Inflammatory Trajectory of Type 2 Diabetes: Novel Opportunities for Early and Late Treatment

Abstract

Low-grade inflammation (LGI) represents a key driver of type 2 diabetes (T2D) and its associated cardiovascular diseases (CVDs). Indeed, inflammatory markers such as hs-CRP and IL-6 predict the development of T2D and its complications, suggesting that LGI already increases before T2D diagnosis and remains elevated even after treatment. Overnutrition, unhealthy diets, physical inactivity, obesity, and aging are all recognized triggers of LGI, promoting insulin resistance and sustaining the pathogenesis of T2D. Once developed, and even before frank appearance, people with T2D undergo a pathological metabolic remodeling, with an alteration of multiple CVD risk factors, i.e., glycemia, lipids, blood pressure, and renal function. In turn, such variables foster a range of inflammatory pathways and mechanisms, e.g., immune cell stimulation, the accrual of senescent cells, long-lasting epigenetic changes, and trained immunity, which are held to chronically fuel LGI at the systemic and tissue levels. Targeting of CVD risk factors partially ameliorates LGI. However, some long-lasting inflammatory pathways are unaffected by common therapies, and LGI burden is still increased in many T2D patients, a phenomenon possibly underlying the residual inflammatory risk (i.e., having hs-CRP > 2 mg/dL despite optimal LDL cholesterol control). On the other hand, selected disease-modifying drugs, e.g., GLP-1RA, seem to also act on the pathogenesis of T2D, curbing the inflammatory trajectory of the disease and possibly preventing it if introduced early. In addition, selected trials demonstrated the potential of canonical anti-inflammatory therapies in reducing the rate of CVDs in patients with this condition or at high risk for it, many of whom had T2D. Since colchicine, an inhibitor of immune cell activation, is now approved for the prevention of CVDs, it might be worth exploring a possible therapeutic paradigm to identify subjects with T2D and an increased LGI burden to treat them with this drug. Upcoming studies will reveal whether disease-modifying drugs reverse early T2D by suppressing sources of LGI and whether colchicine has a broad benefit in people with this condition.

Keywords: GLP-1RA; IL-6; SGLT-2i; canakinumab; colchicine; epigenetics; hs-CRP; inflammaging; metabolic memory; obesity; senescence; trained immunity.

Figure 1

Trigger mechanisms sustaining inflammation in T2D. Aging, overnutrition, and a sedentary lifestyle promote early inflammation through multiple mechanisms involving the adipose tissue and other diabetes-relevant organs. After T2D development, the canonical risk factors for CVD typical of T2D, e.g., hyperglycemia, promote the activation of a range of long-lasting mechanisms and pathways chronically fueling LGI even after normalization of such risk factors. The resulting proinflammatory program might underly the so-called residual inflammatory risk, the persistent elevation of hs-CRP despite LDL cholesterol control, which represents a risk factor for CVD development. This deleterious progression of inflammation might be targeted both early by introducing disease-modifying drugs such as GLP-1RA and late by treating residual inflammatory risk with colchicine.

Figure 2

The inflammatory trajectory of type 2 diabetes. A postulated hypothetical trajectory of low-grade inflammation (LGI) in type 2 diabetes (T2D), which deviates early from a healthy status (black line) years before T2D development, when people are often characterized by prediabetes or other metabolic abnormalities (blue line). When T2D is diagnosed, individuals are usually treated to reach specific goals for multiple CVD risk factors, but this approach only partially attenuates LGI (orange line) since the triggers of LGI are not removed, and many long-lasting inflammatory mechanisms are unaffected by conventional therapies. If left undisturbed, LGI will promote cardiovascular disease (CVD) development, but this could still be attenuated by the use of colchicine or other canonical anti-inflammatory therapies with proven benefits for CVDs (pink line). Alternately, an early interception of T2D with a prompt introduction of disease-modifying drugs, such as GLP-1RA, which remove overnutrition and obesity and thus key triggers of LGI, might allow an efficient curbing of the inflammatory trajectory (green line), possibly folding it to a healthy status and avoiding the noxious long-term consequences of the disease. Further studies are needed to clarify this latter aspect.