Lipid-induced β-cell dysfunction in vivo in models of progressive β-cell failure

Abstract

We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive ␤-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased Cpeptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of ␤-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese "prediabetic" ZDF rats with mild hyperglycemia, the FFA-induced decrease in ␤-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired ␤-cell function. In conclusion, 1) the FFA-induced impairment in ␤-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the ␤-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing.free fatty acid; obesity; insulin secretion; hyperglycemic clamp; Zucker diabetic fatty rat TYPE 2 DIABETES IS CHARACTERIZED by impaired insulin secretion and action (19,24). An early characteristic of the defect in insulin secretion is selective impairment of glucose-stimulated insulin secretion (GSIS). More than 80% of type 2 diabetic individuals are obese, and obese individuals often have elevated plasma levels of free fatty acids (FFA) (4) because of their expanded (3, 4) and more lipolytically active (41) adipose tissue stores. It is well known that FFA can impair insulin action (4); however, it is less clear whether FFA can also impair ␤-cell function, thus playing a role in the defect in GSIS that characterizes type 2 diabetes. Acutely, FFA increase insulin secretion both in vitro (13, 46) and in vivo (15, 21, 45). However, in vitro and ex vivo studies (8,28,43,47,48) have shown that, chronically, FFA impair GSIS. The effect of prolonged FFA elevation on GSIS in vivo is more controversial. We have found that prolonged elevation of plasma FFA results in decreased GSIS in vivo in normal female Wistar rats (34). The decrease was marked with oleate infusion but was also seen at high glucose levels with infusion of Intralipid ϩ heparin (IH). In that study, a mild elevation of FFA was obtained that did not significantly decrease insulin sensitivity during a hyperglycemic clamp. Howeve...

Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets

“…2C). Consistently, the disposition index, an index of insulin secretion corrected for insulin sensitivity (15), calculated as M/I index ϫ C-peptide, was not significantly different across the four groups (Fig. 2D).…”

“…2A). However, the M/I index, which serves as an index of insulin sensitivity (15) and is obtained by normalizing the glucose infusion rate with circulating insulin levels, was similar among all four groups (Fig. 2B).…”

“…As assessed by hyperglycemic clamp, insulin secretion in vivo at 13 mmol/l (upper physiological level for rats [15]) was not significantly different among rats infused with glucose or Intralipid alone, or in combination. However, it is possible that differences might have been seen at maximal stimulatory glucose levels.…”

Maternal taurine supplementation in rats partially prevents the adverse effects of early-life protein deprivation on β-cell function and insulin sensitivity

“…In rats, insulin secretion rate cannot be calculated because their C-peptide kinetics has not been determined (the specific rat C-peptide is unavailable for injection). Thus, we used the C-peptide levels as an approximation of insulin secretion rate as in our earlier studies (Goh et al 2007). Previously, we showed a hyperbolic relationship between the M/I index and the C-peptide levels during the hyperglycemic clamp in rats (Goh et al 2007).…”

“…Thus, we used the C-peptide levels as an approximation of insulin secretion rate as in our earlier studies (Goh et al 2007). Previously, we showed a hyperbolic relationship between the M/I index and the C-peptide levels during the hyperglycemic clamp in rats (Goh et al 2007). The DI was calculated by multiplying the average last 30-min M/I index (from the hyperinsulinemiceuglycemic clamp) by the C-peptide levels during the hyperglycemic clamp.…”