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

Abstract

Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I–stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes.

Apolipoprotein A‐l improves pancreatic β‐cell function independent of the ATP‐binding cassette transporters ABCA1 and ABCG1

“…Whether this is also the case for b-DKO mice treated acutely with a single injection of apoA-I remains to be determined. However, because a single 14 mg/kg apoA-I injection has been reported to improve GSIS in normal and high-fat fed C57BL6 mice (16), it seems reasonable to assume that apoA-I may have a similar effect in b-DKO mice.…”

“…Elevated plasma HDL cholesterol levels are associated with a reduced risk of developing cardiovascular disease (13). We and others have reported that HDLs and apolipoprotein A-I (apoA-I), the main HDL apolipoprotein, also have antidiabetic properties (14)(15)(16). In addition to increasing insulin synthesis and improving insulin secretion in b cells, HDLs and apoA-I alleviate insulin resistance by increasing glucose uptake into skeletal muscle (14,16,17).…”

“…We and others have reported that HDLs and apolipoprotein A-I (apoA-I), the main HDL apolipoprotein, also have antidiabetic properties (14)(15)(16). In addition to increasing insulin synthesis and improving insulin secretion in b cells, HDLs and apoA-I alleviate insulin resistance by increasing glucose uptake into skeletal muscle (14,16,17). These findings are consistent with results from a clinical trial in which a single infusion of reconstituted HDLs consisting of apoA-I complexed with phospholipid improved glycemic control and b-cell function in patients with T2D (18).…”

Cholesteryl ester transfer protein and its inhibitors

“…Both HDLs and apoA-I increase the synthesis and secretion of insulin in pancreatic beta cells (112,113). They also enhance glucose uptake by skeletal muscle (114)(115)(116), and thus improve insulin sensitivity. An increase in either, or both, of these HDL functions in people treated with a CETP inhibitor could explain the improvement in glycemic control and decreased risk of developing diabetes that was observed in these studies.…”

Interplay between cigarette smoking and pulmonary reverse lipid transport

“…The main differences between ApoA-1 deficiency and MDCO-216 treatment in mice exposed to cigarette smoke were that ApoA-1 deficiency caused a significant loss in both lean and fat mass, while MDCO-216 treatment markedly increased lean mass, leaving fat mass unaffected. ApoA-1 is known to affect numerous metabolic functions, including the stimulation of glucose uptake by skeletal muscle [26,27]. It has also been shown that ApoA-1 can increase mitochondrial biogenesis in vitro in myotubes [28].…”