Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.

The mechanisms of adipose tissue activation and inactivation have been a hot topic of research in the last decade, from which countermeasures have been attempted to be found against obesity as well as other lipid metabolism-related diseases, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. Autophagy has been shown to be closely related to the regulation of adipocyte activity, which is involved in the whole process including white adipocyte differentiation/maturation and brown or beige adipocyte generation/activation. Dysregulation of autophagy in adipose tissue has been demonstrated to be associated with obesity. On this basis, we summarize the pathways and mechanisms of autophagy involved in the regulation of lipid metabolism and present a review of its pathophysiological roles in lipid metabolism-related diseases, in the hope of providing ideas for the treatment of these diseases.

Shenzhu Tiaopi granule (STG) has antidiabetic functions. Data-independent acquisition proteomic technology is an integral part of systems biology. Herein, proteomics was used to analyse the effects of STG on type 2 diabetes mellitus (T2DM) and the mechanism by which STG normalizes glucose metabolism.

Goto-Kakizaki (GK) T2DM model (Mod) rats, aged 15-16 weeks and with a fasting blood glucose (FBG) level of ≥11.1 mmol/L, were treated with metformin or STG for 12 weeks. Wistar rats aged 15-16 weeks were included in the control (Con) group. Body weight, FBG, total cholesterol (TC), total triglyceride (TG) levels and low-density lipoprotein (LDL-C) levels were measured, and pathological observation, Western blot analysis and data-independent acquisition proteomics of the liver were performed.

Significant differences in FBG, TC, TG, LDL-C (p < 0.01) and pathological liver morphology were observed between the Mod group and Con group, whereas both metformin and STG normalized the glucose and lipid metabolism indicators (p < 0.05 or p < 0.01). In total, 5856 proteins were identified via proteomic analysis, 97 of which were significantly differentially expressed in the liver and affected fatty acid metabolism, unsaturated fatty acid biosynthesis, the peroxisome proliferator-activated receptor (PPAR) signalling pathway, pyruvate metabolism, and terpenoid backbone biosynthesis. Screening identified 10 target proteins, including perilipin-2 (Plin2), pyruvate dehydrogenase kinase 4, farnesyl diphosphate synthase (Fdps) and farnesyl-diphosphate farnesyltransferase 1. Among these proteins, the key proteins were Plin2 and Fdps, which were found to be associated with the PPAR signalling pathway and terpenoid backbone biosynthesis via relationship networks. Plin2 and Fdps are closely related to hyperglycaemia. STG can downregulate Plin2 and upregulate Fdps (p < 0.01).

STG ameliorated hyperglycaemia by significantly altering the expression of different proteins, especially Fdps and Plin2, in the livers of GK rats. These findings may reveal the potential of traditional Chinese medicine for treating T2DM.

CD36 is a multifunctional protein involved in long chain fatty acid uptake and immune modulation in different cells. Recently it was reported that increased expression of CD36 is evident in the islets of diabetic obese individuals. In this present study we investigated the role of CD36 in regulating intracellular lipid accumulation and inflammation in beta cells and its implication on secretory dysfunction. Additionally, we have elucidated the potential role of fetuinA, a circulatory glycoprotein and an endogenous ligand of TLR4, for aggravating lipid accumulation and insulin secretory defects in beta cells. MIN6 mouse insulinoma cells when incubated with palmitate and fetuinA together showed activation of TLR4-NFkB inflammatory cascade and increased uptake of palmitate, which was rescued by CD36 functional inhibition or knockdown. Moreover, glucose stimulated insulin secretion was restored with consequent downregulation of IL-1β secretion. TLR4 inhibition also decreased intracellular lipid content with a reduction of CD36, suggesting functional crosstalk between them. At physiological level, excess fetuinA in the islet milieu of HFD fed C57BL/6J mice or exogenous fetuinA administration (i.p.) promoted lipid accumulation in the islets resulting in decreased insulin secretion with increased CD36 expression. Interestingly, CD36 inhibition in HFD mice with a pharmacological inhibitor Salvianolic acid B attenuated inflammation, reduced intracellular lipid accumulation in beta cells and restored insulin secretory function. Therefore, our results suggest that inhibition of CD36 protects beta cells from the derogatory effects of lipid and fetuinA and restores secretory function and can be considered as a therapeutic target for obesity mediated beta cell dysfunction.

Objective: This study elucidated the mechanistic role of Cyathulae Radix (CR) in type 2 diabetes mellitus (T2DM) through bioinformatics analysis and experimental validation. Methods: Components and targets of CR were retrieved from the traditional Chinese medical systems pharmacology, while potential T2DM targets were obtained from GeneCards and Online Mendelian Inheritance in Man databases. Intersecting these datasets yielded target genes between CR and T2DM. Differential genes were used for constructing a protein-protein interaction network, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and dynamics simulations were performed using AutoDock and GROMACS, respectively, and in vitro experiments validated the results. Experiments evaluated the effect of CR on T2DM pancreatic β-cells. Results: Bioinformatics analysis identified four active compounds of CR, 157 related genes, and 5431 T2DM target genes, with 141 shared targets. Key targets such as JUN, MAPK1, and MAPK14 were identified through topological analysis of the PPI network. GO analysis presented 2663 entries, while KEGG analysis identified 161 pathways. The molecular docking results demonstrated favorable binding energy between the core components and the core proteins. Among them, JUN-rubrosterone, MAPK1-rubrosterone, and MAPK14-rubrosterone deserved further investigation. Molecular dynamics results indicated that all of them can form stable binding interactions. CR could inhibit the expression of JUN, MAPK1, and MAPK14, promote insulin secretion, alleviate apoptosis, and regulate autophagy in INS-1 cells. Conclusion: This study suggests CR approach to T2DM management by multitarget and multipathway provides a scientific basis for further research on the hypoglycemic effect of CR.

Macroautophagy/autophagy is an essential degradation process that removes abnormal cellular components, maintains homeostasis within cells, and provides nutrition during starvation. Activated autophagy enhances cell survival during stressful conditions, although overactivation of autophagy triggers induction of autophagic cell death. Therefore, early-onset autophagy promotes cell survival whereas late-onset autophagy provokes programmed cell death, which can prevent disease progression. Moreover, autophagy regulates pancreatic β-cell functions by different mechanisms, although the precise role of autophagy in type 2 diabetes (T2D) is not completely understood. Consequently, this mini-review discusses the protective and harmful roles of autophagy in the pancreatic β cell and in the pathophysiology of T2D.

Age-related cataracts is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation, and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Our study identified 101 independent genome-wide significant loci, 57 of which are novel. We identified multiple genes and biological pathways associated with the cataracts, including four drug-gene interactions. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults.

Hyperuricemia can promote both blood lipids and non-alcoholic fatty liver disease (NAFLD). However, the role of the entire uric acid (UA) span, especially low concentrations below hyperuricemia, on lipid metabolism remains unclear.

A cross-sectional study was designed. Data on the age, sex, UA, triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) of 1977 participants, who underwent physical examination, were collected. NAFLD and non-alcoholic fatty pancreas disease (NAFPD) were diagnosed using abdominal ultrasound. Restricted cubic splines (RCS) linear regression model was used to evaluate the effect of the UA span on TG, TC, HDL, and LDL, respectively. RCS logistic regression model was employed to evaluate the effect of the UA span on NAFLD and NAFPD.

RCS linear regression model showed that TG was negatively correlated with UA at first, then exhibiting a positive correlation. Meanwhile, HDL was positively correlated with UA at first, then negatively correlated. There was a positive linear correlation between TC and UA (P for nonlinear = 0.578) and a positive nonlinear correlation between LDL and UA (P for nonlinear = 0.021). RCS logistic regression model showed that NAFLD and NAFPD were negatively correlated with UA at first and then positively correlated with UA.

our study showed that the entire UA span has a J-shaped effect on some lipids, NAFLD, and NAFPD. Besides, TG and HDL, compared with TC or LDL, may better reflect the status of NAFLD and NAFPD.

Intermittent fasting (IF) is a convenient dietary intervention for multiple diseases, including type 2 diabetes. However, whether it can be used as a long-term antidiabetic approach is still unknown. Here, we confirm that IF alone is beneficial for both moderate and severe diabetic mice, but its antidiabetic effects clearly diminish at later stages, especially for severe diabetic db/db mice, which have obviously impaired autophagy. We found that static magnetic fields can directly promote actin assembly and boost IF-induced autophagy. Consequently, the pancreatic islet and liver were improved, and the antidiabetic effects of IF were boosted. In fact, at later stages, combined static magnetic field and IF could reduce the blood glucose level of moderate type 2 diabetic mice by 40.5% (P < 0.001) and severe type 2 diabetes by 34.4% (P < 0.05), when IF alone no longer has significant blood glucose reduction effects. Therefore, although IF is generally beneficial for diabetes, our data reveal its insufficiency for late-stage diabetes, which can be compensated by a simple, noninvasive, long-lasting, and nonpharmacological strategy for effective long-term diabetic control.

Diabetes mellitus (DM) is a progressive, chronic metabolic disorder characterized by high oxidative stress, which can lead to cardiac damage. Methionine sulfoxylation (MetO) of proteins by excessive reactive oxygen species (ROS) can impair the basic functionality of essential cellular proteins, contributing to heart failure. Methionine sulfoxide reductase B2 (MsrB2) can reverse oxidation induced MetO in mitochondrial proteins, so we investigated its role in diabetic cardiomyopathy. We observed that DM-induced heart damage in diabetic mice model is characterized by increased ROS, increased protein MetO with mitochondria structural pathology, and cardiac fibrosis. In addition, MsrB2 was significantly increased in mouse DM cardiomyocytes, supporting the induction of a protective process. Further, MsrB2 directly induces Parkin and LC3 activation (mitophagy markers) in cardiomyocytes. In MsrB2, knockout mice displayed abnormal electrophysiological function, as determined by ECG analysis. Histological analysis confirmed increased cardiac fibrosis and disrupted cardiac tissue in MsrB2 knockout DM mice. We then corroborated our findings in human DM heart samples. Our study demonstrates that increased MsrB2 expression in the heart protects against diabetic cardiomyopathy.

Perilipin 2 (PLIN2) is a protein that contributes to the formation and stability of lipid droplets. It has been associated with the development of several diseases, particularly related to glucose and lipid metabolism. In infants of diabetic mother (IDM), fetal hyperinsulinaemia leads to increased adipose tissue and macrosomia. The aim of this study was to investigate the relationship between PLIN2 levels and anthropometric measurements in the IDM and to investigate the relationship between PLIN2 levels and IGF-1, IGF-2 and leptin levels.

The study group consisted of IDMs, while the control group consisted of infants born to non-diabetic mother, matched for gestational week and gender. Cord blood samples were collected from all patients to determine PLIN2, IGF-1, IGF-2 and leptin levels. Anthropometric measurements were taken for all patients at birth.

There were no differences between the groups in birth weight, birth length, head circumference and body mass index (BMI), but middle arm circumference, triceps, biceps, subscapular and suprailiac skinfold thickness were significantly higher in the IDM. While PLIN2, IGF-1, IGF-2 and leptin levels were similar between groups, there was a strong correlation between PLIN2 levels and IGF-2 and leptin levels.

Even if IDMs were not macrosomic, the presence of high subcutaneous adipose tissue was not associated with PLIN2.

Elucidating the molecular mechanism of autophagy was a landmark in understanding not only the physiology of cells and tissues, but also the pathogenesis of diverse diseases, including diabetes and metabolic disorders. Autophagy of pancreatic β-cells plays a pivotal role in the maintenance of the mass, structure and function of β-cells, whose dysregulation can lead to abnormal metabolic profiles or diabetes. Modulators of autophagy are being developed to improve metabolic profile and β-cell function through the removal of harmful materials and rejuvenation of organelles, such as mitochondria and endoplasmic reticulum. Among the known antidiabetic drugs, glucagon-like peptide-1 receptor agonists enhance the autophagic activity of β-cells, which might contribute to the profound effects of glucagon-like peptide-1 receptor agonists on systemic metabolism. In this review, the results from studies on the role of autophagy in β-cells and their implication in the development of diabetes are discussed. In addition to non-selective (macro)autophagy, the role and mechanisms of selective autophagy and other minor forms of autophagy that might occur in β-cells are discussed. As β-cell failure is the ultimate cause of diabetes and unresponsiveness to conventional therapy, modulation of β-cell autophagy might represent a future antidiabetic treatment approach, particularly in patients who are not well managed with current antidiabetic therapy.

Perilipin 2 (PLIN2) is a lipid droplet (LD)-coating protein playing important roles in lipid homeostasis and suppression of lipotoxicity in different tissues and cell types. Recently, a role for PLIN2 in supporting mitochondrial function has emerged. PLIN2 dysregulation is involved in many metabolic disorders and age-related diseases. However, the exact consequences of PLIN2 dysregulation are not yet completely understood. In this study, we knocked down (KD) PLIN2 in primary human dermal fibroblasts (hDFs) from young (mean age 29 years) and old (mean age 71 years) healthy donors. We have found that PLIN2 KD caused a decline of mitochondrial function only in hDFs from young donors, while mitochondria of hDFs from old donors (that are already partially impaired) did not significantly worsen upon PLIN2 KD. This mitochondrial impairment is associated with the increased expression of the stress-related mitokine growth differentiation factor 15 (GDF15) and the induction of cell senescence. Interestingly, the simultaneous KD of PLIN2 and GDF15 abrogated the induction of cell senescence, suggesting that the increase in GDF15 is the mediator of this phenomenon. Moreover, GDF15 KD caused a profound alteration of gene expression, as observed by RNA-Seq analysis. After a more stringent analysis, this alteration remained statistically significant only in hDFs from young subjects, further supporting the idea that cells from old and young donors react differently when undergoing manipulation of either PLIN2 or GDF15 genes, with the latter being likely a downstream mediator of the former.

Triglyceride (TG), triglyceride-glucose index (TyG), body mass index (BMI), TyG-BMI and triglyceride to high-density lipoprotein ratio (TG/HDL) have been reported to be reliable predictors of non-alcoholic fatty liver disease. However, there are few studies on potential predictors of non-alcoholic fatty pancreas disease (NAFPD). Our aim was to evaluate these and other parameters for predicting NAFPD.

Cross-sectional study design.

Physical examination centre of a tertiary hospital in China.

This study involved 1774 subjects who underwent physical examinations from January 2016 to September 2016.

From each subject, data were collected for 13 basic physical examination and blood biochemical parameters: age, weight, height, BMI, TyG, TyG-BMI, high-density lipoprotein (HDL), low-density lipoprotein, total cholesterol, TG, fasting plasma glucose, TG/HDL and uric acid. NAFPD was diagnosed by abdominal ultrasonography. A logistic regression model with a restricted cubic spline was used to evaluate the relationship between each parameter and NAFPD. The receiver operating characteristic (ROC) curve was used to calculate the area under the curve for each parameter.

HDL was negatively correlated with NAFPD, height was almost uncorrelated with NAFPD and the remaining 11 parameters were positively correlated with NAFPD. ROC curve showed that weight-related parameters (weight, BMI and TyG-BMI) and TG-related parameters (TyG, TG and TG/HDL) had high predictive values for the identification of NAFPD. The combinations of multiple parameters had a better prediction effect than a single parameter. All the predictive effects did not differ by sex.

Weight-related and TG-related parameters are good predictors of NAFPD in all populations. BMI showed the greatest predictive potential. Multiparameter combinations appear to be a good way to predict NAFPD.

Diabetic peripheral neuropathy (DPN) is one of the most prevalent consequences of diabetes, with a high incidence and disability rate. The DPN's pathogenesis is extremely complex and yet to be fully understood. Persistent high glucose metabolism, nerve growth factor deficiency, microvascular disease, oxidative stress, peripheral nerve cell apoptosis, immune factors, and other factors have been implicated in the pathogenesis of DPN. Astragalus mongholicus is a commonly used plant used to treat DPN in clinical settings. Its rich chemical components mainly include Astragalus polysaccharide, Astragalus saponins, Astragalus flavones, etc., which play a vital role in the treatment of DPN. This review aimed to summarize the pathogenesis of DPN and the studies on the mechanism of the effective components of Astragalus mongholicus in treating DPN. This is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.

Lysosomal dysfunction and impaired autophagic flux are involved in the pathogenesis of lipotoxicity in the kidney. Here, we investigated the role of transcription factor EB (TFEB), a master regulator of autophagy-lysosomal pathway, in palmitic acid induced renal tubular epithelial cells injury. We examined lipid accumulation, autophagic flux, expression of Ps211-TFEB, and nuclear translocation of TFEB in HK-2 cells overloaded with palmitic acid (PA). By utilizing immunohistochemistry, we detected TFEB expression in renal biopsy tissues from patients with diabetic nephropathy and normal renal tissue adjacent to surgically removed renal carcinoma (controls), as well as kidney tissues from rat fed with high-fat diet (HFD) and low-fat diet (LFD). We found significant lipid accumulation, increased apoptosis, accompanied with elevated Ps211-TFEB, decreased nuclear TFEB, reduced lysosome biogenesis and insufficient autophagy in HK-2 cells treated with PA. Kidney tissues from patients with diabetic nephropathy had lower nuclear and total levels of TFEB than that in control kidney tissues. Level of renal nuclear TFEB in HFD rats was also lower than that in LFD rats. Exogenous overexpression of TFEB increased the nuclear TFEB level in HK-2 cells treated with PA, promoted lysosomal biogenesis, improved autophagic flux, reduced lipid accumulation and apoptosis. Our results collectively indicate that PA is a strong inducer for TFEB phosphorylation modification at ser211 accompanied with lower nuclear translocation of TFEB. Impairment of TFEB-mediated lysosomal biogenesis and function by palmitic acid may lead to insufficient autophagy and promote HK-2 cells injury.

High amount of fat in the pancreas is linked to poor functioning of β-cells and raises the risk of type 2 diabetes. Here we report the putative role of a circulatory glycoprotein Fetuin-A, a known obesity marker, in promoting lipid accumulation in β-cells and its association with Fatty acid translocase/CD36 for lipid storage culminate in β-cell dysfunction. Additionally, this work reveals regulation of CD36 via Nrf2, a key regulator of oxidative stress, and reduction of lipid accumulation by suppression of Nrf2 that restores β-cell function. Palmitate (0.50 mM) and Fetuin-A (100 μg/mL) exposure showed high levels of intracellular lipid in MIN6 (mouse insulinoma cells) with a concomitant decrease in insulin secretion. This also increased the expression of important lipogenic factors, like CD36, PGC1α, PPARγ, and SREBP1. Flow cytometry analysis of CD36 membrane localization has been corroborated with an increased accumulation of lipids as indicated by Oil-Red-O staining. Immunoblotting and immunofluorescence of Nrf2 indicated its high expression in palmitate-fetuin-A incubation and translocation in the nucleus. Suppression of Nrf2 by siRNA showed a reduced expression of lipogenic genes, ablation of lipid droplets, decrease in the number of apoptotic cells, and restoration of insulin secretion with a corresponding increase of Pdx1, BETA2, and Ins1 gene expression. Our study thus suggested an important aspect of lipid accumulation in the pancreatic β-cells contributing to β-cell dysfunction and demonstrated the role of Fetuin-A in CD36 expression, with a possible way of restoring β-cell function by targeting Nrf2.

Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.

Insulin is a critical hormone that promotes energy storage in various tissues, as well as anabolic functions. Insulin resistance significantly reduces these responses, resulting in pathological conditions, such as obesity and type 2 diabetes mellitus (T2DM). The management of insulin resistance requires better knowledge of its pathophysiological mechanisms to prevent secondary complications, such as cardiovascular diseases (CVDs). Recent evidence regarding the etiological mechanisms behind insulin resistance emphasizes the role of energy imbalance and neurohormonal dysregulation, both of which are closely regulated by autophagy. Autophagy is a conserved process that maintains homeostasis in cells. Accordingly, autophagy abnormalities have been linked to a variety of metabolic disorders, including insulin resistance, T2DM, obesity, and CVDs. Thus, there may be a link between autophagy and insulin resistance. Therefore, the interaction between autophagy and insulin function will be examined in this review, particularly in insulin-responsive tissues, such as adipose tissue, liver, and skeletal muscle.

The chemical complexity of biological tissues creates challenges in the analysis of lipids via imaging mass spectrometry. The presence of isobaric and isomeric compounds introduces chemical noise that makes it difficult to unambiguously identify and accurately map the spatial distributions of these compounds. Electron-induced dissociation (EID) has previously been shown to profile phosphatidylcholine (PCs) sn-isomers directly from rat brain tissue in matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry. However, the acquisition of true pixel-by-pixel images, as opposed to regional profiling measurements, using EID is difficult due to low fragmentation efficiency and precursor ion signal dilution into multiple fragment ion channels, resulting in low sensitivity. In this work, we have developed a sequential collision-induced dissociation (CID)/EID method to visualize the distribution of sn-isomers in MALDI imaging mass spectrometry experiments. Briefly, CID is performed on sodium-adducted PCs, which results in facile loss of the phosphocholine headgroup. This ion is then subjected to an EID analysis. Since the lipid headgroup is removed prior to EID, a major fragmentation pathway common to EID ion activation is eliminated, resulting in a more sensitive analysis. This sequential CID/EID workflow generates sn-specific fragment ions allowing for the assignment of the sn-positions. Carbon-carbon double-bond (C═C) positions are also localized along the fatty acyl tails by the presence of a 2 Da shift pattern in the fragment ions arising from carbon-carbon bond cleavages. Moreover, the integration of the CID/EID method into MALDI imaging mass spectrometry enables the mapping of the absolute and relative distribution of sn-isomers at every pixel. The localized relative abundances of sn-isomers vary throughout brain substructures and likely reflect different biological functions and metabolism.

Globally, cardiovascular disease (CVD) continues to be the primary cause of morbidity and mortality. The risk of cardiovascular disease is markedly increased in individuals with type 2 diabetes mellitus (T2DM), making managing cardiovascular health a top priority. Initially developed for their glucose-lowering properties, sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a transformative class of pharmaceuticals with profound cardiovascular benefits that extend far beyond glycemic control. One of the most striking findings is the substantial reduction in major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality, observed in clinical trials evaluating SGLT2 inhibitors. These extraordinary cardioprotective effects are demonstrated by landmark trials such as EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, which are discussed in detail. In addition, SGLT2 inhibitors have demonstrated positive outcomes in heart failure (HF) with reduced ejection fraction, which has led to their incorporation into HF treatment guidelines. SGLT2 inhibitors offer renoprotection by delaying the progression of diabetic kidney disease, reducing albuminuria, preserving glomerular filtration rates, and their immediate cardiovascular benefits. We investigate the potential mechanisms underlying these renal benefits, focusing on the role of hemodynamic alterations and intraglomerular pressure reduction. In addition, SGLT2 inhibitors have a distinct diuretic effect that can contribute to volume reduction and symptom alleviation in patients with heart failure (HF). This diuretic action, distinct from conventional diuretics, warrants additional research to optimize their use in T2DM and HF patients. The risk of euglycemic diabetic ketoacidosis, genital mycobacterial infections, and bone fractures are also discussed. Understanding these issues is essential for making educated clinical decisions. In conclusion, SGLT2 inhibitors have transcended their initial function as anti-diabetic agents to become essential components of cardiovascular and renal protection strategies in T2DM patients. Their diverse benefits, which include cardioprotection, renoprotection, and the potential for HF management, highlight their potential to transform cardiovascular medicine. Optimizing the use of SGLT2 inhibitors in clinical practice bears the promise of improved cardiovascular outcomes for patients with T2DM and beyond as we navigate this changing landscape.

Mitophagy is an excellent example of selective autophagy that eliminates damaged or dysfunctional mitochondria, and it is crucial for the maintenance of mitochondrial integrity and function. The critical roles of autophagy in pancreatic β-cell structure and function have been clearly shown. Furthermore, morphological abnormalities and decreased function of mitochondria have been observed in autophagy-deficient β-cells, suggesting the importance of β-cell mitophagy. However, the role of authentic mitophagy in β-cell function has not been clearly demonstrated, as mice with pancreatic β-cell-specific disruption of Parkin, one of the most important players in mitophagy, did not exhibit apparent abnormalities in β-cell function or glucose homeostasis. Instead, the role of mitophagy in pancreatic β-cells has been investigated using β-cell-specific Tfeb-knockout mice (TfebΔβ-cell mice); Tfeb is a master regulator of lysosomal biogenesis or autophagy gene expression and participates in mitophagy. TfebΔβ-cell mice were unable to adaptively increase mitophagy or mitochondrial complex activity in response to high-fat diet (HFD)-induced metabolic stress. Consequently, TfebΔβ-cell mice exhibited impaired β-cell responses and further exacerbated metabolic deterioration after HFD feeding. TFEB was activated by mitochondrial or metabolic stress-induced lysosomal Ca2+ release, which led to calcineurin activation and mitophagy. After lysosomal Ca2+ release, depleted lysosomal Ca2+ stores were replenished by ER Ca2+ through ER→lysosomal Ca2+ refilling, which supplemented the low lysosomal Ca2+ capacity. The importance of mitophagy in β-cell function was also demonstrated in mice that developed β-cell dysfunction and glucose intolerance after treatment with a calcineurin inhibitor that hampered TFEB activation and mitophagy.

Green algae are natural bioresources that have excellent bioactive potential, partly due to sulfated polysaccharides (SPs) which are still rarely explored for their biological activities. There is currently an urgent need for studies exploring the anticancer biological activity of SPs extracted from two Indonesian ulvophyte green algae: the sulfated polysaccharide of Caulerpa racemosa (SPCr) and the sulfated polysaccharide of Caulerpa lentillifera (SPCl). The method of isolating SPs and their assessment of biological activities in this study were based on previous and similar studies. The highest yield sulfate/total sugar ratio was presented by SPCr than that of SPCl. Overall, SPCr exhibits a strong antioxidant activity, as indicated by smaller EC₅₀ values obtained from a series of antioxidant activity assays compared to the EC₅₀ values of Trolox (control). As an anti-obesity and antidiabetic, the overall EC₅₀ value of both SPs was close to the EC₅₀ of the positive control (orlistat and acarbose). Even more interesting was that SPCl displayed wide-ranging anticancer effects on colorectal, hepatoma, breast cancer cell lines, and leukemia. Finally, this study reveals new insights in that SPs from two Indonesian green algae have the potential to be promising nutraceuticals as novel antioxidative actors, and to be able to fight obesity, diabetes, and even cancer.

This research investigated secoisolariciresinol diglucoside (SDG) flax extract effects on apoptosis, hedgehog (Hh), autophagy, and the anti-oxidation process in experimentally induced obesity.

Forty rats were separated into two sets regarding either receiving a normal balanced diet or a high-fat diet (HFD) and then distributed into four groups: GI: The control group had a regular diet for 12 weeks. GII: animals received a high-fat meal and saline by gastric gavage. GIII: HFD obese rats treated with SDG extract orally (10 mg/kg/b.w.) and 1.18 mg SDG/kg in the diet for 4 weeks GIV: Normal balanced diet rats received SDG extract orally (10 mg/kg/b.w.) and 1.18 mg SDG/kg of chow for 12 weeks in addition to their regular balanced diet.

The administration of SDG extract exhibited a significant drop in body weight, glucose, lipid profile, and leptin compared to the obese group. It also improved the antioxidant levels (lowering the levels of malondialdehyde while increasing the total antioxidant capacity) and anti-inflammatory status (decreasing interleukin-6 and tumor necrosis factor-alpha). SDG extract downregulates the expression of HH genes (protein patched homolog 1, Hh-interacting protein, glioma-associated oncogene homolog 1, and smoothened receptor) in conjunction with the modulation of autophagy genes and apoptotic proteins.

SDG extract showed improved anti-inflammatory and antioxidant status and downregulated the expression of HH genes while modulating autophagy genes and apoptotic proteins among obese rats, suggesting that it may be used to avert and manage obesity and its correlated complications by modulating oxidation, inflammation, autophagy, and apoptosis. Advanced future research on the SDG autophagy pathway to address obesity and its complications is mandatory.

Phytoestrogens are non-steroid polyphenolic materials present in 300 plants. Regarding their structural similarities to estradiol, phytoestrogens attach to estrogen receptors and display anti- or pro-estrogenic activities. This review explored phytoestrogens' potential advantages and autophagy properties in light of their future application for disease management, highlighting how phytoestrogens could modulate autophagy. Research has examined the prospective benefits of phytoestrogens for the anticipation and management of various conditions, including signs of menopause, tumors, skin deterioration, osteoporosis, heart disease, neurodegenerative conditions, disorders of the immune system, and metabolic syndrome, owing to their therapeutic effects. As phytoestrogens can activate or inhibit autophagy, which has antioxidant, apoptotic, anti-mutagenic, anticancer, transcriptional, and genomic impacts on cancer and aging illnesses, phytoestrogens could influence diseases through the modulation of autophagy. The collaborative research on animal models, utilization of genetic techniques, and administration of pharmacologically active substances has indicated the possible therapeutic benefits of autophagy modulation in various illnesses. Further research is required to illustrate the pathways by which phytoestrogens modulate autophagy and the possible therapeutic effects on these diseases.

(-)-Epigallocatechin gallate (EGCG) is one of the autophagy stimulators that have been reported to protect vascular endothelial cells from oxidative stress-induced damage. In this study, we attempted potentiation of the autophagy-stimulating activity of EGCG in human aortic epithelial cells (HAECs) by using the EGCG-phenylalanine conjugate, E10. Autophagy-stimulating activity of E10 was evaluated by LC3-II measurement in the absence and presence of the lysosomal blocker chloroquine, CTYO-ID staining, and reporter assay using tandem fluorescence-tagged LC3. These experiments revealed significantly enhanced autophagic flux stimulation in HAECs by E10 compared with EGCG. Further elaboration of E10 showed that activation of AMPK through phosphorylation as the major mechanism of its autophagy stimulation. Like other autophagy stimulators, E10 protected HAECs from lipotoxicity as well as accompanying endothelial senescence. Finally, stimulation of autophagy by E10 was shown to protect HAECs from oxidative stress-induced apoptosis. These findings collectively suggest potential clinical implications of E10 for various cardiovascular complications through stimulation of autophagy.

Autophagy is essential in regulating the turnover of macromolecules via removing damaged organelles, misfolded proteins in various tissues, including liver, skeletal muscles, and adipose tissue to maintain the cellular homeostasis. In these tissues, a specific type of autophagy maintains the accumulation of lipid droplets which is directly related to obesity and the development of insulin resistance. It appears to play a protective role in a normal physiological environment by eliminating the invading pathogens, protein aggregates, and damaged organelles and generating energy and new building blocks by recycling the cellular components. Ageing is also a crucial modulator of autophagy process. During stress conditions involving nutrient deficiency, lipids excess, hypoxia etc., autophagy serves as a pro-survival mechanism by recycling the free amino acids to maintain the synthesis of proteins. The dysregulated autophagy has been found in several ageing associated diseases including type 2 diabetes (T2DM), cancer, and neurodegenerative disorders. So, targeting autophagy can be a promising therapeutic strategy against the progression to diabetes related complications. Our article provides a comprehensive outline of understanding of the autophagy process, including its types, mechanisms, regulation, and role in the pathophysiology of T2DM and related complications. We also explored the significance of autophagy in the homeostasis of β-cells, insulin resistance (IR), clearance of protein aggregates such as islet amyloid polypeptide, and various insulin-sensitive tissues. This will further pave the way for developing novel therapeutic strategies for diabetes-related complications.

Pancreatic β cells play a key role in maintaining glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in β cells, but few studies have examined male-female differences in β cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in β cell and islet gene expression and function using both human and rodent samples.

In humans, we compared β cell gene expression and insulin secretion in donors with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with similar insulin sensitivity. Our unbiased gene expression analysis pointed to a sex difference in the endoplasmic reticulum (ER) stress response. Based on this analysis, we hypothesized female islets would be more resilient to ER stress than male islets. To test this, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and β cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress.

Our single-cell analysis of human β cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in human islets isolated from female donors with T2D compared to male donors with T2D. In mice, RNA sequencing revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was physiologically significant, as islets isolated from female mice were more resilient to ER stress induction with thapsigargin. Specifically, female islets showed a greater ability to maintain glucose-stimulated insulin production and secretion during ER stress compared with males.

Our data demonstrate sex differences in β cell gene expression in both humans and mice, and that female β cells show a greater ability to maintain glucose-stimulated insulin secretion across multiple physiological and pathological contexts.

Targeting autophagy is a new therapeutic strategy for the complications of diabetes,such as diabetic cardiomyopathy (DCM). During diabetes, increased or insufficient autophagic activity causes aberrations in cellular homeostasis. Regarding the conflicting and unclear results regarding the effect of HIIT and curcumin supplementation on the expression of genes associated to autophagy, this study aimed to assess whether 4-week high-intensity interval training (HIIT) and curcumin supplementation are able to influence the expression of autophagy-related genes in myocardial cells of diabetic rats.

In an experimental design, 24 male Wistar rats were randomly divided into 4 groups: non-diabetic control (NC), diabetic control (DC), diabetes + HIIT (D + HIIT), and diabetes + curcumin (D + CU). After HIIT program and curcumin treatment, the genes expression of autophagy pathway were assessed in the myocardium by real-time PCR Tanique.

The results indicated that the expression levels of ATG1, Beclin1, ATG5, and LAMP-2 genes were significantly reduced in the DC group compared to the NC group (p < 0.001). Following 4-week HIIT, the expression of Beclin1, ATG-5, and LAMP-2 improved considerably compared to the DC group (p < 0.001, p < 0.001, and p < 0.05, respectively). In addition, after 4 weeks of curcumin supplementation, the expression levels of ATG-5 and Beclin-1 were significantly improved compared to the DC group (p < 0.001, p < 0.05, respectively). It seems HIIT and curcumin supplementation can be an effective approach for inducing autophagy and improving cardiac function in DCM rats.However, HIIT seems more effective than curcumin in this regard.

Obesity with its associated complications represents a social, economic and health problem of utmost importance worldwide. Specifically, obese patients carry a significantly higher risk of developing cardiovascular disease compared to nonobese individuals. Multiple molecular mechanisms contribute to the impaired biological activity of the distinct adipose tissue depots in obesity, including secretion of proinflammatory mediators and reactive oxygen species, ultimately leading to an unfavorable impact on the cardiovascular system. This review summarizes data relating to the contribution of the main adipose tissue depots, including both remote (i.e., intra-abdominal, hepatic, skeletal, pancreatic, renal, and mesenteric adipose fat), and cardiac (i.e., the epicardial fat) adipose locations, on the cardiovascular system. Finally, we discuss both pharmacological and non-pharmacological strategies aimed at reducing cardiovascular risk through acting on adipose tissues, with particular attention to the epicardial fat.

Chronically elevated free fatty acid levels can adversely affect pancreatic β-cells, leading to insulin resistance and eventually type 2 diabetes mellitus (T2DM). Polydatin (PD) from Polygonum cuspidatum has been shown to regulate blood lipid content and lower cholesterol levels. However, there have been no reports on the potential therapeutic effects and actions of PD on lipotoxicity in β-cells.

This study aimed to investigate the protective effects of PD on palmitate (PA)-treated INS-1 insulinoma cells and diabetic mice.

Cells were incubated with PA and varying concentrations of PD for 24 h. Viability assays, morphological observations, flow cytometric analysis, western blotting, and reverse transcription-quantitative polymerase chain reaction were used to assess the effects of PD on PA-induced lipotoxicity. Western blotting was used to measure the endoplasmic reticulum stress (ERS) and the levels of autophagy-related factors after incubation with inducers and inhibitors of ERS and autophagy. Diabetic mice were treated with intragastric PD for 6 weeks followed by the measurement of their physiological and blood lipid indices and assessment of the results of histological and immunofluorescence analyses.

Treatment with PD after PA exposure enhanced insulin secretion and the expression of diabetes-associated genes. PD promoted β-cell function by reducing the levels of proteins associated with ERS and autophagy while also attenuating ERS triggered by tunicamycin. PD also reduced tunicamycin-induced autophagy, indicating that it regulated ERS-mediated autophagy and reduced PA-induced cellular dysfunction. In addition, treatment of db/db mice with PD substantially reduced body weight gain, alleviated dyslipidemia, improved β-cell function, and reduced insulin resistance.

These results suggest that PD protects β-cells from lipotoxicity-induced dysfunction and apoptosis by inhibiting ERS and preventing excessive autophagy. Our study provides a new basis for exploring the potential of PD against β-cell lipotoxicity and T2DM.

Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

During development of type 2 diabetes (T2D), excessive nutritional load is thought to expose pancreatic islets to toxic effects of lipids and reduce β-cell function and mass. However, lipids also play a positive role in cellular metabolism and function. Thus, proper trafficking of lipids is critical for β cells to maximize the beneficial effects of these molecules while preventing their toxic effects. Lipid droplets (LDs) are organelles that play an important role in the storage and trafficking of lipids. In this review, we summarize the discovery of LDs in pancreatic β cells, LD lifecycle, and the effect of LD catabolism on β-cell insulin secretion. We discuss factors affecting LD formation such as age, cell type, species, and nutrient availability. We then outline published studies targeting critical LD regulators, primarily in rat and human β-cell models, to understand the molecular effect of LD formation and degradation on β-cell function and health. Furthermore, based on the abnormal LD accumulation observed in human T2D islets, we discuss the possible role of LDs during the development of β-cell failure in T2D. Current knowledge indicates that proper formation and clearance of LDs are critical to normal insulin secretion, endoplasmic reticulum homeostasis, and mitochondrial integrity in β cells. However, it remains unclear whether LDs positively or negatively affect human β-cell demise in T2D. Thus, we discuss possible research directions to address the knowledge gap regarding the role of LDs in β-cell failure.

The dynamic regulation of autophagy in β-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In β-cells, mechanistic target of rapamycin complex 1 (mTORC1) is inhibited while fasting and is rapidly stimulated during refeeding by a single amino acid, leucine, and glucose. Stimulation of mTORC1 by nutrients inhibited the autophagy initiator ULK1 and the transcription factor TFEB, thereby preventing autophagy when β-cells were continuously exposed to nutrients. Inhibition of mTORC1 by Raptor knockout mimicked the effects of fasting and stimulated autophagy while inhibiting insulin secretion, whereas moderate inhibition of autophagy under these conditions rescued insulin secretion. These results show that mTORC1 regulates insulin secretion through modulation of autophagy under different nutritional situations. In the fasting state, autophagy is regulated in an mTORC1-dependent manner, and its stimulation is required to keep insulin levels low, thereby preventing hypoglycemia. Reciprocally, stimulation of mTORC1 by elevated leucine and glucose, which is common in obesity, may promote hyperinsulinemia by inhibiting autophagy.

Although the follicle-stimulating hormone (FSH) plays a vital role in male reproduction, the molecular relationships among FSH, autophagy, and the secretory function of Sertoli cells remain largely undetermined. In this study, we sought to investigate the effects of FSH on dairy goat Sertoli cell autophagy and the role of autophagy in protein clearance. FSH treatment of primary Sertoli cells was found to enhance the expression level of LC3-II, reduce p62 degradation and the number of lysosomes, and downregulate the levels of LAMP2 protein and lysosomal gene mRNAs. Further analyses revealed that starvation-induced autophagy promotes the translocation of transcription factor EB (TFEB) from the cytoplasm to nucleus and its binding to the promoter region of LAMP2, whereas FSH suppresses the nuclear translocation of TFEB. Moreover, we found that the FSH-mediated inhibition of autophagy extends the biological half-lives of androgen-binding protein (ABP), glial-derived neurotrophic factor (GDNF), and stem cell factor (SCF) and promotes the secretion of these proteins. Collectively, these observations indicate that FSH inhibits autophagy by reducing lysosomal biogenesis, which is associated with the suppression of TFEB nuclear translocation via activation of the PI3K/Akt/mTOR pathway, thereby extending the biological half-lives and enhancing the expression of ABP, GDNF, and SCF in dairy goat Sertoli cells.

Obesity is a complex epidemic disease caused by an imbalance of adipose tissue function that results in hyperglycemia, hyperlipidemia and insulin resistance which further develop into type 2 diabetes, cardiovascular disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adipose tissue is responsible for fat storage; white adipose tissue stores excess energy as fat for availability during starvation, whereas brown adipose tissue regulates thermogenesis through fat oxidation using uncoupling protein 1. However, hypertrophic fat storage results in inflammation and increase the chances for obesity which triggers autophagy genes and lipolytic enzymes to regulate lipid metabolism. Autophagy degrades cargo molecule with the help of lysosome and redistributes the energy back to the cell. Autophagy regulates adipocyte differentiation by modulating master regulators of adipogenesis. Adipogenesis is the process which stores excessive energy in the form of lipid droplets. Lipid droplets (LD) are dynamic cellular organelles that store toxic free-fatty acids into neutral triglycerides in adipose tissue. LD activates both lipolysis and lipophagy to degrade excess triglycerides. In obese tissue, autophagy is activated via pro-inflammatory cytokines produced by surplus fat stored in the adipose tissue. This review focused on the process of autophagy and adipogenesis and the transcription factors that regulate lipogenesis and lipolysis in the adipose tissue. We have also discussed about the importance of autophagic regulation within adipose tissue which controls the onset of obesity and its associated diseases.

The prevalence of Type 2 Diabetes Mellitus (T2DM) in Indonesia has continued to increase over the years. Management of T2DM is challenging across clinical settings, including primary and tertiary care. Uncontrolled T2DM puts patients at risk of the development of T2DM complications, especially early-stage dry skin that is neglected by most of the patients. This study aimed to investigate the comparison between the T2DM management profile and dry skin clinical profile of T2DM patients in primary care and tertiary care settings.

The study was conducted as a cross-sectional epidemiological study by comparing T2DM patient profiles in primary and tertiary care. The data collected included sociodemographic, clinical, and laboratory data that were correlated with T2DM and early dry skin related-T2DM. This study included early dry skin within the SRRC score of 3-11 and excluded infection, ulcer, and severe erythema.

The patients in primary and tertiary care presented poorly controlled T2DM with median HbA1c levels of 7.8% and 7.6%. The patients in primary care also presented with high triglyceride, 179 mg/dl. Furthermore, several significant differences were found in the duration of T2DM, duration of dry skin, and DM treatment (OAD and insulin).

Significant differences in the duration of T2DM, duration of dry skin, and DM treatment (OAD and insulin) might be affected by the parameter of T2DM glycemic control (Blood pressure (BP), body mass index (BMI), HbA1c, random blood glucose (RBG), and triglyceride).

Diabetes mellitus has been identified as a major risk factor for developing severe COVID 19 complications. In this review article, the efforts were directed to provide insights and the possible extent to which some diabetic pharmacological interventions may exacerbate COVID 19 or may not be idyllic options for COVID 19 patients. Articles reviewed were identified using the Google scholar database, and search was done using the English language. Anti-hyperglycemic is associated with undesirable effects including episodes of hypoglycemia, diarrhea, lactic acidosis, and increased risks of cardiovascular and hepatic hazards. These undesirable effects associated with the anti-hyperglycemic agents possess a threat of developing severe COVID19 complications Therefore, this calls for more studies to understand the extent of the risks these agents possess in diabetic COVID 19 patients. Almost all the anti-hyperglycemic agents have the potential to worsen COVID 19, despite their class. COVID 19 may limit the options in terms of available anti-hyperglycemic agents which may not heighten the risk of developing severe COVID 19 complications. The research towards the discovery and development of new compounds and also new therapeutic targets for hyperglycemia should be encouraged and welcome.

Pancreatic fat is a form of ectopic fat. Lipid droplets (LDs) are also observed in β cells; however, the pathophysiological significance, especially for β cell function, has not been elucidated. Our aim was to assess LD accumulation in β cells in various stages of glucose intolerance and to clarify its relationship with clinical and histological parameters.

We examined 42 Japanese patients who underwent pancreatectomy. The BODIPY493/503-positive (BODIPY-positive) area in β cells was measured in pancreatic sections from 32 patients. The insulin granule numbers were counted in an additional 10 patients using electron microscopy.

The BODIPY-positive area in β cells in preexisting type 2 diabetes patients was higher than that in normal glucose tolerance patients (p = 0.031). The BODIPY-positive area in β cells was positively correlated with age (r = 0.45, p = 0.0097), HbA1c (r = 0.38, p = 0.0302), fasting plasma glucose (r = 0.37, p = 0.045), and homeostasis model assessment insulin resistance (r = 0.41, p = 0.049) and negatively correlated with an increase in the C-peptide immunoreactivity level by the glucagon test (r = -0.59, p = 0.018). The ratio of mature insulin granule number to total insulin granule number was reduced in the patients with rich LD accumulation in β cells (p = 0.039).

Type 2 diabetes patients had high LD accumulation in β cells, which was associated with insulin resistance, hyperglycemia, aging and β cell dysfunction involving decreased mature insulin granules.