Hi! I’m sorry it’s been so long since I’ve written here, and I’m sorry I’ve let nearly the whole Diabetes Awareness Month slip by without so much as a peep.
But here I am, alive and well. Well, mostly. It’s been a tough month for blood sugars; I imagine stress doesn’t help, and changing weather doesn’t help, and my mind being on other things doesn’t help, but the nights have been hard recently. Either I trend up and up and up, or I trend down and down and down, and hitting that middle route has been frustratingly difficult.
In other words, Diabetes Awareness Month? Yeah, I’m aware of it all right. Wish it would let me stop being aware long enough to sleep through the night.
I note that Diabetes Awareness Month is also Thanksgiving Month. So I’ll stop complaining now, and move on to what I initially intended on writing about when I started this post: what’s the deal with leptin? I’ve been hearing so many rumors lately; why are the JDRF and the type 1 diabetes world so excited about leptin?
First, some background: leptin is a hormone made by the body’s fat cells mostly, though a host of other cells produce some leptin as well. The protein leptin circulates throughout the body, and acts as part of the energy homeostasis process to signal that you are done eating (that is, that you’ve eaten enough and are full) . This satiety signaling is an important part of the way the body maintains weight and metabolic balance, and people with a particular mutation of the leptin gene cannot regulate food intake and energy expenditure properly, resulting in constant eating and eventual obesity . Similarly, everyone’s favorite ob/ob mouse, the commonly used mouse model of type 2 diabetes, is obese because of leptin deficiency .
As a result of its clear relation to obesity and metabolic disorder, leptin became the Holy Grail of the pharmaceutical industry after its discovery in the nineties, as many hoped it would be the Cure for Obesity. If leptin regulates appetite and leptin deficiency directly causes obesity, why not just give people exogenous leptin and let it tell them to stop eating?
A decent plan in theory; in practice, it’s not so simple. As you may have guessed from the increasing number of fat people in America, leptin has yet to cure obesity. To begin with, manufacturing leptin so that it can be efficiently absorbed by the body turned out to be non-trivial. Then there’s the problem of leptin resistance– as it turns out, leptin circulates in the body in proportion to the amount of adipose tissue in the body. So there is already lots of leptin circulating in obese people and animals; it’s just not doing what it’s supposed to any more. So how do you add more and make it powerful enough to result in weight loss?
Now, some people may jump in here with the most recently alleged Secret to Making Leptin Work– the hormone amylin . You may notice that these “some people” tend to overlap with the people that work at Amylin Pharmaceuticals, which has a vested interest in finding more uses for the hormone amylin. Regardless of their partiality, they may be right that leptin and amylin, in concert, can cause weight loss. They’re running clinical trials , but they’re not to market yet, so in the mean time, better keep counting calories.
Okay, so you’ve probably all made a mental connection now from leptin to obesity, and from obesity to type 2 diabetes. But what does this have to do with type 1? Why has there been news recently about leptin with type 1 patients? Why did the Juvenile Diabetes Research Foundation (JDRF), in collaboration with Amylin Pharmaceuticals, just announce a clinical study to determine the effect of leptin administration in conjunction with insulin therapy for type 1 diabetics?
The study will be conducted at The University of Texas (UT) Southwestern Medical Center, which has played a role recently in a number of animal studies related to the beneficial effects of leptin in mice lacking functional beta-cells [6, 7]. In one study, researchers administered leptin to non-obese diabetic (NOD) mice (that is, type-1-like mice), and found that the leptin greatly reduced the amount of insulin required to maintain glucose homeostasis in the mice. They found further that this reduction could go as far as taking the mice off of insulin treatment entirely. Their results are very promising indeed, as reducing the amount of insulin required is a high-value target for a number of reasons, including the facts that relying too much on insulin often results in overdosing and hypoglycemia, and that the high levels of exogenous insulin used to treat type 1 diabetes are associated with lipid dysregulation and increased risk of coronary disease.
But how does leptin work to maintain glucose and hormone levels in these mice? This is where my eyebrows begin to raise, and I wonder about the wisdom of taking exogenous leptin. The action of leptin in the NOD mice seems to be related to its suppression of glucagon synthesis, but that’s not the whole story, and the researchers theorize that the normalization of lipid metabolism and skeletal muscle regulation are also involved in the ability of leptin to reduce insulin requirements to nothing.
The exact mechanisms are not clear in the initial study, and they become even more mind-boggling in another study from the University of Texas. Researchers took mice whose beta cells had been killed off by the toxin streptozotocin, and administered leptin directly to their brains. Lo and behold, even without any insulin at all, the mice survived and reached normal glucose levels, while the mice not given leptin died as expected from hyperglycemia with no insulin or beta cell function.
Okay, what? Leptin to the brain, no insulin, and the mice have normal blood glucose levels? Leptin levels are hard to measure, and are typically monitored through a number of related molecules, but even so the researchers were able to tell that the leptin was not making its way into the liver in large amounts, so suppression of glucagon couldn’t be the cause. And the mice were eating normal amounts, so it wasn’t just that they were slowly starving themselves from lack of appetite. And the beta cells had not regenerated, and there was little to no measurable C-peptide in the mice, implying there was no insulin synthesis going on somewhere else in the mice.
Wait, what? Really? How? Leptin to the brain? What?
Yeah. And there are some theories proposed by the researchers at UT, but, really, their conclusion is: these are interesting findings, and we should study this phenomenon more. So that’s I guess where clinical trials come in. But the fact that we understand so little about what leptin is actually doing, and how it’s doing whatever it’s doing, makes me very nervous indeed.
So let’s back up a minute; what else do we know about leptin and type 1 diabetes? To begin with, we know type 1 diabetics have low circulating levels of leptin upon diagnosis, likely due to the fact that insulin signaling plays a role in the leptin synthesis process , or the fact that without insulin, the body is starved for nutrients and therefore unlikely to signal that it is sated.
After insulin treatment is initiated, though, type 1 diabetics have high circulating levels of leptin as compared to non-diabetics. Why, you ask? Good question. This is where my lips purse and my head begins to shake to back up my raised eyebrows. You see, leptin is primarily known for its role in regulating appetite, but increasingly it is gaining a reputation as a vital mediator standing between the neuroendocrine and immune systems in the body.
In other words, leptin doesn’t just talk to the brain about food; it talks to the immune system, too, and what it says is in a language we have only begun to understand. Leptin has been shown to interact specifically with T cells, big players in adaptive immunology, and to inhibit receptor signaling in regulatory T cells, to increase receptor signaling in normal T cells, to increase the production of certain cytokines, to prevent T cell death, and to polarize cells toward a Th1 phenotype . In other words, leptin skews the balance of the adaptive immune system so that it is beefier and more attack-ready. And so it does not come as a total surprise that leptin levels are higher in certain autoimmune diseases, like inflammatory bowel disease, vasculitis, rheumatoid arthritis, and, of course, type 1 diabetes. (Conversely, ob/ob leptin-deficient mice have proved somewhat resistant to some T cell mediated autoimmune disorders like arthritis, colitis, and EAE, the mouse model of Multiple Sclerosis.)
So. Leptin– reduces appetite and may bolster insulin signaling? Cool. May cause further dysregulation of my adaptive immune system? Not so cool. Consider: high leptin levels have been shown to accelerate the autoimmune malfunction in female NOD mice. And given the up-regulation of leptin in obesity, and the high incidence of cancer in obesity, and the relationship between T cells and cancer… it’s only a skip, hop, and jump between leptin and cancer . Cancer, people, cancer! So when you tell me you want to add leptin to this witch’s brew of an immune system inside of me? Let’s just wait on that a bit, shall we?
All that said, leptin has been studied extensively and expensively. It might be, after all, the Cure for Obesity– that’s worth a pretty penny. And clinical trials seem to indicate leptin is at least not causing cancer. Plus, the results thus far at the University of Texas are amazing, to say the least– glucose homeostasis with no insulin? Even if that’s not feasible with humans, the idea of supplementing insulin with leptin treatment is an attractive one.
And here one half of me says: “But what on earth is leptin doing? And what if leptin makes cancer worse, or more likely to metastasize! And, autoimmunity! Is that a balance we understand well enough to mess with it? Were they looking at type 1 diabetics in the obesity trials? I doubt it! And what on heaven and earth is leptin doing in those mice anyways?” And the other half says: “That’s what clinical trials are for, though. Think of how many drugs were found to be effective before the mechanisms were understood! That’s most drugs, really; are you willing to hold up progress waiting to understand everything before it’s tried? You’ll wait forever!” So, in order to maintain civility in my divided house, I must conclude: Please, run the trials. And please, let them work; if it helps this insulin regimen be more effective, or less damaging in the long term, that is huge. But I’m sitting on the bench for a while on this one; let those braver than me try out leptin, so that I can come along when the answers are more clear.
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