Metformin is the first-line drug to treat type 2 diabetes mellitus. Its mechanism of action is still debatable, and recent studies report that metformin attenuates oxidative stress. This study evaluated the in vitro antioxidant effects of a broad range of metformin concentrations on insulin-producing cells. The cell cycle, metabolism, glucose-stimulated insulin secretion, and cell death were evaluated to determine the biguanide effects on beta-cell function and survival. Antioxidant potential was based on reactive oxygen species (ROS), reduced glutathione (GSH), oxidative stress biomarker levels, and antioxidant enzyme and transcriptional factor Nrf2 activities. The results demonstrate that metformin disrupted GSIS in a concentration-dependent manner, lowered insulin content, and attenuated beta-cell metabolism. At high concentrations, metformin induced cell death and cell cycle arrest as well as increased ROS generation, consequently reducing GSH content. Although carbonylated protein content was elevated, indicating oxidative stress, the antioxidant enzyme and Nrf2 activities were not altered. In conclusion, our results show that metformin disrupts pancreatic beta-cell functionality but does not exert a putative antioxidant effect. It is important to note that the drug could potentially affect beta-cells, especially at high circulating levels.

Keywords: ROS; beta-cells; insulin secretion; metformin; oxidative stress.

Aims: The CRASH study examined severe hypoglycemia (SH) experiences among people with diabetes (PWD) and caregivers across eight countries. Here we report findings from the Japan cohort, with references to data from the United Kingdom (UK) cohort.

Materials and methods: Adults with type 1 (T1DM) or insulin-treated type 2 diabetes mellitus (T2DM) and caregivers (not necessarily related) were recruited from online patient panels. Participants who had experienced at least one SH event in the past 3 years were eligible for study inclusion. Participants completed an online survey regarding their experience with SH, its treatment, and actions during and after an event.

Results: Of the 9367 PWD and caregivers from the online patient panels, 8475 participants were ineligible and a total of 53 Japanese participants (35 T1DM, 9 T2DM, 9 caregivers) completed the survey. Most SH incidents occurred at home and were unattended by a healthcare provider. For T1DM, 29% of Japan PWD and 13% of the UK PWD called an ambulance during an SH event; of these, 90% (Japan) and 50% (UK) were transported to hospital. Glucagon use was low (3% Japan and 10% UK for T1DM). Japanese respondents reported emotional impacts of SH, including feeling scared (86% T1DM, 56% T2DM), unprepared (63% T1DM, 78% T2DM), and helpless (60% T1DM, 33% T2DM). Despite the emotional burden, most PWD did not immediately discuss their SH event with a healthcare provider, with the majority (75% T1DM, 71% T2DM) waiting until their next doctor's appointment.

Conclusion: Conversations around SH between healthcare providers and PWD appear to be insufficient in Japan. An emotional burden of SH was reported by PWD and caregivers. Education regarding the prevention of SH and available treatment options may reduce SH events and improve treatment preparation, while alleviating PWD concerns.

Keywords: Caregivers; Diabetes; Emotional burden; Glucagon; Japan; Severe hypoglycemia.

Type 2 diabetes mellitus (T2DM)-associated mitochondrial impairment may a key factor leading to liver injury. Transient receptor potential receptor vanilloid 1 (TRPV1) regulates the energy expenditure and cholesterol metabolism in hepatocytes and protects against oxidative toxicity. Optic atrophy 1 (OPA1) is involved in the protection of TRPV1 on cardiac microvascular and lung injury. The aim of this study is to identify the role of TRPV1 in redox signals and liver protection via OPA1. TRPV1 knockout (TRPV1^-/-) mice were used. And T2DM associated liver injury was induced by high glucose and high fatty acid (HG/HF) treatment. Mechanisms were studied by TUNEL staining, transmission electron microscope (TEM) analysis, reverse transcription polymerase chain reaction (RT-PCR) and Western blotting in vivo and in vitro. We determined that HG/HF treatment increased TRPV1 expression in liver tissues and AML12 cells. The knockout of TRPV1 increased the apoptotic hepatocytes rate. The inhibition of TRPV1 by 5'-iRTX in HG/HF group elevated the reactive oxygen species (ROS) levels, whereas TRPV1 agonist capsaicin reduced ROS. Our studies also showed that the OPA1 expression was lower in livers from HG/HF treated mice than the control, and genetic ablation of TRPV1 decreased OPA1 expression to a greater extent than the HG/HF mice. The protective effects of TRPV1 on mitochondrial were blocked by OPA1 siRNA. In conclusion, our study showed that the identified regulation of TRPV1 to OPA1 has important implication to the pathogenesis of T2DM-associated liver injury. Targeting the action of TRPV1 and OPA1 presents a potential therapeutic intervention.

Keywords: OPA1; TRPV1; mitochondria; type 2 diabetes mellitus.

Pluripotent pancreatic stellate cells (PSCs) receive growing interest in past decades. Two types of PSCs are recognized -vitamin A accumulating quiescent PSCs and activated PSCs- the main producents of extracellular matrix in pancreatic tissue. PSCs plays important role in pathogenesis of pancreatic fibrosis in pancreatic cancer and chronic pancreatitis. PSCs are intensively studied as potential therapeutical target because of their important role in developing desmoplastic stroma in pancreatic cancer. There also exists evidence that PSC are involved in other pathologies like type-2 diabetes mellitus. This article brings brief characteristics of PSCs and recent advances in research of these cells.

Objective: Osteoporosis (OP) is a worldwide ailment; we aim to establish new biomarkers in diagnosis by determining the levels of serum osteocalcin and osteopontin along with bone mineral density (BMD) and lumbar T-score, in postmenopausal women with type 2 diabetes mellitus (T2DM) with or without OP.

Methods: This observational study included 160 postmenopausal women who were an attendee at outpatient clinics in Al-Hussein Hospital, Thi-Qar province; subdivided into 3 groups based on their T-score testing: Group I (n = 40) comprised postmenopausal women without T2DM as controls, Group II (n = 60) comprised postmenopausal women with T2DM but without OP, and Group III (n = 60) comprised postmenopausal women with T2DM with OP. The dual-energy X-ray absorptiometry was used to measure the BMD (total body, lumbar spine, and femoral) and T-score for lumbar spine and femoral. Glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), osteocalcin, and osteopontin levels were assessed in all three groups.

Results: Compared with controls, Group III demonstrated significantly lower BMD (total body, lumbar spine, and femoral), T-score for lumbar spine and femoral, serum osteocalcin, and osteopontin levels than Group II and Group I (P < 0.001). FBG and HbA1c levels were significantly higher in Group III than in Groups I and II (P < 0.001). A negative correlation was proved between HbA1c levels with BMD, osteocalcin levels, and osteopontin levels in the three groups.

Conclusions: Iraqi postmenopausal women with T2DM had a significantly lower bone mineral density, serum osteocalcin, and osteopontin levels. These results may serve as adjuvants in screening for OP, particularly among diabetic patients.

Obesity is a known risk factor for type 2 diabetes mellitus (T2DM); however, the associations between underweight and T2DM and between weight status and prediabetes have not been systematically reviewed. We aimed to estimate the relative risks (RRs) of prediabetes/T2DM in underweight/overweight/obesity relative to normal weight. PubMed, Embase, Web of Science, and Cochrane Library were searched from inception to December 8, 2021. Prospective cohort studies with a minimum 12-month follow-up period reporting the association between baseline body mass index (BMI) categories and risk of prediabetes/T2DM in adults were included. Study quality was assessed using the Newcastle-Ottawa Scale. The main analyses of T2DM risk were performed using the ethnic-specific (Asian/non-Asian) BMI classification and additional analyses of prediabetes/T2DM risk by including all eligible studies. Random-effects models with inverse variance weighting were used. Subgroup analyses and meta-regression were conducted to explore the potential effects of pre-specified modifiers. The study protocol was registered with PROSPERO (CRD42020215957). Eighty-four articles involving over 2.69 million participants from 20 countries were included. The pooled RR of prediabetes risk was 1.24 (95% CI: 1.19-1.28, I² = 9.7%, n = 5 studies) for overweight/obesity vs. normal weight. The pooled RRs of T2DM based on the ethnic-specific BMI categories were 0.93 (95% CI: 0.75-1.15, I² = 55.5%, n = 12) for underweight, 2.24 (95% CI: 1.95-2.56, I² = 92.0%, n = 47) for overweight, 4.56 (95% CI: 3.69-5.64, I² = 96%, n = 43) for obesity, and 22.97 (95% CI: 13.58-38.86, I² = 92.1%, n = 6) for severe obesity vs. normal weight. Subgroup analyses indicated that underweight is a protective factor against T2DM in non-Asians (RR = 0.68, 95% CI: 0.40-0.99, I² = 56.1%, n = 6). The magnitude of the RR of T2DM in overweight/obesity decreased with age and varied by region and the assessment methods for weight and T2DM. Overweight/obesity was associated with an increased prediabetes/T2DM risk. Further studies are required to confirm the association between underweight and prediabetes/T2DM, particularly in Asian populations.

Purpose of review: The purpose of this review is to highlight the evidence behind landmark trials involving these two novel drug classes in conjunction with a review of long-standing therapies used to improve cardiovascular (CV) outcomes among patients with peripheral artery disease (PAD) patients and type 2 diabetes mellitus (T2DM).

Recent findings: Recently, societal guideline recommendations have expanded the management of T2DM to incorporate therapies with CV risk factor modification. This is due to CV outcome trials (CVOT) uncovering advantageous cardioprotective effects of several novel therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Providers who manage high-risk patients with T2DM, such as those with concomitant PAD, are expected to incorporate these novel medical therapies into routine patient care. The body of evidence surrounding GLP-1 RA demonstrates a strong benefit in mitigating the innate heightened CV risk among patients with T2DM. Furthermore, SGLT2i not only have a favorable CV profile but also reduce the risk of HF hospitalizations and progression of renal disease. Patients with T2DM and PAD are known to be at a heightened risk for major adverse cardiac and lower extremity events, heart failure, and chronic kidney disease. As such, the use of novel therapies such as GLP-RA and SGLT2i should be strongly considered to minimize morbidity and mortality in this vulnerable population.

Keywords: Diabetes mellitus; GLP-1 RA; Medical therapy; Peripheral artery disease; SGLT2i.

Objectives: This study investigated the effect of the number of metabolic syndrome (MetS) components on all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with MetS.

Methods: The medical records of 93 AAV patients with MetS were retrospectively reviewed. MetS was diagnosed when three or more the following MetS components for Asians were met: (i) increased waist circumference; ii) high blood pressure; (iii) hypertriglyceridaemia; (iv) low level of high-density lipoprotein (HDL)-cholesterol; and (v) impaired fasting glucose (IFG) or type 2 diabetes mellitus (T2DM). All-cause mortality was defined as death owing to any aetiology.

Results: The median age was 61.4 years and 33 patients were men. Among 93 AAV patients with MetS, as the number of MetS components increased, the cumulative patient survival rate significantly decreased (p = 0.024). Compared to surviving AAV patients with MetS, deceased AAV patients with MetS were older, had higher Birmingham vasculitis activity score (BVAS) and Five-factor score (FFS), a lower frequency of IFG or T2DM, and a higher number of MetS components. In the multivariable Cox analysis, AAV patients with MetS who had all five MetS components were approximately 62 times more susceptible to all-cause mortality than those who had only three components. In terms of IFG or T2DM, patients with only IFG exhibited a significantly lower cumulative patients' survival rate than those without.

Conclusions: The presence of many MetS components at the initial diagnosis of AAV was an independent and significant predictor of all-cause mortality in AAV patients with MetS.

Though the relationship between dietary fiber and physical health has been investigated widely, the use of dietary fiber from marine plants has been investigated relatively rarely. The Saccharina japonica byproducts after the production of algin contain a large amount of insoluble polysaccharide, which will cause a waste of resources if ignored. Soluble dietary fiber (SDF)prepared from waste byproducts of Saccharina japonica by alkaline hydrolysis method for the first time had a wrinkled microscopic surface and low crystallinity, which not only significantly reduced liver index, serum levels of aspartate aminotransferase (AST) and alanine amiotransferase (ALT), and liver fat accumulation damage to the livers of obese diabetic mice, but also activated the PI3K/AKT signaling pathway to increase liver glycogen synthesis and glycolysis. By LC-MS/MS employing a Nexera UPLC tandem QE high-resolution mass spectrometer, the 6 potential biomarker metabolites were screened, namely glycerophosphocholine (GPC), phosphocholine (PCho), pantothenic acid, glutathione (GSH), oxidized glutathione (GSSG), and betaine; several pathways of these metabolites were associated with lipid metabolism, glycogen metabolism, and amino acid metabolism in the liver were observed. This study further provided a detailed insight into the mechanisms of SDF from Saccharina japonica byproducts in regulating the livers of obese mice with type 2 diabetes and laid a reliable foundation for the further development and utilization of Saccharina japonica.

Keywords: PI3K/AKT; Saccharina japonica; dietary fiber; liver metabolomics.

Background: It is important to assess the cultural beliefs and practices of diabetic patients since such beliefs and practices greatly influence how patients self-manage the disease. However, how cultural beliefs and practices affect self-management in Javanese diabetic patients in Indonesia is still unclear since research about it is very limited. Therefore, the purpose of this study was to explore the cultural beliefs and practices of diabetes self-management in Javanese diabetic patients.

Methods: An ethnographic study was conducted between July 2020 and March 2021 in Banyumas Regency, Indonesia. Forty-seven participants were included, consisting of 36 type 2 diabetes mellitus (T2DM) patients as key informants and 11 family members and health providers as general informants. Purposive and snowball sampling methods were used, and data was collected through in-depth interviews, observations, and the writing of field notes. The data were analyzed by thematic analyses using NVivo 12 software.

Results: Four themes emerged from the data analysis: (1) misconception about diabetes and management, such as the belief of there being dry sugar and wet sugar types of diabetes; the belief that consuming a lot of cold rice does not increase blood glucose; the belief that insulin causes organ damage; the belief that diabetes can be completely cured; and the belief that walking barefoot is good for the body; (2) cultural beliefs and practices regarding treatment regimen, such as use of medicinal plants to lower blood glucose and home remedies to treat foot ulcers; (3) coping influenced by a blend of culture and religion, such as managing stress by submitting to God and being patients in dealing with their disease; (4) cultural influence on diet management, such as facing difficulties managing their diets at cultural events and difficulties managing the habit of eating sweet-tasting food.

Conclusion: This is the first study to show that Javanese culture strongly influences how diabetic patients in Java self-manage their disease. Various aspects of Javanese culture were found to have either beneficial or detrimental effects on diabetic patients' health status. This study provides new insights for nurses in Indonesia and will help them design a culturally sensitive education program for their diabetic patients.

Keywords: Diabetes mellitus; Indonesia; Javanese culture; Qualitative research; Self-management.