MicroRNA-139-5p mediates BMSCs impairment in diabetes by targeting HOXA9/c-Fos.

The properties and functions of BMSCs were altered by the diabetic microenvironment, and its mechanism was not very clear. In recent years, the regulation of the function of BMSCs by microRNA has become a research hotspot, meanwhile, HOX genes also have been focused on and involved in multiple functions of stem cells. In this study, we investigated the role of miR-139-5p in diabetes-induced BMSC impairment. Since HOXA9 may be a target gene of miR-139-5p, we speculated that miR-139-5p/HOXA9 might be involved in regulating the biological characteristics and the function of BMSCs in diabetes. We demonstrated that the miR-139-5p expression was increased in BMSCs derived from STZ-induced diabetic rats. MiR-139-5p mimics were able to inhibit cell proliferation, and migration and promoted senescence and apoptosis in vitro. MiR-139-5p induced the down-regulated expression of HOXA9 and c-Fos in BMSCs derived from normal rats. Moreover, miR-139-5p inhibitors reversed the tendency in diabetic-derived BMSCs. Further, gain-and-loss function experiments indicated that miR-139-5p regulated the functions of BMSCs by targeting HOXA9 and c-Fos. In vivo wound model experiments showed that the downregulation of miR-139-5p further promoted the epithelialization and angiogenesis of diabetic BMSC-mediated skin. In conclusion, induction of miR-139-5p upregulation mediated the impairment of BMSCs through the HOXA9/c-Fos pathway in diabetic rats. Therefore, miR-139-5p/HOXA9 might be an important therapeutic target in treating diabetic BMSCs and diabetic complications in the future.

The vicious circle of UHRF1 down-regulation and KEAP1/NRF2/HO-1 pathway impairment promotes oxidative stress-induced endothelial cell apoptosis in diabetes.

BACKGROUND: Oxidative stress is recognized as a key factor in the induction of endothelial dysfunction in diabetes. However, the specific mechanisms have not been fully elucidated. We herein hypothesized that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) might have a role in oxidative stress-induced endothelial cell (EC) apoptosis in diabetes. METHODS: Western blot, qPCR, wound healing assay, apoptosis assay, reactive oxygen species (ROS) detection, dual-luciferase reporter assay, methylation-specific PCR, bisulfite sequencing PCR and chromatin immunoprecipitation assay were performed. RESULTS: UHRF1 expression levels were significantly decreased in endothelial colony-forming cells derived from peripheral blood of participants with type 2 diabetes compared with individuals without diabetes. ECs treated with high glucose, palmitate or hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. Silencing of UHRF1 led to decreased migration ability and increased apoptosis and ROS production in ECs, which might be related to impaired Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 pathway. Mechanistically, UHRF1 is closely implicated in epigenetic regulation of chromatin modification status at KEAP1 genomic locus via histone acetylation. NRF2 down-regulation in turn inhibits UHRF1 protein level, which might be due to increased ROS generation. CONCLUSION: Diabetes-induced oxidative stress can mediate down-regulation of UHRF1, which enhances ROS production by regulating KEAP1/p-NRF2 pathway through histone acetylation and might also form a self-perpetuating feedback loop with KEAP1/p-NRF2 to further promote oxidative stress-induced apoptosis of ECs in diabetes.

A case of hyperparathyroidism secondary to tumor-induced osteomalacia. / è‚¿ç˜¤æ€§éª¨è½¯åŒ–ç—‡ç»§å‘ç”²çŠ¶æ—è ºåŠŸèƒ½äº¢è¿›ç—‡1例.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which tumor-induced osteochondrosis is a metabolic bone disease caused by increased renal excretion of phosphorus due to excessive secretion of fibroblast growth factor 23 (FGF23) by tumor tissue. We report here a rare case of TIO in which the tumor was found in the hyoid body and the patient had tertiary hyperparathyroidism. The patient's symptoms did not improve after removal of the tumor from the hyoid body, and the patient's hypophosphatemia was gradually improved after subsequent removal of the left parathyroid gland. TIO derived from the tongue tumor is very rare, and also subsequent tertiary hyperparathyroidism is even rarer. This report helps to improve the understanding of TIO and provides reference in the diagnosis and treatment of TIO.

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.

Identification of Novel Variants in MEN1: A Study Conducted with Four Multiple Endocrine Neoplasia Type 1 Patients.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited endocrine tumor syndrome caused by inactivating variants of the MEN1 gene. The aim of this study is to explore the clinical and genetic characteristics of four MEN1 patients. We isolated genomic deoxyribonucleic acid from lymphocytes, parathyroid, and thymic tumoral tissue specimens from the MEN1 patients. All exons of the MEN1 and CDNK1B genes and adjacent exon-intron sequences were amplified by polymerase chain reaction and subsequently sequenced. Further, the splice alterations were studied by sequencing the amplified RT-PCR products for MEN1 cDNA. We identified four heterozygous MEN1 germline variants: c.564delC, c.1268G>A, IVS5+5delG, and c.1546_1547insC. Both c.564delC and IVS5+5delG were novel variants. The impact of the MEN1 splice variant, IVS5+5delG, was evaluated using bioinformatics and in vitro analyses. The analyses indicated that this variant resulted in skipping of the neighboring exon and was disease-causing. Two novel somatic variants, c.249_252delGTCT and c.313_314insC, were found. Additionally, loss of heterozygosity (LOH) for the MEN1 locus (IVS5+5delG and c.564delC) was found in tumor tissue samples from the MEN1 patients, consistent with Knudson's two-hit mechanism. We identified four MEN1 germline variants and two novel somatic variants. Early recognition of the phenotype coupled with variant screening of the MEN1 gene is the key to diagnosing and treating MEN1 effectively at an early stage.

Efficacy and safety of polyethylene glycol loxenatide as add-on to metformin in patients with type 2 diabetes: A multicentre, randomized, double-blind, placebo-controlled, phase 3b trial.

AIM: To assess the efficacy and safety of polyethylene glycol loxenatide (PEX168), a new glucagon-like peptide-1 receptor agonist, as an add-on to metformin therapy in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, placebo-controlled phase 3b trial. After metformin monotherapy (≥1500 mg/day) for 8 weeks or more, patients with uncontrolled T2D (HbA1c of 7.0%-10.5%) from 44 sites were randomized (1:1:1) to metformin + placebo, metformin + PEX168 100 µg, and metformin + PEX168 200 µg. The core treatment period lasted for 24 weeks, followed by a 28-week extension period. The primary endpoint was the change in HbA1c levels at week 24. The main secondary endpoint was the proportion of patients with an HbA1c of less than 7.0% at week 24. RESULTS: The least-square mean (standard error) change in HbA1c levels was significantly greater (P < .001 for superiority) in the PEX168 groups (-1.16% [0.08%] and -1.14% [0.08%] with 100 and 200 µg, respectively) than in the placebo group (0.35% [0.08%]). The proportion of patients with an HbA1c of less than 7.0% at week 24 was significantly higher in the PEX168 100 µg (37.4%) and PEX168 200 µg (40.6%) groups than in the placebo group (16.8%; both P < .001). The gastrointestinal reactions were mild; the risks of hypoglycaemia and weight gain did not increase. Anti-PEX168 antibodies were noted in less than 2% of patients. No treatment-emergent serious adverse events occurred. CONCLUSION: The subcutaneous injection of PEX168 once a week can effectively, continuously and safely improve HbA1c levels in patients with T2D when combined with metformin.

Identification of two novel mutations in three Chinese families with Kallmann syndrome using whole exome sequencing.

Kallmann syndrome (KS) is a rare developmental disorder that manifests as congenital hypogonadotropic hypogonadism with anosmia. More than 19 genes have been found to be associated with KS. However, approximately 70% of the causes of KS remain unclear. Here, we studied seven KS patients, from three families, who had delayed puberty and olfactory bulb dysplasia. However, the families of these patients showed a range of other unique clinical features, including hearing loss, anosmia (to varying degrees) and unilateral renal agenesis. We performed whole exome sequencing and copy number variation (CNV) sequencing on samples acquired from these patients. We identified two novel mutations (c.844delC in ANOS1, c.475C>T in SOX10) and a novel trigenic pattern, PROKR2/CHD7/FEZF1 (c.337T>C in PROKR2, c.748C>G in FEZF1, c.8773G>A in CHD7). The c.844delC mutation in the ANOS1 gene was predicted to generate a truncated form of the anosmin-1 protein. SIFT and PolyPhen-2 predicted that the c.475C>T mutation in SOX10 had a damaging effect. The PROKR2 mutation (c.337T>C) was previously reported as harmful. No pathogenic copy number alterations were detected. Our study expands the genotypic and phenotypic spectrum of KS, a disease that shows considerable clinical and genetic heterogeneity. The application of whole exome sequencing could facilitate our understanding of the pathogenesis of KS.

[Role of UHRF1 in methylation regulation and angiogenesis].

Many recent studies have proved that ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important nuclear protein associated with tumorigenesis, which plays a significant role in epigenetic regulation, especially in DNA methylation and histone methylation. For its particular domains, UHRF1 plays a critical role in biological behaviors including cell proliferation, cell cycle, and apoptosis. Overexpression of UHRF1 in various tumors is closely associated with the angiogenesis in tumors. This paper will provide a review of the regulation of UHRF1 in DNA methylation and histone methylation, and discuss the potential epigenetic role of UHRF1 in angiogenesis.

Treatment-induced neuropathy in diabetes: A report of 2 cases and literature review. / ç³–å°¿ç— æ²»ç–—è¯±å¯¼çš„ç¥žç»ç— å˜2ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Treatment-induced neuropathy is an distinct, acute form of neuropathic pain which often occur shortly after initiation of intensive glycemic control and is characterized by excruciating neuropathic pain. It is a rare form of diabetic neuropathy and easy to be misdiagnosed. Clinical characteristics were analyzed based on two cases of treatment-induced neuropathy in diabetes accepted by the Third Xiangya Hospital of Central South University. It is proposed that strict glycemic control may lead to the occurrence of the disease. At Present, the pathogenesis is still unclear. Besides, the morbidity is much higher than we expected. It is important to improve the doctors awareness of this disease and avoid the the disease through carful glycemic control.

Multiple endocrine neoplasia-IIb with RET gene mutation p.M918T： A case report. / RETåŸºå› p.M918Tçªå˜å¯¼è‡´å¤šå‘æ€§å† åˆ†æ³Œè‚¿ç˜¤-IIb型1例.

Multiple endocrine neoplasia-IIb (MEN-IIb) is a rare hereditary autosomal dominant syndrome caused by mutations in the RET proto-oncogene. It's characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), mucosal neuromas, and Marfanoid habitus. Because of the rarity of MEN-IIb and finiteness of clinical cognition, the majority of the patients suffer a delayed diagnosis. A MEN-IIb patient with the lingual mucosal neuromas since childhood was admitted in the Third Xiangya Hospital of Central South University in November, 2018. He had surgical history of mitral valve prolapse and spinal deformity. He was diagnosed with MTC and PHEO at the age of 22 and 28, respectively, and received surgical treatments. Sequencing of RET gene revealed a de novo heterozygous p.M918T mutation in the patient. Being aware of the unique clinical phenotype and screening of RET gene mutation may lead to the early diagnosis and better long-term outcome for MEN-IIb.

Factors associated with lower-extremity amputation in patients with diabetic foot ulcers in a Chinese tertiary care hospital.

Providing a better understanding of the risk factors for amputation in this particular region, Hunan province, in China might help patients with diabetic foot ulcers receive timely and appropriate medical care and help prevent amputation. Diabetic foot ulcer patients referred to the Third Xiangya Hospital during the period between December 2014 and September 2018 were enrolled. Participants who underwent amputations and received conservative treatments were compared using univariate and multivariate analyses to identify the independent predictors of amputation. Those who required amputation presented significantly higher levels of white blood cell counts, platelet counts, erythrocyte sedimentation rate, C-reactive protein, and glycated haemoglobin (HbA1c) levels. However, levels of haemoglobin, postprandial plasma C-peptide, triglyceride, high-density lipoprotein cholesterol, albumin, and uric acid were decreased in patients with amputations. Patients with more advanced Wagner grades had much higher rates of amputation. Multivariable-adjusted odds ratios in stepwise logistic regression model was 1.317 for HbA1c (95% CI: 1.015-1.709), 0.255 for triglyceride (95% CI: 0.067-0.975), and 20.947 for Wagner grades (95% CI: 4.216-104.080). Independent risk factors for amputation in these Chinese diabetic foot ulcer patients included an elevated HbA1c level, lower triglyceride level, and higher Wagner grades.

[Nivolumab-induced hypothyroidism: A case report].

Nivolumab is an anti-programmed cell death (anti-PD-1) monoclonal antibody, which is a new drug for tumor immunotherapy. A 73-year-old female patient with colorectal cancer 3 years after surgery was treated in the Endocrinology Department of Third Xiangya Hospital, Central South University, who developed severe hypothyroidism resulting from treatment with nivolumab. After 4 months treatment of nivolumab, this patient presented with symptoms such as fatigue, dizziness, jaundice and palpebral edema, with decreased levels of FT3 and FT4 and elevated levels of TSH. Subsequently, nivolumab treatment was terminated. This patient's symptoms were relieved and thyroid function returned to normal after thyroxine replacement therapy. The clinical diagnosis was considered to be nivolumab-induced autoimmune thyroid damage, which was an immune-related adverse reaction in the treatment.

Identification of a novel GNAS mutation in a case of pseudohypoparathyroidism type 1A with normocalcemia.

BACKGROUND: Pseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disease primarily characterized by resistance to parathyroid hormone along with hormonal resistance and other features of Albright hereditary osteodystrophy (AHO). It is caused by heterozygous inactivating mutations in the maternal allele of the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Herein, we report a case of of PHP1A with atypical clinical manifestations (oligomenorrhea, subclinical hypothyroidism, and normocalcemia) and explore the underlying genetic cause in this patient. METHODS: Blood samples were collected from the patient, her family members, and 100 healthy controls. The 13 exons and flanking splice sites of the GNAS gene were amplified by PCR and sequenced. To further assess whether the novel mutation resulted in gain or loss of function of Gsα, we examined the level of cAMP activity associated with this mutation through in vitro functional studies by introducing the target mutation into a human GNAS plasmid. RESULTS: A novel heterozygous c.715A > G (p.N239D) mutation in exon 9 of the GNAS gene was identified in the patient. This mutation was also found in her mother, who was diagnosed with pseudopseudohypoparathyroidism. An in vitro cAMP assay showed a significant decrease in PTH-induced cAMP production in cells transfected with the mutant plasmid, compared to that in the wild-type control cells (P < 0.01), which was consistent with loss of Gsa activity. CONCLUSION: We identified a novel GNAS mutation that altered Gsα function, which furthers our understanding of the pathogenesis of this disease. Screening for GNAS mutations should be considered in suspected cases of PHP1A even if the classical signs are not present.

ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression.

In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction and oxidative stress form a vicious cycle that promotes neurodegeneration and muscle wasting. To quantify the disease-stage-dependent changes of mitochondrial function and their relationship to the generation of reactive oxygen species (ROS), we generated double transgenic mice (G93A/cpYFP) that carry human ALS mutation SOD1G93A and mt-cpYFP transgenes, in which mt-cpYFP detects dynamic changes of ROS-related mitoflash events at individual mitochondria level. Compared with wild type mice, mitoflash activity in the SOD1G93A (G93A) mouse muscle showed an increased flashing frequency prior to the onset of ALS symptom (at the age of 2 months), whereas the onset of ALS symptoms (at the age of 4 months) is associated with drastic changes in the kinetics property of mitoflash signal with prolonged full duration at half maximum (FDHM). Elevated levels of cytosolic ROS in skeletal muscle derived from the SOD1G93A mice were confirmed with fluorescent probes, MitoSOX™ Red and ROS Brite™570. Immunoblotting analysis of subcellular mitochondrial fractionation of G93A muscle revealed an increased expression level of cyclophilin D (CypD), a regulatory component of the mitochondrial permeability transition pore (mPTP), at the age of 4 months but not at the age of 2 months. Transient overexpressing of SOD1G93A in skeletal muscle of wild type mice directly promoted mitochondrial ROS production with an enhanced mitoflash activity in the absence of motor neuron axonal withdrawal. Remarkably, the SOD1G93A-induced mitoflash activity was attenuated by the application of cyclosporine A (CsA), an inhibitor of CypD. Similar to the observation with the SOD1G93A transgenic mice, an increased expression level of CypD was also detected in skeletal muscle following transient overexpression of SOD1G93A. Overall, this study reveals a disease-stage-dependent change in mitochondrial function that is associated with CypD-dependent mPTP opening; and the ALS mutation SOD1G93A directly contributes to mitochondrial dysfunction in the absence of motor neuron axonal withdrawal.

A novel SLC12A3 homozygous c2039delG mutation in Gitelman syndrome with hypocalcemia.

BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disease, caused by mutations in the SLC12A3 gene, which encodes the renal thiazide-sensitive Na/Cl cotransporter (NCCT) in the distal renal tubule. CASE PRESENTATION: A 23-year-old woman was admitted with limb numbness, recurrent tetany and palpitation. Laboratory tests showed hypokalemic alkalosis, hypomagnesemia, hypocalcemia and secondary hyperaldosteronism, as well as hypocalciuria and transient decreased PTH. Next-generation sequencing detected a novel homozygous mutations c.2039delG in the SLC12A3 gene, and her father and children were all heterozygous carriers. CONCLUSION: We reported a case of GS with a novel homozygous frame-shift mutation of SLC12A3, and reviewed recent literatures about diagnosis, differential diagnosis and treatments. Hypocalcemia in Gitelman syndrome is rare, and may be related to inhibited PTH secretion induced by hypomagnesemia.

[A case of growth hormone deficiency combined with neurofibromatosis Type 1 and its gene analysis].

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder caused by NF1 gene mutations. Café au lait spots, neurofibromatosis, Lisch nodules, axillary freckling, dermal neurofibromas and skeletal dysplasia are the most common manifestations for this disease. A 11-year-old boy visited Third Xiangya Hospital, Central South University due to growth-retardation. He was eventually diagnosed as NF1 with growth hormone deficiency. A novel heterozygous splicing mutation c.6579+2 T>C (IVS 34+2 T>C) of NF1 gene was identified in the patient and his mother. Considering NF1 may present with short stature due to growth hormone deficiency, all children with short stature combined with café au lait spots should be screened for NF1, which may assist the clinical diagnosis and the genetic counseling.

[Two cases of primary hypertrophic osteoarthropathy with SLCO2A1 gene mutations].

Two patients with primary hypertrophic osteoarthropathy (PHO) and their available healthy family members were studied. All exons of the SLCO2A1 and HPGD gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. To assess the damaging effects of missense mutations in silico, the online database, PolyPhen-2 and SIFT were used. We identified two homozygous mutations in SLCO2A1 gene: one was c.1106G>A (p.G369D) in exon 9, the other was c.611C>T (p.S204L) in exon 4. No HPGD mutation was found in the affected individuals. The two mutation were predicted in silico by the bioinformatic tools. Our study further supports the role of mutations in the SLCO2A1 gene in the pathogenesis of PHO. Identification of the genotype in PHO may not only help the clinical diagnosis of PHO but also help the interpretation of genetic information for prenatal diagnosis and genetic counseling.

NLRP3 inflammasome activation in mesenchymal stem cells inhibits osteogenic differentiation and enhances adipogenic differentiation.

Osteoporosis is one of the most common skeletal disease featured by osteopenia and adipose accumulation in bone tissue. NLRP3 inflammasome activation is an essential player in aging-related chronic diseases like osteoporosis, particularly due to the causal caspase-1 activation and its correlation to adipose accumulation in bone tissue. Moreover, the expression of anti-aging/senescence SIRT1 was reported to decline along with aging. As the major cellular contributor of bone formation, mesenchymal stem cells (MSCs) are multipotent stem cells processing mutually exclusive differentiatability toward osteocytes or adipocytes. Therefore, we hypothesized that NLRP3 inflammasome activation promotes adipogenesis and repress osteogenesis in MSCs via inhibiting SIRT1 expression. We activated NLRP3 inflammasome in human MSCs via lipopolysaccharide and palmitic acid (LPS/PA) treatment for self-renewal maintenance, adipogenic differentiation or osteogenic differentiation. LPS/PA treatment significantly increased NLRP3 expression, decreased SIRT1 expression and promoted caspase-1 activity in MSCs. LPS/PA treatment also boosted adipogenesis of MSCs and suppressed osteogenesis. Moreover, inhibition of caspase-1 activity repressed adipogenic differentiation and partially improved osteogenic differentiation of MSCs with LPS/PA treatment. Our study demonstrated the pivotal roles of NLRP3 inflammasome and downstream mediator caspase-1 for the progress of osteo-differentiation MSCs, and offered novel therapeutic target of treatment for osteoporosis.

Phosphatase and tensin homologue (PTEN)-induced putative kinase 1 reduces pancreatic ß-cells apoptosis in glucotoxicity through activation of autophagy.

Chronic elevated glucose is harmful to pancreatic ß-cells, resulting in pancreatic ß-cells dysfunction and apoptosis. Understanding the molecular mechanisms associated with ß-cells survival is pivotal for the prevention of ß-cells injury caused by glucotoxicity. The role of Phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) in the fate of pancreatic ß-cells constantly exposed to high glucose was studied. Sustained high glucose increased PINK1 protein expression both in rat pancreatic ß-cells and INS-1 ß-cells, and that this increase can be inhibited by PINK1 knockdown and further enhanced by PINK1 over-expression. PINK1 deficiency aggravated glucotoxicity-induced pancreatic ß-cells apoptosis and inhibition of autophagy whereas PINK1 could reverse these adverse effects. This study provides fundamental data supporting the potential protective role of PINK1 as a new therapeutic target necessary to preserve ß-cells survival under non-physiological hyperglycemia conditions.