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Advanced Neurology Inflammation in diabetic stroke: Treatment target

type 2 diabetic patients with multiple cardiovascular risk weight gain, and reduced bone density. Clinical trials
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factors. Another glucose-lowering agent, metformin, also showed that metformin decreases leptin levels and
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appears to reduce stroke risk, although the mechanism is increases adiponectin levels, but the relevant mechanisms
not fully understood. 22,23 remain unclear. 38
2.2. Adipokine 2.3. Anti-inflammation and immune modulation
Obesity is the leading cause of insulin resistance, which Chronic hyperglycemia in diabetes is associated with a
is the hallmark of type 2 diabetes. White adipose tissue proinflammatory state, with increased inflammatory cells
secretes humoral factors such as leptin and adiponectin. 24,25 and cytokines. Treatments that directly target inflammation
Leptin is a hormone that increases satiety and suppresses have been studied as stroke prevention avenues. S100A8/
appetite. Originally, it was thought that leptin could be a A9 inhibitors can reduce myeloid progenitors in treated
treatment for diet-induced obesity and associated type 2 mice, reducing circulating inflammatory cells and
diabetes. However, the Jackson Heart study showed plaque formation, independent of hyperlipidemia and
high leptin and low adiponectin levels in people with hyperglycemia. 39,40
type 2 diabetes. In fact, obese type 2 patients have Of the non-selective anti-inflammatory agents,
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hyperleptinemia, resulting in leptin resistance that cannot colchicine is relatively well-studied. Colchicine interferes
be compensated, unlike in insulin-resistant type 2 diabetes with microtubule assembly, resulting in inhibition of
where insulin can be administered to compensate the the inflammasome activation which is required for
effect. Leptin receptors are ubiquitously expressed and proinflammatory cytokine expression. Colchicine also
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distributed in the body and regulate both the innate and inhibits neutrophil function, adhesion molecule expression,
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adaptive immune systems through intracellular signaling and interferes neutrophil-platelet aggregation. Clinical
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pathways, triggering an inflammatory reaction. 29,30 The studies have shown that colchicine reduced MACE, but
primary approach to reduce hyperleptinemia is weight no significant reduction in ischemic stroke was observed
reduction through a balanced diet, cognitive behavioral in subgroup analysis. Several clinical trials on colchicine
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therapy and regular exercise, or even bariatric surgery. in stroke prevention are still underway, including one
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Weight reduction in obese type 2 diabetes individuals is targeting arterial inflammation in patients with diabetes
associated with lower leptin and a reduction in nucleotide- (NCT04181996). 44
binding oligomerization domain-like receptor family
pyrin-domain containing 3 (NLRP3) inflammasome There are also studies on selective anti-inflammatory
activity and interleukin (IL)-1β expression. 27,31 This may treatments, such as, anti-IL-1β, anti-IL-6 and anti-tumor
explain the association between the magnitude of the weight necrosis factor-alpha (TNF-α). In the CANTOS study,
loss and lower risk of cardiovascular disease in overweight canakinumab (an IL-1β antibody) has been shown to
individuals with type 2 diabetes. Interestingly, studies reduce high-sensitivity C-reactive protein (hsCRP) in
32
showed that a reduction in leptin levels restores leptin a dose-dependent manner. High-dose canakinumab
sensitivity. Preclinical studies on partial leptin reduction treatment significantly reduced MACE, but showed no
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by genetic modification or neutralizing antibodies showed significant benefits for stroke. Furthermore, canakinumab
promising results. Both preclinical and clinical studies was associated with a significantly higher incidence of
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showed that leptin reduction does not cause weight gain, fatal infection compared with placebo. There are no
instead, it is associated with further weight reduction in clinical trial data on anti-IL6 and anti-TNF-α in stroke,
the long term. 27,33 Further, clinical trials are warranted. let alone in diabetic stroke. Given their crucial functions
in regulating immune responses, caution must be
Studies have shown that low levels of adiponectin
are associated with all types of stroke, although the exercised for their off-target effects. A preclinical study
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mechanisms are unclear. The expression levels of the has shown that carcinoembryonic antigen-related cellular
adiponectin receptor in human skeletal muscle are adhesion molecule 1 (CEACAM1) regulates matrix
positively associated with insulin sensitivity and can be metalloproteinase 9 (MMP-9) by inhibiting the NF-κB
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increased by exercise. Thiazolidinediones, also known signaling pathway. MMP-9 degrades extracellular matrix
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as glitazones, activate peroxisome proliferator-activated proteins and induces proinflammatory cytokines and
receptor-gamma (PPAR-γ) and increase peripheral chemokines. It has been found that CEACAM1 can be
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insulin sensitivity and adiponectin secretion. A recent a potential treatment for atherosclerosis in patients with
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review of clinical trials showed that PPAR-γ agonists type 2 diabetes.
prevent recurrent stroke. However, rosiglitazone may be Recent studies showed that the binding of diaphanous
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associated with a significant risk of myocardial infarction, homolog 1 (DIAPH1) to the cytoplasmic domain of RAGE
Volume 3 Issue 2 (2024) 3 doi: 10.36922/an.1694