Thursday, July 30, 2020

New Type of Diabetes Medication

 A new type of diabetes medication is being developed, and it sounds great. However, although it works in rodents, human cells, and dogs, there has not yet been a clinical trial of the drug, so it won't be available for some time.

The drug has the decidedly unmemorable name SRI-37330, and it works in part by decreasing glucose output from the liver. Glucose levels are controlled primarily by two hormones: insulin, which lowers blood glucose (BG) levels, and glucagon, which raises them. When you have type 2 diabetes, you not only don't produce enough insulin, but you produce too much glucagon. The glucagon stimulates the liver to produce glucose (gluconeogenesis) and release it into the bloodstream, even if your BG level isn't low.

SRI-37330 inhibits glucagon secretion and function, reduces glucose production in the liver, lowers serum triglyceride levels, and also reduces fatty liver. It does this by inhibiting a protein called TXNIP (thioredoxin-inhibiting protein), which has been shown to be elevated in people with diabetes and to have detrimental effects on islet function. The islets in the pancreas are where the beta cells produce insulin.

The drug has no effect on insulin secretion or function. It has no effect on glucose uptake by muscle or white adipose tissue. It has no effect on the secretion of glucose in urine.

SRI-37330 has no effect on glucagon secretion when BG levels are low, which reduces the chance that it could cause hypoglycemia. And it has no effect on body weight. But in obese, diabetic mice, it reduced BG levels significantly within 3 days, and they eventually returned to normal.

All these effects sound wonderful, and even if they don't turn out to be as dramatic in humans as in animals, it would be nice to have another drug with a different mechanism of action, as we're all different, and a drug that works wonderfully for one person might not be so great for another.

The lead author of this paper, Anath Salev, kindly sent me a copy of the full text. An interview with her can be seen here.

Saturday, July 18, 2020

Metformin and Energy

If you're trying to lose weight, there's a good chance that medical people will tell you that the important factor is that energy coming in is less than energy going out.

This is true.

But most people equate "energy out" with exercise. If you want to lose weight, they suggest that you exercise more. One problem with this advice is that for a lot of people, exercising just increases their appetite and makes them eat more, and so "energy in" goes up along with "energy out" and there's no loss of weight.

But exercise isn't the only part of "energy out." Any physiological process that wastes energy and converts it to heat will mean less energy is available to create fat. One example of this is the so-called biochemical futile cycles in which a chemical reaction converts A to B but then the body just converts B back to A. Because no reaction in the body is 100% efficient, each time the cycle occurs, a little bit of energy is lost as heat.

There are substances called uncoupling agents that increase the wasting of energy, and they were used by patients some years ago. The only problem is that one side effect of these compounds is death, so they weren't very popular.

Another part of "energy out" is any food lost in feces.  For example, if you eat a food that is poorly digested, much of the energy in the food is lost. An example of this is fiber. There's energy in fiber, and some microorganisms can digest it and convert it to useful substances. Humans can't. But sometimes bacteria in the lower bowel digest the fiber and produce substances like butyrate that we can digest.

So just measuring what you eat isn't enough. You need to know how much of what you eat is digested. In animal nutrition this is known as TDN, or total digestible nutrients.

Recently, research has shown that the diabetes drug metformin can increase the amount of sugar that is secreted in feces. This would both lower blood glucose levels and mean fewer calories were metabolized so they couldn't contribute to weight. (In animal nutrition, the goal is usually to get the animal to put on weight as quickly as possible, but the principles are the same.)

When I was diagnosed with type 2 in 1996, no one knew how metformin worked, but I was told it was better than the sulfonylureas (they didn't say why), which were the only other oral drugs available at the time, so I chose it and have been taking it ever since.

Eventually they discovered that metformin causes an increase in a molecule called AMPK, which is an energy sensor, and the recently discovered increased glucose excretion is a second mechanism. I suspect there are others that haven't yet been discovered.

The increased secretion of glucose into stool is analogous to the increased secretion of glucose into urine caused by the drugs called SGLT-2 inhibitors, for example, Invokana and Jardiance. In both cases, you're wasting calories by excreting them rather than converting them to heat.

There's still a lot we don't know about how metformin works, but we do know that it helps a lot of people with type 2 diabetes, and it's relatively inexpensive. On some drug plans, it's free.

Recently, the slow-release form of metformin was shown to contain a substance that increases rates of cancer. So far, only some brands have found this contaminant, but it's possible more will be added to the list when they are tested. If you want to see if your metformin is on the list, you can check here. This list was compiled on July 15, and there might be others added later.

Sunday, July 5, 2020

YMMV revisited

Some time ago, I wrote about "YMMV," or "your mileage may vary," the concept that sometimes what works well for one person doesn't work for another. The diabetes community was aware of that variation, but the evidence was annectotal and no one had studied it formally until a study in an Israeli cohort.

Now someone has done a similar study in mostly midwestern Americans without diabetes. The results are similar. Look at Figure 2A to see how people's blood glucose can vary after the same meal, in this case a bagel with cream cheese. One person's glucose levels went up to 190 and another to only 110. Note that these are people who haven't been diagnosed with diabetes. Whether they're on their way to diabetes is not known.

The researchers took 72 parameters into account in developing their model, which is designed to predict  how someone will react to a particular meal. You'll have to go to the Supplemental Content section to see these parameters, which I won't try to list here. They include species of 23 bacteria in the microbiome as well as usual things like nutrients, BMI, age, and CGM results.

The model is not yet available to the general public.

Tuesday, June 9, 2020

Toxins and Obesity

Some of us have long felt that toxins in our environment, our food as well as chemicals in cleaning products and chemicals used to control pests, could contribute to the obesity epidemic. Many of these chemicals were not available in previous times when very few people were obese.

A recent paper reports a study that so-called obesogens do indeed disrupt normal metabolic processes and cause lipid profiles in the liver to be abnormal. These changes increased susceptibility to weight gain, especially when they occurred early in life.

This is not the first time chemicals have been related to obesity and diabetes. For example, here is a study linking endocrine-disrupting chemicals like bisphenol A, found in tin can linings and cash register receipts; phalates, found in plastics and cosmetics; flame retardants; and pesticides with insulin resistance as well as other health problems including cancer. The effect seems to be greater early in life.

Interestingly, the authors of the recent paper said that rosiglitazone, a drug that used to be used to control diabetes, is among the obesogens,  and it was known to cause weight gain. I took it for a short time as part of a clinical study, and the doctor in charge warned me about weight gain, although she said it was mostly water weight and would go away when I stopped taking it, and the weight did reverse when the study was over.

The authors of the current study tried to find out how the obesogens work, and said they caused an increase in various fats in the liver when the liver cells were exposed to concentrations of obesogens often seen in today's environment.

One thing I found interesting in the current paper is that the authors said that today there are approximately 350,000 chemicals commercially available, compared with 100,000 in 2000, a huge increase in just 20 years. And with so many chemicals available, many of them are undoubtedly getting into our environment, including our food. Even monarch butterflies are threatened by toxins in their only food, milkweed.

So even if we try very hard to eat healthy food and we still gain weight, or can't lose weight, it might be more than genetics and food choices. We may be getting too many obesogens.

So what can we do? In today's world, it's impossible to avoid them completely, but we can try to minimize our exposure. If we can afford to, we can eat mostly organic foods, although they probably also contain some obesogens. We can avoid processed foods, which often contain additives. And we can mostly cook our own food at home, because who knows what restaurant food contains.

I realize that's difficult for many people, when trends are to eat more and more foods in restaurants or get them from takeout.

But we can try.

Saturday, April 25, 2020

Insulin Sensitivity in the Brain

We all know people who go on a diet, lose weight, and manage to keep it off. Others go on a similar diet, lose a little weight, and then regain it all, often ending up heavier than when they started.

Many people would say the latter group probably didn't follow the diet carefully and gradually ate more and more of the things they shouldn't eat.

But now there's some evidence that insulin resistance in the brain can predict weight-loss and weight-gain patterns. A German research group showed that people with insulin resistance in the brain lost less weight than people who were insulin sensitive and then regained the weight, whereas the insulin-sensitive ones were able to keep the weight off.

Apparently, the insulin sensitivity in the brain also determines where fat will be deposited. Those with brain insulin resistance deposited more fat in the visceral area, and this fat is supposed to be more detrimental than subcutaneous fat.

So what can we do with this information? At this time, not much. I don't know about you, but I'm not keen on injecting insulin into my brain.

However, knowing about this effect may help if you're one of the people who doesn't lose much weight even though you're following a diet strictly. When that happens, many health people probably blame you, assuming you're cheating on the diet even though you say you're not.

I know that kind of disbelief by medical people. My endo put me on an ACE inhibitor, which is usually used to lower blood pressure, because she said it would protect the kidneys, and people with diabetes are at risk of kidney disease. When other medical people see I'm on an ACE inhibitor, they ask how long I've had high blood pressure. I say I don't have high blood pressure, and they give me a patronizing look. At that point, I probably do have high blood pressure because I don't like not being believed.

Determining whether or not you have insulin resistance in the brain is not simple. The researchers used magnetoencephalography and functional MRI, techniques not available at your doctor's office.

Presumably, anything that reduces insulin resistance elsewhere in the body should also reduce it in the brain, and that would include exercising and losing weight, things we mostly likely already know we should do.

But if you're still having trouble losing weight, it could be it's not a lack of willpower. It could be insulin resistance in your brain.

Sunday, April 12, 2020


I tried to reply to a Comment yesterday, and it wouldn't post.

After trying this and that and searching the internet for help, I concluded that the problem is Firefox, which is my standard browser. With Chrome, I was able to post.

Computers can be very helpful, but they can also be very time-consuming when things don't go well. I sometimes wonder about returning to paper and pencil. No, I'll be more up to date than that. How about paper and ballpoint pen.

I still remember the time my father, a lawyer, came home with an amazing device to show us all. He had a client who was developing a special pen that wasn't yet for sale, but he had one. It was called a ballpoint. We were awed.

But I digress. I just wanted to give a heads up if anyone else is having problems posting. Try another browser.

I do moderate the Comments. If it's clear that the point of the Comment is to provide a link to someone's website, I don't approve it. So if you've sent such a Comment and it didn't appear, it's the moderation not the browser that is the cause.

Saturday, April 11, 2020

"Pumping" with Regular Insulin

When you use a pump, you fill it with fast-acting insulin like Humalog or Novolog. All day and night, the pump dispenses small amounts of the fast insulin, called basal insulin, and allows you to dispense larger amounts with meals, called bolus insulin.

Now a nonelectronic simple type of insulin pump can be used with regular insulin (R). Because the device is simpler than a regular pump and because R insulin is cheaper than newer insulins, the overall cost could be lower, especially for someone with no insurance.

The basal insulins use chemistry to modify R insulin so it forms depots in the fat that then release slowly. This device uses mechanics to release the R insulin slowly.

The device is called V-Go. It is designed for people with type 2 diabetes who still produce some insulin and thus don't need such exact amounts to be injected.

You fill a reservoir with R insulin and the device releases 20, 30, or 40 units a day as a steady infusion and can also release bolus insulin in increments of 2 units, up to 36 units a day when you press a button. The device has to be filled and placed on the body once a day and then is removed and thrown out after 24 hours. You can see detailed instructions here.

The V-Go had been approved for fast-acting insulins some time ago. But recently the device was shown to be effective with R.

The V-Go is nowhere as sophisticated as a regular pump. For example, it can release insulin at only one rate, whereas pumps can be programmed to release insulin at different rates at different times of day. And if you need less than 20 units or more than 40 a day, it wouldn't work. However, it's also much less expensive.

The device costs about $75 a month if you have no insurance. This would give you enough to use one a day. And you also have to buy insulin: 2 vials for 20 units a month and 3 vials for 30 or 40 units a month. You can get R insulin at Walmart for about $25, so the total cost would be about $125 a month for the 20 and $150 for the 30 or 40. Insurance could bring the price down.

The V-Go requires a prescription; Walmart insulin does not.

And someone with good insurance might find a regular pump at a lower out-of-pocket cost, although insurance, including Medicare, won't usually cover regular pumps for type 2 patients.

If you use only basal insulin, for example, Lantus, Levemir, or Tresiba, and inject only once a day, it might not be worth the extra trouble to set up the V-Go, but if you're doing basal/bolus multiple daily injections, it could be handy, especially if you wanted to bolus at work without hauling out a pen or syringe.

If you're on a low-carbohydrate diet, R insulin actually matches the increases in blood glucose after a meal better than the faster bolus insulins because it starts slowly and lasts longer. When you're eating protein and fat and fiber, your blood glucose also goes up slowly and but stays higher for a longer time, as the fat slows gastric emptying. When you're eating mostly carbohydrate, you get spikes in blood glucose that go up quickly and come down quickly, so the faster bolus insulins are a better match for that type of diet.

Because the insulin release from the V-Go is preset (20, 30, or 40 units for the basal and multiples of 2 for the bolus), you don't have as much flexibility as you do with a regular pump. You might need a bolus of 5 units but you could get only 4 or 6. You might need 25 units a day for the basal but you could use only 20 or 30. For a type 1 patient who produces no insulin of their own, this could be a big drawback. But type 2 patients have a bit of a buffer with their own insulin production.

One caveat: the studies I found had researchers with connections to or stock in Valeritas, Inc., the maker of the device, and some of their press releases are linked to reports on the value of their stock. This doesn't mean the studies are flawed, but it's sometimes a red flag.

Nevertheless, this is an interesting addition to the armamentarium we have to control type 2 diabetes.