OBJECTIVE: The purpose of the present study is to examine the independent association between insulin and high-sensitivity c-reactive protein (hs-CRP), a key marker of systemic inflammation12.
METHODS: The National Health and Nutrition Examination Survey (NHANES) is conducted by the National Centers for Disease Control. It includes a series of two-year cross-sectional observational surveys designed to assess health and nutrition status among non-institutionalized residents in the United States. NHANES 2005-2010 collects data on hs-CRP, fasting insulin level, obesity-related measurements and other characteristics, and provides a unique opportunity to examine the independent association between fasting insulin level and hs-CRP. Details of the sampling design and methodology are described in detail elsewhere13.
To examine the independent effects of insulin on hs-CRP, we included individuals who did not self-report a diagnosis of diabetes or the use of glucose-lowering medications. Prior studies found an association between fasting insulin and hs-CRP in a non-diabetic population10,11,14, although how much this association is mediated by visceral adipose tissue remains unclear. Because insulin levels vary with T2DM duration and treatment, it is difficult to discern the relationship between insulin and hs-CRP in a population with type 2 diabetes. In this way, we reduced confounding due to hyperglycemia, beta cell failure and glucose-lowering medications. Furthermore, many studies examine the relationship between insulin and inflammation in populations with T2DM and hyperglycemia15, which makes it difficult to discern if observed effects are due to achieving glycemic control or a neutral or positive effect of insulin. Therefore, more research is needed to identify the independent effects of insulin on hs-CRP. Understanding such an association may have important implications for T2DM treatment. Exclusion criteria were (1) current pregnancy; (2) use of cholesterol-lowering medications; and (3) age less than 20 years. Generalized linear models with Gamma distribution and identity link function were conducted to estimate the associations due to the skewed distribution of hs-CRP.
RESULTS: The final sample included 4,884 participants with an average age of 46 ± 17 years. Of this sample, 49.9% were male and 50.1% were female. The racial distribution was as follows: 27.0% Hispanic, 49.1% non-Hispanic White, 18.9% Non-Hispanic Black and 5.0% other race or multi-racial. After adjusting for age, race, gender, smoking status, physical activity, and poverty-income ratio, fasting insulin level was significantly associated with hs-CRP (β=.0067, p= .01), independent of waist circumference. Moreover, the associations between fasting insulin and hs-CRP were reduced by 65.8% when including visceral adipose tissue (operationalized as waist circumference) in the model compared to the case without it, indicating some role of visceral adipose tissue in modulating the relationship of insulin and hs-CRP.
DISCUSSION: This secondary analysis investigated the association between fasting insulin and hs-CRP. This study found a significant association between insulin and hs-CRP while controlling for age, race, gender, smoking status, physical activity, poverty-income ratio and waist circumference. This study confirms results of previous research documenting the association between insulin and CRP while controlling for waist circumference14, suggesting this relationship is not entirely mediated by abdominal obesity. Therefore, this study extends our understanding of the relationship between insulin and hs-CRP.
The independent association between insulin and hs-CRP has implications for treatment options recommended to those with type 2 diabetes. Current T2DM treatment guidelines recommend specific glycemic targets without consideration for the treatments’ effect on insulin16. However, if higher insulin levels are associated with higher levels of inflammation, it would be prudent to use therapies that reduce both insulin and glucose levels such as a carbohydrate-restricted diet. Insulin levels are frequently increased through medication to achieve glycemic control in individuals with type 2 diabetes17. If insulin causes increased inflammation, treatment approaches that simultaneously decrease insulin levels as well as glucose, may improve long-term outcomes for patients. Although treatment goals for type 2 diabetes do not currently address inflammation16, research suggests that decreasing inflammation may improve long-term outcomes4. Therefore, future studies are needed to evaluate the effect of therapeutic approaches that simultaneously decrease insulin and glucose levels, on long-term complications for type 2 diabetes.
Limitations exist in the present study due to the nature of cross sectional studies and the inability to determine causal effects. The interplay between insulin and inflammation is complex and likely different based on the level of metabolic dysfunction present. Despite this limitation, this study does provide insight into the independent association between insulin and hs-CRP in adults without diabetes. Additional research is needed to increase our understanding of this relationship.
CONCLUSION: This study found an association between insulin and hs-CRP while controlling for waist circumference, demonstrating a relationship separate from the effects of abdominal obesity. These results suggest that treatment approaches that simultaneously decrease insulin levels while decreasing glucose levels may provide additional anti-inflammatory effects, and therefore may improve long-term outcomes for those diagnosed with type 2 diabetes.
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