NADIR ALI t | OLD & SEDENTARY? MITOCHONDRIA UNHEALTHY …cannot CLEAR FAT …becomes RANCID

Added: 2026-06-01

[00:00:00]I want to talk to you today about fat toxicity or lipotoxicity.

[00:00:07]My talk is completely free of bias because I have no conflict of interest.

[00:00:12]That's another way of saying that I am a low-carber for 10 years and I have my biases.

[00:00:21]But today what I want to do is to talk to you guys about how lipotoxicity or fat toxicity happens and how it can cause insulin resistance and mitochondrial dysfunction.

[00:00:37]And because of Jeff, we have had some very good speakers like how Abby Bleistein said that we talk about metabolic health but we ignore the mesolimbic dopamine system in the brain that drives overconsumption and addiction of food which I want to tie in with these factors.

[00:01:01]Obesity is not just overfilled and overstuffed fat cells but fat spilling into the bloodstream and finding a location to park itself in the organs, the liver the spleen and the pancreas.

[00:01:20]So if you look at normal fat handling after a fat meal the fat gets absorbed into the circulation directly. It bypasses the liver.

[00:01:31]And it's called a chylomicron, a fat-filled globule that tries to find a place to unload its cargo in the muscle or in the fat cell.

[00:01:43]It becomes much smaller, it's called remnant, it's picked up by the liver and then cleared.

[00:01:50]By looking at some clinical parameters of low triglycerides and high HDL, I can say somebody has normal fat handling.

[00:02:00]We'll get into the other parameters in a bit.

[00:02:04]Now, with obesity and with overconsumption you have a lot more fat globules or chylomicrons that are absorbed.

[00:02:15]The trouble is that the fat cells say we are overfilled and we can't take any more.

[00:02:21]The muscle is lipotoxic.

[00:02:24]And so these fat-filled globules remain in circulation.

[00:02:30]And when they remain in circulation, they cause fat deposition in organs that do not and should not have fat.

[00:02:38]And that's called ectopic fat deposition in the liver in the muscle, in the pancreas, and the heart.

[00:02:49]A clinician can recognize this by looking at the fact that these people have high triglycerides, and I say 300 is too big a number. It should be less than 100.

[00:02:59]Low HDL markers of insulin resistance blood markers of liver dysfunction low levels of a hormone that healthy fat cells elaborate called adiponectin high blood pressure and visceral obesity.

[00:03:18]So, let's examine how muscles deal with insulin and food coming in. So, as glucose is coming in insulin recruits a channel called GLUT4 channel to drive the sugar into the muscles.

[00:03:36]The muscles can either burn it for fuel or store it as glycogen.

[00:03:42]The less insulin required to do this job, the more insulin sensitive you are.

[00:03:49]If you have a larger muscle mass, you can recruit a lot more GLUT4 channels.

[00:03:55]You can take in a lot more glucose or sugar before getting insulin resistant.

[00:04:04]Let's examine the intersection of fat and muscles.

[00:04:10]As we take in fat and it gets into the bloodstream, you would be surprised to know that insulin is required for fat metabolism as well.

[00:04:19]And insulin in the setting of an enzyme called LPL drives the fat into the muscle cells.

[00:04:26]The muscles can either burn it or store it as intramyocellular fat.

[00:04:35]If you are physically active, younger, you have better muscle insulin sensitivity.

[00:04:43]You will have more fat in your muscles, but this is accompanied by having a lot more mito-chondria that are healthy, that can burn fat.

[00:04:54]In addition, you have more recruitable GLUT4 to take in glucose, you can make glycogen.

[00:05:00]And because your fat is in a dynamic flux, it does not get converted to toxic metabolites.

[00:05:09]On the other hand, if you have obesity, diabetes, or sendentation, the mitochondria are unhealthy. Chris Palmer talked about mitochondria, and I'm going to get into it into the weeds of this.

[00:05:24]The mitochondria are fewer in number, they're diseased.

[00:05:28]They're not clearing the fat, the fat gets rancid.

[00:05:32]And as the fat gets rancid, it can get converted to toxic fat molecules called ceramide and diacylglycerol.

[00:05:41]Now, we as low-carbers tend to think that glucotoxicity carbs are the main cause of insulin resistance.

[00:05:52]Dr. Schulman has clearly shown, and I think that this is the accurate picture, that it is lipotoxicity that causes insulin resistance.

[00:06:02]With lipotoxicity, you get convert the fat inside the cells to ceramides and diacylglycerol, and this prevents intracellular insulin signaling, so that you cannot recruit the GLUT4 channels through which you can take in glucose.

[00:06:20]In addition, the toxic fat damages your mitochondria.

[00:06:26]The mitochondria don't burn cleanly.

[00:06:29]They make a lot of free radicals.

[00:06:32]The cell gets energy starved, inflamed, and dies.

[00:06:39]Now, let's turn our liver as to how the liver interfaces with food.

[00:06:44]In the setting of fasting, the liver is charged with the main responsibility of supplying the brain with fuel.

[00:06:52]Our brain refuses to fast. It needs a certain amount of food all the time.

[00:06:57]And so, amino acids from muscle breakdown, and glycerol from fat breakdown is converted in the liver through a process called gluconeogenesis, to provide what is called hepatic glucose output for the brain.

[00:07:13]In addition, the fatty acids get taken up by the mitochondria in the liver, and because insulin levels are low when you're fasting, they convert they get converted to ketones, which is fuel for the brain.

[00:07:28]When you eat a meal, glucose is coming in, the liver can use what it needs and then store it as glycogen. And because glucose is coming in, hepatic glucose output should get shut down.

[00:07:42]However, in the setting of insulin resistance, the insulin cannot recruit the GLUT4 channels.

[00:07:51]The amino acids from fat breakdown and the glycerol from lipolysis continue to be taken up by the liver and in the midst of plenty of food coming in, the liver puts out glucose when it shouldn't.

[00:08:07]It also jacks up the fat manufacturing machinery to become fatty.

[00:08:15]The fatty acids that are picked up by the liver get cannot get converted to ketones because of high insulin levels and the liver spews out these triglyceride-rich lipoproteins.

[00:08:31]Now, I have several patients who tell me, "Doc, I have had a marginally elevated hemoglobin A1C for about 10 to 15 years. It means nothing."

[00:08:42]But what they need to realize is that it takes two to three decades of a fatty pancreas before you progress to type 2 diabetics type 2 diabetes.

[00:08:53]But the fatty pancreas initially is actually making more insulin.

[00:09:00]But phase 1 insulin response, what that means is that when there is a slight shift in glucose, the pancreas squirts a amount of insulin into the vicinity and it reduces glucagon production. That is gone.

[00:09:15]I've been accused of being a little nerdy, so that was a little nerdy fact.

[00:09:21]Now, Lidia Shishkova has shown that as you progress from normal to obesity to type 2 diabetes or pre-diabetes and type 2 diabetes, the amount of fat in your pancreas goes up.

[00:09:38]So, here is a study that has looked at obese men and women and compared them to lean controls.

[00:09:46]You can see that the body mass index of obese men and women is similar.

[00:09:52]They are higher than the lean controls.

[00:09:56]However, women are blessed and the reason I say that is because for the same BMI the men had more visceral fat, had higher liver and pancreatic fat content.

[00:10:13]They were also more insulin resistant as evidenced by high fasting insulin and high HOMA-IR scores.

[00:10:22]And this was accompanied by them having lower levels of the healthy fat hormone called adiponectin as well as leptin.

[00:10:31]And they had higher markers blood markers of liver disease.

[00:10:37]Now, one does not need to get into their 40s to get lipotoxicity. This is a study in teenage Mexican-American girls, 16 or 17.

[00:10:50]And you find that when their weight goes up, they become insulin resistant.

[00:10:54]And not only do they get insulin resistant, but muscle fat, liver fat, and pancreatic fat goes up dramatically even at this young age.

[00:11:08]Now, you don't need to actually become obese to have insulin resistance and lipotoxicity because this study looked at offsprings of type 2 diabetics and compared them with lean controls.

[00:11:25]And what was found is that even though they were similar in age, similar in weight, and in hemoglobin A1c.

[00:11:37]These individuals on a craft glucose tolerance test had higher sugars and higher insulin at each time point indicating that they were insulin resistant.

[00:11:48]This was accompanied by high amount of muscle fat and by lower ability to generate ATP. In other words, they had poor mitochondrial function.

[00:12:02]Let's take another group, older people.

[00:12:05]I'm getting older.

[00:12:08]Age is associated with mitochondrial dysfunction, insulin resistance, and lipotoxicity.

[00:12:15]Because this group took individuals that were younger, in their 20s, versus older, in their 70s.

[00:12:23]That was the only difference, age.

[00:12:25]They were similar for their weight, their fat mass, their lean mass, and body mass index.

[00:12:33]But when a group glucose tolerance test was done on them, the older individuals had higher glucose and higher insulin levels indicating that they were insulin resistant.

[00:12:46]This was also accompanied by them having larger amount of muscle fat and liver fat.

[00:12:54]And their mitochondria didn't function well because they were able to generate less ATP or less energy currency.

[00:13:03]Now, my previous speaker, Horam, talked a lot about statins.

[00:13:07]I think that these are perhaps the most worthless drugs on the planet.

[00:13:14]>> [applause] >> There is lack of data, but I think there is a lot of infer- inferential information, even from my clinical practice, that statins cause insulin resistance.

[00:13:27]They poison the mitochondria by depleting CoQ10.

[00:13:31]And because they increase the VLDL receptor, it's a receptor that picks up fat from the circulation. When you take statins, your receptor goes up, so your visceral organs take up more fat and become fat toxic or lipotoxic.

[00:13:46]Now, I'm going to take a page from Abby Blayney and Chris Palmer's book and talk about mitochondria.

[00:13:53]Mitochondria try their best to protect themselves.

[00:13:59]What is shown out here is that damaged mitochondria fuses with a healthy mitochondria in a process called complementation so that it can work better and not generate free radicals.

[00:14:14]In the middle panel, the mitochondria can segregate the damaged parts, divide into a daughter mitochondria which is unhealthy, damaged, and a daughter mitochondria that is healthy.

[00:14:27]The damaged mitochondria can be cleared by a process called autophagy or mitophagy.

[00:14:34]The healthy mitochondria and you can say that I'm a cyclist because that is Pogacha.

[00:14:43]With in the setting of exercise, healthy mitochondria they use up ATP. I mean, the body when it's exercising uses up ATP as energy fuel, AMP goes up as ADP goes down, AMP goes up, and this gives a strong signal to the cell to start producing this master mitochondrial biogenesis factor which is called PGC1 alpha. But, you don't need to remember that.

[00:15:13]But, it initiates mitophagy.

[00:15:17]Uh It also initiates fusion, fission, and creates more mitochondria.

[00:15:23]On the other hand, if you have sendentation, lipotoxicity, or insulin resistance, you are creating a lot more of that toxic fat that damages the mitochondria. These mitochondria don't burn cleanly.

[00:15:36]They generate a lot of free radicals that can cause aging.

[00:15:40]And the toxic fat called ceramide can form a channel through which important mitochondrial proteins leach out and program the cell for cell death, resulting in muscle atrophy or sarcopenia.