Elevated NEFA Impairs Insulin Secretion in Non-Diabetics Genetically Predisposed to Develop Diabetes

A Sustained Increase in Plasma Free Fatty Acids Impairs Insulin Secretion in Nondiabetic Subjects Genetically Predisposed to Develop Type 2 Diabetes

Type 2 diabetes is characterized by defects in both insulin secretion and insulin action (1). Subtle defects in β-cell function and insulin resistance precede the development of hyperglycemia in individuals at high risk of developing type 2 diabetes

• strong family history of type 2 diabetes (2–5)  

• obese subjects (6,7)

•  individuals with impaired glucose tolerance (IGT) (2,4,5)  

• women with polycystic ovary syndrome (PCOS) (8,9) 

• women with a history of gestational diabetes (10).

In these groups hyperglycemia develops as a result of a progressive decline in β-cell function, a finding reported across multiple ethnic populations (4,10 –12).

Adipose tissue insulin resistance is believed to play an important role in the development of type 2 diabetes (1,13–16). Insulin resistance in adipose tissue is characterized by excessive rates of lipolysis, increased plasma free fatty acid (FFA) levels despite hyperinsulinemia, and impaired suppression of plasma FFA levels by insulin (1,14 –16). Excessive rates of lipid turnover have been shown to precede the development of type 2 diabetes in subjects with a family history of type 2 diabetes (3–5) and nondiabetic obese individuals (6,7). The negative effect on glucose homeostasis of an elevation in plasma FFA concentration has been referred to as “lipotoxicity” (13).  Elevation in the plasma FFA causes hepatic and skeletal muscle insulin resistance in healthy individuals (1,14 –18) 

However, the effect of increased plasma FFA on insulin secretion has been less well studied, and it remains unknown whether a chronic elevation in plasma FFA concentration can impair β-cell function in subjects genetically predisposed to type 2 diabetes.

These researchers studied the impact of (artificially) chronically elevated FFA on pancreatic β-cell function.  It is important to remember that both glucose and FFA stimulate insulin production but in different ways/circumstances.

This study involved a long (4 days) lipid infusion at the physiological "elevated" levels seen in diabetics (500-800 μmol/L) in normal individuals with a strong family history of type 2 diabetes (FH).

The most striking finding is that, in FH subjects, a sustained physiological increase in plasma FFA concentration for 3 days markedly impaired both acute (firstphase) and second-phase insulin secretion by 60 and 35%, respectively.

Lipid infusion caused a 42% decrease in the metabolic clearance rate of insulin in the FH group but not in control subjects. 

Insulin sensitivity was measured on different days by two methods: euglycemic and hyperglycemic clamps. The authors note that the different measurements on different days were very closely correlated, "indicating that lipid induced insulin resistance was already established by day 3".

I'm not going to C&P the entire discussion here.  It's chock full of references to other works and proposed explanations for the results of this and other studies.   Most of it focuses on explaining the elevated insulin levels in the FH group despite impaired insulin secretion.  

In conclusion, we have demonstrated for the first time the deleterious effect of a sustained increase of plasma FFA concentration on insulin secretion in nondiabetic subjects who are genetically predisposed to develop type 2 diabetes. In addition, lipid infusion caused a mild increase in basal EGP [endogenous glucose production] and impaired the suppression of EGP by insulin, changes characteristic of the early stages of type 2 diabetes.

In contrast, healthy control subjects adapted to FFA-induced insulin resistance by mounting an adequate compensatory β-cell response.

We hypothesize that chronically elevated plasma FFA concentrations may contribute to progressive β-cell failure in at least some individuals who are genetically predisposed to develop type 2 diabetes. This hypothesis emphasizes the important role of adipose tissue insulin resistance in the natural history of progressive β-cell failure leading to type 2 diabetes.

I would only note that these changes were seen at NEFA levels sustained in the VLC dieters in other studies I've cited.  Is this lipotoxicity reversible?  One hopes so.  On the bright side, it appears those w/o strong disposition towards diabetes were not adversely effected.