Role of High‐Density Lipoproteins in Cholesterol Homeostasis and Glycemic Control | Journal of the American Heart Association

Emerging evidence (summarized in Table) indicates that HDL‐ and apoA‐I–targeted therapies are a potential option for conserving residual β‐cell function and improving insulin sensitivity in patients who are progressing toward, or have already developed, T1DM and T2DM. The recent failures of HDL‐raising agents in cardiovascular clinical outcome trials highlight the need to develop novel and innovative HDL‐targeted approaches to achieve these goals. Elucidating the mechanism(s) underlying the antidiabetic functions of HDLs and apoA‐I will also provide opportunities to identify and develop new HDL‐targeted therapies for diabetes mellitus. Achievement of these goals could be particularly advantageous for patients with T1DM for whom treatment options are currently limited to insulin replacement therapy, and for patients with T2DM that are refractory to currently available therapies.

Table 1.Role of HDL and apoA‐I in Glycemic Control, Insulin Sensitivity and β‐Cell Function
Topic Outcome Reference
Association of HDL‐C and apoA‐I levels with glycemic control
Subjects with T2DM Serum HDL‐C, apoA‐I, and HDL‐C/apoA‐I levels are inversely associated with insulin resistance by HOMA‐IR 9
Subjects with impaired glucose tolerance ApoA‐I level is an independent risk factor for glucose tolerance 10
HDL and apoA‐I in glucose disposal/insulin sensitivity
Primary human skeletal muscle cells ApoA‐I improves insulin‐dependent and ‐independent glucose uptake 27
C2C12 skeletal muscle cells ApoA‐I increases glucose uptake by phosphorylation of AMPK 35
High‐fat–fed C57BL/6 mice ApoA‐I improves insulin sensitivity by reducing systemic and hepatic inflammation 40
db/db mice Long‐term HDL infusion improves glucose tolerance by activating GSK‐3 and AMPK in skeletal muscle 37
Pregnant female Wistar rats ApoA‐I infusions increase insulin sensitivity, reduces systemic inflammation and protects against pregnancy‐induced insulin resistance 45
Subjects with T2DM A single rHDL infusion reduces plasma glucose levels by increasing insulin secretion and promoting glucose uptake in skeletal muscle 2
HDL and apoA‐I in β‐cell function
Min6 insulinoma cells HDLs isolated from normal human plasma, rHDLs, and apoA‐I increase Ins1 and Ins2 gene transcription and GSIS 58
Ins‐1E insulinoma cells ApoA‐I increases Pdx1 gene transcription and GSIS 57
βTC3 insulinoma cells Incubation with HDL protects βTC3 cells against LDL‐induced apoptosis 70
C57BL/6 mice ApoA‐I infusions increase insulin secretion and improve glucose tolerance 52
High‐fat–fed C57BL/6 mice Short‐term apoA‐I treatment increases GSIS and improves glucose clearance independent of insulin secretion 53
Mice with conditional deletion of ABCA1 and ABCG1 in β cells ApoA‐I infusions increase GSIS in islets isolated from mice with elevated islet cholesterol levels 54
Healthy subjects and Min6 cells CETP inhibition increases plasma HDL‐C, apoA‐I, and insulin levels in normal human subjects. Plasma from these subjects also increases GSIS in Min6 cells pretreated with oxidized LDLs 60
Isolated human islets HDL protects human islets against oxidized LDL‐induced apoptosis 71
Isolated human and mouse islets HDL protects human and mouse islets from interleukin‐1β– and glucose‐induced apoptosis 72
AMPK indicates adenosine monophosphate‐activated protein kinase; apoA‐I, apolipoprotein A‐I; CETP, cholesteryl ester transfer protein; GSIS, glucose‐stimulated insulin secretion; GSK, glycogen synthase kinase‐3; HDL, high‐density lipoprotein; HDL‐C, high‐density lipoprotein cholesterol; HOMA‐IR, Homeostatic model assessment of insulin resistance; LDL, low‐density lipoprotein; rHDL, reconstituted HDL.

https://www.ahajournals.org/doi/10.1161/JAHA.119.013531