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Understanding Insulin Sensitivity, Adiposity, and Atherosclerosis, with Gregory Weiss, MD

Diabetes and insulin resistance are well described risk factors for cardiovascular diseases (CVD). Both diabetes and adipose or fat dysregulation are strongly implicated in the development of atherosclerosis.

The primary mechanism by which excess adiposity in obese patients leads to vascular endothelial dysfunction has been elusive, however, recent evidence published in Circulation Research links vascular endothelial sugar metabolism to the development of healthy brown fat versus obesity causing white fat.1

Although endothelial nitric oxide release is known to promote vascular heath and inhibit atherosclerosis, it has been unclear how insulin sensitivity and the effect of insulin on endothelial nitric oxide synthetase offers protection against CVD. George King, MD, and colleges at the Joslin Diabetes Center sought to determine if, through activation of endothelial nitric oxide synthetase, insulin can regulate perivascular progenitor cells (PPCs) to differentiate into brown adipose tissue leading to weight reduction and the prevention of endothelial dysfunction (ED).1

“In people with diabetes and insulin resistance, the idea has always been that white fat and inflammation causes dysfunction in the blood vessels, leading to the prevalence of heart disease, eye disease and kidney disease in this patient population,” wrote investigators.

What the researchers did not expect was to learn that blood vessels themselves could have a controlling effect. Utilizing a mouse model, King and colleagues demonstrated that mice engineered with increased vascular sensitivity to insulin weighed less, even when fed primarily fat.1 These same engineered mice also had more brown fat and less endothelial dysfunction.1

These data required explanation. After further investigation the researchers found that insulin triggered the vascular endothelial cells to produce nitric oxide which led to the differentiation of progenitor cells into brown fat preferentially.1 Because of this relationship the team believes that smaller brown fat stores may be a risk factor for diabetes rather than a symptom of it.1

The implications of these results range from utilizing brown fat stores as a biomarker for diabetic risk to stimulating brown fat in an effort to control weight and prevent vascular disease.1

“We think blood vessels and endothelial cells play an important role not just in regulating brown fat, but also in regulating whole body’s metabolism. Thus, these endothelial cells are a key factor in regulating weight and developing diabetes and, as other labs have shown, blood vessels appear to be a major regulator of brain function as well. Interveningat the level of endothelial cells could have a major impact on many diseases,” investigators added.

It is rare that new scientific information comes along that calls into question tried and true dogma. One of the fundamental principles of endocrinology and cardiovascular disease has been the likely causative effect obesity and insulin resistance have on vascular dysfunction and diabetes. These results suggest that the vascular endothelium itself may regulate body mass and composition. The lead author concedes “Everything is connected”. He now believes that the endothelial cells themselves play a crucial role in regulating the entire body metabolism.1

Although these data themselves pave the way for exciting new avenues of investigation, they also uncover a fundamental truth of research. Never rest on your laurels. It is easy to accept reproducible data and build on it without question. The authors of this study, through keeping an open mind, have changed the way we look at insulin sensitivity and vascular disease. We once thought that diabetes and obesity were the cause of inadequate nitric oxide release from the vascular endothelium. We now know it is possible that a predisposition to vascular insulin resistance is a contributor to white fat obesity and diabetes. Although a great deal of research is still needed, this important work adds volumes to the conversation.

Reference:

  1. K. Park, Q. Li, M. D. Lynes, et al. Endothelial cells induced progenitors into brown fat to reduce atherosclerosis. Circulation Research. 2022;131:168–183. DOI: 10.1161/CIRCRESAHA.121.319582