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~ Charles Darwin (it's evolutionary baybeee!)

Friday, January 21, 2011

Deleterious Effects of NEFA II: Panceatic beta cell impairment

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Progression from normal glucose tolerance to Type 2 diabetes results from a gradual deterioration in beta-cell function, in the presence of insulin resistance [1]. Over the past 10 years, the role of excess glucose in the alteration of beta-cell function has become increasingly clear and has led to the concept of glucotoxicity [2, 3].  At the same time, the deleterious effect of increased NEFA was suggested by studies on Zucker diabetic fatty (ZDF) rats, an animal model of Type 2 diabetes combined with obesity. The authors showed that altered beta-cell function was preceded by an important increase in the plasma concentration of NEFA and subsequent triglyceride (TG) accumulation in pancreatic islets [4, 5]. This hypothesis, also referred to as lipotoxicity, was confirmed by in vitro exposure of isolated islets to NEFA [6, 7, 8]. However, whether glucose and NEFA alter beta-cell function synergistically or separately, remains controversial.
...In this study, we examined the influence of NEFA on human islet function with or without concomitant increased glucose concentrations. Because lipid metabolism seems to have a crucial role in lipotoxicity [8], we also studied the expression of genes involved in this metabolism. 
NOTE:  GSIS = glucose stimulated insulin secretion  aka your acute or Phase I insulin response to carbs that is lacking in T2's.

With our model of in-vitro human islets, we showed that beta-cell alterations characteristic of clinical Type 2 diabetes, including loss of GSIS and decrease in insulin content, can be reproduced with either increased glucose or NEFA concentrations. The deleterious effect of high glucose is well established [2, 3], but increased NEFA at physiological glucose concentrations were also able to significantly alter GSIS and insulin content. These results are in accordance with previous studies [6, 10, 33], but argue against the hypothesis that increased glucose is a prerequisite for the deleterious effect of NEFA on betacell function [11, 12, 13, 14]. 
Bottom line:  NEFA alone can alter beta cell function.


kds said...

Very interesting study, CarbSane. Obviously we would've preferred in vivo experimentation since glucose metabolism is much more complex than just bathing some beta cells in various solutions for 48 hrs (indeed, the in vivo flux between oral intake, glycolysis/gluconeogenesis, glycogenesis/glycogenolysis and the rest of the metabolic milieu that contributes to the plasma BG molecules that actually reach a beta cell is staggeringly complex), but one thing I would've liked to have seen within the paramaters of this study is a broader range of glucose and NEFA concentrations. 5.5, 16, and 30mmol/l? Jeez, that's like 102, 290, and 540mg/dl glucose, respectively. Didn't the authors realize that the median BG range is around 72mg/dl? And why would they only use 1mmol and 2mmol/L for NEFA when they even state that "In vivo, the normal plasma concentration of NEFA is less than 0.6mmol/l, but could exceed 1mmol/l in Type 2 diabetic patients"? The M&M says that they sourced the cells from pancreata of non-obese, non-diabetic men, but then they proceeded to expose all three groups to supraphysiologic glucose and NEFA levels. Not having an honest control certainly makes results interpretation just a wee bit trickier.

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