Fat Fails First?

In my previous blog post, I explained what initially made me skeptical of the idea that insulin resistance develops first in the liver and skeletal muscles and last in fat tissue. Now I'd like to argue the opposite: that insulin resistance develops first in fat tissue and this leads, over time, to less insulin sensitivity in liver and muscle cells eventually resulting in the development of the metabolic syndrome.

Consider the fact that people with congenital generalized lipodystrophy, in whom fat cells are lacking from birth, typically develop components of the metabolic syndrome such as insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes at a much earlier age and in more severe forms than do obese humans. This is believed to happen because a dearth of fat cells causes the body to have no "safe" place for excess fatty acids to be stored, and people with lipodystrophy tend to generate excess fatty acids because they cannot make much leptin, a major adipose-derived satiety hormone, and hence have a strong drive to eat. Some of the excess fatty acids will end up being stored in the liver and muscles as well as in other non-adipose tissues (aka lipotoxicity) resulting in decreased insulin sensitivity in these organs and the metabolic syndrome.

Obese humans, on the other hand, are not lacking fat cells so they can, and do, store a lot of excess fatty acids in their fat cells. I'm sure we've all known overweight or obese individuals who possess good health with no obvious signs of the metabolic syndrome - normal blood pressure, normal blood sugar, normal lipid profile, etc. These individuals will often bring these things up when a friend or family member urges them to lose weight - "All my blood tests are good and I'm not on any medication; my doctor says I'm healthy so I feel no urgent need to lose weight." And they may be able to go their entire lives without a hint of the metabolic syndrome if their fat cells maintain their insulin sensitivity. If they don't, these corpulent individuals will become, in essence, like a person with congenital generalized lipodystrophy: unable to store excess fatty acids in adipose tissue which will lead to lipotoxicity and metabolic syndrome. Unfortunately, the majority of obese individuals will develop metabolic problems related to their weight at some point in their lives.

It has been shown that many people's free fatty acid blood levels are elevated years before a diagnosis of type 2 diabetes (which is based solely on some measure of high blood sugar). In other words, blood sugar can remain within normal limits while fatty acid levels are soaring. Knowing that the inhibitory effects of insulin are the more physiologically important, this indicates that adipose tissue becomes resistant to insulin (resulting in increased free fatty acids via unrestrained fat cell lipolysis) before the liver does (resulting in increased blood sugar via unrestrained hepatic glucose production). 

It's also important to note that a class of diabetes drugs called thiazolidinediones (TZDs) lowers blood sugar primarily by increasing fatty acid uptake and storage in fat cells. By taking excess fatty acids out of the circulation, the liver becomes less affected by lipotoxicity and regains its sensitivity to insulin. Hepatic glucose production is restrained by insulin in a more normal fashion and blood glucose concentrations fall. 

Further, it has been demonstrated that serum free fatty acids are the main source of liver triglycerides in people with NAFLD; therefore, fat cell insulin resistance to lipolysis is likely a major contributor to fat accumulation in the liver.

Using the above information, the following scenario makes sense to me:

Chronic caloric surplus (possibly caused by a diet high in sugar and fat along with a sedentary lifestyle) causes fat tissue to expand to sequester toxic fatty acids that would otherwise damage organs. When fat tissue can no longer expand, it becomes resistant to insulin. This leads to increased fat cell lipolysis and elevated free fatty acids which leads to "ectopic" fat deposits in the liver and muscles. The liver and muscles then become resistant to insulin. This leads to increased hepatic glucose production with substrate partially supplied by amino acids coming from skeletal muscle because of increased proteolysis. The increase in blood sugar results in stimulation of insulin secretion from the pancreas. We now have chronic hyperinsulinemia and hyperglycemia - these conditions are associated with and possibly cause many of the problems linked with the metabolic syndrome like hypertension, coronary artery disease, kidney disease etc.

To be continued...

References

• From the metabolic syndrome to NAFLD or vice versa?
• Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity.

How the "Black Age" of Endocrinology May Be Affecting Your Understanding of Insulin Resistance & Obesity

If, on a Physiology exam, you were to answer that the primary action of insulin is to allow glucose entry into liver and muscle cells, you would probably be marked correct although the answer would be wrong!  The fact of the matter is, insulin is not required for glucose to enter cells.  During what is sometime referred to as the "black age" of Endocrinology (approximately from 1960 - 1980), scientists studying the actions of insulin using in vitro techniques with rodent tissues mistakenly assumed that their data mirrored what happens in living, breathing human beings.  It's now known, and has been for many years, that insulin's inhibitory effects on processes such as liver glycogenolysis and fat cell lipolysis are much stronger and more metabolically important than its excitatory effects on processes such as de novo lipogenesis and cellular glucose uptake.  Yet, despite this new knowledge, the old misconceptions about insulin still persist and have become dogma.  For an illuminating discussion of this topic, please see this article in the Journal of Endocrinology.

I think all would agree that understanding the true nature of insulin action is critical to understanding the development and progression of insulin resistance and obesity.  A common theory in the low-carb community, spurred in part by the book Good Calories, Bad Calories, is that insulin resistance develops first in the liver, progresses next in skeletal muscle before finally developing in fat cells.  This progression leads to obesity and ultimately, for those genetically unfortunate folks, to type 2 diabetes.  From page 393 of GCBC:

"…fat cells remain sensitive to insulin long after muscle cells become resistant to it. Once muscle cells become resistant to the insulin in the bloodstream, as Yalow and Berson explained, the fat cells have to remain sensitive to provide a place to store blood sugar, which would otherwise either accumulate to toxic levels or overflow into the urine and be lost to the body. As insulin levels rise, the storage of fat in the fat cells continues, long after the muscles become resistant to taking up any more glucose. Nonetheless, the pancreas may compensate for this insulin resistance, if it can, by secreting still more insulin. This will further elevate the level of insulin in the circulation and serve to increase further the storage of fat in the fat cells and the synthesis of carbohydrates from fat (note: I think it’s supposed to be ‘fat from carbohydrates’)."

There is some evidence to support this contention (most notably an experiment conducted by Ethan Sims which purported to show that fat tissue surgically removed at different time intervals from study subjects who were gaining weight from forced over-nutrition became progressively more insulin sensitive while muscle tissue did not), but the matter is far from settled.   A major problem I see with this hypothesis is that it is partially based on the incorrect notion that insulin (and by extension insulin sensitivity) is needed for muscle cells to take up glucose from the blood.  Human skeletal muscle in vivo can import glucose in the total absence of insulin.  Carefully designed studies have shown that type 1 diabetics, withdrawn from insulin for 24 hours, take up more glucose into their cells during the insulin depleted state than when they are re-administered insulin in the physiological range.  Knowing this, it's difficult for me to believe, at least without more concrete evidence, that insulin resistant muscles cannot take up a considerable amount of blood glucose and that this results in a physiologic imperative for fat cells to remain insulin sensitive in order to act as a "sink" for excess blood sugar.  Remember, the excitatory or stimulatory effects of insulin (of which cellular glucose uptake is one) are relatively unimportant.  Again, please read this article for clarification.

To be continued...