Single injections of apoA-I acutely improve in vivo glucose tolerance in insulin-resistant mice

Abstract

Aims/hypothesisApolipoprotein A-I (apoA-I), the main protein constituent of HDL, has a central role in the reverse cholesterol-transport pathway, which together with the anti-inflammatory properties of apoA-I/HDL provide cardioprotection. Recent findings of direct stimulation of glucose uptake in muscle by apoA-I/HDL suggest that altered apoA-I and HDL functionality may be a contributing factor to the development of diabetes. We have studied the in vivo effects of short treatments with human apoA-I in a high-fat diet fed mouse model. In addition to native apoA-I, we investigated the effects of the cardioprotective Milano variant (Arg173Cys).MethodsMale C57Bl6 mice on a high-fat diet for 2 weeks that received a single injection of human apoA-I proteins (wild-type and Milano) were analysed for blood glucose and insulin levels during a 3 h incubation followed by glucose tolerance tests. Incorporation of injected human apoA-I protein into HDLs was analysed by native gel electrophoresis.ResultsApoA-I treatment significantly improved insulin secretion and blood glucose clearance in the glucose tolerance test, with an efficiency exceeding that of lean control animals, and led to decreased basal glucose during the 3 h incubation. Notably, the two apoA-I variants triggered insulin secretion and glucose clearance to the same extent.Conclusions/interpretationApoA-I treatment leads to insulin- and non-insulin-dependent effects on glucose homeostasis. The experimental model of short-term (2 weeks) feeding of a high-fat diet to C57Bl6 mice provides a suitable and time-efficient system to unravel the resulting tissue-specific mechanisms of acute apoA-I treatment that lead to improved glucose homeostasis.

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal

“…HFDfed mice received a glucose load (50 mg/mouse i.p. ), with or without propranolol (5 mg/kg) and epinephrine (0.1 mg/kg), to block insulin secretion, 3 h after a single injection (14 mg/kg body wt) of apoA-I protein or NaCl control followed by the determination of glucose (C) and insulin (E) Short-term apoA-I treatment of insulin-resistant DIO mice leads to a remarkable increase in blood glucose clearance (9).…”

In vivo PET imaging with [18F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes

“…Furthermore, treatment with HDL or apoA-I increases insulin secretion and production in isolated pancreatic islets and insulinoma beta cell lines [7,8]. Recent studies have demonstrated that both single and repeated doses of apoA-I can also improve insulin resistance in fat-fed C57Bl6 mice [9,10], as can overexpression of apoA-I [11].…”

Development of Type-2 Diabetes Mellitus is associated with Low Levels of ApoA1

“…However, this association has not been found to be consistent in previous studies [22][23][24][25] although previous research suggested that ApoA1 affects glucose metabolism via multiple mechanisms, including enhanced insulin secretion [26], increased insulin-independent glucose uptake in muscle and adipose tissues [27,28], improved insulin sensitivity [29], and reversed adipocyte dysfunction [30] and restored adiponectin expression and insulin sensitivity [31] with ApoA1 mimetic peptide. Furthermore, genetic studies suggested that genetic variation in ABCA1 has been associated with the increased risk of T2DM [32], and one study suggested that loss-of-function mutations in ABCA1 were associated with impaired b-cell function, but not with the development of T2DM [33].…”