Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

Frankwich, Karen A.; Tibble, Courtney; Torres-Gonzalez, Moises; Bonner, Mariah; Lefkowitz, Roy B.; Tyndall, Matt; Schmid‐Schönbein, Geert W.; Villarreal, Francisco; Heller, Mike; Herbst, Karen L.

doi:10.1186/1476-9255-9-35

Cited by 31 publications

(30 citation statements)

References 39 publications

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“…It has been shown that a 3-month doxycycline medication of patients with type 2 DM resulted in decreased inflammation and improved insulin sensitivity [39]. However, the levels of MMP-8 were not measured.…”

Section: Discussionmentioning

confidence: 99%

Association of MMP‐8 with obesity, smoking and insulin resistance

Lauhio

Färkkilä

Pietiläinen

et al. 2016

Eur J Clin Investigation

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Obesity associated with elevated circulating MMP-8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP-8 can be inhibited by synthetic MMP-8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP-8 levels. Our results suggest that MMP-8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target.

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Section: Discussionmentioning

confidence: 99%

Association of MMP‐8 with obesity, smoking and insulin resistance

Lauhio

Färkkilä

Pietiläinen

et al. 2016

Eur J Clin Investigation

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“…In particular, cytokines such as IL-1 and TNF-a can stimulate the synthesis of MMPs [32]. In animal models of diabetes, excessive proteolytic MMP activity cleaves the extracellular domain of the insulin receptor, as well as other receptors, resulting in loss of function, including a reduction in insulin sensitivity [33].…”

Section: Diabetic Neuropathymentioning

confidence: 99%

Matrix metalloproteinases: potential therapeutic target for diabetic neuropathic pain

Kuhad

Singh

Chopra

2014

Expert Opinion on Therapeutic Targets

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In diabetes, hyperglycemia activates MMPs that along with the other pathogenic mediators cause neuronal injury and precipitates neuropathic pain. Thus, MMPs play a crucial role in the development of neuropathic pain among diabetics. However, MMPs are not only responsible for deleterious ECM abnormalities but are also required for beneficial remodeling of ECM under normal physiological conditions. Therefore, highly selective and specific inhibitors must be designed and explored for their clinical potential for treatment/prevention of diabetic neuropathic pain.

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“…Supporting the notion that MMPs are upregulated in many forms of the metabolic syndrome, recent studies in humans have shown that short-term MMP inhibition in diabetic patients serves to improve insulin receptor expression and signaling concomitantly decreasing the level of inflammatory markers [90]. …”

Section: Receptor Cleavage In Diabetes and Insulin Resistancementioning

confidence: 99%

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

Mazor

Schmid‐Schönbein

2016

BIR

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Abnormal blood rheological properties seldom occur in isolation and instead are accompanied by other complications, often designated as co-morbidities. In the metabolic syndrome with complications like hypertension, diabetes and lack of normal microvascular blood flow, the underlying molecular mechanisms that simultaneously lead to elevated blood pressure and diabetes as well as abnormal microvascular rheology and other cell dysfunctions have remained largely unknown. In this review, we propose a new hypothesis for the origin of abnormal cell functions as well as multiple co-morbidities. Utilizing experimental models for the metabolic disease with diverse co-morbidities we summarize evidence for the presence of an uncontrolled extracellular proteolytic activity that causes ectodomain receptor cleavage and loss of their associated cell function. We summarize evidence for unchecked degrading proteinase activity, e.g. due to matrix metalloproteases, in patients with hypertension, Type II diabetes and obesity, in addition to evidence for receptor cleavage in the form of receptor fragments and decreased extracellular membrane expression levels. The evidence suggest that a shift in blood rheological properties and other co-morbidities may in fact be derived from a common mechanism that is due to uncontrolled proteolytic activity, i.e. an early form of autodigestion. Identification of the particular proteases involved and the mechanisms of their activation may open the door to treatment that simultaneously targets multiple co-morbidities in the metabolic syndrome.

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Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

Cited by 31 publications

References 39 publications

Association of MMP‐8 with obesity, smoking and insulin resistance

Association of MMP‐8 with obesity, smoking and insulin resistance

Matrix metalloproteinases: potential therapeutic target for diabetic neuropathic pain

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

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