Association Between Serum IGF-1 and Diabetes Among U.S. Adults
[h=2]OBJECTIVE[/h]Serum insulin-like growth factor (IGF)-1 may have a role in the maintenance of glucose homeostasis. We examined the association between serum IGF-1 and diabetes in a representative sample of U.S. adults.
[h=2]RESEARCH DESIGN AND METHODS[/h]Third National Health and Nutrition Examination Survey (NHANES III) participants aged ≥18 years (n = 5,511) were the subjects of the study. The main outcome was the presence of diabetes (n = 387).
[h=2]RESULTS[/h]Lower serum IGF-1 levels were positively associated with diabetes after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, BMI, hypertension, glomerular filtration rate, and serum cholesterol. Compared with quartile 4 of IGF-1 (referent), the odds ratio (OR) of diabetes associated with quartile 1 was OR 2.16 (95% CI 1.24–3.76); P-trend = 0.002. However, the observed association between IGF-1 and diabetes was present only in those <65 years of age (OR = 3.05; P-trend = 0.006) and disappeared in those ≥65 years of age (OR = 0.51; P-trend = 0.18); P-interaction = 0.0056.
[h=2]CONCLUSIONS[/h]Low IGF-1 levels are associated with diabetes among young subjects.
Insulin-like growth factor (IGF)-1 is involved in the regulation of growth and cellular proliferation in the human body (1,2). IGF-1 is similar in structure to insulin. Reduced IGF-1 levels have been proposed to have a role in diabetes (3–5). The two previous studies on IGF-1 and diabetes were restricted to elderly populations (6) or had limited sample size (7). There also is some inconsistency in the findings of the two studies: one study (7) found a positive association with decreasing IGF-1, while the other study (6) did not find an association. Therefore, this study examined the independent association between IGF-1 and diabetes in a representative sample of U.S. adults.
[h=2]RESEARCH DESIGN AND METHODS[/h]We used data from the Third National Health and Nutrition Examination Survey (NHANES III) (8–11), which included a probability sample of the U.S. population. We examined subjects ≥18 years of age randomly assigned to the morning exam after an overnight fast. Serum IGF-1 was measured in 6,059 participants. Subjects were excluded that had cardiovascular disease (n = 400) and missing data (n = 148) on covariates included in the multivariable model. This resulted in 5,511 participants, 387 of whom had diabetes.
Diabetes was defined as serum glucose ≥126 mg/dl (if fasting ≥8 h), a serum glucose ≥200 mg/dl (if fasting <8 h), history of diabetes diagnosis, or current use of oral hypoglycemics or insulin. IGF-1 measurement has been previously described (10).
We hypothesized that low IGF-1 levels are associated with diabetes. The odds ratio (OR) of diabetes for IGF-1 was calculated by taking the highest IGF-1 quartile as the referent using multivariable logistic regression models. Sample weights for the complex survey design were applied for all analyses using SAS and SUDAAN software.
[h=2]RESULTS[/h]Decreasing levels of IGF-1 were positively associated with diabetes in the multivariable-adjusted model (Table 1). In a subgroup analysis by age, decreasing levels of serum IGF-1 were positively associated with diabetes in those aged <65 years (P-trend = 0.008); the association disappeared in those aged ≥65 years (P-trend = 0.19).
[h=3]Table 1[/h]Association between serum IGF-1 levels and diabetes
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†Adjusted for age (years), gender, race-ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), education categories (<high school, high school, >high school), smoking (never, former, current), alcohol intake (never, former, current), BMI (normal, overweight, obese), hypertension (absent, present), estimated glomerular filtration rate (ml/min per 1.73 m[SUP]2[/SUP]), and total cholesterol (mg/dl). P-interaction for cross-product age × IGF-1 quartile variable was 0.0056.
In a supplementary analysis to examine if the association between IGF-1 and diabetes was explained by inflammation, we additionally adjusted for high-sensitivity C-reactive protein levels. The results were unaltered. In a second supplementary analysis, we examined the IGF-1 and diabetes association after additionally adjusting for IGF binding protein (IGFBP)-3 levels. Compared with quartile 4 (referent) of IGF-1, the OR of diabetes was 1.57 (95% CI 0.81–3.02) for quartile 3; 2.79 (1.68–4.63) for quartile 2; and 3.83 (1.98–7.39) for quartile 1; P-trend < 0.0001. In a third supplementary analysis, we examined the independent association between IGFBP-3 and diabetes after adjusting for variables in the multivariable model and, additionally, IGF-1 levels. Compared with quartile 1 (referent) of IGFBP-3, the OR of diabetes was 0.85 (0.54–1.36) for quartile 2; 1.08 (0.51–2.30) for quartile 3; and 2.50 (1.27–4.93) for quartile 4; P-trend = 0.01. In a fourth supplementary analysis, we examined the IGF-diabetes association by sex. Decreasing levels of serum IGF-1 were associated with diabetes in both men and women; P-interaction for cross-product sex × IGF-1 term = 0.3431. In a final supplementary analysis, we examined the IGF-diabetes association according to the two main categories of diabetes definition: past history/self-reported diabetes and elevated fasting glucose. For self-reported diabetes, compared with quartile 4 (referent) of IGF-1, the OR of self-reported diabetes was 1.43 (0.46–4.44) for quartile 3; 1.29 (0.50–3.31) for quartile 2; and 3.28 (1.11–9.66) for quartile 1; P-trend = 0.06. For diabetes defined based on blood glucose levels, compared with quartile 4 (referent) of IGF-1, the OR of diabetes was 1.86 (0.79–4.36) for quartile 3; 3.77 (1.83–7.76) for quartile 2; and 5.59 (2.09–15.00) for quartile 4; P-trend < 0.0001.
[h=2]CONCLUSIONS[/h]In a representative sample of U.S. adults without clinical cardiovascular disease, we found low levels of serum IGF-1 to be positively associated with diabetes. When we examined the association between serum IGF-1 and diabetes by age, low serum IGF-1 was positively associated with diabetes only in subjects <65 years of age and not in those ≥65 years of age. Our results contribute to the existing literature (6,7) by suggesting that low IGF-1 may be a predictor of diabetes only in younger subjects. However, the cross-sectional nature of our study precludes conclusions regarding the temporal nature of the association between IGF-1 and diabetes.
Sandhu et al. (7) reported a positive association between low IGF-1 levels and glucose intolerance/diabetes in a sample of 615 subjects 45–65 years of age. In contrast, Rajpatak et al. (6) recently did not find an independent association between IGF-1 and diabetes among 922 subjects ≥65 years of age from the Cardiovascular Health Study. It has been shown that growth hormone and IGF-1 levels decline with age. Therefore, if IGF-1 has an independent role in glucose homeostasis, it is possible that this effect is less pronounced in older individuals.
In the current study, we had an adequate sample size to examine the association between IGF-1 and diabetes separately among younger and older subjects. We found that the association between low IGF-1 and diabetes was strongly present among subjects who were <65 years of age, but the association disappeared in those ≥65 years of age. Therefore, this clarifies the seeming inconsistency in previous literature (6,7) by suggesting that the difference in the age groups of subjects examined in those studies may be a reason for their difference in findings. However, the robustness of our findings of an interaction by age in the IGF-diabetes association should be interpreted with caution and needs to be confirmed in future larger studies with follow-up data.
IGFBP-3 may inhibit the bioactivity of IGF-1 by sequestering IGF-1 into a circulating reservoir, thereby reducing the free-circulating fraction of IGF-1 (12). In the current study, adjusting for IGFBP-3 levels in the multivariable model accentuated the association between IGF-1 and diabetes, suggesting that the observed association is mainly due to the effect of IGFBP-independent free fraction of IGF-1. We also found that IGFBP levels were positively associated with diabetes, even after additionally adjusting for serum IGF-1 levels, suggesting that IGFBP may have IGF-1–independent effects (13). In conclusion, lower IGF-1 levels were positively associated with diabetes in younger subjects.
[h=2]OBJECTIVE[/h]Serum insulin-like growth factor (IGF)-1 may have a role in the maintenance of glucose homeostasis. We examined the association between serum IGF-1 and diabetes in a representative sample of U.S. adults.
[h=2]RESEARCH DESIGN AND METHODS[/h]Third National Health and Nutrition Examination Survey (NHANES III) participants aged ≥18 years (n = 5,511) were the subjects of the study. The main outcome was the presence of diabetes (n = 387).
[h=2]RESULTS[/h]Lower serum IGF-1 levels were positively associated with diabetes after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, BMI, hypertension, glomerular filtration rate, and serum cholesterol. Compared with quartile 4 of IGF-1 (referent), the odds ratio (OR) of diabetes associated with quartile 1 was OR 2.16 (95% CI 1.24–3.76); P-trend = 0.002. However, the observed association between IGF-1 and diabetes was present only in those <65 years of age (OR = 3.05; P-trend = 0.006) and disappeared in those ≥65 years of age (OR = 0.51; P-trend = 0.18); P-interaction = 0.0056.
[h=2]CONCLUSIONS[/h]Low IGF-1 levels are associated with diabetes among young subjects.
Insulin-like growth factor (IGF)-1 is involved in the regulation of growth and cellular proliferation in the human body (1,2). IGF-1 is similar in structure to insulin. Reduced IGF-1 levels have been proposed to have a role in diabetes (3–5). The two previous studies on IGF-1 and diabetes were restricted to elderly populations (6) or had limited sample size (7). There also is some inconsistency in the findings of the two studies: one study (7) found a positive association with decreasing IGF-1, while the other study (6) did not find an association. Therefore, this study examined the independent association between IGF-1 and diabetes in a representative sample of U.S. adults.
[h=2]RESEARCH DESIGN AND METHODS[/h]We used data from the Third National Health and Nutrition Examination Survey (NHANES III) (8–11), which included a probability sample of the U.S. population. We examined subjects ≥18 years of age randomly assigned to the morning exam after an overnight fast. Serum IGF-1 was measured in 6,059 participants. Subjects were excluded that had cardiovascular disease (n = 400) and missing data (n = 148) on covariates included in the multivariable model. This resulted in 5,511 participants, 387 of whom had diabetes.
Diabetes was defined as serum glucose ≥126 mg/dl (if fasting ≥8 h), a serum glucose ≥200 mg/dl (if fasting <8 h), history of diabetes diagnosis, or current use of oral hypoglycemics or insulin. IGF-1 measurement has been previously described (10).
We hypothesized that low IGF-1 levels are associated with diabetes. The odds ratio (OR) of diabetes for IGF-1 was calculated by taking the highest IGF-1 quartile as the referent using multivariable logistic regression models. Sample weights for the complex survey design were applied for all analyses using SAS and SUDAAN software.
[h=2]RESULTS[/h]Decreasing levels of IGF-1 were positively associated with diabetes in the multivariable-adjusted model (Table 1). In a subgroup analysis by age, decreasing levels of serum IGF-1 were positively associated with diabetes in those aged <65 years (P-trend = 0.008); the association disappeared in those aged ≥65 years (P-trend = 0.19).
[h=3]Table 1[/h]Association between serum IGF-1 levels and diabetes
| Serum IGF-1 quartiles | P-trend | ||||
|---|---|---|---|---|---|
| Highest quartile (>322 ng/ml) | Third quartile (248–322 ng/ml) | Second quartile (186–247 ng/ml) | Lowest quartile (<186 ng/ml) | ||
| Whole cohort (n = 5,511) | |||||
| Number at risk (cases) | 1,377 (47) | 1,378 (78) | 1,378 (105) | 1,378 (157) | |
| Age, sex-adjusted OR (95% CI) | 1 (referent) | 1.69 (0.94–3.04) | 2.71 (1.77–4.17) | 3.16 (1.81–5.51) | <0.0001 |
| Multivariable-adjusted OR (95% CI)[SUP]†[/SUP] | 1 (referent) | 1.33 (0.69–2.53) | 2.02 (1.28–3.19) | 2.16 (1.24–3.76) | 0.002 |
| Age <65 years | |||||
| Number at risk (cases) | 1,316 (30) | 1,211 (49) | 1,086 (71) | 886 (94) | |
| Age, sex-adjusted OR (95% CI) | 1 (referent) | 1.91 (0.91–4.01) | 3.61 (1.96–6.66) | 4.54 (1.89–10.93) | 0.0003 |
| Multivariable-adjusted OR (95% CI)[SUP]†[/SUP] | 1 (referent) | 1.54 (0.70–3.38) | 2.63 (1.40–4.95) | 3.05 (1.31–7.08) | 0.006 |
| Age >65 years | |||||
| Number at risk (cases) | 61 (17) | 167 (29) | 292 (34) | 492 (63) | |
| Age, sex-adjusted OR (95% CI) | 1 (referent) | 0.52 (0.23–1.15) | 0.42 (0.23–0.78) | 0.47 (0.24–0.90) | 0.11 |
| Multivariable-adjusted OR (95% CI)[SUP]†[/SUP] | 1 (referent) | 0.55 (0.20–1.52) | 0.55 (0.20–1.52) | 0.51 (0.24–1.06) | 0.18 |
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†Adjusted for age (years), gender, race-ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), education categories (<high school, high school, >high school), smoking (never, former, current), alcohol intake (never, former, current), BMI (normal, overweight, obese), hypertension (absent, present), estimated glomerular filtration rate (ml/min per 1.73 m[SUP]2[/SUP]), and total cholesterol (mg/dl). P-interaction for cross-product age × IGF-1 quartile variable was 0.0056.
In a supplementary analysis to examine if the association between IGF-1 and diabetes was explained by inflammation, we additionally adjusted for high-sensitivity C-reactive protein levels. The results were unaltered. In a second supplementary analysis, we examined the IGF-1 and diabetes association after additionally adjusting for IGF binding protein (IGFBP)-3 levels. Compared with quartile 4 (referent) of IGF-1, the OR of diabetes was 1.57 (95% CI 0.81–3.02) for quartile 3; 2.79 (1.68–4.63) for quartile 2; and 3.83 (1.98–7.39) for quartile 1; P-trend < 0.0001. In a third supplementary analysis, we examined the independent association between IGFBP-3 and diabetes after adjusting for variables in the multivariable model and, additionally, IGF-1 levels. Compared with quartile 1 (referent) of IGFBP-3, the OR of diabetes was 0.85 (0.54–1.36) for quartile 2; 1.08 (0.51–2.30) for quartile 3; and 2.50 (1.27–4.93) for quartile 4; P-trend = 0.01. In a fourth supplementary analysis, we examined the IGF-diabetes association by sex. Decreasing levels of serum IGF-1 were associated with diabetes in both men and women; P-interaction for cross-product sex × IGF-1 term = 0.3431. In a final supplementary analysis, we examined the IGF-diabetes association according to the two main categories of diabetes definition: past history/self-reported diabetes and elevated fasting glucose. For self-reported diabetes, compared with quartile 4 (referent) of IGF-1, the OR of self-reported diabetes was 1.43 (0.46–4.44) for quartile 3; 1.29 (0.50–3.31) for quartile 2; and 3.28 (1.11–9.66) for quartile 1; P-trend = 0.06. For diabetes defined based on blood glucose levels, compared with quartile 4 (referent) of IGF-1, the OR of diabetes was 1.86 (0.79–4.36) for quartile 3; 3.77 (1.83–7.76) for quartile 2; and 5.59 (2.09–15.00) for quartile 4; P-trend < 0.0001.
[h=2]CONCLUSIONS[/h]In a representative sample of U.S. adults without clinical cardiovascular disease, we found low levels of serum IGF-1 to be positively associated with diabetes. When we examined the association between serum IGF-1 and diabetes by age, low serum IGF-1 was positively associated with diabetes only in subjects <65 years of age and not in those ≥65 years of age. Our results contribute to the existing literature (6,7) by suggesting that low IGF-1 may be a predictor of diabetes only in younger subjects. However, the cross-sectional nature of our study precludes conclusions regarding the temporal nature of the association between IGF-1 and diabetes.
Sandhu et al. (7) reported a positive association between low IGF-1 levels and glucose intolerance/diabetes in a sample of 615 subjects 45–65 years of age. In contrast, Rajpatak et al. (6) recently did not find an independent association between IGF-1 and diabetes among 922 subjects ≥65 years of age from the Cardiovascular Health Study. It has been shown that growth hormone and IGF-1 levels decline with age. Therefore, if IGF-1 has an independent role in glucose homeostasis, it is possible that this effect is less pronounced in older individuals.
In the current study, we had an adequate sample size to examine the association between IGF-1 and diabetes separately among younger and older subjects. We found that the association between low IGF-1 and diabetes was strongly present among subjects who were <65 years of age, but the association disappeared in those ≥65 years of age. Therefore, this clarifies the seeming inconsistency in previous literature (6,7) by suggesting that the difference in the age groups of subjects examined in those studies may be a reason for their difference in findings. However, the robustness of our findings of an interaction by age in the IGF-diabetes association should be interpreted with caution and needs to be confirmed in future larger studies with follow-up data.
IGFBP-3 may inhibit the bioactivity of IGF-1 by sequestering IGF-1 into a circulating reservoir, thereby reducing the free-circulating fraction of IGF-1 (12). In the current study, adjusting for IGFBP-3 levels in the multivariable model accentuated the association between IGF-1 and diabetes, suggesting that the observed association is mainly due to the effect of IGFBP-independent free fraction of IGF-1. We also found that IGFBP levels were positively associated with diabetes, even after additionally adjusting for serum IGF-1 levels, suggesting that IGFBP may have IGF-1–independent effects (13). In conclusion, lower IGF-1 levels were positively associated with diabetes in younger subjects.
Therapeutic potential of insulin-like growth factor-1 in patients with diabetes mellitus.
Type 1 DM results from the pancreas's failure to produce enough insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". The cause is unknown. Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly.
Mohamed-Ali V1, Pinkney J.
Author information
Abstract
Insulin-like growth factor-1 (IGF-1) and its receptors share considerable homology with insulin and insulin receptors, and their respective signaling pathways interact at the post receptor level. While the growth hormone (GH)-IGF-1 axis principally regulates tissue growth and differentiation, insulin exerts it primary effects on fuel metabolism. However, these two endocrine systems interact at multiple levels and in diabetes mellitus the GH-IGF-1 axis is grossly disturbed, with increased secretion of GH, reduced plasma levels of IGF-1, and complex tissue-specific changes in IGF binding proteins (IGFBPs). These observations have given rise to the view that GH-IGF-1 axis dysfunction, particularly low plasma levels of circulating IGF-1, probably play a significant role in several aspects of the pathophysiology of diabetes mellitus, including insulin resistance and poor glycemic control, and may also influence the development of microvascular complications.
The availability of recombinant human IGF-1 (rhIGF-1; mecasermin), used either alone or in combination with insulin, has led to experimental studies and clinical trials in humans testing these hypotheses. These studies have examined the impact of subcutaneous rhIGF-1 injections on sensitivity and metabolic parameters. In patients with type 1 and 2 diabetes mellitus, insulin sensitivity is significantly improved, insulin requirements are reduced, and glycemic control of dyslipidemia is generally improved in short-term studies. rhIGF-1 is a particularly attractive possibility in patients with type 2 diabetes mellitus, where insulin resistance is the fundamental problem.
Some patients with genetic syndromes of severe insulin resistance also benefit from treatment with rhIGF-1, which can bypass blocks in the insulin signaling pathway.
The common adverse effects reported for rhIGF-1 are dose-related and include edema, jaw pain, arthralgia, myalgia, hypotension, injection site pain, and less commonly, Bell's palsy and raised intracranial pressure. Although disturbance of the GH-IGF-1 axis participates in the development of diabetic complications, the functional consequences of the complex changes in IGFBP expression at the tissue level are uncertain, and it is not known whether systemic IGF-1 therapy or other manipulations of the GH-IGF-1 axis would be helpful or harmful. Experimentally, IGF-1 has a protective effect on neuropathy, and could find an application in the healing of neuropathic ulcers. The potential benefits of IGF-1 therapy in diabetes mellitus have yet to be realised.
