Treatment Of Hyperglycemia Research Articles

(208) Associations Between SGLT-2 Inhibitor Usage and Urologic Diagnoses: Implications for Sexual Health and Lower Urinary Tract Symptoms

Abstract Introduction Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are used for the treatment of hyperglycemia in patients with type 2 diabetes. Due to the amount of glucose that is being filtered, SGLT-2 inhibitors may be associated with or cause concern for balanitis, balanoposthitis, and increased lowery urinary tract symptoms (LUTS), such as overactive bladder (OAB). Objective In this retrospective, IRB approved study, we sought to characterize the frequency of new urologic visits and urologic diagnoses, such as balanitis or balanoposthitis, LUTS, and OAB, among others, in patients who had been recently started on SGLT-2 inhibitors. Methods We reviewed records from our institution from 2007 to 2022 of patients who had been to a urology outpatient visit within 2 years. Patients were stratified based on whether they had been prescribed an SGLT-2 inhibitor within two years of the scheduled urology appointment at the time of analysis. Data was collected and analyzed utilizing two-tailed t test and Chi-squared analyses in Microsoft Excel (Microsoft Corporation, Redmond, WA, USA Results A total of n = 337,342 patients met our inclusion criteria. Of these, n= 41102 had been prescribed a SGLT-2 inhibitor between 2007-2022. N= 296240 had not been prescribed SGLT2 inhibitors but had seen a urologist in the outpatient setting and served as control. The frequency of any of the urologic diagnoses listed in Table 1 or circumcision, dorsal slit, or buried penis repair within 2 years was 835/41102 (2.03%) for the SGLT-2 group and 4484/296240 (1.51%) for the non-SGLT2 group, respectively (p<0.0001). Urology appointments made within one year had the same frequency and statistical significance between groups. Frequency of balanitis((27/41102, 0.0657%) vs (94/296240, 0.0317%)) (p=0.0007) and balanoposthitis ((9/41102, 0.0218%) vs (20/296240, 0.00675%)) (p=0.002) was higher in the SGLT-2 group. Similarly, OAB was 111/41102 (0.27%) in the SGLT-2 group and 488/296240 (0.1%) in the non-SGLT-2 group (p<0.0001). Finally, urinary frequency ((306/41102, 0.74%) vs (1268/296240,0.43%)) (p<0.0001) and urinary urgency ((213/41102, 0.53%) vs (998/296240, 0.34%)) (p<0.0001) were found more often in the SGLT-2 group. Urinary incontinence (p=0.145), urologic surgery within 1 year of visit (p=0.135), and recurrent urinary tract infection (p=0.812) were not different between groups. Full results are listed in Table 1. Conclusions Our results demonstrate that patients prescribed SGLT-2 inhibitors were found to have a variety of new penile inflammatory and lower urinary tract diagnoses following medication usage. Overactive bladder, specifically, seems to occur more often than other conditions allowing SGLT-2 usage. Additionally, urologic visits within a year of medication were significantly associated with SGLT-2 usage, reflecting that patients on SGLT-2 inhibitors may face substantial urologic sequalae. Based on these results, we suggest that urologists, endocrinologists, and primary care physicians should work collaboratively to monitor patients on SGLT-2 inhibitors. Further, urologists should be aware of the association between these drugs, sexual health issues and LUTS, and plan accordingly when patients on SGLT-2 inhibitors enter their care. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Boston scientific.

Glucometabolism in Kidney Transplant Recipients with and without Posttransplant Diabetes: Focus on Beta-Cell Function.

Posttransplant diabetes mellitus (PTDM) is a common complication after kidney transplantation. Pathophysiologically, whether beta-cell dysfunction rather than insulin resistance may be the predominant defect in PTDM has been a matter of debate. The aim of the present analysis was to compare glucometabolism in kidney transplant recipients with and without PTDM. To this aim, we included 191 patients from a randomized controlled trial who underwent oral glucose tolerance tests (OGTTs) 6 months after transplantation. We derived several basic indices of beta-cell function and insulin resistance as well as variables from mathematical modeling for a more robust beta-cell function assessment. Mean ± standard deviation of the insulin sensitivity parameter PREDIM was 3.65 ± 1.68 in PTDM versus 5.46 ± 2.57 in NON-PTDM. Model-based glucose sensitivity (indicator of beta-cell function) was 68.44 ± 57.82 pmol∙min-1∙m-2∙mM-1 in PTDM versus 143.73 ± 112.91 pmol∙min-1∙m-2∙mM-1 in NON-PTDM, respectively. Both basic indices and model-based parameters of beta-cell function were more than 50% lower in patients with PTDM, indicating severe beta-cell impairment. Nonetheless, some defects in insulin sensitivity were also present, although less marked. We conclude that in PTDM, the prominent defect appears to be beta-cell dysfunction. From a pathophysiological point of view, patients at high risk for developing PTDM may benefit from intensive treatment of hyperglycemia over the insulin secretion axis.

Treatment of glucocorticoid- induced hyperglycemia in hospitalized patients - a systematic review and meta- analysis

PurposeGlucocorticoid (GC)-induced hyperglycemia is a frequent issue, however there are no specific guidelines for this diabetes subtype. Although treat-to-target insulin is recommended in general to correct hyperglycemia, it remains unclear which treatment strategy has a positive effect on outcomes. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess whether treating GC-induced hyperglycemia improves clinical outcomes.MethodsMEDLINE and EMBASE were systematically searched for RCTs on adults reporting treatment and outcomes of GC-induced hyperglycemia since the beginning of the data bases until October 21, 2023. Glucose-lowering strategies as compared to usual care were investigated.ResultsWe found 17 RCTs with 808 patients and included seven trials in the quantitative analysis. Patients with an intensive glucose-lowering strategy had lower standardized mean glucose levels of – 0.29 mmol/l (95%CI -0.64 to -0.05) compared to usual care group patients. There was no increase in hypoglycemic events in the intensively treated groups (RR 0.91, 95%CI 0.70–1.17). Overall, we did not have enough trials reporting clinical outcomes for a quantitative analysis with only one trial reporting mortality.ConclusionIn GC-induced hyperglycemia, tight glucose control has a moderate effect on mean glucose levels with no apparent harmful effect regarding hypoglycemia. There is insufficient data whether insulin treatment improves clinical outcomes, and data on non-insulin based treatment regimens are currently too sparse to draw any conclusions.Systematic review registrationRegistered as CRD42020147409 at PROSPERO (https://www.crd.york.ac.uk/prospero/) on April 28, 2020

Glycemic Trends in Patients with Thyroid Eye Disease Treated with Teprotumumab in 3 Clinical Trials

ObjectiveAssess incidence, severity, and outcomes of serum glucose excursions in patients with thyroid eye disease who received the insulin-like growth factor-1 receptor inhibitor, teprotumumab, during pivotal clinical trials. DesignAnalysis of pooled glycemic data and longitudinal trends. Subjectsphase 2 and phase 3 (OPTIC) pooled analysis: 170 patients (84 teprotumumab, 86 placebo); OPTIC-X: 51 patients from OPTIC. MethodsTeprotumumab administered as 8 intravenous infusions over 21 weeks. In the phase 2 trial, serum glucose was measured at weeks 1, 4, 15, and 21, with fasting blood collections weeks 1 and 4. In OPTIC and OPTIC-X, serum glucose was measured at each study visit, with fasting draws weeks 1 and 4 (non-diabetic patients) or all visits (diabetic patients). In all studies, hemoglobin A1c (HbA1c) was measured at baseline, 12, and 24 weeks plus weeks 36 and 48 of OPTIC-X. Main Outcome MeasuresSerum glucose and HbA1c over time. ResultsIn the pooled analysis, 9 hyperglycemic episodes were reported in 8 teprotumumab patients; mean HbA1c in teprotumumab patients increased 0.22% from baseline to week 24 (to 5.8%, range 5.0%–7.9%) versus 0.04% in placebo patients (to 5.6%, range 4.6%–8.1%). At study end, 78% of teprotumumab and 87% of placebo patients were normoglycemic. Normoglycemia was maintained from baseline to week 24 in 84% (57/68) of teprotumumab and 93% (64/69) of placebo patients. Of prediabetic patients, 43% (3/7) remained prediabetic in both groups and 29% (2/7) of teprotumumab and 14% (1/7) of placebo patients were diabetic at week 24. OPTIC-X showed a trend toward increased fasting glucose and HbA1c during teprotumumab retreatment and initial therapy (placebo patients from OPTIC). Fasting glucose commonly rose following the first 2-3 infusions and stabilized over subsequent infusions. Most hyperglycemic incidents occurred in patients with baseline prediabetes or diabetes and were controlled with medication. There was no evidence of progression or increased incidence of hyperglycemia with subsequent doses. ConclusionsSerious glycemic excursions are uncommon in patients who are normoglycemic before teprotumumab therapy. Patients with controlled diabetes or impaired glucose tolerance can be treated safely if baseline screening, regular monitoring of glycemic control, and treatment of hyperglycemia are ensured.

Antidiabetic activity of Akar Kuning (Fibraurea tinctoria Lour) Extract in Alloxan-Induced Diabetic White Male Rats

The Akar kuning (Fibraurea tinctoria Lour) is a well-known plant for its potential for the treatment of liver damage and hyperglycemia. However, the main constituent responsible for the anti-diabetic effect is unknown. This study was conducted to investigate the effect of administration of Fibraurea tinctoria Lour ethanol extract on the blood sugar levels in alloxan-induced diabetic male albino rats. All animals were acclimatized with normal feed, and were subsequently divided into 5groups (3rats/ group). Group 1 (negative control group) was given 0.3% NaCMC; Groups 2, 3, and 4 (treatment groups), were given 50, 100, and 200mg/kg BW of Fibraurea tinctoria Lour ethanol extract, respectively once daily for 15 days, while Group 5(positive control group) received 0.65mg/kg BW glibenclamide. Before the treatments, the rats were induced intraperitoneally with 175mg/kg BW alloxan monohydrate. The blood glucose levels were observed every five days. The results showed that the ethanol extract at the doses of 50, 100, and 200mg/kg BW caused a significant decrease (p <0.05) in the blood glucose levels compared to the negative control group. Also, the highest decrease in the blood glucose level was observed in the 100mg/kg BW treatment group. The findings from this study indicate that the ethanol extract of Fibraurea tinctoria Lour has an antidiabetic effect and the 100mg/kg BW dose was the most effective in lowering blood glucose levels.

Blood glucose control in acute stroke patients under total energy restriction with different carbohydrate intake and SGLT2 inhibitors availability: a retrospective cohort study

Hyperglycemia in acute stroke patients worsens neurological outcomes. However, effective and safe management during the acute stage has not been established. Therefore, we aimed to compare the effect of medications and nutrition therapy on blood glucose control in three cohorts with different carbohydrate content and availability of sodium-glucose cotransporter 2 inhibitors (SGLT2is) to identify the current optimal treatment for acute-stage hyperglycemia. We retrospectively studied patients with acute stroke admitted to our hospital between 2011 and 2019. We divided the study period into three periods as follows: traditional (Td, 2011–2013), transition (Ts, 2013–2014), and novel (N, 2014–2019). To evaluate glucose-lowering efficacy and safety, we included conscious patients with glycated hemoglobin A1c ≥6.5%, blood glucose levels ≥11.1 mmol/L, normal renal function at admission, oral diet and medications, and fasting blood glucose (FBG) test on day 7. We performed total energy restriction (TER) in each period with different carbohydrate contents: 60% in Td, 40% in Ts, and N. The attending physicians chose glucose-lowering medications. SGLT2is were available in the N period only. Our target FBG was <7 mmol/L by day 7. The 26, 22 and 36 patients were enrolled in the Td, Ts and N periods. The blood glucose levels significantly decreased by day 7 in all periods. The target FBG was achieved in 30.8% of Td patients, 31.8% of Ts patients, and 72.2% of N patients. The N period had the highest population of achieving the target FBG. The 40%-carbohydrate diet based on TER plus SGLT2is was the most effective way to lower blood glucose levels. The N period had the highest population of positive urine ketones. However, no symptomatic ketoacidosis occurred. A 40%-carbohydrate diet based on TER combined with SGLT2is might be a potentially effective and safe treatment for hyperglycemia in acute stroke-conscious patients.

Pgam5 aggravates hyperglycemia-induced myocardial dysfunction through disrupting Phb2-dependent mitochondrial dynamics.

This study aims to elucidate the roles of Phosphoglycerate Mutase Family Member 5 (Pgam5) and Prohibitin 2 (Phb2) in the context of hyperglycemia-induced myocardial dysfunction, a critical aspect of diabetic cardiomyopathy. The research employed primary cardiomyocytes, which were then subjected to hyperglycemia treatment to mimic diabetic conditions. We used siRNA transfection to knock down Pgam5 and overexpressed Phb2 using adenovirus transfection to assess their individual and combined effects on cardiomyocyte health. Mitochondrial function was evaluated through measurements of mitochondrial membrane potential using the JC-1 probe, and levels of mitochondrial reactive oxygen species (ROS) were assessed. Additionally, the study involved qPCR analysis to quantify the transcriptional changes in genes related to mitochondrial fission and mitophagy. Our findings indicate that hyperglycemia significantly reduces cardiomyocyte viability and impairs mitochondrial function, as evidenced by decreased mitochondrial membrane potential and increased ROS levels. Pgam5 knockdown was observed to mitigate these adverse effects, preserving mitochondrial function and cardiomyocyte viability. On the molecular level, Pgam5 was found to regulate genes associated with mitochondrial fission (such as Drp1, Mff, and Fis1) and mitophagy (including Parkin, Bnip3, and Fundc1). Furthermore, overexpression of Phb2 countered the hyperglycemia-induced mitochondrial dysfunction and normalized the levels of key mitochondrial antioxidant enzymes. The combined data suggest a protective role for both Pgam5 knockdown and Phb2 overexpression against hyperglycemia-induced cellular and mitochondrial damage. The study elucidates the critical roles of Pgam5 and Phb2 in regulating mitochondrial dynamics in the setting of hyperglycemia-induced myocardial dysfunction. By modulating mitochondrial fission and mitophagy, Pgam5 and Phb2 emerge as key players in preserving mitochondrial integrity and cardiomyocyte health under diabetic conditions. These findings contribute significantly to our understanding of the molecular mechanisms underlying diabetic cardiomyopathy and suggest potential therapeutic targets for mitigating myocardial dysfunction in diabetes.

The integrated analysis and underlying mechanisms of FNDC5 on diabetic induced cognitive deficits.

Chronic hyperglycemia is considered as an important factor to promote the neurodegenerative process of brain, and the synaptic plasticity as well as heterogeneity of hippocampal cells are thought to be associated with cognitive dysfunction in the early process of neurodegeneration. To date, fibronectin type III domain-containing protein 5 (FNDC5) has been highlighted its protective role in multiple neurodegenerative diseases. However, the potential molecular and cellular mechanisms of FNDC5 on synaptic plasticity regulation in cognitive impairment (CI) induced by diabetics are still need to known. To investigate the heterogeneity and synaptic plasticity of hippocampus in animals with CI state induced by hyperglycemia, and explore the potential role of FNDC5 involved in this process. Firstly, the single cell sequencing was performed based on the hippocampal tissue from db diabetic mice induced CI and normal health control mice by ex vivo experiments; and then the integrated analysis and observations validation using Quantitative Real-time PCR, western blot as well as other in vitro studies. We observed and clarified the sub-cluster of type IC spiral ganglion neurons expressed marker genes as Trmp3 and sub-cluster of astrocytes with marker gene as Atp1a2 in hippocampal cells from diabetic animals induced CI and the effect of those on neuron-glial communication. We also found that FNDC5\BDNF-Trk axis was involved in the synaptic plasticity regulation of hippocampus. In high glucose induced brain injury model in vitro, we investigated that FNDC5 significantly regulates BDNF expression and that over-expression of FNDC5 up-regulated BDNF expression (p<0.05) and can also significantly increase the expression of synapsin-1 (p<0.05), which is related to synaptic plasticity, In addition, the unbalanced methylation level between H3K4 and H3K9 in Fndc5 gene promoter correlated with significantly down-regulated expression of FNDC5 (p<0.05) in the hyperglycemia state. The current study revealed that the synaptic plasticity of hippocampal cells in hyperglycemia might be regulated by FNDC5\BDNF-Trk axis, playing the protective role in the process of CI induced by hyperglycemia and providing a target for the early treatment of hyperglycemia induced cognitive dysfunction in clinic.

Hypoglycemic activity of immature persimmon (Diospyros kaki Thunb.) extracts and its inhibition mechanism for α-amylase and α-glucosidase

Persimmon tannins, particularly in immature persimmons, haven't yet received corresponding attention to research on therapy of diabetes mellitus in spite of high hypoglycemic activity. To accurately screening key hypoglycemic components, immature persimmon extracts were isolated and identified using enzyme affinity ultrafiltration and HRLC-ESI-MS/MS. Among them, Hederagenin (IC50 = 0.077 ± 0.003 mg/mL), Ursolic acid (IC50 = 0.001 ± 0.000 mg/mL) and Quercetin dehydrate (IC50 = 0.081 ± 0.001 mg/mL) exhibited the strongest inhibitory effect on α-amylase (HSA and PPA) and α-glucosidase, respectively. And their inhibition mechanisms were analyzed using multi-spectral analysis, atomic force microscope and molecular docking, indicating the bonding with starch digestion enzymes through hydrogen bonding and hydrophobic interaction, and generating the enzyme aggregation. In vivo starch-tolerance experiment further verified that these inhibitors could improve postprandial hyperglycemia (17.18 % ∼ 40.29 %), far more than acarbose. Suppressing, Hederagenin and Ursolic acid as triterpenoids appeared amazing potentiality to alleviate postprandial hyperglycemia, which suggested that IPE were comprehensive exploration values on prevention and treatment of hyperglycemia.

Active peptides with hypoglycemic effect obtained from hemp (Cannabis sativa L) protein through identification, molecular docking, and virtual screening.

Hemp (Cannabis sativa L) seeds are rich in proteins of high nutritional value, which makes the study of beneficial properties of hemp seed proteins and peptides, such as hypotensive and hypoglycemic effects, increasingly attractive. The present results confirm the good processability and stability of the hemp protein hydrolysate obtained by enzymatic hydrolysis of non-dehulled hemp seed meal (NDHM). Six peptides with potential hypoglycemic activity were obtained by ethanol-graded precipitation, Nano LC-Q-Orbitrap-MS/MS mass spectrometry, and computerized virtual screening. Further, validation experiments for in vitro synthesis showed that TGLGR, SPVI, FY, and FR exhibited good α-glucosidase inhibitory activity, respectively. Animal experiments showed that the hemp protein peptides modulated blood glucose and blood lipids in hyperglycemic rats. These results indicate that hemp protein peptides can reduce blood glucose levels in hyperglycemic rats, suggesting that hemp proteins may be a promising natural source for the prevention and treatment of hyperglycemia.

A Case of Appetite Loss Did Not Improve After Treatment for Hyperglycemia and Diabetic Ketoacidosis

A Case of Appetite Loss Did Not Improve After Treatment for Hyperglycemia and Diabetic Ketoacidosis

In Vitro Anti-Oxidant, In Vivo Anti-Hyperglycemic, and Untargeted Metabolomics-Aided-In Silico Screening of Macroalgae Lipophilic Extracts for Anti-Diabetes Mellitus and Anti-COVID-19 Potential Metabolites.

COVID-19 patients with comorbid DM face more severe outcomes, indicating that hyperglycemic conditions exacerbate SARS-CoV-2 infection. Negative side effects from existing hyperglycemia treatments have urged the need for safer compounds. Therefore, sourcing potential compounds from marine resources becomes a new potential approach. Algal lipids are known to possess beneficial activities for human health. However, due to limitations in analyzing large amounts of potential anti-hyperglycemic and anti-COVID-19-related marine metabolites, there is an increasing need for new approaches to reduce risks and costs. Therefore, the main aim of this study was to identify potential compounds in macroalgae Sargassum cristaefolium, Tricleocarpa cylindrica, and Ulva lactuca lipophilic extracts for treating DM and COVID-19 by an integrated approach utilizing in vitro anti-oxidant, in vivo anti-hyperglycemic, and metabolomic-integrated in silico approaches. Among them, S. cristaefolium and T. cylindrica showed potential anti-hyperglycemic activity, with S. cristaefolium showing the highest anti-oxidant activity. A GC-MS-based untargeted metabolomic analysis was used to profile the lipophilic compounds in the extracts followed by an in silico molecular docking analysis to examine the binding affinity of the compounds to anti-DM and anti-COVID-19 targets, e.g., α-amylase, α-glucosidase, ACE2, and TMPRSS2. Notably, this study reveals for the first time that steroid-derived compounds in the macroalgae T. cylindrica had higher binding activity than known ligands for all the targets mentioned. Studies on drug likeliness indicate that these compounds possess favorable drug properties. These findings suggest the potential for these compounds to be further developed to treat COVID-19 patients with comorbid DM. The information in this study would be a basis for further in vitro and in vivo analysis. It would also be useful for the development of these candidate compounds into drug formulations.

Hyperglycaemia Among Diabetes Patients: A Preventive Approach

Hyperglycaemia is a presence of too much high glucose (sugar) in the bloodstream if it is not well-controlled. When the blood glucose level (BGL) is above 15 mmol/l, the situation is considered as hyperglycaemia. Long-term uncontrolled hyperglycaemia can affect type 1 diabetes (T1D) and type 2 diabetes (T2D) patients, as well as pregnant women with gestational diabetes. If it is not treated for a long-time, different vital organs of the body, such as the eyes, nerves, kidneys, and blood vessels may permanently damage. Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are diabetes emergencies and life-threatening complications in hyperglycaemia. Prevention and treatment of hyperglycaemia and its related complications are necessary for a healthy life of diabetes patients. This study tries to discuss the causes, symptoms, prevention, and treatment of hyperglycaemia with highlights on DKA and HHS.

Pumpkin seeds and leaves as an alternative medicine for the treatment of hyperglycemia

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia due to unhealthy dietary patterns, sedentary lifestyle behavior, and obesity. Among the two types of diabetes, type 2 is the most common in the world and the drugs used to treat hyperglycemia in type 2 DM cause adverse side effects. Hence, it is important to search for an effective natural anti-diabetic treatment to combat hyperglycemia and its complications in diabetic patients. Among the different herbal plants, pumpkin is very popular in terms of reducing blood glucose levels. Pumpkin is a popular vegetable cultivated all over the world and a rich source of bioactive compounds including phenolic compounds, unsaturated fatty acids, vitamin E and carotenoids. Currently, considerable attention is given to the seeds, leaves, and flesh of pumpkins due to their nutritional value and health benefits. However, this article focuses on the potency of pumpkin seeds and leaves to treat hyperglycemia.

The crosstalk between glomerular endothelial cells and podocytes controls their responses to metabolic stimuli in diabetic nephropathy

In diabetic nephropathy (DN), glomerular endothelial cells (GECs) and podocytes undergo pathological alterations, which are influenced by metabolic changes characteristic of diabetes, including hyperglycaemia (HG) and elevated methylglyoxal (MGO) levels. However, it remains insufficiently understood what effects these metabolic factors have on GEC and podocytes and to what extent the interactions between the two cell types can modulate these effects. To address these questions, we established a co-culture system in which GECs and podocytes were grown together in close proximity, and assessed transcriptional changes in each cell type after exposure to HG and MGO. We found that HG and MGO had distinct effects on gene expression and that the effect of each treatment was markedly different between GECs and podocytes. HG treatment led to upregulation of “immediate early response” genes, particularly those of the EGR family, as well as genes involved in inflammatory responses (in GECs) or DNA replication/cell cycle (in podocytes). Interestingly, both HG and MGO led to downregulation of genes related to extracellular matrix organisation in podocytes. Crucially, the transcriptional responses of GECs and podocytes were dependent on their interaction with each other, as many of the prominently regulated genes in co-culture of the two cell types were not significantly changed when monocultures of the cells were exposed to the same stimuli. Finally, the changes in the expression of selected genes were validated in BTBR ob/ob mice, an established model of DN. This work highlights the molecular alterations in GECs and podocytes in response to the key diabetic metabolic triggers HG and MGO, as well as the central role of GEC-podocyte crosstalk in governing these responses.

Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer.

The combination of fulvestrant with alpelisib, a PI3K inhibitor, improves progression-free survival in metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. This study describes the incidence, risk factors, and treatment of alpelisib-associated hyperglycemia. Patients with metastatic breast cancer who received alpelisib from 2013 to 2021 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Alpelisib prescription dates and patient/tumor characteristics were abstracted from medical records. Risk factors associated with hyperglycemia and alpelisib dose reduction/discontinuation were evaluated using Pearson's χ2 tests. Among 247 patients, baseline median body mass index was 25.4kg/m2 and median hemoglobin A1c (HbA1c) was 5.5%. A total of 152 patients (61.5%) developed any-grade hyperglycemia and 72 patients (29.2%) developed grade 3-4 hyperglycemia; median time to onset was 16days. A total of 100 patients (40.5%) received alpelisib on a clinical trial; rates of hyperglycemia were significantly higher in patients treated as standard care versus on a clinical trial (any-grade hyperglycemia 80.3% vs. 34.0%, grade 3-4 hyperglycemia 40.2% vs. 13.0%, p<.001). Baseline HbA1c was significantly associated with development of hyperglycemia (p<.001) and alpelisib dose reduction/discontinuation (p=.015). Among those who developed hyperglycemia, 101 (40.9%) received treatment, most commonly with metformin. A total of 49 patients (19.8%) were referred to an endocrinologist, which was associated with SGLT2 inhibitor prescription (p=.007). Rates of hyperglycemia among patients treated with alpelisib as standard care were significantly higher than patients treated on clinical trials. Elevated baseline HbA1c is associated with alpelisib-induced hyperglycemia and requiring dose modification. Optimization of glycemic status before alpelisib initiation should become routine practice.

Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition.

Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition. We conducted a single-center retrospective review of adults initiating the PI3K inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes. We identified 103 patients meeting eligibility criteria with median follow-up of 92days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -46mg/dL (95% CI -77 to -15) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 48 DKA cases per 100 patient-years (95% CI 6, 171); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 15 (95% CI 2, 53); alpelisib only, 4 (95% CI 0.1, 22). SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition.

Amelioration of Type 2 Diabetes Mellitus by Plant-derived Natural Dipeptidyl Peptidase-4 Inhibitors through Incretin Degradation Lowering Effect: An Updated Review

Abstract: Glucagon-like peptide-1 and Glucose-dependent insulinotropic polypeptides are the most investigated gut peptides concerned with the biological glucose milieu. Early and late metabolism of incretin governs glucose homeostasis in diabetes mellitus. Dipeptidyl Peptidase-4, present in pancreatic alpha cells, is responsible for incretin degradation. Emerging biotechnological and molecular approaches established the pathophysiological role of Dipeptidyl Peptidase-4 and incretin in type 2 diabetes mellitus. Thus, various conventional synthetic Dipeptidyl Peptidase-4 inhibitors have been formulated, but they have serious adverse effects such as cancer, pancreatitis, cardiovascular risks, hepatic dysfunctions, etc. So, the concoction of a Dipeptidyl Peptidase-4 inhibitor entity with less or no severe adverse event becomes a need for society and medical corridor. Over the last two decades, natural or conventional herbal remedies have emerged as an alternate therapy for diabetes and treating its complications. This review summarized various plants (Emblica officinalis, Adenia viridiflora, Cleome droserifolia, Lens culinaris, Hedera nepalensis Melicope glabra, etc.) Dipeptidyl Peptidase-4 inhibitors, which have been preclinically proven for hyperglycemia treatment.

Diabetes exacerbates inflammatory bowel disease in mice with diet-induced obesity.

The increased prevalence of inflammatory bowel disease (IBD) among patients with obesity and type 2 diabetes suggests a causal link between these diseases, potentially involving the effect of hyperglycemia to disrupt intestinal barrier integrity. To investigate whether the deleterious impact of diabetes on the intestinal barrier is associated with increased IBD severity in a murine model of colitis in mice with and without diet-induced obesity. Mice were fed chow or a high-fat diet and subsequently received streptozotocin to induce diabetic-range hyperglycemia. Six weeks later, dextran sodium sulfate was given to induce colitis. In select experiments, a subset of diabetic mice was treated with the antidiabetic drug dapagliflozin prior to colitis onset. Endpoints included both clinical and histological measures of colitis activity as well as histochemical markers of colonic epithelial barrier integrity. In mice given a high-fat diet, but not chow-fed animals, diabetes was associated with significantly increased clinical colitis activity and histopathologic markers of disease severity. Diabetes was also associated with a decrease in key components that regulate colonic epithelial barrier integrity (colonic mucin layer content and epithelial tight junction proteins) in diet-induced obese mice. Each of these effects of diabetes in diet-induced obese mice was ameliorated by restoring normoglycemia. In obese mice, diabetes worsened clinical and pathologic outcomes of colitis via mechanisms that are reversible with treatment of hyperglycemia. Hyperglycemia-induced intestinal barrier dysfunction offers a plausible mechanism linking diabetes to increased colitis severity. These findings suggest that effective diabetes management may decrease the clinical severity of IBD.

Bringing precision medicine to the management of pregnancy in women with glucokinase-MODY: a study of diagnostic accuracy and feasibility of non-invasive prenatal testing.

In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management. We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021. In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3-8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18-24), with 23/25 (92%) reported before 28 weeks. Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies.