepS may explain these inconsistencies.

To dissect the effect of T2D diagnosis and treatment from the influences of biomarkers, it is crucial to examine associations prospectively between insulin and glucose levels and DepS and controlling for T2D status. It is also crucial to take into account the wide range of factors that could act as confounders. For example, the associations between levels of glucose and insulin and DepS may be explained by common causes such as obesity, low socioeconomic status, or stroke.

In the present large-scale longitudinal study, we examined whether measures of glucose and insulin were prospectively associated with new-onset DepS over 5 years of follow-up. To minimize the depressogenic effects of T2D diagnosis and treatment, analyses took into account T2D status at study baseline and repeated in a subgroup of nondiabetic participants. We tested the strength of the findings by controlling for a wide range of potential confounders and mediators, including sociodemographic characteristics; health behaviors; inflammatory markers; cortisol; and health factors, such as cardiovascular and cerebrovascular diseases.

RESEARCH DESIGN AND METHODS

Population and study design

Data were from the Whitehall II Study (27), a large-scale prospective cohort study of 10,308 civil servants (6,895 men and 3,413 women) aged 35–55 years at the start of the study (phase 1 1985–1988). Since phase 1, follow-up examinations have taken place approximately every 5 years, as follows: phase 3 (1991–1993) n = 8,104, phase 5 (1997–1999) n = 7,263, phase 7 (2003–2004) n = 6,943, and phase 9 (2008–2009) n = 6,354. After a complete description of the study to the subjects, written informed consent was obtained; the University College London ethics committee approved the study.

Phase 7, when DepS were first measured using the Center for Epidemiologic Studies Depression Scale (CES-D), serves as the baseline for the current analysis. As described in the study flowchart (Supplementary Fig. 1), 3,145 participants (2,406 men and 739 women) of the 4,978 participants free from DepS at phase 7 were included in the analysis. Compared with those excluded, included participants were younger, less likely to be women, and from the lowest occupational grades (all P < 0.001). They were also less likely to have prevalent T2D (P < 0.001) and to develop DepS at phase 9 (P = 0.03) and had lower levels of fasting glucose, fasting insulin, insulin secretion, and insulin resistance (all P < 0.001) at phase 7.

Data collection

Measurement of fasting glucose and fasting insulin at phase 7 (baseline) and phase 9 (follow-up).

Blood samples were taken in the morning from participants after ≥8 h of fasting or after ≥5 h if afternoon sampling was done. Glucose samples were drawn into fluoride monovette tubes and insulin samples into native tubes, which were centrifuged on site within 1 h. Plasma or serum was immediately removed from the monovette tubes and moved into microtubes and stored at −70°C. Blood glucose level was measured with the glucose oxidase method on YSI model 2300 STAT Plus analyzer (YSI Corporation, Yellow Springs, OH), and serum insulin was measured with an insulin enzyme-linked immunosorbent assay kit (DakoCytomation Ltd, Ely, U.K.) following standard procedures detailed elsewhere (28). Based on updated homeostasis model assessment (HOMA) methods, HOMA insulin resistance (HOMA2-%IR) and HOMA β-cell insulin secretion (HOMA2-%B) were calculated by the HOMA2 calculator version 2.2 (http://www.dtu.ox.ac.uk/homacalculator/index.php) (29).

Prevalent cases of T2D at phase 7.

Diabetes was defined by a fasting glucose level of ≥7.0 mmol/L or a 2-h postload glucose level of ≥11.1 mmol/L during a 75-g oral glucose tolerance test (8) assessed at phases 3, 5, and 7; use of antidiabetic drugs; or self-report of a physician’s diagnosis.

Assessment of DepS at phases 7 and 9.

At both phases, DepS was defined by either a score ≥16 on the CES-D or the use of antidepressants. After excluding participants with prevalent or unknown DepS at phase 7 (n = 1,965), incident DepS over the 5-year follow-up was defined by the presence of DepS at phase 9.

Assessment of covariates at phase 7.

Sociodemographic variables comprised sex, age, ethnicity (white, South Asian, black), marital status (married, cohabiting/single, divorced, widowed), and civil service employment grade (three levels, with grade 1 representing the highest level and grade 3 the lowest in terms of salary, social status, and level of responsibility). Health status was ascertained using the following measures: prevalence of coronary heart disease (CHD) based on clinically verified nonfatal myocardial infarction or definite angina; self-reported stroke or transient ischemic attack; hypertension (systolic or diastolic blood pressure ≥140 or ≥90 mmHg, respectively, or use of hypertensive drugs); HDL cholesterol and use of lipid-lowering drugs; smoking status (non-, former, or current smoker); central obesity (waist circumference >102 cm in men and >88 cm in women); and cognitive impairment defined as a score ≤27 on the Mini-Mental State Examination.

At phase 7, we also assessed levels of inflammatory markers (interleukin [IL]-6 and C-reactive protein [CRP]) (30) and cortisol secretion (31), as previously described. Women’s health factors included menstruation status (still menstruating versus natural menopause) and for women with natural menopause, use of hormone replacement therapy (HRT) (never, past, or current use).

Statistical analyses

Logistic regression models were performed to assess the association between quintiles of fasting glucose and fasting insulin at phase 7 and new-onset DepS at phase 9. The statistical evidence of sex differences in the insulin-DepS association led us to conduct all these analyses separately in men and women (P for sex interaction = 0.004). Odds ratios (ORs) were sequentially adjusted for age and ethnicity (model 1); T2D status at phase 7 (model 2); and occupational grade, marital status, smoking behavior, stroke, CHD, hypertension, use of lipid-lowering drugs, decreased HDL cholesterol, central obesity, and cognitive impairment (Mini-Mental State Examination) (model 3). Similar logistic regression models were performed to assess the association between indices of insulin resistance (HOMA2-%IR) and insulin secretion (HOMA2-%B) categorized in quintiles at phase 7 and new-onset DepS at phase 9. To assess the extent to which the associations were driven by biological processes involved in T2D or the depressogenic effect of treatment and management of T2D, analyses were repeated after excluding participants with T2D at phase 7.

To examine the robustness of the associations studied and to obtain information on potential mechanisms that could mediate the observed associations, we conducted several sets of supplementary analyses that were adjusted successively for inflammatory markers, women’s health measures, and cortisol secretion variables. All analyses were conducted with SAS version 9 (SAS Institute, Cary, NC) statistical software.

RESULTS

Over the 5-year follow-up, 142 men (5.9%) and 84 women (11.4%) developed DepS. Table 1 presents the characteristics of participants as a function of new-onset DepS separately for men and women. Mean (SD) fasting insulin and fasting glucose levels were significantly higher in men (insulin 9.26 (6.27) μIU/mL, glucose 5.45 (0.76) mmol/L) than in women (insulin 8.51 (5.38) μIU/mL, glucose 5.19 (0.60) mmol/L).

Table 1
Characteristics of participants according to onset of DepS as measured by CES-D between phase 7 and phase 9

Analyses of the associations of quintiles of fasting glucose and fasting insulin with new-onset DepS over the 5-year follow-up were performed separately for men (Supplementary Table 1) and women (Supplementary Table 2). No association between fasting glucose level and onset of DepS was observed before or after taking into account T2D status and other covariates at baseline.

Women in the lowest quintile of the insulin distribution tended to show higher odds of new-onset DepS than those in other quintiles, although the overall heterogeneity between quintiles did not reach statistical significance (P = 0.09). Compared with women in the first insulin quintile, the fully adjusted odds of developing DepS was reduced by 51, 56, 43, and 62% for women in the second, third, fourth, and fifth quintiles, respectively (Supplementary Table 2, model 3). Similar analyses carried out in 2,929 nondiabetic participants showed that although the direction and magnitude of associations were similar, the results in the nondiabetic women were attenuated. No significant association between insulin level and DepS was observed in men (Supplementary Table 1).

To further examine insulin metabolism in women, we analyzed the associations of insulin resistance (assessed by HOMA2-%IR) and insulin secretion (assessed by HOMA2-%B) with new-onset DepS (Fig. 1). The first quintile of HOMA2-%IR (i.e., women with a lower level of insulin resistance or higher level of insulin sensitivity) tended to be associated with increased odds of new-onset DepS, although this association did not reach statistical significance. In contrast, women in the first quintile of HOMA2-%B (i.e., women with lower levels of insulin secretion) showed significantly increased odds of developing DepS than those in the other quintiles (Fig. 1). This association was not attenuated after adjustment for T2D and other potential confounders or when analyses were confined to nondiabetic women only. Figure 1 also shows that the odds of developing DepS did not differ significantly among women with insulin secretion in the second, third, fourth, or fifth quintiles, suggesting that a low level of insulin secretion may be a risk factor for DepS in women.

Figure 1
Association between indices of insulin resistance and insulin secretion and new-onset DepS as measured by the CES-D over the 5-year follow-up in women. Median (range) ORs for HOMA2 insulin resistance quintiles are as follows: Q1 0.45 (0.34–0.52), ...

To examine the robustness of this finding, we performed a set of logistic regression models comparing risk of DepS between women in the lowest insulin secretion group (HOMA2-%B ≤55.3%) and women in the highest insulin secretion group (HOMA2-%B >55.3%) (Table 2). Even after adjustment for sociodemographic, health behavior, and health factors, women with low insulin secretion levels had a twofold increased odds of developing DepS over the 5-year follow-up compared with those with higher insulin secretion levels (models A and B). This association was not accounted for by the inflammatory markers IL-6 and CRP (model C); HPA axis-related indicators, such as diurnal slope of cortisol secretion and waking cortisol (model D); or women’s health factors, such as menopausal status and use of HRT (model E). Supplementary analyses showed that women in the first quintile of insulin secretion (HOMA2-%B ≤55.3%) were more likely to have higher levels of fasting glucose and insulin sensitivity and a lower level of insulin than other women (data not shown but available upon request).

Table 2
Association between low insulin secretion and new onset DepS in nondiabetic women (n = 687)

To examine the robustness of the findings, we repeated analyses after defining DepS by a CES-D score ≥23 or use of antidepressive drugs, a measure indicating more severe DepS, and after excluding participants who had DepS at phase 3 or phase 5 (i.e., before study baseline), as assessed by the use of antidepressive drugs or a score ≥4 on the four-item depression subscale of the 30-item General Health Questionnaire (32). The results changed little in these sensitivity analyses (data not shown but available upon request). No associations of indices of insulin resistance and insulin secretion with new-onset DepS were observed in men (data not shown).

CONCLUSIONS

We investigated the prospective association between glucose metabolism and DepS in a large cohort of pre-elderly participants. Although no longitudinal association was found between fasting glucose level and DepS in either sex, we found that women with low insulin secretion levels (HOMA2-%B ≤55.3%) had a twofold increased odds of developing DepS over the 5-year follow-up compared with those with higher insulin secretion levels (HOMA2-%B >55.3%). This association was independent of T2D status and associated common metabolic disorders, CHD, and cognitive impairment. The association was also robust when adjusted for inflammatory markers, cortisol secretion profiles, menopause status, and HRT.

Some previous studies suggested that disturbed glucose homeostasis per se is an implausible cause of DepS (3,4). One investigation found an increased prevalence of DepS among participants aware of their T2D status but not among undiagnosed diabetic subjects (4). Another study provided evidence that treated T2D patients but not untreated patients with impaired fasting glucose had a higher incidence of DepS, suggesting that DepS may be a consequence of the treatment regimen (3). The lack of evidence supporting an association between fasting glucose level and DepS in the present study accords with these previous studies and suggests that the process linking T2D to depression may not involve a direct path between hyperglycemia and related glucose transport alteration and depression risk.

Previous findings on the association between insulin levels, indices of insulin resistance, and DepS are mixed and mostly come from cross-sectional studies (1726). By investigating these associations prospectively in a large pre-elderly population, including both men and women, the present analyses contribute to this area of research. Women with low levels of insulin secretion and insulin resistance appeared to have an increased risk of developing DepS. These women, compared with other women, had a slightly elevated fasting glucose level. From our understanding of the trajectories of insulin secretion leading to T2D development (7), the biomarker profile of these women—characterized by a decrease in insulin secretion together with an increase in glucose levels—could actually correspond to nondiabetic women who are very close to the onset of T2D and whose insulin secretion does not increase in response to increasing glucose levels.

The present findings are in accordance with the cross-sectional data from the British Women’s Heart and Health Study (n = 4,286 women aged 60–79 years), in which prevalence of depression was inversely associated with insulin resistance (26). The present results also agree with a prospective study reporting that accumulation of factors related to high insulin sensitivity is associated with an increased risk of suicide in a Finnish population (33).

The reason why this association was found in only women remains unclear. To study whether this sex difference might reflect sex-specific characteristics of insulin metabolism, we performed additional analyses in which menopausal status and HRT were taken into account. We found no evidence to suggest that menopausal status or HRT mediate the association between insulin secretion and DepS, making these factors an unlikely explanation of the results. A further possible explanation, although untestable with the present dataset, is that the instrument we used to assess DepS may be less sensitive to male depression. It has been suggested that the CES-D scale may measure different phenomena in men and women (34,35). Further prospective studies using clinical interview or other sensitive measures to detect depression in both men and women are needed to understand the underpinnings of these sex differences.

The present analysis took into account a wide range of clinical characteristics and health behaviors. Inflammatory markers, such as CRP and IL-6, and activation of the HPA axis have previously been linked with development of both T2D (11,36) and DepS (11,37) and may confound the studied association. However, we found no evidence to suggest that the inflammatory factors measured or diurnal cortisol patterns were driving the observed association between insulin metabolism and DepS.

Further investigations are needed to better understand the mechanism underlying the low insulin secretion-DepS association. In particular, we suggest that future research consider the possible physiologic pathway between inadequate insulin action and DepS through increased central serotonin production, as proposed by Golomb et al. (33). Briefly, because insulin action may suppress postprandial mobilization of nonesterified fatty acids from adipose tissue, lower postprandial free fatty acid levels are expected in a state of low insulin secretion. This would translate into lower availability of the free fraction of tryptophan, which is a rate-limiting substrate of serotonin production and is associated with mood disorders, as illustrated in Supplementary Fig. 2.

Limitations of the present findings include, first, the use of the CES-D scale to assess DepS because it is not a measure of clinically recognized psychiatric disorder. Although the CES-D has been validated in epidemiological studies carried out in the general population, it does not indicate the severity or the chronicity of depression. Furthermore, as the recall period for CES-D-measured symptoms is over the past week, with only two measures over a 5-year period, it is difficult to provide accurate information on incidence of DepS. However, this is unlikely to cause a major bias in the results given that a similar pattern of insulin secretion-DepS association was observed after excluding DepS cases identified using the General Health Questionnaire over a 10-year period before the study baseline.

A second limitation relates to HOMA models as measures of insulin resistance and insulin secretion. Because HOMA2-%IR and HOMA2-%B use the same fasting values for estimation, we were unable to calculate the disposition index, which is a measure of insulin secretion that accounts for the underlying degree of insulin resistance (38). We therefore interpret the present findings cautiously. In the current study, the group of nondiabetic women with low HOMA2-%B values and increased risk of developing DepS tended to have low HOMA2-%IR and elevated fasting glucose values. This suggests that these women were in a prediabetic state, although at this stage, we do not have data to confirm this hypothesis.

A third drawback is related to the fact that participants of the Whitehall II Study are mainly office-based civil servants who are not fully representative of the British population. This may limit the generalizability of the findings. We cannot exclude the possibility that we observed the higher odds of DepS in women with the lowest insulin and insulin secretion levels by chance. In addition, with observational data, the possibility remains that unmeasured confounders may explain the observed association. However, the robustness of the association between insulin levels and DepS after taking into account a wide range of potential confounders and mediators, including sociodemographic characteristics, health behavior, health factors such as chronic diseases, inflammatory factors, and cognitive performance, makes less probable that the observed association between insulin secretion and onset of DepS was an artifact.

In conclusion, the findings suggest that low insulin secretion is associated with an increased risk of DepS in middle-aged women after taking into account potential confounders, such as common cardiometabolic disorders, cognitive impairment, inflammatory markers, cortisol secretion profiles, menopausal status, and HRT. This study supports the hypothesis of a direct impact of insulin secretion on new-onset depression risk in women. However, it does not exclude the possibility that DepS relate to T2D because, as in participants with longstanding T2D, insulin secretion is decreasing. Further research is needed to establish the exact biological mechanisms linking insulin metabolism and depression risk and to clarify reasons for the observed gender differences.

Supplementary Material

Supplementary Data:

Acknowledgments

The Whitehall II Study is supported by grants from the British Medical Research Council (G8802774); the British Heart Foundation; the British Health and Safety Executive; the British Department of Health; the National Heart, Lung, and Blood Institute (R01-HL-036310); the National Institute on Aging (R01-AG-013196 and R01-AG-034454); and the Agency for Health Care Policy and Research (HS06516). M.Ki. is supported by an Economic and Social Research Council professorial fellowship.

No potential conflicts of interest relevant to this article were reported.

The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

T.N.A. carried out the statistical analyses, researched data, and wrote the manuscript. M.Ku., J.H., E.B., M.G.M., and J.E.F. researched data and reviewed and edited the manuscript. K.R., M.-L.A., and I.C. reviewed and edited the manuscript. A.G.T. and M.J.S. researched data, contributed to the discussion, and reviewed and edited the manuscript. M.Ki. researched data and cowrote the manuscript. T.N.A. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors thank all participating men and women in the Whitehall II Study; all participating Civil Service departments and their welfare, personnel, and establishment officers; the Occupational Health and Safety Agency; and the Council of Civil Service Unions. The Whitehall II Study team comprises research scientists, statisticians, study coordinators, nurses, data managers, administrative assistants, and data entry staff who made the study possible.

Footnotes

This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc12-0239/-/DC1.

References

1. Ali S, Stone MA, Peters JL, Davies MJ, Khunti K. The prevalence of co-morbid depression in adults with type 2 diabetes: a systematic review and meta-analysis. Diabet Med 2006;23:1165–1173. [PubMed]
2. Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 2008;31:2383–2390. [PMC free article] [PubMed]
3. Golden SH, Lazo M, Carnethon M, et al. Examining a bidirectional association between depressive symptoms and diabetes. JAMA 2008;299:2751–2759. [PMC free article] [PubMed]
4. Knol MJ, Heerdink ER, Egberts AC, et al. Depressive symptoms in subjects with diagnosed and undiagnosed type 2 diabetes. Psychosom Med 2007;69:300–305. [PubMed]
5. Musselman DL, Betan E, Larsen H, Phillips LS. Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry 2003;54:317–329. [PubMed]
6. Talbot F, Nouwen A. A review of the relationship between depression and diabetes in adults: is there a link? Diabetes Care 2000;23:1556–1562. [PubMed]
7. Kivimaki M, Tabak AG, Batty GD, et al. Hyperglycemia, type 2 diabetes, and depressive symptoms: the British Whitehall II study. Diabetes Care 2009;32:1867–1869. [PMC free article] [PubMed]
8. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539–553. [PubMed]
9. Cameron OG, Kronfol Z, Greden JF, Carroll BJ. Hypothalamic-pituitary-adrenocortical activity in patients with diabetes mellitus. Arch Gen Psychiatry 1984;41:1090–1095. [PubMed]
10. Chan O, Inouye K, Riddell MC, Vranic M, Matthews SG. Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis. Minerva Endocrinol 2003;28:87–102. [PubMed]
11. Gale CR, Kivimaki M, Lawlor DA, Carroll D, Phillips AC, Batty GD. Fasting glucose, diagnosis of type 2 diabetes, and depression: the Vietnam Experience Study. Biol Psychiatry 2010;67:189–192. [PubMed]
12. Hamer M, Batty GD, Kivimaki M. Haemoglobin A1C, fasting glucose and future risk of elevated depressive symptoms over 2 years of follow-up in the English Longitudinal Study of Ageing. Psychol Med 2011;41:1889–1896. [PMC free article] [PubMed]
13. Aujla N, Abrams KR, Davies MJ, Taub N, Skinner TC, Khunti K. The prevalence of depression in white-European and South-Asian people with impaired glucose regulation and screen-detected type 2 diabetes mellitus. PLoS ONE 2009;4:e7755. [PMC free article] [PubMed]
14. Hamer M, Stamatakis E, Kivimaki M, Pascal Kengne A, Batty GD. Psychological distress, glycated hemoglobin, and mortality in adults with and without diabetes. Psychosom Med 2010;72:882–886. [PubMed]
15. Rhee MK, Musselman D, Ziemer DC, et al. Unrecognized glucose intolerance is not associated with depression. Screening for Impaired Glucose Tolerance study 3 (SIGT 3). Diabet Med 2008;25:1361–1365. [PMC free article] [PubMed]
16. Adriaanse MC, Dekker JM, Heine RJ, et al. Symptoms of depression in people with impaired glucose metabolism or type 2 diabetes mellitus: The Hoorn Study. Diabet Med 2008;25:843–849. [PubMed]
17. Holt RI, Phillips DI, Jameson KA, Cooper C, Dennison EM, Peveler RC, Hertfordshire Cohort Study Group The relationship between depression and diabetes mellitus: findings from the Hertfordshire Cohort Study. Diabet Med 2009;26:641–648. [PubMed]
18. Adriaanse MC, Dekker JM, Nijpels G, Heine RJ, Snoek FJ, Pouwer F. Associations between depressive symptoms and insulin resistance: the Hoorn Study. Diabetologia 2006;49:2874–2877. [PubMed]
19. Pan A, Ye X, Franco OH, et al. Insulin resistance and depressive symptoms in middle-aged and elderly Chinese: findings from the Nutrition and Health of Aging Population in China Study. J Affect Disord 2008;109:75–82. [PubMed]
20. Pearson S, Schmidt M, Patton G, et al. Depression and insulin resistance: cross-sectional associations in young adults. Diabetes Care 2010;33:1128–1133. [PMC free article] [PubMed]
21. Timonen M, Laakso M, Jokelainen J, Rajala U, Meyer-Rochow VB, Keinänen-Kiukaanniemi S. Insulin resistance and depression: cross sectional study. BMJ 2005;330:17–18. [PMC free article] [PubMed]
22. Timonen M, Rajala U, Jokelainen J, Keinänen-Kiukaanniemi S, Meyer-Rochow VB, Räsänen P. Depressive symptoms and insulin resistance in young adult males: results from the Northern Finland 1966 birth cohort. Mol Psychiatry 2006;11:929–933. [PubMed]
23. Timonen M, Salmenkaita I, Jokelainen J, et al. Insulin resistance and depressive symptoms in young adult males: findings from Finnish military conscripts. Psychosom Med 2007;69:723–728. [PubMed]
24. Lawlor DA, Ben-Shlomo Y, Ebrahim S, et al. Insulin resistance and depressive symptoms in middle aged men: findings from the Caerphilly Prospective Cohort Study. BMJ 2005;330:705–706. [PMC free article] [PubMed]
25. Roos C, Lidfeldt J, Agardh CD, et al. Insulin resistance and self-rated symptoms of depression in Swedish women with risk factors for diabetes: the Women’s Health in the Lund Area study. Metabolism 2007;56:825–829. [PubMed]
26. Lawlor DA, Smith GD, Ebrahim S. British Women’s Heart and Health Study Association of insulin resistance with depression: cross sectional findings from the British Women’s Heart and Health Study. BMJ 2003;327:1383–1384. [PMC free article] [PubMed]
27. Marmot M, Brunner E. Cohort profile: the Whitehall II study. Int J Epidemiol 2005;34:251–256. [PubMed]
28. Tabák AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimäki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 2009;373:2215–2221. [PMC free article] [PubMed]
29. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004;27:1487–1495. [PubMed]
30. Collett D. Modelling Survival Data in Medical Research. 2nd ed. Boca Raton, Chapman & Hall/CRC, 2003.
31. Kumari M, Chandola T, Brunner E, Kivimaki M. A nonlinear relationship of generalized and central obesity with diurnal cortisol secretion in the Whitehall II study. J Clin Endocrinol Metab 2010;95:4415–4423. [PubMed]
32. Goldberg DP, Hillier VF. A scaled version of the General Health Questionnaire. Psychol Med 1979;9:139–145. [PubMed]
33. Golomb BA, Tenkanen L, Alikoski T, et al. Insulin sensitivity markers: predictors of accidents and suicides in Helsinki Heart Study screenees. J Clin Epidemiol 2002;55:767–773. [PubMed]
34. Callahan CM, Wolinsky FD. The effect of gender and race on the measurement properties of the CES-D in older adults. Med Care 1994;32:341–356. [PubMed]
35. Love AS, Love RJ. Measurement suitability of the Center for Epidemiological Studies-Depression Scale among older urban black men. Int J Mens Health 2006. Available from http://mensstudies.metapress.com/content/v468242581232565/?p=e789902545b141169e82024d4ea7caf1&pi=3Accessed 14 November 2012.
36. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327–334. [PubMed]
37. Weiss LA, Pan L, Abney M, Ober C. The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 2006;38:218–222. [PubMed]
38. Tabák AG, Herder C, Rathmann W, Brunner EJ, Kivimäki M. Prediabetes: a high-risk state for diabetes development. Lancet 2012;379:2279–2290. [PMC free article] [PubMed]

Articles from Diabetes Care are provided here courtesy of American Diabetes Association