Diabetes for the day

The New York Times has an article by Kevin Corbit, a senior scientist at the biotechnology company Amgen, about how another species deals with diabetes:

Clinically speaking, about one and a half billion people worldwide are overweight. According to the World Health Organization, more than ten percent of the world’s adults are obese, arguably making them the largest patient population in existence. We can debate the causes, but the long-term consequences of obesity— diabetes, heart disease, cancer— place huge burdens on our society. Public health campaigns have made little impression on this spreading medical crisis.
The biotechnology industry, where I work, strives to develop therapies for the greatest unmet medical needs. Can it provide a solution to a problem for which, so far, there have been few clinical responses? Only three drugs are currently approved for long-term treatment of obesity; they promote moderate weight loss and often have significant side effects.
Why don’t we have better options? It’s not as if very smart people with lots of resources aren’t trying. A major concern when developing medications to treat obesity is that drug testing, for the most part, is limited to using highly formulaic rodent models. These laboratory animals are genetically and environmentally manipulated to mimic human weight gain, and do not reproduce certain adverse drug events— such as suicidal ideation— that can be encountered when tested in humans. The result is a plethora of mice and rats that are metabolically healthy thanks to the drugs, while about a fifth of the world’s population, and more than a third of Americans, stay overweight.
So maybe we’ve been on the wrong track. An alternative approach looks at whether nature, through millions of years of evolutionary experimentation, has already figured out how to appropriately cope with biological threats.
Many fascinating examples exist. A diminutive rodent, the grasshopper mouse, is resistant to the excruciating sting of the bark scorpion. For longevity, nothing can top the naked mole rat, which is naturally resistant to types of pain, cancer and, possibly, Alzheimer’s disease. After weeks of fasting, Burmese pythons are able to enlarge their hearts by as much as forty percent within two to three days of eating in order to accommodate the increased metabolism— a degree of cardiac hypertrophy that would be a leading predictor of mortality in humans.
All of these animals have evolved ways to overcome conditions considered pathological in humans through unique mutations in key genes. I believe Nature has even figured out how to convert profound obesity into a benign state. Enter my object of study: the grizzly.
Hibernation by bears is an astonishing feat of evolution. After an epic period of late-summer gorging, during which, every day, a bear may consume more than fifty thousand calories and gain up to sixteen pounds, it will fast for up to seven months. Then it subsists solely on stored fat, without eating, drinking, urinating, or defecating. Bears also shut down their renal function during hibernation, resulting in badly scarred kidneys and high levels of blood toxins that would kill a human. What is truly remarkable is that the bears’ kidney failure is reversible: upon awakening from hibernation, their kidney function is fully restored, with no lasting damage.
These observations make bears a veritable cornucopia of biological discovery. The problem, of course, has been to figure out how to practically and safely study seven hundred-pound animals with uncommon strength and a reputation for being surly.
Luckily for me, Charles T. Robbins at Washington State University has spent 28 years working out how to house rescue grizzlies and have them hibernate in captivity. Collaborating since 2011, we have discovered some fascinating features of bear metabolism that may lead to valuable innovations in treating obesity. (My company has invested in our research.)
We started by asking if the unparalleled gains in weight and body fat necessary to survive hibernation are accompanied by consequences, like diabetes, that are typically observed in humans. The type of diabetes associated with human obesity is a result of the body’s inability to respond to the hormone insulin and so is referred to as “insulin resistance”.
In a healthy human, an injection of insulin will cause a drop in blood sugar as the hormone facilitates the transport of sugars from the blood into cells, where it is either used to produce energy or stored as fuel. In a diabetic subject, the cells fail to respond to the insulin and their blood sugar stays high— with long-term effects like obesity, hypertension, and cardiovascular disease.
But bears are able to modulate their insulin responsiveness, so that when they are most obese, in the fall, they are most insulin sensitive. In other words, even as they pile on the pounds, their cells retain the capacity to take instructions from insulin. Just weeks later, the bears render themselves completely insulin resistant while in hibernation; they become, in essence, diabetic. But hibernating bears differ from diabetic humans in that they maintain normal blood sugar levels while in this insulin-resistant state. Once they wake, in the spring, the grizzlies restore their insulin responsiveness. So bears modulate insulin sensitivity, not to maintain normal blood sugar levels, but to control when fat is stored and when it is broken down. Put another way, bears naturally and reversibly succumb to diabetes. Since we know when they make this switch, we hope to pinpoint how they do this.
Grizzlies also handle obesity in a much different manner than humans— without tissue inflammation or storing fat where it does harm. Bears store their winter fuel only in fat tissue, not in the liver or in muscle, as occurs in humans with pathological obesity. These findings suggest that bears have mastered a kind of “healthy” maintenance obesity— despite huge fat accumulation, weight gain and perpetually high cholesterol.
This phenomenon of healthy obesity may also occur in a small number of humans with specific mutations in a gene known as PTEN, such that, while obese, they remain exquisitely sensitive to insulin. Thus humans with this mutation are quite grizzly-like in their metabolism.
Interestingly, we have found that bears control the activity of PTEN, the protein encoded by the PTEN gene, in a manner similar to a dimmer switch, cranking the activity up and down at specific times of the year to control how responsive to insulin they are. As we know exactly when bears modulate PTEN activity and where (in fat cells), we expect to discover the mechanism.
Millions of years of evolutionary experimentation have produced genetic adaptations that enabled bears to cope with obesity, converting it to a benign state in which weight gain has much-reduced health threats. If nature has figured this stuff out for grizzlies, maybe we can for humans.

Rico says that this is a great candidate for genetic manipulation; given that his nickname (courtesy of the Japanese) is Kuma (meaning bear), Rico will volunteer for the study...