Insulin Secretagogues Research Articles

Hyperglycemia secondary to phosphatidylinositol-3 kinase (PI3K) inhibition.

Phosphatidylinositol-3 kinase (PI3K) is a critical intracellular pathway that regulates cell growth, metabolism, and survival and has been implicated in most human cancers. Targeting this pathway has been approved as a therapeutic option for breast cancer and lymphoma (e.g. alpelisib, idelalisib), and there are several clinical trials underway in additional types of cancer. However, PI3K is an important mediator of the action of insulin, and the use of PI3K inhibitors has been associated with hyperglycemia. We report the case of a 53-year-old female with metastatic breast cancer who developed acute grade 3 hyperglycemia from a novel PI3K inhibitor, inavolisib. We review the treatment options for PI3K inhibitor-associated hyperglycemia. Treatment strategies that minimize hyperinsulinemia may be preferable considering animal models have demonstrated that hyperinsulinemia may result in partial reactivation of the PI3K pathway and counter the anti-cancer effectiveness of PI3K inhibitors. Phosphatidylinositol-3 kinase (PI3K) is an intracellular pathway that regulates a range of physiological functions, including cell growth, metabolism, survival, and angiogenesis. Hyperactivation of the PI3K pathway is associated with almost all human cancers, and thus PI3K inhibition has been proposed as a treatment option for selected cancers. The action of insulin after binding to the insulin receptor on the cell surface (e.g. glucose uptake in skeletal muscle, inhibition of glycogenolysis and gluconeogenesis) is mediated by the intracellular PI3K pathway, and thus PI3K inhibition may lead to hyperinsulinemic hyperglycemia. All patients treated with PI3K inhibitors should receive pre-treatment screening for hyperglycemia, lifestyle advice, and a glucometer to measure fasting BGL and 2-h post-dinner BGL levels twice per week for at least the first 30 days of treatment. Insulin or insulin secretagogues (e.g. sulfonylurea) may inhibit the anti-tumor activity of PI3K inhibitors, and thus treatment of PI3K inhibitor-associated hyperglycemia should prefer alternative approaches such as a low carbohydrate diet, metformin, SGLT2i, or dose reduction of the PI3K inhibitor.

Vitamin B1 and calcitriol enhance glibenclamide suppression of diabetic nephropathy: Role of HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories

Glibenclamide is one of the most prescribed insulin secretagogues in diabetes due to its low cost, but its efficacy on suppressing diabetic complications is limited. Here, we examine whether addition of either vitamin B1 or calcitriol to glibenclamide could produce more suppression of diabetic nephropathy. Type 2 diabetes was induced by high fructose (10 % in drinking water), high salt (3 % in diet), and high fat diet (25 % in diet) for 3 weeks, followed by single dose of STZ (40 mg/kg, i.p.). Diabetic rats were treated with either glibenclamide (0.6 mg/kg), vitamin B1 (70 mg/kg), glibenclamide/vitamin B1, calcitriol (0.1 μg/kg), or glibenclamide/calcitriol. Addition of either vitamin B1 or calcitriol to glibenclamide therapy enabled more suppression of diabetic nephropathy development as evidenced by more preserved creatinine clearance and less renal damage scores. Combination therapy resulted in mild enhancement in the effect of glibenclamide on glucose tolerance without affecting the area under the curve. Combination therapy was associated with more suppression of inflammatory cascades as evidenced by reducing the expression of high mobility group box-1 (HMGB1), toll-like receptor-4 (TLR4), nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α). In addition, combination therapy enhanced the antioxidant mechanisms as evidenced by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione content and reducing malondialdehyde and nitric oxide levels. Furthermore, combination therapy provided more suppression of fibrotic pathways as appear from reducing collagen deposition and the expression of α- smooth muscle actin (α-SMA). In conclusion, addition of vitamin B1 or calcitriol to glibenclamide therapy can enhance the therapeutic efficiency of glibenclamide in suppressing diabetic nephropathy progression to the same extend, the protective effect is mediated through modulating HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories.

Nano-cubosomes of the phyto-active principle in Withania somnifera: LC-MS-NMR, anti-microbial, and insights of the anti-neuropathic and anti-inflammatory mechanism

Withania somnifera (W. somnifera) has a long history of safety in the amelioration of neuro-active ailments. The current study aims to explore Withania somnifera phyto-active principle anti-microbial, ant-neuropathic, and anti-inflammatory activities, and to modify these activities utilizing nano-cubosomes exploiting their mechanisms of action. Bio-guided fractionation technique was utilized, to identify the most phyto-active compound, using LC-MS-NMR online technique and biological models of diabetes, neuropathy, and inflammation. In-vitro antibacterial activity was also monitored. The HbA1c, in-vivo antioxidant (serum-catalase, TBARS, and GSH), serum insulin, and pro-inflammatory serum cytokines (TNF alpha, IL-six, and IL-ten) levels have been assessed to establish the anti-neuropathic and anti-inflammatory mechanisms. The nano-cubosomal formulations (CUB 1–3) were utilized to improve the W. somnifera most active compound efficacy. W. somnifera has shown ten major peaks; coagulin Q (10.2 %), dihydrowithanolide A (2.4 %), dihydrowithaferin D (1.8 %), physagulin D (7.6 %), withanoside V (2.3 %), withanolide A (WDA, 10.3 %), withafrin A (4.9 %), withaferin D (7.7 %), withanone 9 (9.9 %), withanolide D (4.8 %). The bio-guided fractionation technique utilizing LC-MS-NMR technique has proved that withanolide A (WDA) is the most phyto-active compound in W. somnifera. The latter has shown better results than WDA, which might be due to other effective compounds in Ws. However, CUB 3 (WDA nano-cubosomes dispersion) has shown more prominent anti-diabetic, anti-neuropathic, anti-inflammatory, and anti-bacterial potentials than Ws and WDA. Thus, CUB 3 modified WDA activity, and improved its efficacy. The normalization of HbA1c levels, increased insulin secretagogue potential, and the amelioration of the oxidative-stress may be the underlying Ws, WDA, and CUB 3 antidiabetic neuropathy mechanism. Moreover, the Ws, WDA, and CUB 1–3 anti-inflammatory mechanism might be due to the amelioration of the pro-inflammatory serum cytokines (decreasing TNF alpha and IL-six levels and increasing IL-ten). Thus, CUB 3 might be a powerful tool in augmenting Withania somnifera activity as an oral drug-delivery system and improving its efficacy against neuropathy and inflammation.

Mechanisms of Antidiabetic Effects of Medicinal Plants: A Systematic Review

Introduction: Diabetes mellitus is a worldwide concern as its rising prevalence has resulted in severe health problems. Some people employ traditional medicine to manage their diabetes. AIM: This review aims to identify medicinal plants used in diabetes management and to review their non-clinical data on its efficacy, toxicity studies, and mechanism of action. Methods: The databases used to search for information were PubMed, Scopus, ScienceDirect, and Google Scholar, reporting from Jan 2018 until Nov 2023. The search terms involved “diabetes”, “hypoglycemic” “medicinal plants”, “chemical compound”, “traditional use”, “extracts”, “reduce blood glucose” and “toxicity”. Results: A total of twenty plants were identified, showing blood glucose reduction from 14.3% to 80%, and their mechanism of action was thematically categorized under three mechanisms which are 1) insulin secretagogue, 2) insulin sensitizer, and 3) retard intestinal absorption of glucose. The plant extracts showed no sign of acute toxicity between 1.5 to 5 g/kg. Conclusion: To optimize their effectiveness, further research is required to evaluate chronic toxicity and identify plant extract bioactive compounds.

Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study)

BackgroundOral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world.MethodsWe retrospectively studied subjects > 65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65–74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity.ResultsWe studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (− 13.1 ± 7.5 mmol/mol and − 3.0 ± 2.4 kg, respectively; P < 0.01). Although cognitive function was lower in the late older group (r = −0.57, P < 0.01), changes in HbA1c showed no difference between the two subgroups (P = 0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r = −0.49, P < 0.05). Glycemic targets were more likely to be achieved (P < 0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n = 2, Late; n = 4).ConclusionsOral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation because of adverse events in subjects of ≥ 75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence.

Decline in use of high-risk agents for tight glucose control among older adults with diabetes in New York City: 2017-2022.

This study aimed to examine the prevalence of inappropriate tight glycemic control in older adults with type 2 diabetes and other chronic conditions in New York City, and to identify factors associated with this practice. We conducted a retrospective cohort study using the INSIGHT Clinical Research Network. The study population included 11,728 and 15,196 older adults in New York City (age ≥ 75 years) with a diagnosis of type 2 diabetes, and at least one other chronic medical condition, in 2017 and 2022, respectively. The main outcome of interest was inappropriate tight glycemic control, defined as HbA1c <7.0% (<53 mmol/mol) with prescription of at least one high-risk agent (insulin or insulin secretagogue). The proportion of older adults with inappropriate tight glycemic control decreased by nearly 19% over a five-year period (19.4% in 2017 to 15.8% in 2022). There was a significant decrease in insulin (27.8% in 2017; 24.3% in 2022) and sulfonylurea (29.4% in 2017; 21.7% in 2022) medication prescription, and increase in use of GLP-1 agonists (1.8% in 2017; 11.4% in 2022) and SGLT-2 inhibitors (5.8% in 2017; 25.1% in 2022), among the total population. Factors associated with inappropriate tight glycemic control in 2022 included history of heart failure (adjusted odds ratio [aOR] 1.38), chronic kidney disease ([aOR] 1.93), colorectal cancer ([aOR] 1.38), acute myocardial infarction ([aOR] 1.28), "other" ([aOR] 0.72) or "unknown" ([aOR] 0.72) race, and a point increase in BMI ([aOR] 0.98). We found an encouraging trend toward less use of high-risk medication strategies for older adults with type 2 diabetes and multiple chronic conditions. However, one in six patients in 2022 still had inappropriate tight glycemic control, indicating a need for continued efforts to optimize diabetes management in this population.

Hypoglycemic Response to Dorzagliatin in a Patient With GCK-MODY.

Metformin, insulin, and insulin secretagogues do not alter HbA1c levels in glucokinase maturity-onset diabetes of the young (GCK-MODY). However, the efficacy of the new hypoglycemic drugs on GCK-MODY remains unclear. We describe a case of GCK-MODY with unchanged blood glucose under different therapies during an 8 years' follow-up. His HbA1c and biochemical indices under different hypoglycemic treatments were recorded. Oral glucose-lowering drugs, including thiazolidinediones, dipeptidyl peptidase 4 inhibitor, α-glucosidase inhibitor, and sodium-glucose cotransporter 2 inhibitor that had not been evaluated previously, did not improve the HbA1c level in this patient. However, the glucokinase activator dorzagliatin effectively and safely lowered his HbA1c level. Dorzagliatin was effective and safe in this patient with GCK-MODY, providing potential application prospects for precise treatment of GCK-MODY with dorzagliatin.

Pancreatic β cell models for screening insulin secretagogues and cytotoxicity

Pancreatic β cell models for screening insulin secretagogues and cytotoxicity

Apigenin potentiates glucose-stimulated insulin secretion through the PKA-MEK kinase signaling pathway independent of K-ATP channels

AimApigenin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, cause stimulation of insulin action and secretion, manage ROS, and prevent diabetes complications. Apigenin was identified as a new insulin secretagogue that enhances glucose-stimulated insulin secretion and seems like a better antidiabetic drug candidate. Here we explored the insulinotropic mechanism(s) of apigenin in vitro in mice islets and in vivo in diabetic rats. MethodsSize-matched pancreatic islets were divided into groups and incubated in the presence or absence of apigenin and agonists or antagonists of major insulin signaling pathways. The secreted insulin was measured by ELISA. The intracellular cAMP was estimated by cAMP acetylation assay. The acute and chronic effects of apigenin were evaluated in diabetic rats. Resultsapigenin dose-dependently enhanced insulin secretion in isolated mice islets, and its insulinotropic effect was exerted at high glucose concentrations distinctly different from glibenclamide. Furthermore, apigenin amplified glucose-induced insulin secretion in depolarized and glibenclamide-treated islets. Apigenin showed no effect on intracellular cAMP concentration; however, an additive effect was observed by apigenin in both forskolin and IBMX-induced insulin secretion. Interestingly, H89, a PKA inhibitor, and U0126, a MEK kinase inhibitor, significantly inhibited apigenin-induced insulin secretion; however, no significant effect was observed by using ESI-05, an epac2 inhibitor. Apigenin improved glucose tolerance and increased glucose-stimulated plasma insulin levels in diabetic rats. Apigenin also lowered blood glucose in diabetic rats upon chronic treatment. ConclusionApigenin exerts glucose-stimulated insulin secretion by modulating the PKA-MEK kinase signaling cascade independent of K-ATP channels.

Cell identity dynamics and insight into insulin secretagogues when employing stem cell-derived islets for disease modeling.

Stem cell-derived islets (SC-islets) are not only an unlimited source for cell-based therapy of type 1 diabetes but have also emerged as an attractive material for modeling diabetes and conducting screening for treatment options. Prior to SC-islets becoming the established standard for disease modeling and drug development, it is essential to understand their response to various nutrient sources in vitro. This study demonstrates an enhanced efficiency of pancreatic endocrine cell differentiation through the incorporation of WNT signaling inhibition following the definitive endoderm stage. We have identified a tri-hormonal cell population within SC-islets, which undergoes reduction concurrent with the emergence of elevated numbers of glucagon-positive cells during extended in vitro culture. Over a 6-week period of in vitro culture, the SC-islets consistently demonstrated robust insulin secretion in response to glucose stimulation. Moreover, they manifested diverse reactivity patterns when exposed to distinct nutrient sources and exhibited deviant glycolytic metabolic characteristics in comparison to human primary islets. Although the SC-islets demonstrated an aberrant glucose metabolism trafficking, the evaluation of a potential antidiabetic drug, pyruvate kinase agonist known as TEPP46, significantly improved in vitro insulin secretion of SC-islets. Overall, this study provided cell identity dynamics investigation of SC-islets during prolonged culturing in vitro, and insights into insulin secretagogues. Associated advantages and limitations were discussed when employing SC-islets for disease modeling.

Novel Approaches for the Management of Type 2 Diabetes Mellitus: An Update.

Diabetes mellitus is an irreversible, chronic metabolic disorder indicated by hyperglycemia. It is now considered a worldwide pandemic. T2DM, a spectrum of diseases initially caused by tissue insulin resistance and slowly developing to a state characterized by absolute loss of secretory action of the β cells of the pancreas, is thought to be caused by reduced insulin secretion, resistance to tissue activities of insulin, or a combination of both. Insulin secretagogues, biguanides, insulin sensitizers, alpha-glucosidase inhibitors, incretin mimetics, amylin antagonists, and sodium-glucose co-transporter-2 (SGLT2) inhibitors are the main medications used to treat T2DM. Several of these medication's traditional dosage forms have some disadvantages, including frequent dosing, a brief half-life, and limited absorption. Hence, attempts have been made to develop new drug delivery systems for oral antidiabetics to ameliorate the difficulties associated with conventional dosage forms. In comparison to traditional treatments, this review examines the utilization of various innovative therapies (such as microparticles, nanoparticles, liposomes, niosomes, phytosomes, and transdermal drug delivery systems) to improve the distribution of various oral hypoglycemic medications. In this review, we have also discussed some new promising candidates that have been approved recently by the US Food and Drug Administration for the treatment of T2DM, like semaglutide, tirzepatide, and ertugliflozin. They are used as a single therapy and also as combination therapy with drugs like metformin and sitagliptin.

Sulfonylureas Compromise Microvascular Flow in Mouse Skeletal Muscle

Sulfonylureas are among the most prescribed oral anti-hyperglycaemics, particularly in low- and middle-income countries. Sulfonylureas are insulin secretagogues through blocking ATP-sensitive potassium channels (KATP) in β-cells of the pancreas. Despite wide usage, sulfonylureas are associated with increased cardiovascular disease morbidity and all-cause mortality, with ill-defined mechanisms. We tested the hypothesis that glyburide could block KATP channels in the microvasculature, thereby disrupting tissue oxygen demand-supply balance. We further investigated the contribution of other potassium channels to capillary-to-arteriole signalling. Experiments were conducted using an in-vivo anesthetized mouse skeletal muscle preparation (extensor digitorum longus, EDL); exteriorized and situated at in-situ length, overtop an oxygen-permeable membrane covering a gas chamber, and bathed in PlasmaLyte. C57BL/6 mice were employed (n=6-8). Brightfield images were captured at two wavelengths: oxygen-dependent and oxygen-independent, enabling the simultaneous determination of capillary hemodynamics and RBC oxygen content. Low oxygen challenges were achieved by dropping oxygen levels in the gas chamber from 7% to 2% for 3 minutes. Challenges were conducted before (control) and after drugs were added to bathing solution. Parameters were obtained before the challenge (baseline), during the challenge (2 regions) and after the challenge (recovery). Statistical significance was determined using a paired Student’s t-test. Target channels localization was investigated using immunofluorescence in formalin-fixed EDL. Oxygen challenges augmented EDL surface capillary hematocrit and RBC velocity and supply rate, while reducing RBC oxygen saturation. Incubation of the EDL with 10 μM glyburide decreased the baseline RBC supply rate (p&lt;0.05 vs control) and blunted the magnitude of capillary responses to the oxygen challenge (p&lt;0.05 vs control). Immunofluorescence confirmed the localization of KATP channels in EDL capillaries. Normal capillary responses were obtained when small and intermediate conductance or inward rectifier potassium channels were neutralized. This implies minimal or no contribution of these channels in oxygen signaling in the microvasculature. This data begins to elucidate the acute and direct effects of systemic KATP blockers on capillary-to-arteriole conducted signaling, which is likely key to optimal tissue oxygen regulation. Further experiments are warranted to confirm this conclusion. This work was supported by the Natural Science and Engineering Research Council of Canada (NSERC, RGPIN/04659-2017), an Ontario Graduate Scholarship (M.A.E) and a CIHR doctoral award (M.A.E). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diabetes-related hypoglycemia, contributing risk factors, glucagon prescriptions in two community hospitals

IntroductionHypoglycemia has long been recognized as a dangerous adverse effect of the treatment of diabetes mellitus with insulin or insulin secretagogues. ObjectiveOur study was aimed to identify the number of diabetic patients presenting to the emergency department (ED) with hypoglycemia, contributing risk factors for hypoglycemia (including antidiabetic medication regimens), the number of episodes of hypoglycemia requiring medical attention, and how many patients were prescribed glucagon at discharge. Study designOur study is a retrospective analysis across two hospitals from October 2019 to March 2022, including the population of adult persons with diabetes mellitus, above 18 years of age, presenting to the emergency department with hypoglycemia. ResultsOf the women were 2 African Americans, 25 Caucasians, 17 Hispanics, and 39 from other ethnicities. Of the men were 8 African Americans, 32 Caucasians, 27 Hispanics, and 44 from other ethnicities. The mean age of males was 66.2 years, and females was 72.9 years. 131 patients had no prior visits for hypoglycemia. Of the 194 patients, 54 were discharged from the ED, and 140 were admitted to the hospital. The most common risk factors associated with hypoglycemia requiring medical attention were age > 65, having more than one comorbidity, decreased oral intake, and poor socioeconomic status. Regarding recurrent presentations with hypoglycemia, there was a significant association with insulin use (p-value = 0.0007), with a higher-than-expected number of insulin users having a previous visit for hypoglycemia. Only 16.7 % of non-insulin-using patients had prior visits, compared to 40.6 % of insulin users. Pairwise Chi-square testing did not reveal a significant association between any other medication class and prior visits for hypoglycemia, nor was there an association between risk factors and prior visits. To obtain optimal glycemic control, early identification of hypoglycemia risk factors, self-monitoring of blood glucose, and proper selection of anti-diabetic regimens are important to prevent long-term complications. ConclusionUnfortunately, the three elements that would prevent subsequent severe hypoglycemic events (i.e., education, adjustment of medication, and glucagon prescription) are underutilized. Hypoglycemia is more common in the elderly population which remains an unmodifiable risk factor. Identifying patients with persistent poor oral intake is extremely important as they may be prone to hypoglycemic episodes on their current anti-diabetic regimen and will need medication adjustments accordingly. Our future research focuses on whether giving glucagon prescriptions to patients with diabetes mellitus at discharge prevents recurrent ED visits for hypoglycemia.

Retatruide' drug trial: A paradigm shift in Type 2 Diabetes management.

Type 2 diabetes mellitus (T2DM) is a chronic medical condition characterised by persistent hyperglycemia caused by insulin resistance and impaired beta cell function. Typically, it occurs in individuals aged 45 and above, but due to the growing prevalence of obesity and sedentary lifestyle, it is increasingly being diagnosed in younger adults and adolescents. A positive family history of T2DM and specific genes such as TCF7L2 and PPARG also play an essential role.[1] Consequently, persistent hyperglycemia in type 2 DM can give rise to a range of microvascular complications such as retinopathy, neuropathy and nephropathy and macrovascular complications such as coronary artery and cerebrovascular diseases. T2DM accounts for 90% of the cases of diabetes, raising concern among the healthcare sector worldwide. In 2017, approximately 462 million individuals were affected by type 2 DM, accounting for 6.28% of the world’s population. By 2030, it is estimated that the global prevalence will rise to 7079 individuals per 100,000.[2] To prevent the complications caused by T2DM, it is essential to prioritize glycemic control. First and foremost, effective dietary control is pivotal. It has been established that obesity in individuals with T2DM is closely associated with insulin resistance and defects in insulin secretions thus managing the calorie intake is mandatory. However, pharmacologic intervention with oral glucose-lowering agents or insulin therapy is necessary when the patient’s blood glucose doesn’t fall within normal limits despite weight reduction, exercise and dietary modifications. The first line pharmacological agent used is Metformin, an oral medication that reduces glucose production in the liver. Additionally, insulin secretagogues such as sulfonylureas and glinides promote insulin release by stimulating beta cells. Thiazolidinediones is another example of an oral agent used to treat diabetes by enhancing glucose uptake by the muscle, liver and adipose tissue.[3] Furthermore, it is crucial to understand that the Incretin effect, responsible for stimulating insulin secretion after meals, is primarily mediated by gut-derived incretin hormones known as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). However, patients with type 2 diabetes (T2DM) commonly exhibit defects in this process. To address this issue, in addition to oral medications, injectable drugs such as RA-GLP1 (Semaglutide, Dulaglutide) are administered to emulate the actions of human GLP-1 effectively. These injectable treatments are vital in reducing postprandial hyperglycemia and have become indispensable in managing T2DM. ---Continue

Associations between change in BMI and the risk of hypertension and dyslipidaemia in people receiving integrase strand-transfer inhibitors, tenofovir alafenamide, or both compared with other contemporary antiretroviral regimens: a multicentre, prospective observational study from the RESPOND consortium cohorts

Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens. This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI. Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (pinteraction=0·46 for hypertension; pinteraction=0·31 for dyslipidaemia). Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV. The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.

Pharmacological and phytochemical insights on the pancreatic β-cell modulation by Angelica L. roots

Ethnopharmacological relevanceAngelica roots are a significant source of traditional medicines for various cultures around the northern hemisphere, from indigenous communities in North America to Japan. Among its many applications, the roots are used to treat type 2 diabetes mellitus; however, this application is not mentioned often. Ethnopharmacological studies have reported the use of A. japonica var. hirsutiflora, A. furcijuga, A. shikokiana, and A. keiskei to treat diabetes symptoms, and further reports have demonstrated the three angelica roots, i.e., A. japonica var. hirsutiflora, A. reflexa, and A. dahurica, exhibit insulin secretagogue activity. Aim of the studyThis study aimed to phytochemically characterize and compare angelica roots monographed in the European Pharmacopeia 11th, isolate major plant metabolites, and assess extracts and isolates' capability to modulate pancreatic β-cell function. Materials and methodsRoot extracts of Angelica archangelica, Angelica dahurica, Angelica biserrata, and Angelica sinensis were phytochemically profiled using liquid chromatography method coupled with mass spectrometry. Based on this analysis, simple and furanocoumarins were isolated using chromatography techniques. Extracts (1.6–50 μg/mL) and isolated compounds (5–40 μmol/L) were studied for their ability to modulate insulin secretion in the rat insulinoma INS-1 pancreatic β-cell model. Insulin was quantified by the homogeneous time-resolved fluorescence method. ResultsForty-one secondary metabolites, mostly coumarins, were identified in angelica root extracts. A. archangelica, A. dahurica, and A. biserrata root extracts at concentration of 12.5–50 μg/mL potentiated glucose-induced insulin secretion, which correlated with their high coumarin content. Subsequently, 23 coumarins were isolated from these roots and screened using the same protocol. Coumarins substituted with the isoprenyl group were found to be responsible for the extracts' insulinotropic effect. ConclusionsInsulinotropic effects of three pharmacopeial angelica roots were found, the metabolite profiles and pharmacological activities of the roots were correlated, and key structures responsible for the modulation of pancreatic β-cell function were identified. These findings may have implications for the traditional use of angelica roots in treating diabetes. Active plant metabolites may also become lead structures in the search for new antidiabetic treatments.

A combination of gliclazide and metformin attenuates obesity-induced polycystic ovary syndrome in female Wistar rats

Presently, it is known that the progression of obesity concomitantly leads to polycystic ovary syndrome and infertility. This study aimed to evaluate the potential effects of metformin (M; insulin secretagogues) and gliclazide (G; insulin sensitizer) alone and their combination at different doses to treat obesity-induced PCOS. High high-fat diet was given to all female Wistar rats for nine weeks to induce obesity except for the normal control group which received a normal chow diet. Estradiol valerate (0.8 mg/kg) was also given to all obese rats to induce polycystic ovarian syndrome. After the induction, M (100, 300 mg/kg) and G (5, 10 mg/kg) were given orally either individually or in combination for 28 days. The notable (p < 0.0001) reduction in body weight and blood glucose level was observed in treatment groups in contrast to disease control (DCG). The marked (p < 0.05–0.0001) decrease in hemocylated hemoglobin, serum insulin, cholesterol, triglycerides, and testosterone was observed in treated groups, notably in combination groups (M100+G10 mg/kg) in contrast to DCG. There was a considerable (p < 0.01–0.0001) increase in progesterone E2, estradiol, luteinizing, and follicle-stimulating hormones in treated groups as compared to DCG. Treatment with M and G treated groups also exhibited marked (p < 0.05–0.0001) increases in SOD, CAT, and GSH while decreased in NO and MDA levels in ovary tissue as evidenced by the histological study of the ovary. Treatment with M and G alone and in combination significantly (p < 0.0001) restored the serum IL-6, NrF2, and NF-κB levels as compared to DCG. The results inveterate that the M and G combination (M100+G10, and M300+G10) was useful in treating obesity-induced infertility due to antioxidant properties, hypolipidemic effects, and modulation of inflammatory markers.

C-peptide Level in Patients With Uncontrolled Type 2 Diabetes Mellitus on Oral Anti-diabetic Drugs.

In the development and progression of type 2 diabetes mellitus, β-cell dysfunction occurs after insulin resistance. Despite poor glycaemic control, there is a practice of increasing the dose of oral anti-diabetics or adding more drugs to the regimen due to the common perception that low endogenous insulin secretion is related to type 1 diabetes mellitus only and patient'spoor compliance to injectables. Keeping this perspective in mind, this study was conducted to assess the prevalence of beta cell dysfunction by low serum C-peptide levels and its correlation with poor glycaemic control. A total of 134 patients with type 2 diabetes mellitus for more than 10 years on oral anti-diabetic drugs fulfilling our eligibility criteria were enrolled in our study. Blood samples for fasting blood sugar and fasting C-peptide level were taken before breakfast and uptake of anti-diabetic drugs. Correlation analysis was performed to evaluate the relationship between fasting C-peptide and glycaemic control with respect to glycated haemoglobin (HbA1c). Of the patients,19.40% had insufficient beta cell reserve serumlevels (C-peptide < 0.5 ng/ml), of which most of the patients (14/26 = 53.85%) had poor glycaemic control (HbA1c < 8.0%). Overall, there was a significant correlation between poor glycaemic control with respect to HbA1c and low serum C-peptide levels (p < 0.05). We found a significant association of beta cell dysfunction (low fasting C-peptide level) with the use of insulin secretagogue. The proportion of patients with C-peptide levels less than 0.5 ng/ml was lower in patients using sodium-glucose cotransporter-2 (SGLT-2) inhibitors as compared to insulin secretagogue. SGLT-2 inhibitors should be preferred over other anti-diabetic drugs as an add-on to existing metformin therapy. Insulin requirement must be assessed in patients who have long-term type 2 diabetes mellitus.

Amphiphilic, lauric acid-coupled pluronic-based nano-micellar system for efficient glipizide delivery

Glipizide; an insulin secretagogue belonging to the sulfonylurea class, is a widely used antidiabetic drug for managing type 2 diabetes. However, the need for life-long administration and repeated doses poses challenges in maintaining optimal blood glucose levels. In this regard, orally active sustained-release nano-formulations can be a better alternative to traditional antidiabetic formulations. The present study explored an innovative approach by formulating orally active sustained-release nano-micelles using the amphiphilic lauric acid-conjugated-F127 (LAF127) block copolymer. LAF127 block copolymer was synthesized through esterification and thoroughly characterized before being employed to develop glipizide-loaded nano-micelles (GNM) via the thin-film hydration technique. The optimized formulation exhibited mean particle size of 341.40 ± 3.21 nm and depicted homogeneous particle size distribution with a polydispersity index (PDI) < 0.2. The formulation revealed a surface charge of −17.11 ± 6.23 mV. The in vitro release studies of glipizide from developed formulation depicted a sustained release profile. Drug loaded micelles exhibited a substantial reduction in blood glucose levels in diabetic rats for a duration of up to 24 h. Notably, neither the blank nano-micelles of LAF127 nor the drug loaded micelles manifested any indications of toxicity in healthy rats. This study provides an insight on suitability of synthesized LAF127 block copolymer for development of effective oral drug delivery systems for anti-diabetic activity without any significant adverse effects.

Causes of In-Hospital Death and Pharmaceutical Associations with Age of Death during a 10-Year Period (2011-2020) in Individuals with and without Diabetes at a Japanese Community General Hospital.

Since diabetes and its complications have been thought to exaggerate cardiorenal disease, resulting in a short lifespan, we investigated causes of death and lifespans in individuals with and without diabetes at a Japanese community general hospital during the period from 2011 to 2020. Causes of death and age of death in individuals with and those without diabetes were compared, and associations between medications used and age of death were statistically analyzed. A total of 2326 deaths were recorded during the 10-year period. There was no significant difference between the mean ages of death in individuals with and those without diabetes. Diabetic individuals had higher rates of hepato-pancreatic cancer and cardio-renal failure as causes of death. The prescription rates of antihypertensives, antiplatelets, and statins in diabetic individuals were larger than those in non-diabetic individuals. Furthermore, the use of sulfonyl urea or glinides and insulin was independently and inversely associated with the age of death. In conclusion, individuals with diabetes were treated with comprehensive pharmaceutical interventions and had life spans comparable to those of individuals without diabetes. This study's discovery of an inverse relationship between the use of insulin secretagogues or insulin and the age of death suggests that the prevention of life-threatening hypoglycemia is crucial for individuals with diabetes.