LA JOLLA, CA—Practicing physicians and researchers have known for decades that obesity, diabetes and heart disease are intimately entwined. The question is how?

Answers to that question are slowly emerging, and they’re telling us a lot about why it is so difficult for obese and overweight people to slim down. Physicians and patients themselves often blame laziness or lack of “will power,” but the issue may be more physiological than previously realized.

“To really understand how overweight, diabetes and heart disease are related, you need to understand something about the nature of white adipose tissue (WAT),” said Jay Udani, MD, at a conference on natural supplements in clinical practice, sponsored by Scripps Center for Integrative Medicine.

The stuff of love handles and abdominal “spare tires,” WAT is not the passive blob of inert tissue it was once thought to be. In fact, it is a highly active tissue churning out lots of signals with profound metabolic effects. One could almost think of WAT as an endocrine organ unto itself. TNF-α, IL-1β, IL-6, IL-8, IL-10, leptin, haptogen, and vascular endothelial growth factor (VEGF), are a few on the long list of adipokines—signaling molecules emanating from adipose deposits.

With the exception of adiponectin, which activates PPAR, increases HDL, reduces TGL, and increases insulin sensitivity, all of the other adipokines are bad news, said Dr. Udani, Medical Director of the Northridge Hospital Integrative Medicine Program, an affiliate of UCLA School of Medicine. Many are pro-inflammatory, impair glucose metabolism by increasing insulin resistance, increase coagulability, and promote lipid deposition in the endothelium.

In short, the more WAT someone’s got, the more they’re flooding their circulation with pro-diabetes and pro-atherosclerosis signals, creating something of a forward-feedback loop: adipokines induce endocrine dysregulation leading to greater accumulation of free fatty acids, and further deposition of adipose tissue, leading to more adipokine secretion.

Visceral Fat Predicts Risk

Visceral fat thickness (VFT) is extremely predictive of cardiovascular, metabolic and inflammatory complications. “When measured via ultrasound, VFT is very highly correlated with risk. We can use it as a reliable measurement for assessing CAD risk in overweight diabetics,” Dr. Udani said.

The size of adipocytes is a critical factor in the disease process. “Everyone is born with a more-or-less set number of lipid cells, but as you eat they grow in size,” he explained. Abdominal adiposity is not so much a function of increased numbers of fat cells as increased size of those already present.

Higher adipose cell mass eventually leads to hypoxia within the adipose tissue itself. Simply put, the cells expand to such large sizes that WAT outstrips microvascular oxygen delivery. “It is almost like a tumor that is outgrowing its blood supply,” said Dr. Udani. When WAT becomes hypoxic, it sends out even more pro-inflammatory cytokines.

Nowhere to Go

This phenomenon is the key to understanding why it is so difficult for overweight people to lose weight. Engorged adipocytes release a lot of adiponectin, which is a signal to itself to unload stored fatty acids. But because the vasculature is inadequate, there’s nowhere for the fatty acids to go. They end up being reabsorbed by the same tissue from which they were released. Think of it as the metabolic equivalent of an infinite loop glitch on your computer.

“It is not so much that metabolism slows (in obese people), it is more like the blood supply is inadequate, and there’s no place for the fat to go, so it just stays where it is.” Once WAT increases beyond a certain size, it is very difficult to lose. “Exercise increases lipolysis and fatty acid release. But the net result is limited by the poor blood flow. Very little of the fatty acid actually gets into circulation.”

Unfortunately, many people try to lose weight only after the diabetic or heart disease processes are well advanced. It is never too late to adopt healthier lifestyles, but once someone is obese and shows signs of diabetes, it is much harder to reduce risk. Dr. Udani cited a study of 33 postmenopausal women with type 2 diabetes, all of whom lost 10 pounds through diet and exercise. Despite this, adipokine and cytokine levels changed very little.

The message, of course, is that physicians need to identify at-risk people much earlier, and impress upon them that the window of opportunity to obtain the positive benefits of lifestyle change is before the problem gets out of hand.

Oxidative Stress, Inflammation and Complications

Most of the devastating end-stage complications of diabetes are due to vascular damage. Inflammation and oxidative stress are major drivers. Hyperglycemia induces free radicals and inflammatory signals such as CRP, amyloid, fibrinogen, IL-6, and sialic acid. These are strong indicators of an accelerating disease process. A recent study of 28,000 women followed for 4 years, showed that elevated IL-6 carries a 2-fold increased risk of diabetes, and elevated CRP confers a 4-fold risk increase. NIH’s ongoing Atherosclerosis Risk in Communities (ARIC) study shows that inflammatory markers correlate strongly with onset of diabetes. The quartiles with the highest levels of inflammation were 20% to 60% more likely to progress to diabetes than the lowest quartile.

CRP strongly correlates with abdominal obesity and hyperglycemia, according to a study of nearly 15,000 women. “You can really identify who you need to pay attention to by looking at inflammatory mediators,” said Dr. Udani.

WAT is prone to producing reactive oxygen species. This is amplified by hyperglycemia. In the vessels, hyperglycemia promotes endothelial dysfunction. It also activates nuclear enzyme poly (ADP-ribose) polymerase, and depletes NAD, which in turn slows glycolysis, ATP formation, and electron transport. “This is the Big Mac phenomenon. The high-fat, high-sugar surge leads to a clampdown of the arteries.” Oxidative stress, already elevated in diabetics, becomes even greater with the development of neuropathy.

Dr. Udani cautioned that while the correlations between oxidative stress, free radicals and diabetes seem clear, there are not yet any studies showing that antioxidants such as vitamin E, vitamin C or vitamin A will prevent or delay onset of diabetic complications. This remains an open question.

Targeting HSD and PPAR

Obese people show high levels of 11-β-hydroxysteroid dehydrogenase (HSD-1), an enzyme responsible for conversion of metabolically active cortisol into inactive cortisone. HSD-1 has lately become a focus of interest among obesity researchers. Inhibition of HSD-1 would, according to some, improve cortisol-mediated metabolism, which would in turn support weight loss. “If Corti-Slim actually worked, it would do this (inhibit HSD),” said Dr. Udani.

Though he gives little credence to Corti-Slim or other quick fix weight loss supplements, he noted that there are a number of herbs including Glycyrrhiza glabra (Licorice), Perillae frutescens (Perilla), Zyzyphus vulgaris (Jujube), Magnolia officinalis, and Scutellaria baicalensis (Skullcap), that contain compounds that inhibit HSD (Homma M, et al. J Pharma Pharmacol. 1994). These herbs may benefit people trying to lose weight.

Another hot topic among obesity researchers is the role of PPARs. These molecules regulate lipid and glucose metabolism, and also influence inflammation. Actos (pioglitazone), Avandia (rosiglitazone) and other insulin-sensitizing drugs are agonists for PPAR-γ, which results in an increase in adiponectin, a decrease in resistin, and other beneficial anti-inflammatory effects.

Dr. Udani noted that conjugated linoleic acid (CLA) also has PPAR-γ agonist effects, as does Bitter Melon (Momordica charantia), an Asian vegetable that contains high levels of CLA, and is among the leading herbal/nutritional therapies for insulin resistance and diabetes. Extracts of Mulberry leaf (Folium mori), Korean red ginseng (Panax), Punica granatum (Pomegranate) and Banaba (Lagerstroemia) also have PPAR agonist effects. The role of herbal therapies in managing adiposity and preventing insulin resistance and diabetes is a promising subject that warrants far greater research than it has yet received.