Non-alcoholic fatty liver disease biomarkers estimate cardiovascular risk based on coronary artery calcium score in type 2 diabetes: a cross-sectional study with two independent cohorts.

BACKGROUND: Studies have demonstrated that coronary artery calcification on one hand and non-alcoholic fatty liver disease (NAFLD) on the other hand are strongly associated with cardiovascular events. However, it remains unclear whether NAFLD biomarkers could help estimate cardiovascular risk in individuals with type 2 diabetes (T2D). The primary objective of the present study was to investigate whether the biomarkers of NAFLD included in the FibroMax® panels are associated with the degree of coronary artery calcification in patients with T2D. METHODS: A total of 157 and 460 patients with T2D were included from the DIACART and ACCoDiab cohorts, respectively. The coronary artery calcium score (CACS) was measured in both cohorts using computed tomography. FibroMax® panels (i.e., SteatoTest®, FibroTest®, NashTest®, and ActiTest®) were determined from blood samples as scores and stages in the DIACART cohort and as stages in the ACCoDiab cohort. RESULTS: CACS significantly increased with the FibroTest® stages in both the DIACART and ACCoDiab cohorts (p-value for trend = 0.0009 and 0.0001, respectively). In DIACART, the FibroTest® score was positively correlated with CACS in univariate analysis (r = 0.293, p = 0.0002) and remained associated with CACS independently of the traditional cardiovascular risk factors included in the SCORE2-Diabetes model [ß = 941 ± 425 (estimate ± standard error), p = 0.028]. In the ACCoDiab cohort, the FibroTest® F3-F4 stage was positively correlated with CACS in point-biserial analysis (rpbi = 0.104, p = 0.024) and remained associated with CACS after adjustment for the traditional cardiovascular risk factors included in the SCORE2-Diabetes model (ß = 234 ± 97, p = 0.016). Finally, the prediction of CACS was improved by adding FibroTest® to the traditional cardiovascular risk factors included in the SCORE2-Diabetes model (goodness-of-fit of prediction models multiplied by 4.1 and 6.7 in the DIACART and ACCoDiab cohorts, respectively). In contrast, no significant relationship was found between FibroMax® panels other than FibroTest® and CACS in either cohort. CONCLUSIONS: FibroTest® is independently and positively associated with the degree of coronary artery calcification in patients with T2D, suggesting that FibroTest® could be a relevant biomarker of coronary calcification and cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02431234 and NCT03920683.

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.

Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl 4 ) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.

Ceramide analog C2-cer induces a loss in insulin sensitivity in muscle cells through the salvage/recycling pathway.

Ceramides have been shown to play a major role in the onset of skeletal muscle insulin resistance and therefore in the prevalence of type 2 diabetes. However, many of the studies involved in the discovery of deleterious ceramide actions used a nonphysiological, cell-permeable, short-chain ceramide analog, the C2-ceramide (C2-cer). In the present study, we determined how C2-cer promotes insulin resistance in muscle cells. We demonstrate that C2-cer enters the salvage/recycling pathway and becomes deacylated, yielding sphingosine, re-acylation of which depends on the availability of long chain fatty acids provided by the lipogenesis pathway in muscle cells. Importantly, we show these salvaged ceramides are actually responsible for the inhibition of insulin signaling induced by C2-cer. Interestingly, we also show that the exogenous and endogenous monounsaturated fatty acid oleate prevents C2-cer to be recycled into endogenous ceramide species in a diacylglycerol O-acyltransferase 1-dependent mechanism, which forces free fatty acid metabolism towards triacylglyceride production. Altogether, the study highlights for the first time that C2-cer induces a loss in insulin sensitivity through the salvage/recycling pathway in muscle cells. This study also validates C2-cer as a convenient tool to decipher mechanisms by which long-chain ceramides mediate insulin resistance in muscle cells and suggests that in addition to the de novo ceramide synthesis, recycling of ceramide could contribute to muscle insulin resistance observed in obesity and type 2 diabetes.

Hepatic deletion of serine palmitoyl transferase 2 impairs ceramide/sphingomyelin balance, bile acids homeostasis and leads to liver damage in mice.

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell-signaling pathways, leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic ceramide synthesis in energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of ceramide de novo synthesis, in liver under albumin promoter. Liver function, glucose homeostasis, bile acid (BA) metabolism and hepatic sphingolipids content were assessed using metabolic tests and LC-MS. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, associated with a 10-fold increase in neutral sphingomyelinase 2 (nSMase2) expression, and a decreased sphingomyelin content in the liver. Sptlc2ΔLiv mice were protected against obesity induced by high fat diet and displayed a defect in lipid absorption. In addition, an important increase in tauro-muricholic acid was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production, while the latter effect was dampened in presence of nSMase2 inhibitor. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis, worsening with age. Our data suggest a compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the involvement of hepatic sphingolipid modulation in BA metabolism and hepatic glucose production in an insulin-independent manner, which highlight the still under-researched role of ceramides in many metabolic functions.

Mineralocorticoid Receptor Antagonism Prevents the Synergistic Effect of Metabolic Challenge and Chronic Kidney Disease on Renal Fibrosis and Inflammation in Mice.

Obesity and/or metabolic diseases are frequently associated with chronic kidney disease and several factors associated with obesity may contribute to proteinuria and extracellular matrix production. Mineralocorticoid receptor antagonists have proven their clinical efficacy in diabetic kidney disease with preclinical data suggesting that they may also be efficient in non-diabetic chronic kidney disease associated to metabolic diseases. In the present study we developed a novel mouse model combining severe nephron reduction and High Fat Diet challenge that led to chronic kidney disease with metabolic alterations. We showed that the Mineralocorticoid Receptor antagonist canrenoate improved metabolic function, reduced albuminuria and prevented the synergistic effect of high fat diet on renal fibrosis and inflammation in chronic kidney disease mice.

SREBP-1c and lipogenesis in the liver: an update1.

Sterol Regulatory Element Binding Protein-1c is a transcription factor that controls the synthesis of lipids from glucose in the liver, a process which is of utmost importance for the storage of energy. Discovered in the early nineties by B. Spiegelman and by M. Brown and J. Goldstein, it has generated more than 5000 studies in order to elucidate its mechanism of activation and its role in physiology and pathology. Synthetized as a precursor found in the membranes of the endoplasmic reticulum, it has to be exported to the Golgi and cleaved by a mechanism called regulated intramembrane proteolysis. We reviewed in 2002 its main characteristics, its activation process and its role in the regulation of hepatic glycolytic and lipogenic genes. We particularly emphasized that Sterol Regulatory Element Binding Protein-1c is the mediator of insulin effects on these genes. In the present review, we would like to update these informations and focus on the response to insulin and to another actor in Sterol Regulatory Element Binding Protein-1c activation, the endoplasmic reticulum stress.

Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue.

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

Roles of Ceramides in Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease is one of the most common chronic liver diseases, ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Its prevalence is rapidly increasing and presently affects around 25% of the general population of Western countries, due to the obesity epidemic. Liver fat accumulation induces the synthesis of specific lipid species and particularly ceramides, a sphingolipid. In turn, ceramides have deleterious effects on hepatic metabolism, a phenomenon called lipotoxicity. We review here the evidence showing the role of ceramides in non-alcoholic fatty liver disease and the mechanisms underlying their effects.

Dihydroceramides: their emerging physiological roles and functions in cancer and metabolic diseases.

Dihydroceramides (DhCers) are a type of sphingolipids that for a long time were regarded as biologically inactive. They are metabolic intermediates of the de novo sphingolipid synthesis pathway, and are converted into ceramides (Cers) with the addition of a double bond. Ceramides are abundant in tissues and have well-established biological functions. On the contrary, dihydroceramides are less prevalent, and despite their hitherto characterization as inert lipids, studies of the past decade began to unravel their implication in various biological processes distinct from those involving ceramides. These processes include cellular stress responses and autophagy, cell growth, pro-death or pro-survival pathways, hypoxia, and immune responses. In addition, their plasma concentration has been related to metabolic diseases and shown as a long-term predictor of type 2 diabetes onset. They are thus important players and potential biomarkers in pathologies ranging from diabetes to cancer and neurodegenerative diseases. The purpose of this mini-review is to highlight the emergence of dihydroceramides as a new class of bioactive sphingolipids by reporting recent advances on their biological characterization and pathological implications, focusing on cancer and metabolic diseases.

Dihydroceramides in Triglyceride-Enriched VLDL Are Associated with Nonalcoholic Fatty Liver Disease Severity in Type 2 Diabetes.

Plasma dihydroceramides are predictors of type 2 diabetes and related to metabolic dysfunctions, but the underlying mechanisms are not characterized. We compare the relationships between plasma dihydroceramides and biochemical and hepatic parameters in two cohorts of diabetic patients. Hepatic steatosis, steatohepatitis, and fibrosis are assessed by their plasma biomarkers. Plasma lipoprotein sphingolipids are studied in a sub-group of diabetic patients. Liver biopsies from subjects with suspected non-alcoholic fatty liver disease are analyzed for sphingolipid synthesis enzyme expression. Dihydroceramides, contained in triglyceride-rich very-low-density lipoprotein (VLDL), are associated with steatosis and steatohepatitis. Expression of sphingolipid synthesis enzymes is correlated with histological steatosis and inflammation grades. In conclusion, association of plasma dihydroceramides with nonalcoholic fatty liver might explain their predictive character for type 2 diabetes. Our results suggest a relationship between hepatic sphingolipid metabolism and steatohepatitis and an involvement of dihydroceramides in the synthesis/secretion of triglyceride-rich VLDL, a hallmark of NAFLD and type 2 diabetes dyslipidemia.

Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α.

Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype.

[ER stress and NAFLD]. / Stress du réticulum endoplasmique et stéatopathies métaboliques.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent pathology associated with obesity. It encompasses a spectrum of hepatic disorders ranging from steatosis to non-alcoholic steatohepatitis (NASH), which may lead to cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress has been widely involved to drive in NAFLD progression through the activation of the unfolded protein response (UPR). While transient UPR activation can boost hepatic ER functions, its continuous activation upon a chronic ER stress contributes to lipid accumulation, inflammation and hepatocyte death, which are determinant factors for the progression to more severe stages. The aim of this review is to describe the mechanisms through which the UPR can take part in the transition from a healthy to a diseased liver and to report on possible ways of pharmacological manipulation against these pathological mechanisms.

TITLE: Stress du réticulum endoplasmique et stéatopathies métaboliques. ABSTRACT: Les stéatopathies métaboliques sont des pathologies en pleine expansion car très associées à l'obésité. Elles englobent un éventail de troubles hépatiques allant de la stéatose à la stéatohépatite non alcoolique (NASH) pouvant conduire à la cirrhose et au carcinome hépatocellulaire (CHC). Le stress du réticulum endoplasmique (RE), à travers l'activation de la voie UPR (Unfolded Protein Response), a été largement impliqué dans le développement et la progression de ces maladies métaboliques hépatiques. Alors que l'activation transitoire de la voie UPR fait partie intégrante de la physiologie hépatique, son activation chronique contribue à la stimulation de voies métaboliques et cellulaires (synthèse des lipides, inflammation, apoptose) qui sont déterminantes dans la progression vers des stades sévères. Le but de cette revue est de décrire comment la voie UPR participe au passage d'un foie sain à un foie malade au cours de l'obésité et d'analyser les perspectives thérapeutiques liées à la manipulation pharmacologique de cette voie.

Rapid glycemic regulation in poorly controlled patients living with diabetes, a new associated factor in the pathophysiology of Charcot's acute neuroarthropathy.

OBJECTIVE: Aggressive antidiabetic therapy and rapid glycemic control are associated with diabetic neuropathy. Here we investigated if this is also the case for Charcot neuroarthropathy. RESEARCH DESIGN AND METHODS: HbA1c levels and other relevant data were extracted from medical databases of 44 cases of acute Charcot neuroarthropathy. RESULTS: HbA1c levels significantly declined from 8.25% (67mmol/mol) [7.1%-9.4%](54-79mmol/mol), at -6 months (M-6), to 7.40%(54mmol/mol) [6.70%-8.03%] (50-64 mmol/mol) during the six months preceding the diagnosis of Charcot neuroarthropathy (P <0.001). CONCLUSIONS: HbA1c levels significantly declined during the six months preceding the onset of Charcot neuroarthropathy. This decline seems to be a associated factor with the appearance of an active phase of Charcot neuroarthropathy in poorly controlled patients with diabetic sensitive neuropathy.

Hepatic stellate cell hypertrophy is associated with metabolic liver fibrosis.

Hepatic fibrosis is a major consequence of chronic liver disease such as non-alcoholic steatohepatitis which is undergoing a dramatic evolution given the obesity progression worldwide, and has no treatment to date. Hepatic stellate cells (HSCs) play a key role in the fibrosis process, because in chronic liver damage, they transdifferentiate from a "quiescent" to an "activated" phenotype responsible for most the collagen deposition in liver tissue. Here, using a diet-induced liver fibrosis murine model (choline-deficient amino acid-defined, high fat diet), we characterized a specific population of HSCs organized as clusters presenting simultaneously hypertrophy of retinoid droplets, quiescent and activated HSC markers. We showed that hypertrophied HSCs co-localized with fibrosis areas in space and time. Importantly, we reported the existence of this phenotype and its association with collagen deposition in three other mouse fibrosis models, including CCl4-induced fibrosis model. Moreover, we have also shown its relevance in human liver fibrosis associated with different etiologies (obesity, non-alcoholic steatohepatitis, viral hepatitis C and alcoholism). In particular, we have demonstrated a significant positive correlation between the stage of liver fibrosis and HSC hypertrophy in a cohort of obese patients with hepatic fibrosis. These results lead us to conclude that hypertrophied HSCs are closely associated with hepatic fibrosis in a metabolic disease context and may represent a new marker of metabolic liver disease progression.

Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease.

BACKGROUND & AIMS: In non-alcoholic fatty liver disease (NAFLD), hepatocytes can undergo necroptosis: a regulated form of necrotic cell death mediated by the receptor-interacting protein kinase (RIPK) 1. Herein, we assessed the potential for RIPK1 and its downstream effector mixed lineage kinase domain-like protein (MLKL) to act as therapeutic targets and markers of activity in NAFLD. METHODS: C57/BL6J-mice were fed a normal chow diet or a high-fat diet (HFD). The effect of RIPA-56, a highly specific inhibitor of RIPK1, was evaluated in HFD-fed mice and in primary human steatotic hepatocytes. RIPK1 and MLKL concentrations were measured in the serum of patients with NAFLD. RESULTS: When used as either a prophylactic or curative treatment for HFD-fed mice, RIPA-56 caused a downregulation of MLKL and a reduction of liver injury, inflammation and fibrosis, characteristic of non-alcoholic steatohepatitis (NASH), as well as of steatosis. This latter effect was reproduced by treating primary human steatotic hepatocytes with RIPA-56 or necrosulfonamide, a specific inhibitor of human MLKL, and by knockout (KO) of Mlkl in fat-loaded AML-12 mouse hepatocytes. Mlkl-KO led to activation of mitochondrial respiration and an increase in ß-oxidation in steatotic hepatocytes. Along with decreased MLKL activation, Ripk3-KO mice exhibited increased activities of the liver mitochondrial respiratory chain complexes in experimental NASH. In patients with NAFLD, serum concentrations of RIPK1 and MLKL increased in correlation with activity. CONCLUSION: The inhibition of RIPK1 improves NASH features in HFD-fed mice and reverses steatosis via an MLKL-dependent mechanism that, at least partly, involves an increase in mitochondrial respiration. RIPK1 and MLKL are potential serum markers of activity and promising therapeutic targets in NAFLD. LAY SUMMARY: There are currently no pharmacological treatment options for non-alcoholic fatty liver disease (NAFLD), which is now the most frequent liver disease. Necroptosis is a regulated process of cell death that can occur in hepatocytes during NAFLD. Herein, we show that RIPK1, a gatekeeper of the necroptosis pathway that is activated in NAFLD, can be inhibited by RIPA-56 to reduce not only liver injury, inflammation and fibrosis, but also steatosis in experimental models. These results highlight the potential of RIPK1 as a therapeutic target in NAFLD.

Multifocal (tarsus and knee) activation of neuroarthropathy following rapid glycaemic correction.

OBJECTIVE: To report a case of neuroarthropathy in the tarsus and knee following rapid glycaemic normalisation in a female patient with type I diabetes. METHODS: A retrospective review of case notes. RESULTS: We describe the case of a female patient with type I diabetes who had developed a multifocal neuroarthropathy in only six months, probably due to a rapid glycaemic normalisation. The onset of this neuroarthropathy was not only fast but mostly multifocal affecting two levels of joints. CONCLUSION: The link between the onset of multifocal neuroarthropathy and the rapid correction of chronic hyperglycaemia is probably proven in our case. Patients with chronic hyperglycaemia with sensitive neuropathy should benefit from a gradual correction of their glycaemic imbalance in order to avoid the apparition of neuroarthropathy.

GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation.

Hypertrophic white adipose tissue (WAT) represents a maladaptive mechanism linked to the risk for developing type 2 diabetes in humans. However, the molecular events that predispose WAT to hypertrophy are poorly defined. Here, we demonstrate that adipocyte hypertrophy is triggered by loss of the corepressor GPS2 during obesity. Adipocyte-specific GPS2 deficiency in mice (GPS2 AKO) causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction during surplus energy. This phenotype is driven by HIF1A activation that orchestrates inadequate WAT remodeling and disrupts mitochondrial activity, which can be reversed by pharmacological or genetic HIF1A inhibition. Correlation analysis of gene expression in human adipose tissue reveals a negative relationship between GPS2 and HIF1A, adipocyte hypertrophy, and insulin resistance. We propose therefore that the obesity-associated loss of GPS2 in adipocytes predisposes for a maladaptive WAT expansion and a pro-diabetic status in mice and humans.

Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.

In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.

Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.

Human herpesvirus 8 infection DNA positivity is associated with low insulin secretion: A case-control study in a sub-Saharan African population with diabetes.

BACKGROUND: Viruses have been considered potential triggers for the development of diabetes. This study assessed insulin secretion and insulin sensitivity in human herpesvirus 8 (HHV8)-infected and uninfected sub-Saharan African people with diabetes. METHODS: In all, 173 people with non-autoimmune diabetes were enrolled consecutively: 124 with type 2 diabetes mellitus (T2DM) and 49 with ketosis-prone diabetes (KPD) admitted in hyperglycemic crisis. Those with KPD were further subdivided into those with new-onset ketotic-phase KPD (n = 34) or non-ketotic phase KPD (n = 15). All participants were screened for HHV8-specific antibodies and genomic DNA. Blood samples were collected for analysis of fasting glucose, HbA1c, lipid profile, and C-peptide, with insulin resistance and secretion estimated by homeostasis model assessment. RESULTS: Among the 173 diabetic participants, 88 (50.9%) were positive for HHV8 antibodies (Ac-HHV8+), including 15 (8.7%) positive for HHV8 DNA (DNA-HHV8+). The seroprevalence of HHV8 was similar between T2DM (55.6%) and KPD (61.2%) subjects. Of those with and without ketotic-phase KPD, 35.3% and 46.7% were Ac-HHV8+, respectively. Body mass index was significantly in lower DNA-HHV8+ than DNA-HHV8- subjects. Low-density lipoprotein and total cholesterol were significantly higher, but C-peptide and homeostatic model assessment of ß-cell function (HOMA-ß) were significantly lower in DNA-HHV8+ than DNA-HHV8- participants. After excluding DNA-HHV8+ participants, triglyceride concentrations were significantly higher in Ac-HHV8+ (n = 73) than Ac-HHV8- (n = 85) subjects. In contrast, HOMA-ß was significantly higher among Ac-HHV8+ than Ac-HHV8- participants. CONCLUSIONS: In the present study, HHV8 DNA positivity was associated with low insulin secretion in this sub-Saharan African diabetes population.