Primary hypercholesterolaemia impairs glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice independently of high-fat diet and obesity

Cholesterol toxicity in pancreatic islets from LDL receptor-deficient mice

“…Such results are associated with reduced glucose uptake and oxidation by Ldlr -/-islets. This impairment is not related to altered islet or beta cell mass, and is sufficient to elicit glucose intolerance in the absence of peripheral insulin resistance [2]. Using the same technique as Kruit et al [1], and in contrast to their findings, we observed a significant increase (32%) in islet cholesterol content in Ldlr -/-mice [2].…”

“…Thus, both works are in agreement that excess cholesterol impairs while removal of islet cholesterol improves insulin secretion. However, we provided data demonstrating that the absence of the LDL receptor increased islet cholesterol content and did not protect beta cells against hypercholesterolemia [2], as proposed by Kruit and colleagues [1]. Unfortunately, they did not measure insulin secretion or glucose tolerance in chow-fed Ldlr -/-mice as we did.…”

“…Almost simultaneously, our group published results showing that islets from Ldlr -/-knockout mice have increased cholesterol content and impaired beta cell function [2]. We reported that glucose-stimulated insulin secretion is reduced in Ldlr -/-mice, and that the doseresponse curve is shifted to the right, indicating that islets from these mice are less sensitive to glucose.…”

“…Under these conditions they showed that ABCA1 transporters have a protective role in beta cell functioning. Conversely, our group demonstrated that, in the absence of metabolic confounding factors induced by unbalanced diets or obesity, hypercholesterolaemia induced by a lack of the LDL receptor has a deleterious effect on glucose homeostasis and beta cell function [2].…”

Cholesterol toxicity in pancreatic islets from LDL receptor-deficient mice. Reply to: de Souza JC, de Oliveira CAM, Carneiro EM et al. [letter]

“…In contrast to their data [3], we did not detect a significant difference between islet cholesterol levels in mice lacking LDLr (Ldlr -/-) and control mice [2]. Accordingly, we found no difference in glucose tolerance or insulin secretion in Abca1 ;Ldlr -/-mice on a chow diet.…”