Consider a hamburger. When most of us eat a burger, we stop thinking about it the moment the hunger pangs disappear. You may think about it for an extra few minutes if it was especially greasy and it gives you a stomachache, but that’s it. In fact, the really interesting stuff doesn’t even start until after the burger’s been broken down to its chemical building blocks and absorbed. These chemicals are carbohydrates, amino acids (from the protein), and lipids, including cholesterol and triglycerides. Your body has to orchestrate an extremely complex set of maneuvers to get all that stuff to where it belongs (muscle, liver, or adipose tissue?), and to dispose of it in the proper way (burn it or store it?). For example, amino acids can go lots of places, where they should be used to make new protein, and not broken down to make sugar. Carbohydrates, now in the form of simple sugars, are taken up by many tissues, especially muscle, liver, and fat. In liver and muscle, some of the sugar will be burned for energy, and some will be stored as glycogen for later consumption. Lipids are mainly sent to adipose tissue (fat), where they can be stored until needed for energy, usually several hours after that burger went down.
In type 2 diabetes, this complicated dance moves to a slightly different rhythm, with quite serious consequences. While aberrations can be found in almost any metabolic process you care to look at, attention has recently been focusing on the deposition of lipids in tissue where it doesn’t belong, mainly muscle and liver. Too much fat in these organs seems to mess up their normal behavior, particularly when it comes to listening to the hormone insulin, which is one the most important conductors of the metabolic orchestra.
In fact, scientists have long been puzzled by the fact that insulin resistance and diabetes occurs in two opposite conditions, obesity and lipodystrophy. In obesity, there is too much body fat, and in lipodystrophy (a relatively rare condition in humans) there is almost no fat whatsoever. The common denominator seems to be that excess fat is stored in muscle and liver in both of these conditions. As much as we tend not to love our adipose tissue, it’s job is to keep lipid locked up where it can’t do any harm; if it’s capacity is overwhelmed (i.e. obesity) or there’s not enough (i.e. lipodystrophy), problems result. Interestingly, excess fat also seems to be deposited in the insulin-producing beta cells of the pancreas as well, and this may have something to do with the disturbances in insulin secretion seen in obesity and type 2 diabetes.
So what we need is some way to get all that fat out of our tissues. Now here’s the good news – this is exactly what some current diabetes medications appear to be doing. And the better news is: new discoveries hold the promise of making the process of removing that unwanted lipid even more efficient.
Let’s start with the drugs called thiazolidinediones, or TZDs. These include pioglitazone (ActosTM) and rosiglitazone (AvandiaTM), and although we have known for a while that these compounds activate a protein called PPAR-gamma, we have not known how that makes insulin resistance get better. A recent paper from a group at GlaxoSmithKline1 may shed some light on this issue, as they showed that the net effect of these drugs is to move lipid out of muscle and liver, and into fat cells where it belongs. This makes the body more sensitive to insulin, although there is a downside as well. Depositing all that lipid back into adipose tissue makes you fatter, which is not where most people with type 2 diabetes want to go.
Another commonly prescribed antidiabetic drug is metformin (GlucophageTM), which improves insulin sensitivity in the liver. Despite intense investigation, it has remained unclear how metformin works to make this happen. Another recent paper, this time by a group at Merck2, shows that metformin reduces the amount of lipid stored inappropriately in the liver. It does this by suppressing enzymes that promote lipid deposition in the liver, and also by activating an enzyme called AMP-activated protein kinase (AMPK).
AMPK has really burst onto the scene in diabetes research in the past few years, so it’s worth spending a moment discussing what it does. AMPK (or a version of it) is found in organisms as evolutionarily distant as yeast, humans, and mice. It serves as a fuel gauge for cells, telling them when energy stores are low and need to be replenished. When activated, AMPK directs the burning of lipids and sugars, so it comes as no real surprise to find that AMPK is involved in the regulation of insulin sensitivity. This connection was just made even clearer by another paper, just published this week in Nature3. These authors were studying how the hormone leptin improves insulin sensitivity, and found that (surprise!) it activates AMPK in muscle. Again, activation of AMPK caused lipid to be burned, providing energy to the cells and reducing inappropriate fat storage there. Interestingly, exercise stimulates AMPK as well, which is one way that physical activity improves insulin sensitivity.
The result of all this work will be to stimulate researchers to take a much harder look at AMPK. New drugs will likely be developed specifically because they activate AMPK, and other therapies that clear fat out of muscle and liver will be sought. While we all want to lose a little extra fat, these studies demonstrate that the worst stuff is in the cells where it shouldn’t be.
1. Way JM, Harrington WW, Brown KK, Gottschalk WK, Sundseth SS, Mansfield TA, Ramachandran RK, Willson TM, Kliewer SA. Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues. Endocrinology. 2001 Mar;142(3):1269-77.
2. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation. 2001 Oct;108(8):1167-74.
Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002 Jan 17;415(6869):339-43.