We previously demonstrated in the rat that long term exposure to fatty acids inhibits B-cell function in vivo and in vitro. To further assess the clinical significance of these findings, we tested in human islets the effects of fatty acids on glucose-induced insulin release and biosynthesis and on pyruvate dehydrogenase (PDH) activity.PDH is the enzyme thought to control the entry of acetyl CoA from glycolysis into the Kreb's / TCA /Citric Acid Cycle.
These authors did an in vitro study with human cells to see if the results compared with those seen both in vitro and in vivo in rats. While in vitro observations don't always correlate with what we see in whole organisms, this did correlate for the rat. Therefore it is reasonable to believe that the results of this experiment are applicable to human metabolism.
Human islets were obtained from the β-Cell Transplant Unit (Brussels, Belgium). Exposure to 0.125 mmol/l palmitate or oleate for 48 h during tissue culture (RPMI-1640 and 5.5 mmol/l glucose) inhibited the postculture insulin response to 27 mmol/l glucose by 40% and 42% (P<0.01 for difference). Inhibition was partly prevented by coculture with 1 μmol/l etomoxir, a carnitine-palmitoyl-transferase-I inhibitor (P<0.05 for effect of etomoxir).
Etomoxir inhibits fatty acid oxidation. Recent developments employ this to treat chronic heart failure associated with Type II Diabetes.
Inhibitory effects on glucose-induced insulin secretion by previous palmitate were additive to the inhibitory effects exerted by previous high glucose (11 and 27 mmol/l). Palmitate-induced inhibition of insulin secretion was evident after exposure to 25 μmol/l added fatty acid. The insulin content of islets exposed to fatty acids was significantly reduced, and glucose-induced proinsulin biosynthesis was inhibited by 59% after palmitate addition and by 51% after oleate exposure (P<0.01). These effects were partly prevented by etomoxir (P<0.05). The activity of PDH in mitochondrial extracts of islets preexposed for 48 h to palmitate was decreased by 35% (P<0.05) υs. that in control islets, whereas the activity of PDH kinase (which inactivates PDH) was significantly increased in the same preparations (P<0.05).This underlines that high levels of both -- glucose/carbs and fatty acids -- wreak havoc on the body.
The effects of ketones were tested by 48-h exposure to β-hydroxybutyrate (β-D-OHB). Ten millimoles of D-β-OHB per L inbibited the subsequently tested insulin response to 27 mmol/L glucose by 56% (P<0.001). Half-maximal inhibitory effects of D-β-OHB on insulin secretion and insulin content were seen at concentrations between 0.5-2.5 mmol/l. Inhibition by D-β-OHB was partially reversed by etomoxir, whereas exposure to D-β-OHB failed to affect PDH and PDH kinase activities.
We conclude that fatty acids as well as ketone bodies diminish B-cell responsiveness to glucose in human islets by way of a glucose-fatty acid cycle. Increased plasma concentrations of fatty acids and ketones are likely to be important factors behind the negative influences on B-cell function exerted by a diabetic state in botb type 1 and type 2 diabetes.
I don't have access to the full-text. Seems "long term exposure" consisted of 48 hours. I am curious what long term exposure of a ketogenic VHF diet does to someone in the long haul. At least early on, Type II's make insulin just fine -- just that they make too much of it b/c their cells are insulin resistant. In researching to determine for myself if my low carb diet is healthy for the long haul, I've come across a lot of disturbing information on free fatty acids. If by lowering BG we send FFA levels skyrocketing through the roof, do we mask a problem that still exists?
I see no reason why IR cannot be reversed. Indeed I believe the "lose 10% of weight cure" for T2 basically demonstrates this for persons whose pancreas has not yet been compromised (e.g. still able to produce insulin). Indeed even the T2's with insufficient insulin responses may well have that inhibited by high NEFA/FFA -- restore fuel balance and there's no reason to believe this too can be reversed.
The relationship between high NEFA and sudden cardiac death continues to haunt me, and VLC/VHF diets have been shown to dramatically increase these! So I remain skeptical of LC for weight maintenance and/or especially if one is gaining weight on such a diet.