Diabetes and Insulin Resistance

Let's dive into articles that have been critical to understanding type 2 diabetes and Insulin Resistance: the Ominous Octet and now the Egregious Eleven from the BMC Medicine paper and the 2009 Diabetes paper by Dr. Ralph DeFronzo. Peter Attia recently interviewed Dr. Defronzo and I am on listen #3 because it is so good and yet incredibly complicated. This piece is a compilation of that interview and reviewing Dr. DeFronzo's papers.

“…all too often, the risk factors for these disorders are not addressed promptly in clinical practice, leading to irreversible pathologic progression… Traditional approaches to treatment involving sequential therapy, in which agents are added only after one has failed, contribute to clinical inertia and often prevent goal attainment, leading to adverse outcomes…. in turn contributing to increased morbidity and mortality. In contrast, early diagnosis and prompt, intensive intervention, often with initial combination therapy, leads to faster goal attainment and improved outcomes for at-risk patients.” (Handelsman et al. 2023)(Schwartz et. al. 2024)

This work has completely reshaped how we should tackle this disease. He took the old “triumvirate” model of liver, muscle, and pancreatic beta-cell dysfunction and blew it wide open, showing us eight interconnected defects driving insulin resistance and hyperglycemia. This is a roadmap to what’s breaking down in your body and how we can fight it. Let’s look at these eight culprits, because understanding them can change the game for managing diabetes and IR well before they take root or even when truly rooted in, i.e. reversibility.

Insulin resistance occurs over a relatively long continuum when your cells stop listening to insulin, the hormone that moves glucose into muscle, fat and liver cells primarily for energy storage. In the disease type 2 diabetes, this IR process goes off the rails, spiking blood glucose, insulin, free fatty acids and setting off a cascade of problems including kidney, nerve and vascular damage. DeFronzo’s Ominous Octet shows it’s not just one or two issues, but a whole team of dysfunctions working in concert like a symphony to drive disease.

The first and most important player is the liver. Normally, insulin tells the liver to stop making glucose when your blood sugar’s high, especially overnight. But in insulin resistance, the liver doesn’t get the sticky note. It keeps pumping out glucose, a process called increased hepatic glucose production or gluconeogenesis, leading to high fasting blood sugar. It’s like an assembly line that won’t shut off even when the end of the line is at capacity. Studies show this can account for up to 3/4 or more of fasting hyperglycemia in type 2 diabetes, and it’s a big reason why morning numbers are often sky-high. The other big reason is cortisol levels remaining high from stress which drives glucose production in the liver and blocks insulins effect at the muscle and fat cell.

Next up, skeletal muscle. Your muscle cells are supposed to soak up glucose after you eat, but when they’re insulin-resistant, they don’t. The GLUT4 receptor, a proverbial straw for glucose muscle cell entry, is impaired meaning that sugar stays in your blood, driving postprandial (after-meal) hyperglycemia. DeFronzo’s research, using euglycemic clamps, shows that muscle insulin resistance can cut glucose cellular uptake by 50% or more in diabetic patients. It’s like the doors to your cells are locked, and the sugar can’t get in.

Third, we have the insulin producing beta cell in your pancreas. By the time someone’s in the upper range of impaired glucose tolerance, they’ve already lost over 90% of their beta-cell function. (Schwartz et. al. 2024) That’s not a late-stage issue, it’s happening early, over decades before a diabetes diagnosis. Think about a resistant insulin receptor leading to increased blood glucose volume. The pancreatic response is to make more insulin to flood the receptors. This works for a while. Eventually, these cells can’t keep up with the demand to overcome the insulin receptor resistance, so insulin levels drop, and blood sugar climbs. It’s a slow burn that sets the stage for full-blown diabetes.

The fourth player is the fat cell, or adipocyte. In insulin resistance, they break down fat too fast, a process called accelerated lipolysis. This floods your blood with free fatty acids (FFAs), which DeFronzo calls lipotoxicity. This gets back to Gerry Shulman's work with diacyl glycerol and impaired GLUT4 activity. FFAs wreak havoc. They impair beta-cell function, cut insulin secretion and make the liver and muscles even more resistant. Studies show FFAs can increase hepatic glucose output significantly and slash muscle glucose uptake. It’s a vicious loop effect, more fat breakdown, more resistance, less insulin action. Not good.

Fifth, the gastrointestinal tract gets in on the action, specifically through incretin hormones like GLP-1. These hormones, released after you eat, are supposed to boost insulin secretion and slow gastric emptying. But in type 2 diabetes, the incretin effect is blunted. GLP-1 and GIP account for 70% of insulin secretion and this response drops a lot in IR. This means less insulin gets made when you eat, and glucose control takes a hit. It’s why drugs like GLP-1 agonists (think Ozempic) have become such a big deal. They try to fix this defect. The way that they are being used today is up for debate, the science is not.

Sixth, the alpha cell in the pancreas. These guys make glucagon, a hormone that tells the liver to release glucose. In a healthy system, insulin keeps glucagon in check and visa versa. But in IR/type 2 diabetes, alpha cells go rogue, overproducing glucagon even when blood sugar’s high. This hyperglucagonemia drives more liver glucose output. It’s like having a gas pedal stuck on while you’re trying to brake. The end result is a high blood glucose in the AM when it should be low.

Seventh, the kidneys. Normally, they reabsorb some glucose back into your blood, but in diabetes, they overdo it. SGLT2 transporters in the kidneys reabsorb more glucose than they should adding to hyperglycemia. This is why SGLT2 inhibitors medications work as they block this reabsorption, letting excess sugar spill into urine. In normal states, if blood sugar gets too high, the kidney will dump the excess. That process is broken in IR.

Eight, the brain. Dr. DeFronzo points to the hypothalamus, which regulates appetite and energy balance. In insulin resistance, the brain’s insulin signaling goes off-kilter, leading to overeating and weight gain. The desire to eat and overeat are secondary key drivers of diabetes. This neuroimmunoendocrine defect ties the whole octet together, showing how the brain, liver, muscles, and more are all in cahoots.

Here’s the big takeaway: the Ominous Octet tells us type 2 diabetes isn’t just about one fix. It’s a systemic problem of many cell types including the liver cell, muscle cell, beta cell, fat cell, gut cell, alpha cell, kidney cell, and brain cell. They all play their role in the concert. Dr. DeFronzo’s work pushes us to think beyond metformin or insulin shots which are incomplete and not achieving the goals that we care about - euglycemia and health. He thinks, and I agree, that we need a multi-pronged approach.

For me and for pediatrics and pregnant women specifically:

First and most importantly are the lifestyle changes -

1) Cut ultra processed foods with excessive fat and refined carbohydrates especially the liquid beverages to reduce the fructose and free fatty acid liver energy load hit (that must be processed)

2) Exercise and move to boost muscle insulin sensitivity and glucose uptake independent of IR issues and Glut 4 activity - exercise = decreased blood glucose and decreased liver fat. Take the stairs and not the elevator or escalator when possible, park farther away from the entrance and walk more, etc...

3) Work to minimize mental and physical stress that is chronic and troublesome in nature - stress is a major impetus to hepatic gluconeogenesis

4) Sleep 7 to 9 hours nightly and follow the circadian rhythms of sleep to reduce abnormal neuroimmunoendocrine responses to being awake at the wrong times of night

5) Consider drugs like GLP-1 agonists, metformin and SGLT2 inhibitors to hit specific defects for people farther down the IR continuum

6) Consider addressing elevated uric acid levels with reducing all forms or flour and sugar based foods, especially the liquid sugars. Consider tart cherry extract and or allopurinol to lower uric acid. I like a product called UAX pro

7) Consider therapy and take a hard look at how you are addressing the brain’s role in your appetite

8) Avoid endocrine disrupting chemicals that trigger IR. The list is long but especially phthalates, bisphenol and plastics in general

Dr. M

Glass Cell Metabolism

Coughlan J Endo Diabetes Obesity

Lustig Pediatrics

Patel J Obesity

Peterson Physiology Reviews

Peter Attia MD #140/149