Human Diabetes Research Articles

Central Nervous System Tuberculosis: Risk Factors for Mortality in a Propensity Score-Matched Case-Control Study.

Despite advancements in tuberculosis (TB) control and treatment in the United States (US), patients with central nervous system TB (CNS-TB) continue to experience significantly higher mortality rates than those without CNS-TB. This raises concerns regarding clinical management and the need for a deeper understanding of the risk factors contributing to these deaths. This study aimed to determine the predictors of mortality in patients with CNS-TB. We conducted a retrospective 1:2 propensity score-matched case-control study. Cases were TB patients diagnosed with TB of the meninges, brain, spinal cord, or peripheral nerves, as documented in the Florida Department of Health (FDOH) TB registry, between 2009 and 2021. Controls were TB patients without CNS-TB, also reported in the FDOH TB registry during the same timeframe. We employed conditional logistic regression models to investigate the factors contributing to mortality in cases compared with controls. We analyzed data from 116 cases and 232 matched controls. Patients with CNS-TB had a 5.69-fold higher risk of death than those without CNS-TB (adjusted odds ratio [aOR], 5.69 [95% confidence interval {CI}, 2.91-11.6]). Increased risk of death was associated with human immunodeficiency virus (HIV) coinfection (aOR, 1.93 [95% CI, .82-4.37]) and diabetes (aOR, 3.13 [95% CI, 1.28-7.47]). Miliary TB and non-HIV immunosuppression were significantly associated with being a case, while cavitary TB was less likely to be associated with being a case. Clinical management should prioritize screening and close monitoring of patients with HIV coinfection and diabetes to improve patient outcomes.

Abstract 16831: Deficiency of Cholesterol Efflux Pathways in Smooth Muscle Cells Enhances Vasoconstriction but Does Not Affect Atherosclerosis

Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-adrenergic receptors (α-ARs). Plasma membrane cholesterol may affect α 1 -AR signaling, but consequences for SMC-mediated vasoconstriction are unclear. Cholesterol loading promotes SMC to macrophage transition in vitro , which may enhance atherosclerotic plaque vulnerability. However, the role of ATP Binding Cassette A1 and G1 (ABCA1/G1)-cholesterol efflux pathways in SMC-mediated vasoconstriction and atherogenesis remains poorly understood. We generated mice with SMC-specific Abca1/g1 deficiency on the low-density lipoprotein receptor deficient ( Ldlr -/- ) background by crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr -/- mice with Myh11-Cre ERT2 transgenic mice and feeding them tamoxifen-diet. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11-Cre ERT2 Abca1 fl/fl Abcg1 fl/fl Ldlr -/- and Myh11-Cre ERT2 Ldlr -/- mice Western-type diet (WTD) for 16 weeks. Combined SMC-Abca1/g1 deficiency increased vasoconstriction in aortic rings induced by the α 1 -AR agonist phenylephrine, with reversal by methyl-β-cyclodextrin, substantiating its cholesterol-dependency. Unexpectedly, SMC - Abca1/g1 deficiency induced urinary bladder enlargement by >20-fold, resembling bladder outlet obstruction (BOO). This was reversed by the α 1 -AR antagonist tamsulosin, indicating its dependence on SMC constriction. Moreover, SMC - Abca1/g1 deficiency decreased SMC markers and increased macrophage- and fibroblast-markers in the bladder wall, enhancing collagen deposition, consistent with SMC transdifferentiation. However, after 16 weeks WTD, SMC - Abca1/g1 deficiency did not affect atherosclerotic lesion size, fibrous cap thickness, necrotic core, collagen, or macrophage content, suggesting that SMCs in atherosclerotic plaques were not affected. This may be due to low Abca1/g1 expression in intimal SMCs. We uncover a new role of SMC cholesterol efflux pathways in suppressing α 1 -AR mediated vasoconstriction and bladder SMC transdifferentiation, decreasing BOO. Our data may provide a mechanistic link for the association between BOO and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux.

A RETROSPECTIVE REVIEW OF THE BACTERIOLOGY OF HAND SEPSIS AT A TERTIARY HOSPITAL IN GAUTENG

The aim of this investigation is to firstly quantify the burden of disease, and secondly qualify the organisms being cultured during debridement to establish their sensitivities to available antibiotics. This study will also look at the concomitant burden of Human Immunodeficiency Virus (HIV) and Diabetes Mellitus (DM) in cases of hand sepsis, to establish whether these two disease processes require special consideration and treatment tailoring.The method employed to collect the data will be retrospective collection of patient information, using random sampling. Included patients will be adult patients who undergo debridement and have a sample registered on the National Health Laboratory System (NHLS). The daily intake sheet will be used to collect patients details and these details will then be used to collect results of intra-operative specimens using the NHLS. These patient details will also be used to check patients’ HIV results and HBA1c (Glycated Haemoglobin A1c) results.Majority of the specimens revealed Methicillin Sensitive Staphylococcus Aureus (MSSA), with a reassuringly low rate of Methicillin Resistant Staphylococcus Aureus (MRSA) when compared to international data. The yield of patients tested for HIV or DM was lower than expected, despite this being the standard of care.The projected impact of this study will be assessment of the current burden of disease and then clarification of our current management strategy, in order to assess if it would be possible to change to a more cost-effective antibiotic with a narrower spectrum of bacteria coverage. The potential exists to not only implement cost saving measures, but also promote antibiotic stewardship by decreasing the practice of empiric broad-spectrum antibiotic use.

An Experimental Models (In-Vivo and In-Vitro) Used for the Study of Antidiabetic agents

Diabetes is divided into two main types, type 1 (insulin-dependent diabetes Mellitus) and type 2 (non-insulin dependent diabetes). About 90% worldwide diabetics have type 2 diabetes. They are different in vivo and in vitro methods for screening new diabetes drugs. Mainly in life models uses chemicals like streptozotocin, alloxan, etc. to induce diabetes in vitro methods directly demonstrate its effect on cells responsible for induction of diabetes in humans. In vitro techniques provide more accurate information and possible Mechanisms related to diabetes. Now the latest techniques of the day such as the induction of diabetes by viruses that have also been introduced proves to be a good tool in the evaluation of diabetes drugs. This review can prove it be a good tool for researchers who want to investigate the diabetes it provides a comprehensive resource on the diabetes model under one roof.

Blueberry intervention mitigates detrimental microbial metabolite trimethylamine N-oxide by modulating gut microbes.

Gut microbes play a pivotal role in host physiology by producing beneficial or detrimental metabolites. Gut bacteria metabolize dietary choline and L-carnitine to trimethylamine (TMA) which is then converted to trimethylamine-N-oxide (TMAO). An elevated circulating TMAO is associated with diabetes, obesity, cardiovascular disease, and cancer in humans. In the present study, we investigated the effect of dietary blueberries and strawberries at a nutritional dosage on TMA/TMAO production and the possible role of gut microbes. Blueberry cohort mice received a control (C) or freeze-dried blueberry supplemented (CB) diet for 12 weeks and subgroups received an antibiotics cocktail (CA and CBA). Strawberry cohort mice received a control (N) or strawberry-supplemented (NS) diet and subgroups received antibiotics (NA and NSA). Metabolic parameters, choline, TMA, and TMAO were assessed in addition to microbial profiling and characterization of berry powders. Blueberry supplementation (equivalent to 1.5 human servings) reduced circulating TMAO in CB versus C mice (~48%) without changing choline or TMA. This effect was not mediated through alterations in metabolic parameters. Dietary strawberries did not reduce choline, TMA, or TMAO. Depleting gut microbes with antibiotics in these cohorts drastically reduced TMA and TMAO to not-quantified levels. Further, dietary blueberries increased the abundance of bacterial taxa that are negatively associated with circulating TMA/TMAO suggesting the role of gut microbes. Our phenolic profiling indicates that this effect could be due to chlorogenic acid and increased phenolic contents in blueberries. Our study provides evidence for considering dietary blueberries to reduce TMAO and prevent TMAO-induced complications.

Effect of macrophage polarization on parasitic protection against type 1 diabetes mellitus

Type 1 diabetes mellitus is a chronic disease caused by the destruction of pancreatic beta cells. Based on the hygiene hypothesis, a growing body of evidence suggests a negative association between parasitic infections and diabetes in humans and animal models. The mechanism of parasite-mediated prevention of type 1 diabetes mellitus may be related to the adaptive and innate immune systems. Macrophage polarization is a new paradigm for the treatment of type 1 diabetes mellitus, and different host macrophage subsets play various roles during parasite infection. Proinflammatory cytokines are released by M1 macrophages, which are important in the development of type 1 diabetes mellitus. Parasite-activated M2 macrophages prevent the development of type 1 diabetes mellitus and can influence the development of adaptive immune responses through several mechanisms, including Th2 cells and regulatory T cells. Here, we review the role and mechanism of macrophage polarization in parasitic protection against type 1 diabetes mellitus.

Impact of physical fitness and exercise training on subcutaneous adipose tissue beiging markers in humans with and without diabetes and a high-fat diet-fed mouse model.

Exercise training induces white adipose tissue (WAT) beiging and improves glucose homeostasis and mitochondrial function in rodents. This could be relevant for type 2 diabetes in humans, but the effect of physical fitness on beiging of subcutaneous WAT (scWAT) remains unclear. This translational study investigates if beiging of scWAT associates with physical fitness in healthy humans and recent-onset type 2 diabetes and if a voluntary running wheel intervention is sufficient to induce beiging in mice. Gene expression levels of established beiging markers were measured in scWAT biopsies of humans with (n = 28) or without type 2 diabetes (n = 28), stratified by spiroergometry into low (L-FIT; n = 14 each) and high physical fitness (H-FIT; n = 14 each). High-fat diet-fed FVB/N mice underwent voluntary wheel running, treadmill training or no training (n = 8 each group). Following the training intervention, mitochondrial respiration and content of scWAT were assessed by high-resolution respirometry and citrate synthase activity, respectively. Secreted CD137 antigen (Tnfrsf9/Cd137) expression was three-fold higher in glucose-tolerant H-FIT than in L-FIT, but not different between H-FIT and L-FIT with type 2 diabetes. In mice, both training modalities increased Cd137 expression and enhanced mitochondrial content without changing respiration in scWAT. Treadmill but not voluntary wheel running led to improved whole-body insulin sensitivity. Higher physical fitness and different exercise interventions associated with higher gene expression levels of the beiging marker CD137 in healthy humans and mice on a high-fat diet. Humans with recent-onset type 2 diabetes show an impaired adipose tissue-specific response to physical activity.

Diet-induced obesity and diabetes enhance mortality and reduce vaccine efficacy for SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a wide spectrum of diseases in the human population, from asymptomatic infections to death. It is important to study the host differences that may alter the pathogenesis of this virus. One clinical finding in coronavirus disease 2019 (COVID-19) patients is that people with obesity or diabetes are at increased risk of severe illness from SARS-CoV-2 infection. We used a high-fat diet model in mice to study the effects of obesity and type 2 diabetes on SARS-CoV-2 infection as well as how these comorbidities alter the response to vaccination. We find that diabetic/obese mice have increased disease after SARS-CoV-2 infection and they have slower clearance of the virus. We find that the lungs of these mice have increased neutrophils and that removing these neutrophils protects diabetic/obese mice from disease. This demonstrates why these diseases have increased risk of severe disease and suggests specific interventions upon infection.

Increased physical activity is not related to markers of cardiometabolic health in two lemur species.

Insufficient physical activity is a major risk factor for cardiometabolic disease (i.e., unhealthy weight gain, heart disease, and diabetes) in humans and may also negatively affect health of primates in human care. Effects of physical activity on energy expenditure and cardiometabolic health are virtually unstudied in nonhuman primates. We investigated physical activity and metabolic markers in 15 adult ring-tailed lemurs (Lemur catta) and 11 Coquerel's sifakas (Propithecus coquereli) at the Duke Lemur Center during a period of low activity in winter when the animals were housed in buildings (with outdoor access) and a period of high activity when individuals were free-ranging in large, outdoor, forested enclosures. We compared body mass, blood glucose, triglycerides, HDL- and LDL-cholesterol, physical activity via accelerometry, and total energy expenditure (TEE) via the doubly labeled water method (in ring-tailed lemurs only) between both conditions. Both species were more active and had a lower body mass in summer. Ring-tailed lemurs had a higher TEE and lower triglyceride levels in summer, whereas sifaka had higher triglyceride levels in summer. Individuals that increased their activity more, also lost more body mass. Individuals that lost more body mass, also had a positive change in HDL-cholesterol (i.e., higher values in summer). Changes in activity were not associated with changes in markers of metabolic health, body fat percentage and TEE (both unadjusted and adjusted for body composition). Older age was associated with lower activity in both species, and decreased glucose in ring-tailed lemurs, but was otherwise unrelated to metabolic markers and, for ring-tailed lemurs, adjusted TEE. Overall, body mass was lower during summer but the increase in physical activity did not strongly influence metabolic health or TEE in these populations.

Phytochemistry, Biological, and Toxicity Study on Aqueous and Methanol Extracts of Chromolaena odorata.

The medicinal plant Chromolaena odorata is traditionally used by people living in different communities of Nepal and the globe against diabetes, soft tissue wounds, skin infections, diarrhea, malaria, and several other infectious diseases. The present study focuses on the qualitative and quantitative phytochemical analyses and antioxidant, antidiabetic, antibacterial, and toxicity of the plant for assessing its pharmacological potential. The extracts of flowers, leaves, and stems were prepared using methanol and distilled water as the extracting solvents. Total phenolic content (TPC) and total flavonoid content (TFC) were estimated by using the Folin-Ciocalteu phenol reagent method and the aluminum chloride colorimetric method. Antioxidant and antidiabetic activities were assessed using the DPPH assay and α-glucosidase inhibition assay. A brine shrimp assay was performed to study the toxicity, and the antibacterial activity test was performed by the agar well diffusion method. Phytochemical analysis revealed the presence of phenols, flavonoids, quinones, terpenoids, and coumarins as secondary metabolites. The methanol extract of leaves and flowers displayed the highest phenolic and flavonoid content with 182.26 ± 1.99 mg GAE/g, 128.57 ± 7.62 mg QE/g and 172.65 ± 0.48 mg GAE/g, 121.74 ± 7.06 mg QE/g, respectively. The crude extracts showed the highest DPPH free radical scavenging activity with half maximal inhibitory concentration (IC50) of 32.81 ± 5.26 µg/mL and 41.00 ± 1.10 µg/mL, respectively. The methanol extract of the leaves was found to be effective against bacterial strains such as K. pneumoniae (ZOI = 9.67 ± 0.32 mm), B. subtilis (ZOI = 15.00 ± 0 mm), and E. coli (7.3 ± 0.32 mm). The methanol extract of the flowers showed the most α-glucosidase inhibitory activity (IC50 227.63 ± 11.38 µg/mL), followed by the methanol extract of leaves (IC50 249.50 ± 0.97 µg/mL). The aqueous extract of the flowers showed the toxic effect with LC50 107.31 ± 49.04 µg/mL against the brine shrimp nauplii. In conclusion, C. odorata was found to be a rich source of plant secondary metabolites such as phenolics and flavonoids with potential effects against bacterial infection, diabetes, and oxidative stress in humans. The toxicity study showed that the aqueous extract of flowers possesses pharmacological activities. This study supports the traditional use of the plant against infectious diseases and diabetes and provides some scientific validation.

SAT038 Dietary Trans-10,cis-12 Conjugated Linoleic Acid Regulates Glucose Levels In Mice With Severe Insulin Resistance: Potential Effects On The Liver Via HNF4α And FOX01

Abstract Disclosure: S.M. Lee: None. J.T. Muratalla: None. C.W. Liew: None. J. Cordoba-Chacon: None. Plasma trans-10 cis-12-conjugated linoleic acid CLA (t10c12-CLA) is inversely associated with increased risk of diabetes in humans. In mice, it is well-known that t10c12-CLA induces whole-body insulin resistance due to severe lipodystrophy (loss of whole-body adipose tissue). However, t10c12-CLA-fed mice show normal glucose levels and, t10c12-CLA improved glucose clearance in models with preexisting insulin resistance: Zucker fatty/diabetic rats, obese and insulin resistant Ldlr-/- mice, and diet-induced obese and insulin resistant male mice. In this study, we assessed whether supplementation of t10c12-CLA in a low-fat diet reduces glucose levels in adipocyte-specific insulin receptor knockout (IRFKO) mice, which is a mouse model of congenital lipodystrophy. In addition to lipodystrophy, IRFKO mice show liver steatosis and increased blood glucose levels that are consequences of whole-body insulin resistance and increased hepatic gluconeogenesis. Briefly, 5-6-week-old male and female control and IRFKO mice were fed with a low-fat diet supplemented with 0.8% t10c12-CLA for 5 weeks. In IRFKO mice, dietary t10c12-CLA did not reduce adipose tissue mass. However, dietary t10c12-CLA increased liver steatosis and plasma insulin levels. Surprisingly, dietary t10c12-CLA reduced glucose levels in both male and female IRFKO mice. Also, dietary t10c12-CLA reduced food intake and polydipsia, which were increased in IRFKO mice due to lipodystrophy and hyperglycemia, respectively. A transcriptomic analysis (RNA-seq) of livers of control and IRFKO male mice fed with a t10c12-CLA diet showed that t10c12-CLA reduced the expression of the key gluconeogenic and mitochondrial fatty oxidation genes. Previous studies have suggested that t10c12-CLA reduces the expression of Forkhead box 01 (Fox01) and Hepatocyte nuclear factor 4 alpha (HNF4α). Of note, the livers of t10c12-CLA-fed control and IRFKO male mice showed a downregulation of positive targets of FoxO1 and HNF4α. In addition, livers of t10c12-CLA-fed mice showed reduced total FOXO1 protein levels, and increased phosphorylation of FOXO1 in t10c12-CLA-fed IRFKO mice. These findings suggest that t10c12-CLA could be directly acting on the liver to alter HNF4α and FOXO1-dependent regulation of hepatic fatty acid oxidation and glucose production. These actions may explain why t10c12-CLA-fed mice do not show increased glucose levels and is potentially linked to the inverse association between t10c12-CLA levels and diabetes risk. Presentation: Saturday, June 17, 2023

Ngu-Vi-Tieu-Khat decoction, a Vietnamese traditional medicine, possesses hypoglycemic and hypolipidemic effects on streptozotocin-induced type-2 diabetic rat model

This study aims to assess the hypoglycemic effects of Ngu-Vi-Tieu-Khat (NVTK) decoction, a traditional Vietnamese medicine, in a rat model of type-2 diabetes. The NVTK decoction was prepared using the maceration method and tested for its hypoglycemic effects by measuring blood glucose levels, insulin resistance indicators, and pancreatic mass. The results showed that NVTK decoction improved diabetes symptoms, increased insulin levels, reduced insulin resistance, restored pancreatic mass, and decreased total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C). The hypoglycemic effects of NVTK were comparable to those of gliclazide at a dose of 10 mg/kg. In conclusion, NVTK decoction possesses hypoglycemic properties and could be explored as a potential traditional medicine for treating type-2 diabetes in humans.

Effect of SIRT1 gene single-nucleotide polymorphisms on susceptibility to type 1 diabetes in a Han Chinese population

AimsSIRT1 deficiency has been associated with diabetes, and a variant of the SIRT1 gene has been found to be involved in human autoimmune diabetes; however, it is unclear whether this genetic variation exists in Han Chinese with type 1 diabetes (T1D) and whether it contributes to development of T1D. Therefore, we aimed to explore the association of the SIRT1 gene single-nucleotide polymorphisms (SNPs) rs10997866 and rs3818292 in a Han Chinese population with T1D.MethodsThis study recruited 2653 unrelated Han Chinese individuals, of whom 1289 had T1D and 1364 were healthy controls. Allelic and genotypic distributions of SIRT1 polymorphisms (rs10997866 and rs3818292) were determined by MassARRAY. Basic characteristics, genotype and allele frequencies of selected SNPs were compared between the T1D patients and healthy controls. Further genotype–phenotype association analysis of the SNPs was performed on the T1D patients divided into three groups according to genotype. Statistical analyses included the chi-square test, Mann‒Whitney U test, Kruskal‒Wallis H test and logistic regression.ResultsThe allelic (G vs. A) and genotypic (GA vs. AA) distributions of SIRT1 rs10997866 were significantly different in T1D patients and healthy controls (P = 0.039, P = 0.027), and rs10997866 was associated with T1D susceptibility under dominant, overdominant and additive models (P = 0.026, P = 0.030 and P = 0.027, respectively). Moreover, genotype–phenotype association analysis showed the GG genotype of rs10997866 and the GG genotype of rs3818292 to be associated with higher titers of IA-2A (P = 0.013 and P = 0.038, respectively).ConclusionSIRT1 rs10997866 is significantly associated with T1D susceptibility, with the minor allele G conferring a higher risk of T1D. Moreover, SIRT1 gene rs10997866 and rs3818292 correlate with the titer of IA-2A in Han Chinese individuals with T1D.

Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

A narrative review on nutritional and health benefits of underutilized summer crop to address agriculture challenges: Moth bean (Vigna aconitifolia L.)

AbstractA reasonable plant‐based protein supply needs to be found in order to fight protein undernourishment, especially in developing nations. One of the most prominent and underutilized members of the Fabaceae family, moth bean (Vigna aconitifolia L.), has outstanding nutritional and bioactive components. Moth bean is a tropical crop and has ability to grow well at arid and semiarid areas. In addition to vitamins, minerals, lipids, fatty acid, and carbohydrate, moth bean seeds also provide an abundant protein source. Furthermore, the antioxidant and phenolic content of moth bean seeds is also high. If consumed on a regular basis, moth bean legume possesses countless beneficial effect on health and immune system, including the ability to prevent obesity, diabetes, and cardiac diseases in humans. This review focuses on the uses, improved varieties, adaptive constrain, nutritional bioavailability, and health benefits of V. aconitifolia seeds.

A fluorescent sensor based on strand displacement amplification and primer exchange reaction coupling for label-free detection of miRNA

MicroRNAs (miRNAs) are closely associated with human disease occurrence, including cancers, diabetes, inflammation, heart diseases, and viral infections, and their rapid and accurate detection is vital for the diagnosis and treatment of these diseases. Based on one-step reaction of strand displacement amplification (SDA) and primer exchange reaction (PER), a label-free and highly sensitive miRNA-21 detection strategy was developed. In this strategy, the target miRNA-21 binds directly to the hairpin template, triggering the SDA reaction and generating a large number of single strand DNAs as primers for PER amplification. With the help of polymerase, plenty of G-quadruplex fragments of different lengths were accumulated, and the organic dye thioflavin T selectively binds to these G-quadruplex fragments to produce a strong fluorescent signal. There is a wide detection range in this method, miRNA-21 can be detected in the range of 10 fM - 1 nM, the detection limit is low (1.25 fM). This method has good specificity and can effectively distinguish single-base mismatches of miRNA. In addition, the versatility of the method was validated by changing the target recognition site of SDA template.

The role of candidate transport proteins in β-cell long-chain fatty acid uptake: Where are we now?

Type 2 diabetes (T2D) in humans is typically preceded by elevated levels of circulatory long-chain free fatty acids (LC-FFA). These excess LC-FFA are widely thought to be taken up by pancreatic β-cells, contributing to their dysfunction and death during the development of T2D; a process that has been termed lipotoxicity. Depending on their degree of saturation and carbon chain length, LC-FFA can exert different effects on pancreatic β-cells viability and function in vitro. Long-chain saturated fatty acids (LC-SFA) are thought to be toxic, whereas monounsaturated fatty acids are not and may even offer protection against the toxic effects of LC-SFAs. However, the mechanism of LC-FFA uptake into pancreatic β-cells is poorly understood, partly because it has been an understudied area of research. Determining how LC-FFA are taken up into β-cells is crucial for later formulation of therapies to prevent potential cellular overload of LC-FFA, thereby slowing the onset of T2D. In this work, we detail more than 40 years of literature investigating the role of membrane-associated transport proteins in LC-FFA uptake. By focussing on what is known in other cell types, we highlight where we can extrapolate our current understanding of protein-mediated transport to β-cells and uncover where further understanding is required.

Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies.

Cellular senescence is a response to a wide variety of stressors, including DNA damage, oncogene activation and physiologic aging, and pathologically accelerated senescence contributes to human disease, including diabetes mellitus. Indeed, recent work in this field has demonstrated a role for pancreatic β-cell senescence in the pathogenesis of Type 1 Diabetes, Type 2 Diabetes and monogenic diabetes. Small molecule or genetic targeting of senescent β-cells has shown promise as a novel therapeutic approach for preventing and treating diabetes. Despite these advances, major questions remain around the molecular mechanisms driving senescence in the β-cell, identification of molecular markers that distinguish senescent from non-senescent β-cell subpopulations, and translation of proof-of-concept therapies into novel treatments for diabetes in humans. Here, we summarize the current state of the field of β-cell senescence, highlighting insights from mouse models as well as studies on human islets and β-cells. We identify markers that have been used to detect β-cell senescence to unify future research efforts in this field. We discuss emerging concepts of the natural history of senescence in β-cells, heterogeneity of senescent β-cells subpopulations, role of sex differences in senescent responses, and the consequences of senescence on integrated islet function and microenvironment. As a young and developing field, there remain many open research questions which need to be addressed to move senescence-targeted approaches towards clinical investigation.

Susceptibility to Low Vitamin B6 Diet-induced Gestational Diabetes Is Modulated by Strain Differences in Mice.

Gestational diabetes is a common pregnancy complication that adversely influences the health and survival of mother and child. Pancreatic islet serotonin signaling plays an important role in β-cell proliferation in pregnancy, and environmental and genetic factors that disrupt serotonin signaling are associated with gestational diabetes in mice. Our previous studies show that pregnant C57BL/6J mice fed a diet that is low in vitamin B6, a critical co-factor in serotonin synthesis, develop hyperglycemia and glucose intolerance, phenotypes that are consistent with gestational diabetes in humans. The current study shows that, unlike in the C57BL/6J mice, low vitamin B6 diet does not alter glucose tolerance and insulin secretion in pregnant DBA/2J mice. The hypothesis to be tested in the current study is that pregnant DBA/2J mice are protected against low vitamin B6-induced gestational diabetes due to their higher expression and enzymatic activities of tissue nonspecific alkaline phosphatase (ALPL) relative to C57BL/6J. ALPL is a rate-limiting enzyme that regulates vitamin B6 bioavailability. Interestingly, treating pregnant DBA/2J mice with 7.5 mg/kg/day of the ALPL inhibitor SBI-425 is associated with glucose intolerance in low vitamin B6-fed mice, implying that inhibition of ALPL activity is sufficient to modulate resilience to low vitamin B6-induced metabolic impairment.

Sex-specific transgenerational effects of preconception exposure to arsenite: metabolic phenotypes of C57BL/6 offspring.

Chronic exposure to inorganic arsenic (iAs) has been linked to diabetes in both humans and mice, but the role of iAs exposure prior to conception and its transgenerational effects are understudied. The present study investigated transgenerational effects of preconception iAs exposure in C57BL/6J mice, focusing on metabolic phenotypes of G1 and G2 offspring. Body composition and diabetes indicators, including fasting blood glucose, fasting plasma insulin, glucose tolerance, and indicators of insulin resistance and beta cell function, were examined in both generations. The results suggest that the preconception iAs exposure in the parental (G0) generation induced diabetic phenotypes in G1 and G2 offspring in a sex-dependent manner. G1 females from iAs-exposed parents developed insulin resistance while no significant effects were found in G1 males. In the G2 generation, insulin resistance was observed only in males from iAs-exposed grandparents and was associated with higher bodyweights and adiposity. Similar trends were observed in G2 females from iAs-exposed grandparents, but these did not reach statistical significance. Thus, preconception iAs exposure altered metabolic phenotype across two generations of mouse offspring. Future research will investigate the molecular mechanisms underlying these transgenerational effects, including epigenomic and transcriptomic profiles of germ cells and tissues from G0, G1 and G2 generations.