Failure to repair endogenous DNA damage in ß-cells causes adult-onset diabetes in mice.

Age is the greatest risk factor for the development of type 2 diabetes mellitus (T2DM). Age-related decline in organ function is attributed to the accumulation of stochastic damage, including damage to the nuclear genome. Islets of T2DM patients display increased levels of DNA damage. However, whether this is a cause or consequence of the disease has not been elucidated. Here, we asked if spontaneous, endogenous DNA damage in ß-cells can drive ß-cell dysfunction and diabetes, via deletion of Ercc1, a key DNA repair gene, in ß-cells. Mice harboring Ercc1-deficient ß-cells developed adult-onset diabetes as demonstrated by increased random and fasted blood glucose levels, impaired glucose tolerance, and reduced insulin secretion. The inability to repair endogenous DNA damage led to an increase in oxidative DNA damage and apoptosis in ß-cells and a significant loss of ß-cell mass. Using electron microscopy, we identified ß-cells in clear distress that showed an increased cell size, enlarged nuclear size, reduced number of mature insulin granules, and decreased number of mitochondria. Some ß-cells were more affected than others consistent with the stochastic nature of spontaneous DNA damage. Ercc1-deficiency in ß-cells also resulted in loss of ß-cell function as glucose-stimulated insulin secretion and mitochondrial function were impaired in islets isolated from mice harboring Ercc1-deficient ß-cells. These data reveal that unrepaired endogenous DNA damage is sufficient to drive ß-cell dysfunction and provide a mechanism by which age increases the risk of T2DM.

The chemotherapeutic drug doxorubicin does not exacerbate p16Ink4a-positive senescent cell accumulation and cardiometabolic disease development in young adult female LDLR-deficient mice.

Cancer survivors who received chemotherapy, such as the anthracycline doxorubicin (DOX), have an increased risk of developing complications later in life, including the development of chronic metabolic diseases. Although the etiology of this increased risk for late metabolic complications in cancer survivors is poorly understood, a causal role of therapy-induced senescent cells has been suggested. To study the role of cellular senescence in chemotherapy-induced metabolic complications, young adult female low-density lipoprotein receptor-deficient (Ldlr-/-)-p16-3MR mice, in which p16Ink4a-positive (p16Ink4a+) senescent cells can be genetically eliminated, were treated with four weekly injections of DOX (2.5 mg/kg) followed by a high-fat high-cholesterol diet for 12 weeks. While DOX treatment induced known short-term effects, such as reduction in body weight, gonadal fat mass, and adipose tissue inflammation, it was not associated with significant long-term effects on glucose homeostasis, hepatic steatosis, or atherosclerosis. We further found no evidence of DOX-induced accumulation of p16Ink4a+-senescent cells at 1 or 12 weeks after DOX treatment. Neither did we observe an effect of elimination of p16Ink4a+-senescent cells on the development of diet-induced cardiometabolic complications in DOX-treated mice. Other markers for senescence were generally also not affected except for an increase in p21 and Cxcl10 in gonadal white adipose tissue long-term after DOX treatment. Together, our study does not support a significant role for p16Ink4a+-senescent cells in the development of diet-induced cardiometabolic disease in young adult DOX-treated female Ldlr-/- mice. These findings illustrate the need of further studies to understand the link between cancer therapy and cardiometabolic disease development in cancer survivors.

Autocrine FGF1 signaling promotes glucose uptake in adipocytes.

Fibroblast growth factor 1 (FGF1) is an autocrine growth factor released from adipose tissue during over-nutrition or fasting to feeding transition. While local actions underlie the majority of FGF1's anti-diabetic functions, the molecular mechanisms downstream of adipose FGF receptor signaling are unclear. We investigated the effects of FGF1 on glucose uptake and its underlying mechanism in murine 3T3-L1 adipocytes and in ex vivo adipose explants from mice. FGF1 increased glucose uptake in 3T3-L1 adipocytes and epididymal WAT (eWAT) and inguinal WAT (iWAT). Conversely, glucose uptake was reduced in eWAT and iWAT of FGF1 knockout mice. We show that FGF1 acutely increased adipocyte glucose uptake via activation of the insulin-sensitive glucose transporter GLUT4, involving dynamic crosstalk between the MEK1/2 and Akt signaling proteins. Prolonged exposure to FGF1 stimulated adipocyte glucose uptake by MEK1/2-dependent transcription of the basal glucose transporter GLUT1. We have thus identified an alternative pathway to stimulate glucose uptake in adipocytes, independent from insulin, which could open new avenues for treating patients with type 2 diabetes.

Age-related susceptibility to insulin resistance arises from a combination of CPT1B decline and lipid overload.

BACKGROUND: The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). RESULTS: As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial ß-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most ß-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. CONCLUSION: We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1d/- mice.

BACKGROUND: Type 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whether DNA damage plays a role in the pathogenesis of the disease is unclear. Here, we used mice deficient for the DNA excision-repair gene Ercc1 to study the impact of persistent endogenous DNA damage accumulation on energy metabolism, glucose homeostasis and beta-cell function. METHODS: ERCC1-XPF is an endonuclease required for multiple DNA repair pathways and reduced expression of ERCC1-XPF causes accelerated accumulation of unrepaired endogenous DNA damage and accelerated aging in humans and mice. In this study, energy metabolism, glucose metabolism, beta-cell function and insulin sensitivity were studied in Ercc1d/- mice, which model a human progeroid syndrome. RESULTS: Ercc1d/- mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivity was increased, whereas, plasma insulin levels were decreased in Ercc1d/- mice. Fasting induced hypoglycemia in Ercc1d/- mice, which was the result of increased glucose disposal. Ercc1d/- mice exhibit a significantly reduced beta-cell area, even compared to control mice of similar weight. Glucose-stimulated insulin secretion in vivo was decreased in Ercc1d/- mice. Islets isolated from Ercc1d/- mice showed increased DNA damage markers, decreased glucose-stimulated insulin secretion and increased susceptibility to apoptosis. CONCLUSION: Spontaneous DNA damage accumulation triggers an adaptive response resulting in improved insulin sensitivity. Loss of DNA repair, however, does negatively impacts beta-cell survival and function in Ercc1d/- mice.

Short-term protein restriction at advanced age stimulates FGF21 signalling, energy expenditure and browning of white adipose tissue.

Dietary protein restriction has been demonstrated to improve metabolic health under various conditions. However, the relevance of ageing and age-related decline in metabolic flexibility on the effects of dietary protein restriction has not been addressed. Therefore, we investigated the effect of short-term dietary protein restriction on metabolic health in young and aged mice. Young adult (3 months old) and aged (18 months old) C57Bl/6J mice were subjected to a 3-month dietary protein restriction. Outcome parameters included fibroblast growth factor 21 (FGF21) levels, muscle strength, glucose tolerance, energy expenditure (EE) and transcriptomics of brown and white adipose tissue (WAT). Here, we report that a low-protein diet had beneficial effects in aged mice by reducing some aspects of age-related metabolic decline. These effects were characterized by increased plasma levels of FGF21, browning of subcutaneous WAT, increased body temperature and EE, while no changes were observed in glucose homeostasis and insulin sensitivity. Moreover, the low-protein diet used in this study was well-tolerated in aged mice indicated by the absence of adverse effects on body weight, locomotor activity and muscle performance. In conclusion, our study demonstrates that a short-term reduction in dietary protein intake can impact age-related metabolic health alongside increased FGF21 signalling, without negatively affecting muscle function. These findings highlight the potential of protein restriction as a strategy to induce EE and browning of WAT in aged individuals.

Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR.

Fructose has become a major constituent of our modern diet and is implicated as an underlying cause in the development of metabolic diseases. The fructose transporter GLUT5 (SLC2A5) is required for intestinal fructose absorption. GLUT5 expression is induced in the intestine and skeletal muscle of type 2 diabetes (T2D) patients and in certain cancers that are dependent on fructose metabolism, indicating that modulation of GLUT5 levels could have potential in the treatment of these diseases. Using an unbiased screen for transcriptional control of the human GLUT5 promoter we identified a strong and specific regulation by liver X receptor α (LXRα, NR1H3). Using promoter truncations and site-directed mutagenesis we identified a functional LXR response element (LXRE) in the human GLUT5 promoter, located at -385 bp relative to the transcriptional start site (TSS). Finally, mice treated with LXR agonist T0901317 showed an increase in Glut5 mRNA and protein levels in duodenum and adipose tissue, underscoring the in vivo relevance of its regulation by LXR. Together, our findings show that LXRα regulates GLUT5 in mice and humans. As a ligand-activated transcription factor, LXRα might provide novel pharmacologic strategies for the selective modulation of GLUT5 activity in the treatment of metabolic disease as well as cancer.

Senescent cells in the development of cardiometabolic disease.

PURPOSE OF REVIEW: Senescent cells have recently been identified as key players in the development of metabolic dysfunction. In this review, we will highlight recent developments in this field and discuss the concept of targeting these cells to prevent or treat cardiometabolic diseases. RECENT FINDINGS: Evidence is accumulating that cellular senescence contributes to adipose tissue dysfunction, presumably through induction of low-grade inflammation and inhibition of adipogenic differentiation leading to insulin resistance and dyslipidaemia. Senescent cells modulate their surroundings through their bioactive secretome and only a relatively small number of senescent cells is sufficient to cause persistent physical dysfunction even in young mice. Proof-of-principle studies showed that selective elimination of senescent cells can prevent or delay the development of cardiometabolic diseases in mice. SUMMARY: The metabolic consequences of senescent cell accumulation in various tissues are now unravelling and point to new therapeutic opportunities for the treatment of cardiometabolic diseases.

Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic ß Cell Death and May Contribute to Type 1 Diabetes Development.

Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the ß cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to ß cells favoring apoptosis. Inactivation of these miRNAs in recipient ß cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation. Looking at the mechanisms underlying exosome action, we found that T lymphocyte exosomes trigger apoptosis and the expression of genes involved in chemokine signaling, including Ccl2, Ccl7, and Cxcl10, exclusively in ß cells. The induction of these genes may promote the recruitment of immune cells and exacerbate ß cell death during the autoimmune attack. Our data point to exosomal-miRNA transfer as a communication mode between immune and insulin-secreting cells.

AAV8-mediated gene transfer of microRNA-132 improves beta cell function in mice fed a high-fat diet.

MicroRNAs have emerged as essential regulators of beta cell function and beta cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta cell function in vivo. To overexpress miR-132 specifically in beta cells, we employed adeno-associated virus (AAV8)-mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR-132 did not impact glucose homeostasis in chow-fed animals. Overexpression of miR-132 did improve insulin secretion and hence glucose homeostasis in high-fat diet-fed mice. Furthermore, miR-132 overexpression increased beta cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8-mediated gene transfer of miR-132 to beta cells improves beta cell function in mice in response to a high-fat diet. This suggests that increased miR-132 expression is beneficial for beta cell function during hyperglycemia and obesity.

Metabolic effects of short-term caloric restriction in mice with reduced insulin gene dosage.

Caloric restriction (CR) is the only environmental intervention with robust evidence that it extends lifespan and delays the symptoms of aging, but its mechanisms are incompletely understood. Based on the prolonged longevity of knockout models, it was hypothesized that the insulin-IGF pathway could be a target for developing a CR mimic. This study aimed to test whether CR has additive effects on glucose homeostasis and beta-cell function in mice with reduced insulin gene dosage. To study models with a range of basal insulin levels, wild-type C57BL/6J and mice on an Ins2-/- background, were put on 8 weeks of 40% CR at various ages. Both male and female mice rapidly lost weight due to a reduced WAT mass. Glucose tolerance was improved and fasting glucose levels were reduced by CR in both wild type and 45- and 70-week-old Ins2-/- mice. The effects of CR and reduced insulin on glucose tolerance were non-additive in 20-week-old mice. Interestingly, mice on CR generally exhibited an inability to further depress blood glucose after insulin injection, pointing to possible alterations in insulin sensitivity. In conclusion, our results demonstrate that CR can cause weight loss in the context of reduced insulin production, but that CR-improved glucose homeostasis does not occur near the 'insulin floor' in young mice. Collectively, these data shed further light on the relationships between CR, insulin and glucose homeostasis.

NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-or diet-induced inflammation.

The NF-κB family of transcription factors is essential for an effective immune response, but also controls cell metabolism, proliferation and apoptosis. Its broad relevance and the high connectivity to diverse signaling pathways require a tight control of NF-κB activity. To investigate the control of NF-κB activity by phosphorylation of the NF-κB p65 subunit, we generated a knock-in mouse model in which serine 467 (the mouse homolog of human p65 serine 468) was replaced with a non-phosphorylatable alanine (S467A). This substitution caused reduced p65 protein synthesis and diminished TNFα-induced expression of a selected group of NF-κB-dependent genes. Intriguingly, high-fat fed S467A mice displayed increased locomotor activity and energy expenditure, which coincided with a reduced body weight gain. Although glucose metabolism or insulin sensitivity was not improved, diet-induced liver inflammation was diminished in S467A mice. Altogether, this study demonstrates that phosphorylation of p65 serine 467 augment NF-κB activity and exacerbates various deleterious effects of overnutrition in mice.

Carriers of loss-of-function mutations in EXT display impaired pancreatic beta-cell reserve due to smaller pancreas volume.

Exotosin (EXT) proteins are involved in the chain elongation step of heparan sulfate (HS) biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF) in EXT1 and EXT2 result in hereditary exostoses (HME). Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT) followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS) in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI). OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46-1.16] vs. controls 1.53 [0.69-3.36] nmol·l-1·min-1, p<0.05). Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22-10.5] vs. controls 10.2 [7.91-12.70] nmol·l-1·min-1 p<0.05), indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04). In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors.

ABCA1 influences neuroinflammation and neuronal death.

ATP-binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux in the brain and influences whole brain cholesterol homeostasis. Activation of liver X receptors (LXRs), transcription factors that increase the expression of cholesterol transport genes including ABCA1, reduces neuroinflammation and pathology in neurodegenerative animal models suggesting that in addition to its involvement in cholesterol transport, ABCA1 may play a role in modulating the inflammatory response in the brain. We investigated the cell-type specific role of ABCA1 in neuroinflammation in vivo using mice specifically lacking brain ABCA1 (ABCA1(-B/-B)) as well as mice lacking neuronal (ABCA1(-N/-N)) and astrocytic (ABCA1(-Ast/-Ast)) ABCA1. ABCA1(-B/-B) mice exhibit cortical astrogliosis, increased inflammatory gene expression as well as activation of mitogen-activated protein kinases (MAPKs) following acute lipopolysaccharide (LPS) administration. Microglia cultured from ABCA1(-B/-B) mice exhibit augmented LPS-induced secretion of tumor necrosis factor α (TNFα) and decreased phagocytic activity, indicating an increase in a pro-inflammatory response. ABCA1(-N/-N) mice develop astrogliosis but show no change in inflammatory gene expression. Intriguingly, ABCA1(-Ast/-Ast) mice show neither astrogliosis nor elevated expression of inflammatory markers. Cortical apolipoprotein E (apoE) levels are reduced in ABCA1(-Ast/-Ast) but not in ABCA1(-N/-N) mice, providing in vivo evidence for the specific role of astrocyte ABCA1 in regulating brain apoE levels. Interestingly, cortical neuronal death is increased in 17month-old ABCA1(-B/-B) mice but not in ABCA1(-N/-N) or ABCA1(-Ast/-Ast) mice. Our findings suggest that coordinated ABCA1 activity across neurons and glial cells influences neuroinflammation and neurodegeneration.

Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired ß-cell function.

Cellular cholesterol homeostasis is important for normal ß-cell function. Disruption of cholesterol transport by decreased function of the ATP-binding cassette (ABC) transporter ABCA1 results in impaired insulin secretion. Mice lacking ß-cell ABCA1 have increased islet expression of ABCG1, another cholesterol transporter implicated in ß-cell function. To determine whether ABCA1 and ABCG1 have complementary roles in ß-cells, mice lacking ABCG1 and ß-cell ABCA1 were generated and glucose tolerance, islet sterol levels, and ß-cell function were assessed. Lack of both ABCG1 and ß-cell ABCA1 resulted in increased fasting glucose levels and a greater impairment in glucose tolerance compared with either ABCG1 deletion or loss of ABCA1 in ß-cells alone. In addition, glucose-stimulated insulin secretion was decreased and sterol accumulation increased in islets lacking both transporters compared with those isolated from knockout mice with each gene alone. Combined deficiency of ABCA1 and ABCG1 also resulted in significant islet inflammation as indicated by increased expression of interleukin-1ß and macrophage infiltration. Thus, lack of both ABCA1 and ABCG1 induces greater defects in ß-cell function than deficiency of either transporter individually. These data suggest that ABCA1 and ABCG1 each make complimentary and important contributions to ß-cell function by maintaining islet cholesterol homeostasis in vivo.

Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules.

OBJECTIVE: The ATP-binding cassette transporter A1 (ABCA1) is essential for normal insulin secretion from ß-cells. The aim of this study was to elucidate the mechanisms underlying the impaired insulin secretion in islets lacking ß-cell ABCA1. RESEARCH DESIGN AND METHODS: Calcium imaging, patch clamp, and membrane capacitance were used to assess the effect of ABCA1 deficiency on calcium flux, ion channel function, and exocytosis in islet cells. Electron microscopy was used to analyze ß-cell ultrastructure. The quantity and distribution of proteins involved in insulin-granule exocytosis were also investigated. RESULTS: We show that a lack of ß-cell ABCA1 results in impaired depolarization-induced exocytotic fusion of insulin granules. We observed disturbances in membrane microdomain organization and Golgi and insulin granule morphology in ß-cells as well as elevated fasting plasma proinsulin levels in mice in the absence of ß-cell ABCA1. Acute cholesterol depletion rescued the exocytotic defect in ß-cells lacking ABCA1, indicating that elevated islet cholesterol accumulation directly impairs granule fusion and insulin secretion. CONCLUSIONS: Our data highlight a crucial role of ABCA1 and cellular cholesterol in ß-cells that is necessary for regulated insulin granule fusion events. These data suggest that abnormalities of cholesterol metabolism may contribute to the impaired ß-cell function in diabetes.

HDL and LDL cholesterol significantly influence beta-cell function in type 2 diabetes mellitus.

PURPOSE OF REVIEW: Patients with type 2 diabetes mellitus (T2DM) display significant abnormalities in both LDL and HDL particles. Recent data suggest that these changes in lipoprotein particles could contribute to the pathogenesis of T2DM. In this review, we focus on these abnormalities and discuss their possible impact on beta-cell function and beta-cell mass. RECENT FINDINGS: Infusion of reconstituted HDL in T2DM patients improves beta-cell function, whereas carriers of loss-of-function mutations in the cholesterol transporter ABCA1, who have decreased HDL levels, have impaired beta-cell function. In addition, recent studies show that HDL protects against stress-induced beta-cell apoptosis in vitro. Finally, increasing evidence points to a role for islet inflammation in the pathogenesis of T2DM. ABCA1 and ABCG1 may also modulate these inflammatory responses, suggesting an additional pathway by which HDL may impact T2DM. SUMMARY: Recent findings indicate that HDL protects beta-cells from cholesterol-induced beta-cell dysfunction, stress-induced apoptosis and islet inflammation. As the protective properties of HDL are compromised in patients with metabolic syndrome and T2DM, dysfunctional HDL metabolism could contribute to the pathogenesis of T2DM. Therapeutic normalization of both the quantity and quality of HDL particles may be a novel approach to prevent or treat T2DM.

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

Cholesterol in beta-cell dysfunction: the emerging connection between HDL cholesterol and type 2 diabetes.

Beta-cell dysfunction is a critical step in the pathogenesis of type 2 diabetes. The mechanisms responsible for beta-cell death and dysfunction remain incompletely understood, but include glucolipotoxicity, the deleterious metabolic milieu created by high plasma concentrations of glucose and lipid species. Recently, an important role has emerged for cholesterol in this process. In this article, we review recent advances in our understanding of the role of ABCA1 and cholesterol metabolism in beta-cell function, with particular attention to insights gained from human studies.