Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) and the Risk of Developing Type 2 Diabetes

Wittenbecher, Clemens; Ouni, Meriem; Kuxhaus, Olga; Jähnert, Markus; Gottmann, Pascal; Teichmann, Andrea; Meidtner, Karina; Kriebel, Jennifer; Grallert, Harald; Pischon, Tobias; Boeing, Heiner; Schulze, Matthias B.; Schürmann, Annette

doi:10.2337/db18-0620

Cited by 51 publications

(40 citation statements)

References 39 publications

(51 reference statements)

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“…Compared to IGF-1, IGFBP-1, and IGFBP-3, IGFBP-2 was most strongly associated with the development of T2D in women of the US Nurses' Health Study [51]. The strong inverse association between IGFBP-2 and incident T2D that we also observed has been confirmed in three further studies [53][54][55]. In the Baltimore Longitudinal Study of Aging (BLSA) IGFBP-2 levels were positively correlated with insulin sensitivity at any time point during the study in men and women of middle to older age [56].…”

Section: Pathways Independently Associated With T2d or Chdsupporting

confidence: 84%

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Huth

Bauer

Zierer

et al. 2020

Cardiovasc Diabetol

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Background: Biomarkers may contribute to our understanding of the pathophysiology of various diseases. Type 2 diabetes (T2D) and coronary heart disease (CHD) share many clinical and lifestyle risk factors and several biomarkers are associated with both diseases. The current analysis aims to assess the relevance of biomarkers combined to pathway groups for the development of T2D and CHD in the same cohort. Methods: Forty-seven serum biomarkers were measured in the MONICA/KORA case-cohort study using clinical chemistry assays and ultrasensitive molecular counting technology. The T2D (CHD) analyses included 689 (568) incident cases and 1850 (2004) non-cases from three population-based surveys. At baseline, the study participants were 35-74 years old. The median follow-up was 14 years. We computed Cox regression models for each biomarker, adjusted for age, sex, and survey. Additionally, we assigned the biomarkers to 19 etiological pathways based on information from literature. One age-, sex-, and survey-controlled average variable was built for each pathway. We used the R 2 PM coefficient of determination to assess the explained disease risk. Results: The associations of many biomarkers, such as several cytokines or the iron marker soluble transferrin receptor (sTfR), were similar in strength for T2D and CHD, but we also observed important differences. Lipoprotein (a) (Lp(a)) and N-terminal pro B-type natriuretic peptide (NT-proBNP) even demonstrated opposite effect directions. All pathway variables together explained 49% of the T2D risk and 21% of the CHD risk. The insulin-like growth factor binding protein 2 (IGFBP-2, IGF/IGFBP system pathway) best explained the T2D risk (about 9% explained risk, independent of all other pathway variables). For CHD, the myocardial-injury-and lipid-related-pathways were most important and both explained about 4% of the CHD risk. Conclusions: The biomarker-derived pathway variables explained a higher proportion of the T2D risk compared to CHD. The ranking of the pathways differed between the two diseases, with the IGF/IGFBP-system-pathway being most strongly associated with T2D and the myocardial-injury-and lipid-related-pathways with CHD. Our results help to better understand the pathophysiology of the two diseases, with the ultimate goal of pointing out targets for lifestyle intervention and drug development to ideally prevent both T2D and CHD development.

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Section: Pathways Independently Associated With T2d or Chdsupporting

confidence: 84%

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Huth

Bauer

Zierer

et al. 2020

Cardiovasc Diabetol

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“…In addition, we observed no cross‐sectional association between plasma IGFBP‐2 levels and measures of vascular brain injury, including WMHV or the presence of CBI. Indeed plasma IGFBP‐2 levels have been shown to be inversely associated with plasma triglycerides and risk of diabetes and in our cohort, participants in the higher tertiles of IGFBP2, compared to the bottom tertile, had a lower prevalence of diabetes mellitus. Thus, vascular pathways are unlikely to account for the association we observed.…”

Section: Discussionmentioning

confidence: 50%

Circulating IGFBP‐2: a novel biomarker for incident dementia

McGrath

Himali

Levy

et al. 2019

Ann Clin Transl Neurol

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Objective To determine the association between plasma insulin‐like growth factor binding protein 2 (IGFBP‐2) and cognitive outcomes. Methods We measured plasma IGFBP‐2 levels in 1596 (53% women, mean age 68.7 [SD 5.7] years) dementia‐free Framingham Offspring cohort participants between 1998 and 2001. Multivariable Cox proportional hazards models related plasma IGFBP‐2 to subsequent risk of incident dementia and Alzheimer’s disease. MRI brain measures and cognitive performance were included as secondary outcomes. Results During a median follow‐up of 11.8 (Q1, Q3: 7.1, 13.3) years, 131 participants developed incident dementia, of whom 98 were diagnosed with Alzheimer’s disease. The highest tertile of IGFBP‐2, compared to the lowest tertile, was associated with an increased risk of incident all‐cause dementia (hazard ratio [HR] 2.89, 95% CI 1.63–5.13) and Alzheimer’s disease (HR 3.63, 95% CI 1.76–7.50) in multivariable analysis. Higher circulating IGFBP2 levels were also cross‐sectionally associated with poorer performance on tests of abstract reasoning but not with MRI‐based outcomes. After adding plasma IGFBP‐2 levels to a conventional dementia prediction model, 32% of individuals with dementia were correctly assigned a higher predicted risk, while 8% of individuals without dementia were correctly assigned a lower predicted risk (overall net reclassification improvement index, 0.40, 95% CI 0.22–0.59). Interpretation Elevated circulating IGFBP‐2 levels were associated with an increased risk of both all‐cause dementia and Alzheimer’s disease. Addition of IGFBP2 plasma levels to a model of traditional risk factors significantly improved dementia risk classification. Manipulation of insulin‐like growth factor signaling via IGFBP‐2 may be a promising therapeutic target for dementia.

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“…Ppargc1a expression has been reported to be reduced and linked with islet insulin secretion in patients with T2D,58 as well as to play a pivotal role in regulating energy homeostasis 59. Igfbp2 is involved in the insulin-like growth factor axis influencing cell growth and proliferation,60 and high expression levels have been linked to the protection against T2D in human studies 61. The gene expressions of Lepr Liver (figure 3B), Klb Liver (figure 3C), Ppargc1a Liver (figure 3D) and Igfbp2 Liver (figure 3E) were all significantly increased in the LF and HF+FVT mice compared with the HF mice.…”

Section: Discussionmentioning

confidence: 99%

Faecal virome transplantation decreases symptoms of type 2 diabetes and obesity in a murine model

Rasmussen

Mentzel

Kot

et al. 2020

Gut

162

205

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ObjectiveDevelopment of obesity and type 2 diabetes (T2D) are associated with gut microbiota (GM) changes. The gut viral community is predominated by bacteriophages (phages), which are viruses that attack bacteria in a host-specific manner. The antagonistic behaviour of phages has the potential to alter the GM. As a proof-of-concept, we demonstrate the efficacy of faecal virome transplantation (FVT) from lean donors for shifting the phenotype of obese mice into closer resemblance of lean mice.DesignThe FVT consisted of viromes with distinct profiles extracted from the caecal content of mice from different vendors that were fed a low-fat (LF) diet for 14 weeks. Male C57BL/6NTac mice were divided into five groups: LF (as diet control), high-fat (HF) diet, HF+ampicillin (Amp), HF+Amp+FVT and HF+FVT. At weeks 6 and 7 of the study, the HF+FVT and HF+Amp+FVT mice were treated with FVT by oral gavage. The Amp groups were treated with Amp 24 hours prior to first FVT treatment.ResultsSix weeks after first FVT, the HF+FVT mice showed a significant decrease in weight gain compared with the HF group. Further, glucose tolerance was comparable between the LF and HF+FVT mice, while the other HF groups all had impaired glucose tolerance. These observations were supported by significant shifts in GM composition, blood plasma metabolome and expression levels of genes associated with obesity and T2D development.ConclusionsTransfer of caecal viral communities from mice with a lean phenotype into mice with an obese phenotype led to reduced weight gain and normalised blood glucose parameters relative to lean mice. We hypothesise that this effect is mediated via FVT-induced GM changes.

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Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) and the Risk of Developing Type 2 Diabetes

Cited by 51 publications

References 39 publications

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Circulating IGFBP‐2: a novel biomarker for incident dementia

Faecal virome transplantation decreases symptoms of type 2 diabetes and obesity in a murine model

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