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Hyperglycemia is a symptom of type 2 diabetes mellitus, a chronic metabolic disease characterized by elevated blood glucose concentrations. Antidiabetic drugs are common treatments for this metabolic disorder; however, they may have unpleasant side effects. This study hypothesized that probiotic fermented products could preserve nutritional value, maintain metabolic homeostasis, and attenuate the inflammatory response associated with diabetes while reducing side effects. Lactobacillus plantarum KU985438 and Lactobacillus rhamnosus KU985439 showed the lowest alfa-amylase enzyme (α-amylase) activity among 8 lactobacilli tested. These 2 strains were used to develop functional fermented milk products, and their antidiabetic efficacy was tested in induced diabetic Wistar rats. The treatment of diabetic rats with L. plantarum KU985438 or L. rhamnosus KU985439 fermented yogurt resulted in a considerable reduction in blood glucose concentrations (136.79% and 145.17%, respectively) and α-amylase concentrations (56.84% and 56.84%, respectively) compared with conventional treatments. Diabetes relief began after 4 days of yogurt consumption compared with drug-based treatment. Significant improvements in both liver and kidney enzyme concentrations were also observed, in addition to a significant increase in high-density lipoprotein cholesterol concentrations and improved lipid profiles. Inhibition in nuclear factor κB and an increase in Bcl-2 concentrations were also detected. Histopathological examination of both hepatic and pancreatic cells revealed the positive effects of the studied treatment compared with standard treatment. Therefore, the selected Lactobacilli, which has hypoglycemic potential, could be used to produce functional nutraceutical antidiabetic supplements.

The BETTER (BEhaviors, Therapies, TEchnologies and hypoglycemic Risk in Type 1 diabetes) registry is a type 1 diabetes population surveillance system codeveloped with patient partners to address the burden of hypoglycemia and assess the impact of new therapies and technologies. The aim of this report was to describe the baseline characteristics of the BETTER registry cohort.A cross-sectional baseline evaluation was performed of a Canadian clinical cohort established after distribution of an online questionnaire. Participants were recruited through clinics, public foundations, advertising and social media. As of February 2021, 1,430 persons ≥14 years of age and living with type 1 diabetes or latent-autoimmune diabetes (LADA) were enrolled. The trial was registered on ClinicalTrials.gov (NCT03720197).Participants were (mean ± standard deviation) 41.2±15.7 years old with a diabetes duration of 22.0±14.7 years, 62.0% female, 92.1% Caucasian and 7.8% self-reporting as LADA, with 40.9% using a continuous subcutaneous insulin infusion (CSII) system and 78.0% using a continuous glucose monitoring (CGM) system. The most recent glycated hemoglobin ≤7% was reported by 29.7% of participants. At least 1 episode of hypoglycemia3.0 mmol/L (level 2-H) in the last month was reported by 78.4% of participants, with a median (interquartile range) of 5 (3, 10) episodes. The occurrence of severe hypoglycemia (level 3-H) in the last 12 months was reported by 13.3% of participants. Among these, the median number of episodes was 2 (1, 3).We have established the first surveillance registry for people living with type 1 diabetes in Canada relying on patient-reported outcomes and experiences. Hypoglycemia is a highly prevalent burden despite a relatively wide adoption of CSII and CGM use.

To determine the degree and factors related to non-insulin antidiabetic drug (NIAD) adherence in people with type 2 diabetes mellitus (DM2) treated in primary carecentres in Spain.We did a cross-sectional study. During the study visit, variables related todifferent clinical characteristics, Adherence to Refills and Medications Scale Spanishversion (ARMS-e) and usage of NIAD were collected. We estimated the adherence toNIADs using the proportion of days covered (PDC) equation.In total, 515 participants were included in the study. The mean PDC ratio was70.6 ( ± 28.9), and 50.5% (260) were classified as good adherent (PDC ≥80). Good adherence was highest among users of metformin (67.3%) and lowest among the participants using thiazolidinedione (0.8%). The score for ARMS-e was higher in the poor adherence group. In the multivariable analysis, HbA1c and the use of GLP1-RA or SGLT-2i were negatively associated with good adherence (odds ratio [OR]: 0.67, 95% confidence interval [CI]: 0.54, 0.82, OR: 0.20, 95%CI: 0.08, 0.46; OR: 0.56, 95%CI: 0.35, 0.89, respectively).Adherence to NIADs observed in our study is far from optimal. HbA1c and ARMS-e items could be used as adherence indicators to encourage treatment changes to improve T2DM control.

Aims: To analyse if antidiabetic treatment was associated with better COVID-19 outcomes in type 2 diabetic patients, measured by hospital admission and mortality rates as severe outcomes. Methods: Cohort study including COVID-19 patients registered in the Primary Care electronic records, in March-June 2020, comparing exposed to metformin in monotherapy with exposed to any other antidiabetic. Data source: SIDIAP (Information System for Research in Primary Care), which captures clinical information of 5,8 million people from Catalonia, Spain. Results: We included 31,006 diabetic patients infected with COVID-19, 43.7% previously exposed to metformin, 45.5% of them in monotherapy. 16.4% were admitted to hospital and 15.1% died. Users of insulin in monotherapy (OR 1.29, 95% CI 1.11-1.50), combined with metformin (OR 1.38, 1.13-1.69) or IDPP4 alone (OR 1.29, 1.03-1.63) had higher risk of severe outcomes than those in metformin monotherapy. Users of any insulin (OR 1.61, 1.32-1.97) or combined with metformin (OR 1.69, 1.30-2.20) had a higher risk of mortality. Conclusions: Patients receiving metformin monotherapy in our study showed a lower risk of hospitalization and death in comparison to those treated with other frequent antidiabetic agents. We cannot distinguish if better outcomes are related with the antidiabetic therapy or with other factors, such as metabolic control or interventions applied during the hospital admission.

The life history theory assumes that all organisms are under selective pressure to harvest external resources and allocate them to maximise fitness: only organisms making the best use of energy obtain the greatest fitness benefits. The trade-off of energy spans four functions: maintenance, growth, reproduction, and defence against pathogens. The innovative antihyperglycaemic agents glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease bodyweight and have the potential to counter low-grade inflammation. These key activities could rewire two components of the life history theory operative in adulthood-ie, maintenance and defence. In this Personal View, we postulate that the benefits of these medications on the cardiovascular system, beyond their glucose-lowering effects, could be mediated by the reduction of the maintenance cost driven by obesity and efforts spent on blunting low-grade inflammation.

Emerging evidence showed metformin may have pleiotropic effects on ameliorating depression. However, whether metformin was associated with decreased risk of depression remains unclear.A historical cohort study was conducted based on a medical claim database from 2010 to 2017 in Beijing, China. Patients newly diagnosed with T2D were classified into the metformin and non-metformin groups according to their initial antidiabetic prescription. The incidences of depression between the groups were compared using Cox proportional regression model.There were 193,624 (37.4 %) and 323,930 (62.6 %) T2D patients in the metformin and non-metformin groups. The mean age was 54.9 (SD: 13.1) years and 53.9% were females. With a median follow-up of 3.2 years, 64,963 patients developed depression. The adjusted incidence of depression in the metformin group (30.6, 95 % CI: 30.1, 31.0 per 1000 person-years) was significantly lower than in the non-metformin group (39.6, 95 % CI: 39.3, 40.0 per 1000 person-years, P 0.001). The metformin group was significantly associated with a lower risk of depression compared with the overall non-metformin group (HR: 0.77, 95% CI: 0.75, 0.78), as well as compared with α-glucosidase inhibitors (HR: 0.73, 95 % CI: 0.71, 0.74), sulfonylureas (HR: 0.84, 95 % CI: 0.82, 0.86), and glinides (HR: 0.85, 95 % CI: 0.82, 0.88), except for thiazolidinediones (HR: 0.96, 95 % CI: 0.91, 1.01). The association between metformin and lower depression risk was significant in all the age and sex subgroups.Metformin was associated with a lower risk of depression compared with other oral hypoglycemic agents, indicating a potential pleiotropic effect on depression.

Current treatment guidelines do not provide recommendations to support the selection of treatment for most people with type 2 diabetes. We aimed to develop and validate an algorithm to allow selection of optimal treatment based on glycaemic response, weight change, and tolerability outcomes when choosing between SGLT2 inhibitor or DPP-4 inhibitor therapies.In this retrospective cohort study, we identified patients initiating SGLT2 and DPP-4 inhibitor therapies after Jan 1, 2013, from the UK Clinical Practice Research Datalink (CPRD). We excluded those who received SGLT2 or DPP-4 inhibitors as first-line treatment or insulin at the same time, had estimated glomerular filtration rate (eGFR) of less than 45 mL/min per 1·73 mAmong 10 253 patients initiating SGLT2 inhibitors and 16 624 patients initiating DPP-4 inhibitors in CPRD, baseline HbAA validated treatment selection algorithm for SGLT2 inhibitor and DPP-4 inhibitor therapies can support decisions on optimal treatment for people with type 2 diabetes.BHF-Turing Cardiovascular Data Science Award and the UK Medical Research Council.

Primary care plays an integral role in the management of type 2 diabetes (T2D). We investigated in a large group of individuals in this setting the biochemical profiles, pharmacological management and clinical outcomes as well as their changes over time.This is a register-based study including relevant laboratory test results requested between 2000 and 2015 by general practitioners in the greater Copenhagen area. We identified 72,044 individuals with T2D on whom data concerning prescription medicine and clinical outcomes were obtained from national registries.The number of individuals with T2D greatly increased from 2001 to 2015. Hemoglobin AThe number of individuals with T2D in primary care increased dramatically whereas pharmacological management, control of risk factors and clinical outcomes seem to have improved. Nevertheless, a conspicuous minority did not receive diabetes-related medication.

Nocturnal blood glucose regulation was one of the key challenges in diabetic treatments. However, development of the smart insulin complexes with mild and glucose-responsive delivering performances was mostly relied on experience of the senior researchers and numerous confirmation experiments. In this work, a series of bioinspired fatty-acid-modified glucose-responsive insulin-delivering polymeric nanoparticles were designed. The molecular docking technique was utilized to efficiently screen the fatty-acid-derived functional groups. The results provided the basis for polymer functionalization and simplified the optimization experiments. For the optimized formulation (C10MS), insulin-loaded C10MS successfully fulfilled the nocturnal-glycemic-controlling requirement of the diabetic rats with lower occurrence of hypoglycemia than the conventional insulin injection schemes. Such formulation also possessed good biocompatibility with the moderate elimination kinetics in vivo, which matched the demand of bio-safety in the daily treatments. Overall, this work opened up a new path for efficient design of functional polymeric materials.

This study intended to explore the hypoglycemic and cardioprotective effects of 8-week aerobic interval training combined with liraglutide and elucidate the underlying mechanisms.Male Wistar rats were randomly divided into 5 groups - normal control group (CON), diabetic cardiomyopathy group (DCM), high-dose liraglutide group (DH), low-dose liraglutide group (DL), and aerobic interval training combined with liraglutide group (DLE). High-fat diet and streptozotocin (STZ) were used to induce the DCM model, and both the liraglutide administration group and combination therapy group allocated to 8 weeks of either liraglutide or liraglutide and exercise intervention. Cardiac functions were analyzed by electrocardiography. Blood biochemical parameters were measured to judge glycemic control conditions. Hematoxylin and eosin (HE) staining and Sirus red staining was used to identify cardiac morphology and collagen accumulation, respectively. Advanced glycation end products (AGEs) were determined by enzymatic methods. The mRNA expression of myocardial remodeling genes (BNP, GSK3β, α-MHC, β-MHC and PPARα) and the protein expression of GLP-1, GLP-1R were analyzed.DCM rats developed hyperglycemia, impaired cardiac function with accumulation of AGEs and collagen (P 0.05). The development of hyperglycemia and cardiac dysfunction was significantly attenuated with all interventions, as reduced cardiac fibrosis and improved cardiac function (P 0.05). Cardiac remodeling genes were normalized after all interventions, these positive modifications were due to increased GLP-1 and GLP-1R expression in DCM heart (P 0.05). Liraglutide combined with AIT significantly increased the diameters of cardiomyocytes, increased the α-MHC expressionx, reduced PPARαexpression and reduced the fluctuation of blood glucose level, which showed the safety and effective of medicine combined with exercise.Liraglutide combined with AIT intervention normalized blood glucose alleviates myocardial fibrosis and improves cardiac contractile function in DCM rats, supporting the efficacy and safety of the combination therapy.

Potentially inappropriate prescribing (PIP) in elderly patients is highly prevalent and is associated with an increased risk of adverse drug events, morbidity, and mortality. Accordingly, this study aimed to evaluate the PIP encountered in a geriatric setting and to highlight the role of the clinical pharmacists in this context.A retrospective observational study was conducted during March and April 2018 in an elderly daycare in Beirut area. Patients' files were screened to evaluate each patient's clinical status using a developed tool that included the Medication Appropriateness Index. Statistical analysis was performed using SPSS (version 20). The results were considered significant at P0.05.The results showed a high incidence of hypertension, schizophrenia, and diabetes among the studied sample with percentages of 41.7%, 35.3%, and 26.6%, respectively. As for the PIP, drug therapy duration and cost were the most encountered problems followed by medication indication, dosage, and drug-drug interaction. Moreover, PIP increased with the number of prescribed medications (P0.05). Proton pump inhibitors, low dose aspirin, and antidiabetic medications' users had a significantly higher Medication Appropriateness Index score as compared to non-users.As a conclusion, suboptimal care is proved in this study empowering the collaboration between clinical pharmacists and physicians in minimizing the PIPs in elderly daycares.

Although a large number of drugs are available for the treatment of type 2 diabetes mellitus (T2DM), many patients do not achieve adequate disease control despite adhering to medication. Recent findings indicate that the pharmacological modulation of the stress-induced cytokine growth differentiation factor 15 (GDF15) shows promise for the treatment of T2DM. GDF15 suppresses appetite and reduces inflammation, increases thermogenesis and lipid catabolism, sustains AMP-activated protein kinase (AMPK) activity, and ameliorates insulin resistance and hepatic steatosis. In addition, circulating GDF15 levels are elevated in response to several antidiabetic drugs, including metformin, with GDF15 mediating some of their effects. Here, we review the mechanistic insights into the beneficial effects of recently explored therapeutic approaches that target GDF15 for the treatment of T2DM.

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.

Glucagon-like peptide-1 (GLP-1) receptor agonists mimic the action of the endogenous GLP-1 incretin hormone, improving glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. However, as cardiovascular (CV) morbidity and mortality is common in patients with T2DM, several trials with the use of GLP-1 receptor agonists (RAs) have been performed focusing on endpoints related to cardiovascular disease rather than metabolic control of T2DM. Following the positive cardiovascular effects of liraglutide, dulaglutide and semaglutide observed in these trials, major changes in T2DM management guidelines have occurred. This document from a Eastern and Southern European Diabetes Expert Group discusses the results of GLP-1 RA CV outcomes trials, their impact on recent clinical guidelines for the management of T2DM, and some selected combination regimens utilising GLP-1 RAs. We also propose an algorithm for guiding GLP-1 RA-based treatment according to patients' characteristics, which can be easily applied in every day clinical practice.

Allium cepa (onion) and Allium sativum (garlic) are important members of the Amaryllidaceae (Alliaceae) family and are being used both as food and medicine for centuries in different parts of the world. Polysaccharides have been extracted from different parts of onion and garlic such as bulb, straw and cell wall. The current literature portrays several studies on the extraction of polysaccharides from onion and garlic, their modification and determination of their structural (molecular weight, monosaccharide unit and their arrangement, type and position of glycosidic bond or linkage, degree of polymerization, chain conformation) and functional properties (emulsifying property, moisture retention, hygroscopicity, thermal stability, foaming ability, fat-binding capacity). In this line, this review, summarizes the various extraction techniques used for polysaccharides from onion and garlic, involving methods like solvent extraction method. Furthermore, the antioxidant, anticancer, immunomodulatory, antimicrobial, anti-inflammatory, and antidiabetic properties of onion and garlic polysaccharides as reported in in vivo and in vitro studies are also critically assessed in this review. Different studies have proved onion and garlic polysaccharides as potential antioxidant and immunomodulatory agent. Studies have implemented to improve the functionality of onion and garlic polysaccharides through various modification approaches. Further studies are warranted for utilizing onion and garlic polysaccharides in the food, nutraceutical, pharmaceutical and cosmetic industries.

Opioid use disorder (OUD), like other substance use disorders (SUDs), is widely understood to be a disorder of persistent relapse. Despite the use of three FDA-approved medications for OUD, typically in conjunction with behavioral treatments, relapse rates remain unacceptably high. Whereas medication assisted therapy (MAT) reduces the risk of opioid overdose mortality, the benefits of MAT are negated when people discontinue the medications. Currently approved medications present barriers to efficient use, including daily visits to a treatment center or work restrictions. With spiking increases in opioid relapse and death, it is imperative to identify new treatments that can reduce the risk of relapse. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently FDA-approved to treat obesity and type two diabetes, may be promising candidates to reduce relapse. GLP-1RAs have been shown to reduce relapse in rats, whether elicited by cues, drug, and/or stress. However, GLP-1RAs also can cause gastrointestinal malaise, and therefore, in humans, the medication typically is titrated up to full dose when initiating treatment. Here, we used a rodent model to test whether cue- and drug-induced heroin seeking can be reduced by the GLP-1RA, liraglutide, when the dose is titrated across the abstinence period and prior to test. The results show this titration regimen is effective in reducing both cue-induced heroin seeking and drug-induced reinstatement of heroin seeking, particularly in rats with a history of high drug-taking. Importantly, this treatment regimen had no effect on either circulating glucose or insulin. GLP-1RAs, then, appear strong candidates for the non-opioid prevention of relapse to opioids.

International audience; The invention and approval of innovative anticancer therapies in the last decade have revolutionized oncology treatment. Radiotherapy is one of the three traditional pillars in oncology treatment with surgery and systemic therapies. Some standard-of-care combinations of chemoradiotherapy widened the therapeutic window of radiation, while some other chemotherapies such as gemcitabine caused unacceptable toxicities when combined with radiation in lung cancers. Fast-paced progress are specially focused on immunotherapies, targeted-therapies, anti-angiogenic treatment, DNA repair inhibitors, hormonotherapy and cell cycle inhibitors. New anticancer therapeutic arsenals provided new possibilities of combined oncological treatments. The interactions of the radiotherapy with other systemic treatments, such as non-anticancer immunomodulatory/immunosuppressive medications are sometimes overlooked even though they could offer a real therapeutic benefit. In this review, we summarize the new opportunities and the risks of historical and novel combined therapies with radiation: non-anticancer immunomodulatory/immunosuppressive drugs, systemic reoxygenation, new therapies such as nanoparticles and SMAC mimetics. Key biological mechanisms, pre-clinical and available clinical data will be provided to demonstrate the promising opportunities in the years to come.

Alginate zinc hydrogel loaded with zinc insulin hexamer was prepared and characterized for oral insulin administration. The hydrogel was fabricated by dripping zinc insulin hexamer into sodium alginate solution and followed by crosslinking by zinc chloride. SEM image reveals the zinc insulin hexamer was integrated into the matrix of hydrogel. Zinc insulin hexamer loaded hydrogel shows no obvious cytotoxicity to both HT29 and Caco-2 cells. The developed hydrogel retards the burst release of insulin in simulated gastric fluid but promotes the release when in simulated intestinal fluid. In the diabetic mice, zinc insulin hexamer loaded alginate hydrogel demonstrates significant and prolonged hypoglycemic effect.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) improve the risk for heart and kidney failure. However, their effects on major atherosclerotic cardiovascular events (MACE) are less clear. Although outcomes trials of drugs for diabetes were not powered to prove superiority, the totality of trial data yields an estimate of ∼11% relative reduction for MACE (HR 0.89, 95%CI 0.82-0.96) and neutral on stroke (HR 0.92, 95%CI 0.79-1.08). In animal models, SGLT-2i favorably affects plaque size, composition, and inflammatory pathways; human data in this regard are lacking. Ongoing trials are evaluating SGLT-2i efficacy in heart failure, kidney disease, and postmyocardial infarction populations, independent of diabetes status.

The differential benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) in cardiovascular or renal outcomes have not been fully investigated.Patients with diabetes prescribed SGLT2i or GLP1RA were retrospectively identified. Patients treated with antihyperglycemic medications other than SGLT2i or GLP1RA were used as a control group. Primary outcomes were composite ischemic events (acute coronary syndrome, coronary revascularization, and stroke) and a composite of heart failure and renal events (hospitalization for heart failure, renal death, initiation of renal replacement therapy, and renal admission).During a median 38.7 months of follow-up, the incidence of composite ischemic events tended to be lower in the GLP1RA group (annualized rate 0.82% per person-year) than in the other groups (1.68% per person-year in the SGLT2i group and 1.36% per person-year in the control group). The risk of a composite of heart failure and renal outcomes was significantly lower in the SGLT2i group than in the GLP1RA and control groups (0.86% per person-year, 2.33% per person-year, and 1.48% per person-year, respectively). The SGLT2i group had a slower decline in renal function over time compared to that in other groups.SGLT2i showed more benefits in heart failure and renal outcomes, whereas GLP1RA tended to have more favorable ischemic outcomes.

The treatment of type 2 diabetes mellitus (T2DM) is based on preventive hygiene and dietary measures (HDM), oral antidiabetic drugs (OADs), and insulin. The objective of the present study was to reuse general practice data from electronic health records and describe changes over time among patients with T2DM in primary care.We analyzed data on patients with T2DM collected by three family physicians in Tourcoing (France) from 2006 to 2018.403 patients, 1030 treatment sequences, 39,042 appointments, 2440 glycated hemoglobin (HbA1c) measurements, and 9722 wt measurements were included. On inclusion, the mean age was 57.0, the mean weight was 84.4 kg, the mean body mass index was 30.3 kg/mThe present descriptive results may be of value in helping to predict changes over time in bodyweight and HbA1c in T2DM.

Sodium-glucose cotransporter 2 inhibitors were first discovered as glucose-lowering drugs because of their glycosuric action and good safety profile. Subsequently, they were studied in cardiovascular outcome trials in people with type 2 diabetes, and their cardiovascular benefit was consistently observed as regards heart failure hospitalizations and cardiovascular death. Investigation of the underlying mechanisms granting such benefit is continuously engaging researchers all over the world. The findings described in this article paved the way to a larger use of these drugs in patients with heart failure, with the aim of improving their clinical outcomes and quality of life.

International audience; BACKGROUND: Adults with type 1 diabetes who are treated with multiple daily injections of insulin plus intermittently scanned continuous glucose monitoring (isCGM) can have suboptimal glucose control. We aimed to assess the efficacy of an advanced hybrid closed loop (AHCL) system compared with such therapy in this population. METHODS: The Advanced Hybrid Closed Loop Study in Adult Population with Type 1 Diabetes (ADAPT) trial is a prospective, multicentre, open-label, randomised controlled trial that involved 14 centres in three European countries (France, Germany, and the UK). We enrolled patients who were at least 18 years of age, had a type 1 diabetes duration of at least 2 years, HbA(1c) of at least 8% (64 mmol/mol), and were using multiple daily injections of insulin plus isCGM (cohort A) or real time continuous glucose monitoring (cohort B) for at least 3 months. Here, only results for cohort A are reported. Participants were randomly allocated 1:1 to AHCL therapy or continuation of multiple daily injections of insulin plus continuous glucose monitoring for 6 months with an investigator-blinded block randomisation procedure. Participants and treating clinicians could not be masked to the arm assignment. The primary endpoint was the between-group difference in mean HbA(1c) change from baseline to 6 months in the intention-to-treat population using AHCL therapy and those using multiple daily injections of insulin plus isCGM. The primary endpoint was analysed using a repeated measures random-effects model with the study arm and period as factors. Safety endpoints included the number of device deficiencies, severe hypoglycaemic events, diabetic ketoacidosis, and serious adverse events. This study is registered with ClinicalTrials.gov, NCT04235504. FINDINGS: Between July 13, 2020, and March 12, 2021, 105 people were screened and 82 randomly assigned to treatment (41 in each arm). At 6 months, mean HbA(1c) had decreased by 1·54% (SD 0·73), from 9·00% to 7·32% in the AHCL group and 0·20% (0·80) in the multiple daily injections of insulin plus isCGM from 9·07% to 8·91% (model-based difference -1·42%, 95% CI -1·74 to -1·10; p\textless0·0001). No diabetic ketoacidosis, severe hypoglycaemia, or serious adverse events related to study devices occurred in either group; two severe hypoglycaemic events occurred in the run-in phase. 15 device-related non-serious adverse events occurred in the AHCL group, compared with three in the multiple daily injections of insulin plus isCGM group. Two serious adverse events occurred (one in each group), these were breast cancer (in one patient in the AHCL group) and intravitreous haemorrhage (in one patient in the multiple daily injections of insulin plus isCGM group). INTERPRETATION: In people with type 1 diabetes using multiple daily injections of insulin plus isCGM and with HbA(1c) of at least 8%, the use of AHCL confers benefits in terms of glycaemic control beyond those that can be achieved with multiple daily injections of insulin plus isCGM. These data support wider access to AHCL in people with type 1 diabetes not at target glucose levels. FUNDING: Medtronic International Trading Sàrl.

Autoimmune diabetes (AD) in adults includes both the classical form of type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). LADA shares clinical and metabolic features with type 1 and type 2 diabetes mellitus (T2DM). Ceramide (Cer) levels negatively correlate with insulin sensitivity in humans and animal models. However, only a few studies have focused on other sphingolipids, including sphingomyelin (SM). Therefore, we determined sphingolipids in patients with newly diagnosed diabetes as possible diagnostic biomarkers.We evaluated sphingolipids in a cohort of 59 adults with newly diagnosed diabetes without prior hypoglycemic pharmacotherapy to distinguish diabetes mellitus types and for precise LADA definition. All patients with newly diagnosed diabetes were tested for the concentrations of individual Cer and SM species by gas-liquid chromatography. The study included healthy controls and patients with T1DM, T2DM and LADA.SM species were significantly altered in patients with newly diagnosed diabetes compared to healthy controls. SM-C16:0, C16:1, -C18:0, -C18:1, -C18:2, -C18:3, -C20:4, and -C22:6 species were found to be significantly elevated in LADA patients. In contrast, significant differences were observed for Cer species with saturated acyl chains, especially Cer-C14:0, -C16:0, -C18:0 (AD and T2DM), -C22:0, and -C24:0 (T1DM). Following ROC analysis, SM-C16:0, and particularly -C18:1, and -C20:4 may be supportive diagnostic markers for LADA.SM profiling in patients with newly diagnosed diabetes could be potentially helpful for differential diagnosis of LADA, T1DM, and T2DM in more challenging cases.

The number of total pancreatectomy cases have increased worldwide, expanding the need for new insulin products and high-titer pancrelipases. However, the current data that is focused on hypoglycemic events after a total pancreatectomy from large nationwide series are still lacking. This study is aimed to assess the risk factors associated with hypoglycemic events after a total pancreatectomy.Data were prospectively collected from 216 consecutive patients who underwent total pancreatectomies between August 2015 and December 2017 from 68 Japanese centers. Of the 216 patients, 166 with a follow-up period of 1 year were analyzed. The risk factors for hypoglycemic events at 6 and 12 months (postoperative months 6 and 12) were investigated based on the results of a nationwide multicenter prospective study.Of the 166 patients, 57 (34%) and 70 (42%) experienced moderate or severe hypoglycemic events or hypoglycemia unawareness on a monthly basis at postoperative months 6 and 12, respectively. Multivariate analysis revealed that body weight loss after surgery ≥0.3 kg and total cholesterol level ≤136 mg/dL at postoperative month 6, and glycated hemoglobin level ≤8.9% and rapid-acting insulin use at postoperative month 12 were independent risk factors for hypoglycemic events after a total pancreatectomy. There were different independent risk factors depending on the postoperative period.Patients with body weight loss after surgery, low total cholesterol level, strict glycemic control, and using rapid-acting insulin should be aware of the occurrence of hypoglycemic events after their total pancreatectomy. In order to prevent hypoglycemic events after a total pancreatectomy, we need to consider optimal nutritional and glycemic control according to the postoperative period.

Due to potential ethnic differences in the pathophysiology of type 2 diabetes, new therapeutics need to be evaluated in Japanese patients. We aimed to assess the safety and glycaemic efficacy of tirzepatide as an add-on treatment in Japanese patients with type 2 diabetes who had inadequate glycaemic control with stable doses of various oral antihyperglycaemic monotherapies.This multicentre, open-label, parallel-group, randomised, phase 3 trial was conducted at 34 medical research centres and hospitals in Japan. Eligible participants were aged 20 years or older with inadequately controlled (HbABetween March 30, 2019, and Feb 16, 2021, with recruitment and enrolment continuing until Feb 4, 2020, 484 participants were assessed for eligibility and 443 were randomly assigned to receive at least one dose of tirzepatide (148 [33%] in the 5 mg group, 147 [33%] in the 10 mg group, and 148 [33%] in the 15 mg group). 398 (90%) participants completed the study and treatment. Most participants (343 [77%] of 443) had at least one treatment-emergent adverse event. Treatment-emergent adverse events were more frequent in the tirzepatide 15 mg group (125 [84%] of 148) than the 5 mg (109 [74%] of 148) and 10 mg groups (109 [74%] of 147). The most frequent treatment-emergent adverse events with tirzepatide were mild or moderate nasopharyngitis (75 [17%]), nausea (74 [17%]), constipation (54 [12%]), diarrhoea (51 [12%]), and decreased appetite (44 [10%]). At week 52, mean changes from baseline in bodyweight were -3·8 kg (SE 0·5; -5·1% reduction) in the 5 mg group, -7·5 kg (0·5; -10·1% reduction) in the 10 mg group, and -10·2 kg (0·5; -13·2% reduction) in the 15 mg group. Least squares mean HbATirzepatide was well tolerated as an add-on to oral antihyperglycaemic monotherapy in Japanese participants with type 2 diabetes and showed improvement in glycaemic control and bodyweight, irrespective of background oral antihyperglycaemic medication. Tirzepatide is a potential new treatment option for Japanese patients with type 2 diabetes that is inadequately controlled with single oral antihyperglycaemic medication.Eli Lilly and Company.For the Japanese translation of the abstract see Supplementary Materials section.

Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting with hypoglycemia, lactic acidosis, and hepatopathy. To date, there has been no systematic analysis of its phenotypic, biochemical, and genetic spectrum.All currently published individuals and a novel patient with genetically confirmed PEPCK-C deficiency were included. Clinical, biochemical, and genetic findings were analyzed. Protein and in-silico prediction score modeling was applied to analyze potential variant effects.Thirty-two individuals from 25 families were found, including one previously unreported patient. The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum. Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening. With adequate treatment, biochemical abnormalities usually normalized following a hypoglycemic episode. Symptom onset usually occurred in infancy with a broad range from neonatal age to adulthood. Regardless of the genotype, different phenotypes with a broad clinical spectrum were found. To date, eight genotypes with nine different PCK1 variants were identified, of which alleles with the recurrent variant c.925GA; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population. Protein modeling suggests altered manganese- and substrate-binding as superordinate pathomechanisms.Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1. Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia. It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity. Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood.

This report describes the use of combination therapy in patients with type 2 diabetes mellitus (T2DM) who had been initially prescribed metformin in the United States.Retrospective claims data from a de-identified database were used to identify individuals aged ≥18 years with ≥1 claim for a metformin-containing regimen dated between January 1, 2018, and December 31, 2018. Demographics, insurance type, and prescriber type were compared among subgroups receiving two (dual) or three or more (triple+) anti-diabetes therapies. All analyses were descriptive; no formal comparisons were conducted.Data from 353,062 patients were included. Demographic and other baseline characteristics were similar between the groups receiving dual or triple+ therapy (n = 213,871 and 139,191, respectively). A small age difference was observed between patients receiving dual versus triple+ therapy (mean [SD], 66.5 [11.8] and 65.8 [10.8] years, respectively). Mean (SD) glycosylated hemoglobin levels were lower among patients receiving dual therapy versus triple+ therapy: 7.6% (1.7) versus 8.0% (1.7). The most frequent combination was metformin plus a sulfonylurea (33.4%). The percentage receiving combination therapy with newer treatments was relatively low, and slightly greater in younger patients. Total health care costs were similar with dual and triple+ therapies.The current descriptive analysis demonstrated generally similar features, with regard to the evaluated factors, in cohorts receiving dual versus triple+ T2DM therapy. However, differences between unmeasured factors could exist and require further evaluation. These findings, based on data from a cohort of patients from clinical practice who had initially been prescribed metformin, provide a useful snapshot of current prescribing practices and can be used to inform future research and evidence-based policy decisions.

Coronavirus disease 2019 (COVID-19) is thought to contribute to diabetic ketoacidosis (DKA) and worse outcomes in patients with diabetes. This study compared the cumulative insulin dose required to achieve DKA resolution in the intensive care unit among patients with type 2 diabetes and COVID-19 infection versus without COVID-19 infection.This retrospective cohort study evaluated 100 patients-50 patients with COVID-19 in cohort 1 and 50 patients without COVID-19 in cohort 2-treated with insulin infusions for DKA at a tertiary care teaching hospital. The primary outcome was to compare the cumulative insulin dose required to achieve DKA resolution in each cohort. The secondary outcomes included time to DKA resolution, mean insulin infusion rate, and mean weight-based cumulative insulin infusion dose required to achieve DKA resolution. All endpoints were adjusted for confounders.The mean cumulative insulin dose was 190.3 units in cohort 1 versus 116.4 units in cohort 2 (P = .0038). Patients receiving steroids had a mean time to DKA resolution of 35.9 hours in cohort 1 versus 15.6 hours in cohort 2 (P = .0014). In cohort 1 versus cohort 2, the mean insulin infusion rate was 7.1 units/hour versus 5.3 units/hour (P = .0025), whereas the mean weight-based cumulative insulin infusion dose was 2.1 units/kg versus 1.5 units/kg (P = .0437), respectively.COVID-19-infected patients required a significantly larger cumulative insulin dose, longer time to DKA resolution, higher insulin infusion rate, and higher weight-based insulin infusion dose to achieve DKA resolution versus non-COVID-19-infected patients with type 2 diabetes.

Address treatment burden and general perceptions of pharmacological treatment in patients with diabetes.We surveyed adult patients with diabetes cared for in a tertiary academic medical center about: i) knowledge about the impact of glucose-lowering medication use on diabetes control and complications, ii) common beliefs about natural medicine and insulin use, iii) attitudes towards glucose-lowering medications, iv) burden of treatment, v) general knowledge of diabetes pharmacological treatment, and vi) perceptions of shared decision-making.Two hundred-four participants completed the survey. While most (90%) agreed that adherence to medication would control diabetes and improve quality of life, 30-40% were not certain that it would translate to fewer disease complications. About one of three thought medications could be harmful (29.4%). Over 50% agreed or was unsure that natural remedies were as good/better than prescribed medications. About 30% acknowledged difficulties taking their diabetes medications and monitoring blood glucose, and over 50% were concerned about treatment costs. Nearly 30% denied receiving a detailed explanation from their clinician regarding their disease and is treatment.Our results highlight the importance of patient education regarding pharmacological treatment for diabetes, and eliciting sources of distress and treatment burden among patients with diabetes.

Initiation of insulin is usually delayed even when required. We aim to estimate the association between depressive symptoms on time to become insulin requiring and time to insulin initiation.8-year follow-up of a cohort of newly diagnosed people with T2D recruited in south-east London, UK (2008-2012). Baseline depressive symptoms were assessed using the Patient Health Questionnaire-9. Time to insulin-requiring was defined when optimal glycaemic levels were not achieved (HbA1c58 mmol/mol) at least three months after the 2nd oral antidiabetic was prescribed, and time to insulin initiation was defined as first insulin prescription.Seventy percent (n = 1166) of the baseline cohort was followed up. Median time to insulin requiring was 84 months (IQR 63-100) and to insulin initiation 93 months (IQR 79-105). Participants with depressive symptoms at baseline required insulin earlier (mean [SD] 73.64 [32.16] vs. 79.05 [29.07] months, p = 0.007) and were prescribed insulin sooner (82.53 [30.19] vs. 89.72 [22.02] months, p 0.001). In Cox regression, depressive symptoms at baseline were not associated with time to insulin requiring (HR [95 % CI]; 1.16 [0.86-1.57], p = 0.34) nor to insulin initiation (HR = 1.00 [0.99-1.00], p = 0.49).Depressive symptoms were not associated with time to insulin requiring and initiation after adjusting for potential confounding.

To determine the optimal insulin-to-steroid dose ratio for the attainment of glycemic control in hospitalized patients.We retrospectively studied data collected from the electronic health records within an academic medical center from 18 599 patient-days where patients were treated concurrently with insulin and steroids. Multivariate logistic regression analyses, which included demographic and clinical variables, were performed to assess the relationships between the exposures of total and basal insulin-to-steroid ratios and the outcomes of glycemic control (all blood glucose readings on the following patient-day were70 and ≤180 mg/dL) and hypoglycemia within 3 subgroups of steroid dosing: low (≤10-mg prednisone equivalent dose [PED]), medium (from10-mg to ≤40-mg PED), and high (40-mg PED).Increased insulin-to-steroid ratio was associated with increased odds of both glycemic control and hypoglycemia. The optimal total insulin-to-steroid ratio for attaining glycemic control was 0.294 U/kg/10-mg PED in the low-dose subgroup, 0.257 U/kg/10-mg PED in the medium-dose subgroup, and 0.085 U/kg/10-mg PED in the high-dose subgroup. The optimal basal insulin-to-steroid ratio was 0.215 U/kg/10-mg PED in the low-dose subgroup, 0.126 U/kg/10-mg PED in the medium-dose subgroup, and 0.036 U/kg/10-mg PED in the high-dose subgroup.Increasing insulin-to-steroid ratios are positively associated with glycemic control and hypoglycemia. Our study suggests that approximately 0.3 U/kg/10-mg PED is an optimal dose for low- and medium-dose steroids, whereas approximately 0.1 U/kg/10-mg PED is an optimal dose for high-dose steroids. Further prospective studies are needed to identify insulin regimens that will optimize glycemic control in steroid-treated patients while minimizing the risk of hypoglycemia.

Hemerocallis citrina Borani (daylily) has various health benefits. However, the structural characterization and hypoglycemic effects of its polysaccharide remain unclear. Here, we first report for the first time, the effects of subcritical water extraction temperature on bioactivity of Hemerocallis citrina Borani polysaccharide (HCBP). HCBP extracted at 160 °C had better scavenging ability of free-radical and pancreatic lipase inhibition. This study aimed to investigate the structural characterization and anti-diabetic effects of aforementioned HCBP. HCBP was separated into three fractions using a DEAE-Sepharose Fast Flow. HCBP-1 was the major component with lower molecular weight, HCBP-2 was the least abundant component, HCBP-3 was the component with higher uronic acid and molecular weight. HCBP treatment significantly decreased the concentrations of fasting blood glucose, insulin, total cholesterol, triglyceride, and low density lipoprotein, as well as improved glucose intolerance and insulin resistance in type 2 diabetes mellitus (T2DM) rats. HCBP also protected the kidneys and pancreatic organs by histopathology and immunohistochemical analyses in T2DM rats. In addition, HCBP significantly increased the antioxidant enzymes activities and decreased the level of malonaldehyde to alleviated the oxidative stress injury. The results indicate HCBP extracted by subcritical water is promising functional food ingredients and could be used in T2DM treatment.

Elderly patients have higher risks for complications during Ramadan fasting. Educating patients is essential for fasting safely.To evaluate the impact of pre-Ramadan education in reducing risk of hypoglycemia and achieving glycemic control in elderly.A prospective study carried out in outpatients clinics of Internal Medicine department in Assiut university hospital. It included 316 type 2 diabetic patients who intended to fast. They were grouped into 2 groups; 65 years and ≥ 65 years patients. The patients received pre-Ramadan individual education sessions. A semi-structured questionnaire was used to collect the data to stratify the risk of fasting. The study was carried out in 3 phases. Assessment of hypoglycemia and biochemical parameters after the education was the primary outcome.Fasting blood glucose decreased during and after Ramadan in elderly significantly (p = 0.0001). The patients who achieved fasting blood glucose less than 8 mmol/L increased from 29.3% to 46.6% after Ramadan in elderly patients. HbA1c decreased significantly after Ramadan (p = 0.001). The main cause of breaking fast was hypoglycemia in both groups; 9% vs.7.7% in patients 65 and ≥ 65 years respectively. The waist circumference showed significant decrease in patient with 65 years old or more (p = 0.05). Total cholesterol and LDL increased with no statistical significance in patients ≥ 65 years (p = 0.512, 0.470). Both groups showed improvement of HDL cholesterol during and after Ramadan (P = 0.0001).Pre-fasting education had positive impact on decreasing the risk of symptomatic hypoglycemia in elderly diabetic patients.

This work aims to explore attitudes regarding the management of elderly or frail patients with type 2 diabetes mellitus in the routine clinical practice of a multidisciplinary group of physicians in Spain.A mixed survey was used that included both Delphi and opinion, attitude, and behaviour (OAB) questions. Perceptions in primary care (n = 211) and hospital care (n = 80) were compared.Consensus was obtained on all statements. Eighty-seven percent of participants considered that severe psychiatric disorders conditioned antidiabetic treatment and 72% that a psychocognitive assessment is as relevant as the assessment of other comorbidities. Hospital care physicians more frequently considered that comorbidity affects self-care (95.0% vs. 82.9%), that a lack of de-intensification is a form of therapeutic inertia (88.8% vs. 76.3%), that classifying older adults as frail is fundamental to choosing targets (96.3% vs. 87.7%), that de-intensification of antidiabetic treatment and control of cardiovascular risk factors should be considered in those over 80 years of age (90.0% vs. 78.7%), and that type 2 diabetes mellitus predisposes patients to sarcopenia (86.3% vs. 71.6%). The usefulness of clinical guidelines was more highly valued among primary care participants (79.1% vs. 72.5%).There is room for improvement on several aspects of managing elderly or frail patients with type 2 diabetes mellitus, including inertia in treatment de-intensification, conducting a psychocognitive assessment, or the identification of frailty and sarcopenia.

Data on glycemic control and its determinants among Brazilian patients with type-2 diabetes (DM2) are scarce. The BrazIliaN Type 12 DiabetEs Disease Registry (BINDER) is a multicenter, longitudinal study, designed to investigate the glycemic control in a real-word scenario.1142 patients participated in the five visits of the BINDER study between April/2017 and October/2019. For each visit, glycemic control was assessed using the last measure available for HbA1c. Sociodemographic and anthropometric characteristics were also analyzed.At baseline, the median HbA1c level was 7.1% (4.1-15.0%); 259 (31.4%) participants had HbA1c ≤ 6.5% and 396 (48.2%) had HbA1c ≤ 7.0%. Younger age (p = 0.014), low educational level (p = 0.025) and the type of healthcare service (public sector; p = 0.0058) were independently associated with the elevated HbA1c. After 2 years, there were no statistically significant differences in HbA1c median values in relation to baseline.In this sample of DM2 patients, younger age, low educational level and being treated at the public service were associated with worse glycemic control. Over a 2-year follow-up, there was no significant change in the median HbA1c. These findings suggest that strategies are needed to improve glycemic control, especially in those treated in the public service.

Contemporary guidelines suggest relaxed glycemic targets in populations with type 2 diabetes mellitus (T2DM) at risk of hypoglycemia, including people with multimorbidity, limited life expectancy or frailty. However, overtreatment remains commonplace. To inform safe deprescribing, a previous systematic review investigated the benefits and harms of deprescribing antihyperglycemics, but identified only limited, very low-quality evidence. We sought to update that review and identify and describe newly published literature on the effects of deprescribing antihyperglycemics in older adults with T2DM.We searched MEDLINE, EMBASE and the Cochrane Library (July 2015 to January 2021) for controlled studies published in English addressing the effects of deprescribing vs continuing antihyperglycemics in adults with T2DM. Two independent reviewers performed title, abstract and full-text screening, data extraction and risk-of-bias assessment. Cochrane's risk-of-bias tools, RoB 2 and ROBINS-I, were used. The findings were summarized narratively. GRADE (Grading of Recommendations, Assessment, Development and Evaluations) was used to evaluate the evidence.We identified 4 additional investigations-2 randomized controlled trials and 2 retrospective cohort studies. After deprescribing, 3 studies reported no clinically significant changes in glucose management and 2 studies reported reductions in adverse events (e.g. hypoglycemia, all-cause mortality and nonspine fractures). However, based on GRADE assessment, we found very low certainty of the evidence due to concerns of risk of bias (e.g. unmeasured confounding), imprecision, and indirectness.Deprescribing antihyperglycemic medications in older adults with T2DM is likely feasible and safe, and benefits may outweigh the harms. However, the evidence indicates very low certainty. Additional deprescribing studies are needed with rigorous methodologies and reporting.

This study to assess the incidence rates and risk factors of hypoglycemia in a wide real-life sample of patients with insulin-treated type 2 diabetes mellitus.In a prospective epidemiological study, data from 817 subjects were collected from medical records and via interviews. Over a 3-month period, hypoglycemic episodes were recorded via self-measurement of glucose levels at least twice daily. Cox proportional and negative binomial multivariable models were applied to estimate adjusted and unadjusted hazard ratios and incidence rate ratios of hypoglycemic events.Of the 817 patients, 52.9% experienced hypoglycemia, 38.1% had only nonsevere episodes, and 14.8% had at least 1 severe episode. Total events per patient-year were estimated at 13.3 (±24.8), with 11.8 (±21.6) and 1.4 (±4.7) being nonsevere and severe, respectively. History of hypoglycemia and severe hypoglycemia were consistent risk factors of hypoglycemia. Intensification of therapy was associated with higher incidence rates, whereas the effect on the hazard rates was more moderate. Longer duration of insulin therapy and the presence of congestive heart failure were associated with a higher risk of developing and frequency of hypoglycemia. Hypoglycemia awareness was found to independently affect only mild hypoglycemia.Hypoglycemia is a common complication in patients with insulin-treated type 2 diabetes mellitus. The risk factors of developing hypoglycemia are to some extent different from those of the frequency of hypoglycemic episodes. Particular attention is required for patients with recurrent hypoglycemic events and on intensive antidiabetic therapy.

This study investigated the antioxidant activities, enzyme inhibitory activities and the interaction mechanisms of artocarpin and α-mangostin on α-amylase and α-glucosidase. Results showed that artocarpin and α-mangostin had obvious antioxidant activities and inhibitory activities on α-glucosidase and α-amylase. The inhibitions of the two compounds on α-glucosidase were reversible and non-competitive according to the kinetics studies. Fluorescence intensity measurements indicated that the interaction mechanisms between the inhibitors and the two enzymes were static processes. Isothermal titration calorimetry (ITC) analysis showed that the bindings between the inhibitors and the enzymes complex were all spontaneous. The main driving forces between α-mangostin and artocarpin with α-glucosidase might be hydrogen bonds and electrostatic interactions, respectively. While the forces between the two inhibitors and α-amylase might be hydrophobic interactions. Furthermore, molecular docking results showed that artocarpin and α-mangostin could bind to the allosteric site of the two enzymes, except for artocarpin in the active site pocket of α-amylase. All the results indicated that artocarpin and α-mangostin might be promising candidates for hypoglycemic functional products.

The incidence of type 1 diabetes mellitus is increasing every year requiring substantial expenditure on treatment and complications. A systematic review was conducted on the cost-effectiveness of insulin formulations, including ultralong-, long-, or intermediate-acting insulin, and their biosimilar insulin equivalents.MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, HTA, and NHS EED were searched from inception to June 11, 2021. Cost-effectiveness and cost-utility analyses were included if insulin formulations in adults (≥ 16 years) with type 1 diabetes mellitus were evaluated. Two reviewers independently screened titles, abstracts, and full-text articles, extracted study data, and appraised their quality using the Drummond 10-item checklist. Costs were converted to 2020 US dollars adjusting for inflation and purchasing power parity across currencies.A total of 27 studies were included. Incremental cost-effectiveness ratios ranged widely across the studies. All pairwise comparisons (11 of 11, 100%) found that ultralong-acting insulin was cost-effective compared with other long-acting insulins, including a long-acting biosimilar. Most pairwise comparisons (24 of 27, 89%) concluded that long-acting insulin was cost-effective compared with intermediate-acting insulin. Few studies compared long-acting insulins with one another.Long-acting insulin may be cost-effective compared with intermediate-acting insulin. Future studies should directly compare biosimilar options and long-acting insulin options and evaluate the long-term consequences of ultralong-acting insulins.

Insulin administration is time intensive and costly in facility staffing. When we started nursing home patients with type 2 diabetes (T2D) on DPP-4 inhibitors, we tapered insulin when finger stick blood sugar levels dropped to200 mg/dL. Of 34 patients we were able to stop mealtime insulin in 28 (82%) and stop all insulin in 20 (59%). On average, hemoglobin A1c (HbA1c) decreased 0.5% and weight by 2.8 pounds. Among the 20 who stopped all insulin, HbA1c improved in 11 on average 1% (p=0.02), and weight decreased in 11 on average 4.1 pounds (p=0.66). 12 patients were switched in one day because of a low insulin dose or low HbA1c Tapering duration in the other 8 ranged from 10-727 days with an insulin dose of 28 to 84 units daily. Larger studies are needed to confirm our findings, develop a protocol for tapering insulin, and measure hypoglycemia, comfort and cost.

Chronic kidney disease (CKD) is a major global epidemic associated with increased morbidity and mortality. Despite the effectiveness of kidney protection strategies of hypertension, diabetes, and lipid control and use of newer hypoglycemic agents and anti-angiotensin II drugs, the nephropathy in CKD continues unabated toward irreversible kidney failure. Thus, interventions targeting modifiable risk factors in CKD such as metabolic acidosis (MA) are needed. Acid reduction with sodium-based alkali has been shown to be an effective kidney-protection strategy for patients with CKD and reduced glomerular filtration rate (GFR). Small-scale studies reveal diets emphasizing ingestion of plant-sourced over animal-sourced protein reduce dietary acid, improve MA, and slow further nephropathy progression in patients with CKD and reduced GFR. Additionally, veverimer, an investigational, nonabsorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as a novel treatment for MA. As further studies define how to best use these interventions for kidney protection, clinicians must become aware of their potential utility in the management of patients with CKD. The aim of the present review is to explore the various intervention strategies that increase or normalize serum [HCO

Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site.In this Phase I, randomized, open-label, 4-period, crossover study, healthy subjects received a single dose of 15 U URLi subcutaneously into the abdomen, upper arm, or thigh, or by intravenous injection. Serum insulin lispro concentrations and glucodynamic response during a 10-hour euglycemic clamp procedure were assessed after URLi administration.Total insulin lispro exposure was similar for the abdomen, upper arm, and thigh, and absolute bioavailability was ∼65% at each subcutaneous (SC) injection site. Total and peak insulin action were similar across these SC injection sites. The onset of appearance was1 minute, and the time to early half-maximal drug concentration occurred at ∼10 minutes across these three SC injection sites. Onset of insulin action occurred at ∼22 minutes, and the early insulin action (for the first hour) was also similar across these SC injection sites. URLi was well tolerated after single SC injections and IV bolus administration.The pharmacokinetic and glucodynamic profiles of URLi were similar after a single SC dose into the abdomen, upper arm, or thigh. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh.gov identifier: NCT03232983.

Aims: Long-term clinical trials evaluating the effects of metabolic-bariatric surgery (MBS) on type 2 diabetes (T2D) demonstrate that a significant proportion of patients either fail to achieve remission or experience T2D recurrence over time. Furthermore, patients with recurrent T2D might require reinstitution of pharmacotherapy to control comorbidities (hypertension, dyslipidemia). This paper reviews therapeutic options in patients with T2D relapse. Data synthesis: Although presently there is no recommended pharmacological strategy, the available data support GLP-1 analogues (GLP-1a) as the most suitable option to control hyperglycemia post-MBS. Beside their efficacy in lowering glycemia and body weight while preserving lean mass, GLP-1a exert cardiovascular/renal-protection and are also safe and well tolerated in surgical patients. In addition, the s.c. route of administration of these medications circumvents the problem of changes in oral drugs bioavailability following MBS. Of note, the available data refers to liraglutide and needs to be confirmed with weekly GLP-1a agents. Information regarding the impact of MBS on the pharmacokinetics of lipid lowering and anti-hypertensive drugs is scarce and inconclusive. The findings indicate that timing from intervention is particularly important because of adaptive intestinal mechanisms. Conclusions: The recurrence of T2D following MBS is a clinically relevant issue. GLP-1a therapy represents the best option to improve glycemic and weight control with good tolerability. Long-term clinical trials will clarify the impact of these drugs on cardiovascular outcomes. A close monitoring of MBS patients is advised to guide drug dosage adjustments and ensure the control of cardiovascular risk factors.

In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect.A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively).This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.

New antidiabetic agents (sodium-glucose cotransporter-2 inhibitor [SGLT2i] and glucagon-like peptide-1 receptor agonist [GLP-1RA]) and metabolic surgery have protective effects on metabolic syndromes.To compare the changes of metabolic parameters and costs among patients with obesity and type 2 diabetes undergoing metabolic surgery and initiating new antidiabetic agents over 12 months.Hong Kong Hospital Authority database from 2006-2017.This is a population-wide retrospective cohort study consisting of 2616 patients (1810 SGLT2i, 528 GLP-1RA, 278 metabolic surgery). Inverse probability treatment weighting of propensity score was applied to balance baseline covariates of patients with obesity and type 2 diabetes who underwent metabolic surgery, or initiated SGLT2i or GLP-1RA. Metabolic parameters and direct medical costs were measured and compared from baseline to 12 months in metabolic surgery, SGLT2i, and GLP-1RA groups.Patients in all 3 groups had improved metabolic parameters over a 12-month period. Patients with metabolic surgery achieved significantly better outcomes in BMI (-5.39, -.56, -.40 kg/mBeneficial weight loss and metabolic outcomes at 12 months were observed in all 3 groups, among which the metabolic surgery group showed the most remarkable effects but incurred the greatest medical costs. However, studies with a longer follow-up period are warranted to show long-term outcomes.

Inhibiting α-glucosidase activity is important in controlling postprandial hyperglycemia and, thus, helping to manage type-2 diabetes mellitus (T2DM). In the present study, we purified a hypothetical protein of carrots called DCHP (Daucus Carrot hypoglycemic peptide), and their inhibitory effects on α-glucosidase, as well as related mechanisms, were investigated. The recombinant DCHP protein with a molecular weight of 8 kDa showed strong inhibitory activity against α-glycosidase and maintained good stability in solution. DCHP exhibited no inhibitory activity but was tolerant to trypsin and chymotrypsin. Cellular experiments demonstrated that glucose consumption and lactic acid production increased rapidly when treated with DCHP in Caco-2 and HepG2 cells. DCHP crystal was generated, and the crystal structure, which was similar to that of rBTI and consisted of a central α-helix and a two-stranded β-sheet with a unique loop region. The interaction between DCHP and α-glycosidase was investigated by molecular docking and site-directed mutation, which revealed that Glu43, Pro46, Thr47 Thr48 and Gln49 are the key residues in DCHP that inhibit α-glycosidase activity. This work provides potential bioactive peptides as functional foods or nutraceutical supplements in preventing and managing T2DM.

Sodium/glucose co-transporter-2 inhibitor (SGLT2i) or dipeptidyl peptidase IV inhibitor (DPP4i) is a newer anti-diabetic drug in type II diabetes mellitus (DM), but their use in tacrolimus (TAC)-induced DM is still undetermined. We performed this study to evaluate the effect of these two drugs in TAC-induced DM and nephrotoxicity in ex vivo and in vivo. In the experimental Sprague Dawley rat model of TAC-induced DM and nephrotoxicity, dual inhibition of DPP4 and SGLT2 significantly decreased blood glucose level, HbA1C and increased plasma insulin levels and pancreatic islet size compared with each drug. In the kidney, dual inhibition improved renal function decreased interstitial fibrosis and profibrotic cytokines compared with DPP4i and SGLT2i alone. Increased oxidative stress by TAC was remarkably decreased with DPP4i or SGLT2i in serum, pancreatic and renal tissues and this decrease was much more significant in the combination group. In in vitro study, TAC decreased the cell viability of human kidney-2(HK-2) cells and insulin-secreting beta-cell-derived line(INS-1) cells. SGLT2i protected TAC-induced cell death in HK-2 cells, but not in INS-1 cells. The addition of DPP4i to SGLT2i compensated for a lack of protective effect of SGLT2i on INS-1 cells. This finding provides the rationale for the combined treatment of SGLG2i and DPP4i in TAC-induced DM and nephrotoxicity.