This was the provocative title of the Science Daily piece that made a minor splash across the LC web recently. Perhaps overshadowed by the AHS drama and fallout, but nonetheless picked up on by a number of people. The article begins with:
Newly 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 Jamey D. Marth, Ph.D., director of the Center for Nanomedicine, a collaboration between the University of California, Santa Barbara and Sanford-Burnham Medical Research Institute (Sanford-Burnham), has revealed a pathway that links high-fat diets to a sequence of molecular events responsible for the onset and severity of diabetes.
The article is referring to the journal article linked below:Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport
(I'm sharing the full text with my readers here through Google docs. Feel free to link to it but I'd appreciate the courtesy of identifying the source with a link to this post or my blog. Thanks readers)
A connection between diet, obesity and diabetes exists in multiple species and is the basis of an escalating human health problem. The factors responsible provoke both insulin resistance and pancreatic beta cell dysfunction but remain to be fully identified. We report a combination of molecular events in human and mouse pancreatic beta cells, induced by elevated levels of free fatty acids or by administration of a high-fat diet with associated obesity, that comprise a pathogenic pathway to diabetes. Elevated concentrations of free fatty acids caused nuclear exclusion and reduced expression of the transcription factors FOXA2 and HNF1A in beta cells. This resulted in a deficit of GnT-4a glycosyltransferase expression in beta cells that produced signs of metabolic disease, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis and diminished insulin action in muscle and adipose tissues. Protection from disease was conferred by enforced beta cell–specific GnT-4a protein glycosylation and involved the maintenance of glucose transporter expression and the preservation of glucose transport. We observed that this pathogenic process was active in human islet cells obtained from donors with type 2 diabetes; thus, illuminating a pathway to disease implicated in the diet- and obesity-associated component of type 2 diabetes mellitus.
In a nutshell, the elevated NEFA they observed in an obese mouse model led to a disruption in glucose transport in beta cells, and this same defect is seen in the islet cells donated by humans with type 2 diabetes. The mechanism seems to be elevated NEFA → reduced expression of certain genes → impaired glucose transport. I'm a bit backlogged with other interests to look into this very detailed paper as regards all the exact details here, but I think the following excerpts are sufficient to get the gist.
... Pancreatic beta cell dysfunction is also a diagnostic determinant of type 2 diabetes and includes defective insulin secretion exemplified by the loss of glucose-stimulated insulin secretion (GSIS). Normally, beta cells sense elevations of blood glucose by expressing cell surface glucose transporters that enable concentration-dependent glucose transport across the plasma membrane. This is followed by glucokinase action and ultimately calcium-dependent insulin secretion. Loss of GSIS has been linked to impaired beta cell glucose transporter (Glut) expression among animal models, and failure of GSIS has been proposed to further provoke the pathogenic onset of type 2 diabetes in humans. ...
... Genetics, diet and obesity contribute to the current epidemic of human type 2 diabetes. A substantial proportion of the human population seems predisposed to a combination of these factors, perhaps analogous to different mouse strains that are resistant or susceptible to diet- and obesity-induced diabetes31. Our findings show that the extent of disruption of beta cell glycosylation and glucose transport by diet and obesity directly contributes to disease onset and severity in susceptible mice, illuminating a pathogenic pathway that encompasses lipotoxicity and glucotoxicity32. This pathway seems to be conserved in normal human islet cells and is activated in islets from donors with type 2 diabetes. A pathogenic tipping point in this pathway may occur when elevated free fatty acid (FFA) concentrations impair the expression and function of FOXA2 and HNF1A transcription factors sufficiently in beta cells to deplete GnT-4a glycosylation and glucose transporter expression. The resulting dysfunction of beta cells leads to impaired glucose tolerance and failure of GSIS and further contributes to hyperglycemia, hepatic steatosis and systemic insulin resistance. Preservation of beta cell GnT-4a glycosylation and glucose transporter expression breaks this pathogenic cycle and its link to diet and obesity.
This paper is actually yet another one providing evidence in support of the Fatty Acid Hypothesis for how obesity can cause insulin resistance and diabetes. It does not go into how fat cells become IR first, but rather deals with the mechanism by which the resulting elevation in circulating NEFA leads to pancreatic beta cell dysfunction. That being interfering with glucose transport to the beta cell so your pancreas does not properly sense hyperglycemia.
In my opinion, the title and implications of the Science Daily article are irresponsible, but so too are the knee-jerk responses of many of those favoring low carb high fat diets. It should always be remembered that NEFA is not the equivalent of dietary fat. A high fat diet does not necessarily impact NEFA. However, two articles by Keith Frayn I've discussed here previously, Adipose Tissue as Buffer ... and Fatty Acid Trafficking, present the scenario whereby dietary fatty acids can contribute significantly to NEFA levels. Additionally, VLC diets fail to suppress NEFA release in the postprandial period.
Several are dismissing this whole thing out of hand. The usual "well the high fat diet also has carbs" argument abounds. Perhaps a better title for the article might be How Fattening Diets Cause Diabetes. Clearly some are more genetically predisposed, or all obese would be diabetic which is not the case. But perhaps instead of T2 or NIDDM or "adult onset" diabetes, we can use Diabesity or OIDM (obesity induced diabetes mellitus) as a designation. If your high fat/carb/calorie junky SAD → obesity → elevated NEFA and you are genetically predisposed, it will lead to hyperglycemia. The solution? Stop eating carbs to control the hyperglycemia? Yes, that works (for some, to some degree), but it doesn't appear to restore beta cell function without substantial weight loss. And of all the anecdotal reports of those doing longterm VLC are worth considering it seems the reports of becoming more and more carb intolerant indicate persisting beta cell dysfunction. Considering all of the other important functions of insulin in the body, it may be worthwhile looking at another approach long term. JMO.