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Mouse-typesNewly diagnosed type 2 diabetics tend to have one thing in common: obesity. Exactly how diet and obesity trigger diabetes has long been the subject of intense scientific research. A new study led by a collaboration between the University of California, Santa Barbara and Sanford-Burnham Medical Research Institute, has revealed a pathway that links high-fat diets to a sequence of molecular events responsible for the onset and severity of diabetes.

In studies spanning mice and humans, Dr. Jamey D. Marth’s team discovered a pathway to disease that is activated in pancreatic beta cells, and then leads to metabolic defects in other organs and tissues, including the liver, muscle and adipose (fat). Together, this adds up to diabetes.

“We were initially surprised to learn how much the pancreatic beta cell contributes to the onset and severity of diabetes,” said Dr. Marth.”The observation that beta cell malfunction significantly contributes to multiple disease signs, including insulin resistance, was unexpected. We noted, however, that studies from other laboratories published over the past few decades had alluded to this possibility.”

In this newly discovered pathway, high levels of fat were found to interfere with two key transcription factors — proteins that switch genes on and off. These transcription factors are normally required for the production of an enzyme that modifies proteins with a particular glycan (polysaccharide or sugar) structure. Proper retention of glucose transporters in the cell membrane depends on this modification, but when transcription factors aren’t working properly, enzymatic function is greatly diminished. So when the researchers fed otherwise normal mice a high-fat diet, they found that the animals’ beta cells could not sense and respond to blood glucose.

“Now that we know more fully how states of over-nutrition can lead to type 2 diabetes, we can see more clearly how to intervene,” Dr. Marth said. He and his colleagues are now considering various methods to augment beta cell GnT-4a enzyme activity in humans, as a means to prevent and possibly cure type 2 diabetes.



This just in: High-fat diets cause diabetes—and researchers have proof, doggonit!  At least, that’s what you’d assume from reading this headline. The study’s abstract is officially titled “Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport.”

It might come as a surprise that this study isn’t really about food at all – it’s about the effect of obesity on gene expression – in mice, no less. This is a classic example of the media spinning an article to help it grab attention, because most people wouldn’t read it if they knew what it was really about.

Although this paper doesn’t give us a detailed description of what the mice were eating, it does reference the product numbers for their formula diets. Here’s a PDF from the manufacturer of what the high-fat diet contained.

high_fat_Diet_ingredientsOuch! Where to start? It’s hard to say which part of this diet is the worst. The 175 grams of pure sugar? The splash of high omega-6 soybean oil? The suspiciously disease-promoting casein? The main calorie source as hydrogenated coconut oil? The fact that a quarter of the “high fat” diet consists of refined carbohydrates? The complete absence of anything resembling food?

It’s hard to find any redeeming qualities in this high-fat diet. For starters, the primary fat is an hydrogenated oil, which doesn’t belong in the body of any living organism, whether two-legged or four. As far as obesity goes, rodents have dramatically different responses to the types of fat they eat—with rats, for instance, getting tubby from lard but slimming down with marine oils. And hydrogenation aside, some mice strains gain different amounts of weight when their high-fat diet consists of unsaturated fats rather than saturated fat. So can we extrapolate the effects of this diet to high-fat diets in general? No wayNot for mice, and certainly not for humans.

And let’s remember that we’re dealing with a particularly fat-sensitive creature here. Although most mice turn into metabolically deranged messes when they eat too much fat (which makes sense, considering their natural diet is mostly grains), not all of them succumb to the same fate. These mice are one of the unlucky types that get rapidly obese on high-fat diets, but some other strains remain lean on the same cuisine and are far more resistant to diabetes.

When “High Fat” Isn’t High Fat

This brings us to a major problem with rodent studies in general. As this paper explains, there’s literally no standard for what “high fat” means, and rodent researchers have thrown everything from 20%-fat diets to 60%-fat diets under the same “high fat” umbrella. Usually those diets contain a hefty portion of sugar, too. Not only does this make the rodent literature hard to navigate, but it also gives an incomplete picture of the effect of diet on obesity – because something special happens when mice get a truly high-fat menu.

Case in point: this study on ketogenic diets in rodents. As we might expect, researchers found that mice eating a moderately high-fat diet became obese, leptin resistant, and insulin resistant – but when they dropped the sugar and increased fat to around 78% of calories, the mice “lost all excess body weight, improved glucose tolerance, and increased energy expenditure” without even reducing calorie intake. In other words, a high-fat diet undid the damage of a moderately high-fat diet.

Lessons For Non-Rodents

So what can we learn from all this? Does this study – or rodent research in general – have much relevance for humans? The answer is an equivocal “yes and no.” One reason mice are a favored lab animal is that they share so many genes with humans – 15,187 of them, to be exact.

But that doesn’t mean gene expression always works the same, or that the causes and progression of disease are identical across species. Even when high-fat diets catapult mice towards diabetes, for instance, their markers for disease don’t always resemble ours. Unlike metabolically damaged humans, who tend to have rock-bottom HDL cholesterol and rising triglycerides, some mice experience higher HDL and unchanged (or reduced!) triglycerides when eating the diets that make them diseased. This points to some clear differences between how humans and mice experience diet-induced metabolic problems.

And that includes the diabetes pathway in this study. We have enough high-fat, low-carb research at this point to know that such a diet won’t cause an unstoppable snowball towards obesity in humans like it does in some mice. If anything, its impact on diabetes is beneficial. So even if weight gain (and the associated increase in free fatty acids) sets us down Diabetes Avenue, a high-fat diet isn’t necessarily the instigator in humans. Especially not a high-fat diet that’s based on real food instead of hydrogenated coconut oil.

Bottom line: Mice are actually useful when it comes to studying genes and biochemical processes – but only when we clearly understand the limitations.

So when it comes to studies like this one, white out the headline and read with an open but critical mind.