Special Issue "Targeted Therapies in Diabetes and Its Complications"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 16178

Special Issue Editor

Julius Center for Health Sciences and Primary Care, Department Datascience & Biostatistics, Global Health University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
Interests: personalized medicine; molecular (pharmaco)epidemiology; diabetes; omics biomarkers; novel therapies

Special Issue Information

Dear Colleagues,

Though a substantial proportion of chronic conditions related to diabetes mellitus are associated with aging, glycemic control still plays an important role in the pathogenesis of conditions, such as macro and microvascular diseases. The current treatment algorithm for diabetes is stepwise; drugs are trialed down the long list until an effective medication is reached to control diabetes and its complications. New therapeutic targets, as well as new drug delivery forms in diabetes mellitus treatment, have arisen in recent years. Delivery systems have been found to be potentially beneficial in many aspects for effective diabetes treatment, such as improving the stability of drugs, overcoming different biological barriersin vivoto increase bioavailability, and acting as an intelligent automatized system to mimic endogenous insulin delivery and reduce the risk of hypoglycemia. Guidelines recommend that pharmacological therapy in diabetes should maintain an optimal fasting serum glucose concentration. Yet, favorable responses to such therapeutics are unstable, in which roughly 40% of diabetes patients do not reach the desired glucose level. Several factors may contribute to inter-individual differences in response to medications, including genetic and non-genetic factors. Different factors/biomarkers could potentially predict different responses to glucose-lowering medications.

This Special Issue will cover a wide range of targeting delivery strategies for diabetes treatments. It aims to provide an overview related with the research advances, development trend of drug therapy and the application of delivery systems in the treatment diabetes mellitus, which could offer reference for the application of various drugs in the field of diabetes mellitus treatment. The aim would be to collect studies investigating:

  • drug delivery and controlled-release systems for diabetes treatments
  • pharmaceutical formulation design for diabetes treatments
  • innovative methods to study pathways in response to glucose-lowering medications
  • efficacy/effectiveness or safety of different glucose-lowering medications in the context of observational studies or clinical trials
  • comparing biomarker-guided diabetes therapy and conventional therapy
  • new therapy targets for diabetes and its complications to enable earlier and more effective therapy and prevention
  • different factors related to response to glucose-lowering medications in populations with diabetes, for better understanding of pharmacokinetics and pharmacodynamics in drug development of diabetes, through association or prediction studies.

Dr. Fariba Ahmadizar
Guest Editor

Manuscript Submission Information

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Keywords

  • diabetes mellitus
  • drug delivery system
  • pharmaceutical formulation design
  • vulnerable diabetic people
  • interventions
  • novel therapies biomarker-guided therapy
  • response to medications
  • genomics factors
  • molecular pathways
  • innovative methods

Related Special Issue

Published Papers (9 papers)

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Research

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Article
Pharmacokinetics and Anti-Diabetic Studies of Gliclazide Nanosuspension
Pharmaceutics 2022, 14(9), 1947; https://doi.org/10.3390/pharmaceutics14091947 - 14 Sep 2022
Cited by 2 | Viewed by 1419
Abstract
Gliclazide (GCZ), an antidiabetic medication, has poor solubility and limited oral bioavailability due to substantial first-pass metabolism. Thus, the purpose of the current study was to optimize and formulate a GCZ nanosuspension (NS) employing the antisolvent precipitation technique. A three-factor, three-level Box–Behnken design [...] Read more.
Gliclazide (GCZ), an antidiabetic medication, has poor solubility and limited oral bioavailability due to substantial first-pass metabolism. Thus, the purpose of the current study was to optimize and formulate a GCZ nanosuspension (NS) employing the antisolvent precipitation technique. A three-factor, three-level Box–Behnken design (BBD) was used to examine the impact of the primary formulation factors (drug concentration, stabilizer, and surfactant %) on particle size. The optimized NS contains 29.6 mg/mL drug, 0.739% lecithin, and 0.216% sodium dodecyl sulfate (SDS). Under scanning microscopy, the topography of NS revealed spherical particles. Furthermore, NS had a much better saturation solubility than the pure material, which resulted in a rapid dissolving rate, which was attributed to the amorphous structure and smaller particle size of the NS particles. Studies on intestinal permeability using the in vitro noneverted intestinal sac gut method (duodenum, jejunum, and ileum) and single-pass intestinal permeability (SPIP) techniques showed that the effective permeability was also increased by more than 3 fold. In the pharmacokinetic study, the Cmax and AUC0–t values of NS were approximately 3.35- and 1.9-fold higher than those of the raw medication and marketed formulation (MF). When compared to plain drug and commercial formulations, the antidiabetic efficacy of NS demonstrated that it had a significant impact on lowering glucose levels. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Article
INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression
Pharmaceutics 2022, 14(9), 1833; https://doi.org/10.3390/pharmaceutics14091833 - 31 Aug 2022
Cited by 1 | Viewed by 993
Abstract
Islet transplantation offers a long-term cure for Type 1 Diabetes (T1D), freeing patients from daily insulin injections. Therapeutic peptides have shown potential to increase the insulin output of pancreatic islets, maximizing the impact of grafted cells. The islet neogenesis-associated protein (INGAP), and its [...] Read more.
Islet transplantation offers a long-term cure for Type 1 Diabetes (T1D), freeing patients from daily insulin injections. Therapeutic peptides have shown potential to increase the insulin output of pancreatic islets, maximizing the impact of grafted cells. The islet neogenesis-associated protein (INGAP), and its bioactive core (INGAP-P), stimulate beta-cell function and viability, offering the possibility for islet treatment prior to implant. However, dosing efficacy is limited by low circulation time and enzyme degradation. This proof-of-concept study presents the investigation of novel molecular variants of INGAP-P to find a more bioactive form. Custom-designed peptide variants of INGAP-P were synthesized and tested for their effect on the insulin secretion and gene expression of live human islets. We exposed the live islets of five donors to varying glucose concentrations with INGAP-P variants in solution. We identified four peptide variants (I9, I15Tyr, I19 and I15Cys) which displayed statistically significant enhancements over negative controls (representing a 1.6–2.8-fold increase in stimulation index). This is the first study that has assessed these INGAP-P variants in human islets. It highlights the potential for customized peptides for type 1 diabetes therapy and provides a foundation for future peptide-screening experiments. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Article
Pharmacokinetic–Pharmacometabolomic Approach in Early-Phase Clinical Trials: A Way Forward for Targeted Therapy in Type 2 Diabetes
Pharmaceutics 2022, 14(6), 1268; https://doi.org/10.3390/pharmaceutics14061268 - 15 Jun 2022
Cited by 3 | Viewed by 2357
Abstract
Pharmacometabolomics in early phase clinical trials demonstrate the metabolic profiles of a subject responding to a drug treatment in a controlled environment, whereas pharmacokinetics measure the drug plasma concentration in human circulation. Application of the personalized peak plasma concentration from pharmacokinetics in pharmacometabolomic [...] Read more.
Pharmacometabolomics in early phase clinical trials demonstrate the metabolic profiles of a subject responding to a drug treatment in a controlled environment, whereas pharmacokinetics measure the drug plasma concentration in human circulation. Application of the personalized peak plasma concentration from pharmacokinetics in pharmacometabolomic studies provides insights into drugs’ pharmacological effects through dysregulation of metabolic pathways or pharmacodynamic biomarkers. This proof-of-concept study integrates personalized pharmacokinetic and pharmacometabolomic approaches to determine the predictive pharmacodynamic response of human metabolic pathways for type 2 diabetes. In this study, we use metformin as a model drug. Metformin is a first-line glucose-lowering agent; however, the variation of metabolites that potentially affect the efficacy and safety profile remains inconclusive. Seventeen healthy subjects were given a single dose of 1000 mg of metformin under fasting conditions. Fifteen sampling time-points were collected and analyzed using the validated bioanalytical LCMS method for metformin quantification in plasma. The individualized peak-concentration plasma samples determined from the pharmacokinetic parameters calculated using Matlab Simbiology were further analyzed with pre-dose plasma samples using an untargeted metabolomic approach. Pharmacometabolomic data processing and statistical analysis were performed using MetaboAnalyst with a functional meta-analysis peaks-to-pathway approach to identify dysregulated human metabolic pathways. The validated metformin calibration ranged from 80.4 to 2010 ng/mL for accuracy, precision, stability and others. The median and IQR for Cmax was 1248 (849–1391) ng/mL; AUC0-infinity was 9510 (7314–10,411) ng·h/mL, and Tmax was 2.5 (2.5–3.0) h. The individualized Cmax pharmacokinetics guided the untargeted pharmacometabolomics of metformin, suggesting a series of provisional predictive human metabolic pathways, which include arginine and proline metabolism, branched-chain amino acid (BCAA) metabolism, glutathione metabolism and others that are associated with metformin’s pharmacological effects of increasing insulin sensitivity and lipid metabolism. Integration of pharmacokinetic and pharmacometabolomic approaches in early-phase clinical trials may pave a pathway for developing targeted therapy. This could further reduce variability in a controlled trial environment and aid in identifying surrogates for drug response pathways, increasing the prediction of responders for dose selection in phase II clinical trials. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Article
VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes
Pharmaceutics 2022, 14(5), 1077; https://doi.org/10.3390/pharmaceutics14051077 - 17 May 2022
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Abstract
The number and function of endothelial progenitor cells (EPCs) are reduced in diabetes, contributing to deteriorated vascular repair and the occurrence of cardiovascular complications. Here, we present the results of treating early diabetic dyslipidemic mice or dyslipidemic with disease-matched EPCs modified to overexpress [...] Read more.
The number and function of endothelial progenitor cells (EPCs) are reduced in diabetes, contributing to deteriorated vascular repair and the occurrence of cardiovascular complications. Here, we present the results of treating early diabetic dyslipidemic mice or dyslipidemic with disease-matched EPCs modified to overexpress VLA4 (VLA4-EPCs) as compared with the treatment of EPCs transfected with GFP (GFP-EPCs) as well as EPCs from healthy animals. Organ imaging of injected PKH26-stained cells showed little pulmonary first-pass effects and distribution in highly vascularized organs, with splenic removal from circulation, mostly in non-diabetic animals. Plasma measurements showed pronounced dyslipidemia in all animals and glycaemia indicative of diabetes in streptozotocin-injected animals. Echocardiographic measurements performed 3 days after the treatment showed significantly improved aortic valve function in animals treated with VLA4-overexpressing EPCs compared with GFP-EPCs, and similar results in the groups treated with healthy EPCs and VLA4-EPCs. Immunohistochemical analyses revealed active inflammation and remodelling in all groups but different profiles, with higher MMP9 and lower P-selectin levels in GFP-EPCs, treated animals. In conclusion, our experiments show that genetically modified allogeneic EPCs might be a safe treatment option, with bioavailability in the desired target compartments and the ability to preserve aortic valve function in dyslipidemia and diabetes. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Review

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Review
Gut Dysbiosis and Diabetic Foot Ulcer: Role of Probiotics
Pharmaceutics 2022, 14(11), 2543; https://doi.org/10.3390/pharmaceutics14112543 - 21 Nov 2022
Cited by 2 | Viewed by 1407
Abstract
Diabetic foot ulcer (DFU) is a multifactorial disease and one of the complications of diabetes. The global burden of DFU in the health sector is increasing at a tremendous rate due to its cost management related to hospitalization, medical costs and foot amputation. [...] Read more.
Diabetic foot ulcer (DFU) is a multifactorial disease and one of the complications of diabetes. The global burden of DFU in the health sector is increasing at a tremendous rate due to its cost management related to hospitalization, medical costs and foot amputation. Hence, to manage DFU/DWs, various attempts have been made, including treating wounds systematically/topically using synthetic drugs, herbal drugs, or tissue engineering based surgical dressings. However, less attention has been paid to the intrinsic factors that are also the leading cause of diabetes mellitus (DM) and its complications. One such factor is gut dysbiosis, which is one of the major causes of enhancing the counts of Gram-negative bacteria. These bacteria produce lipopolysaccharides, which are a major contributing factor toward insulin resistance and inflammation due to the generation of oxidative stress and immunopathy. These all lead to DM and DFU. Probiotics are the commercial form of beneficial gut microbes that are taken as nutraceuticals by people of all ages to improve gut immunity and prevent gut dysbiosis. However, the role of probiotics has been less explored in the management of DFU. Hence, the therapeutic potential of probiotics in managing DFU is fully described in the current review. This report covers the linkage between gut dysbiosis and DFU, sources of probiotics, the mechanisms of probiotics in DW healing, and the impact of probiotic supplementation in treating DFU. In addition, techniques for the stabilization of probiotics, market status, and patents related to probiotics have been also covered. The relevant data were gathered from PubMed, Scopus, Taylor and Francis, Science Direct, and Google Scholar. Our systematic review discusses the utilization of probiotic supplementation as a nutraceutical for the management of DFU. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Review
The New Role of SGLT2 Inhibitors in the Management of Heart Failure: Current Evidence and Future Perspective
Pharmaceutics 2022, 14(8), 1730; https://doi.org/10.3390/pharmaceutics14081730 - 18 Aug 2022
Cited by 11 | Viewed by 2830
Abstract
The sodium-glucose transporter 2 inhibitors (SGLT2i) are a relatively new class of medication used in the management of type 2 diabetes. Recent clinical trials and research have demonstrated this class’s effectiveness in treating heart failure, since they reduce the risk of cardiovascular events, [...] Read more.
The sodium-glucose transporter 2 inhibitors (SGLT2i) are a relatively new class of medication used in the management of type 2 diabetes. Recent clinical trials and research have demonstrated this class’s effectiveness in treating heart failure, since they reduce the risk of cardiovascular events, hospitalization, and mortality. The mechanism by which they do so is unclear; however, SGLT2i inhibit the tubular reabsorption of glucose, lowering the interstitial volume. This mechanism leads to a reduction in blood pressure and an improvement of endothelial function. As a result, improvements in hospitalization and mortality rate have been shown. In this review, we focus on the primary outcome of the clinical trials designed to investigate the effect of SGLT2i in heart failure, regardless of patients’ diabetic status. Furthermore, we compare the various SGLT2i regarding their risk reduction to investigate their potential as a treatment option for patients with reduced ejection fraction and preserved ejection fraction. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Review
Host Response Modulation Therapy in the Diabetes Mellitus—Periodontitis Conjuncture: A Narrative Review
Pharmaceutics 2022, 14(8), 1728; https://doi.org/10.3390/pharmaceutics14081728 - 18 Aug 2022
Viewed by 1301
Abstract
The inflammatory response of the host in periodontitis is the phenomenon that underlies the onset and evolution of periodontal destructive phenomena. A number of systemic factors, such as diabetes mellitus (DM), can negatively affect the patient with periodontitis, just as the periodontal disease [...] Read more.
The inflammatory response of the host in periodontitis is the phenomenon that underlies the onset and evolution of periodontal destructive phenomena. A number of systemic factors, such as diabetes mellitus (DM), can negatively affect the patient with periodontitis, just as the periodontal disease can aggravate the status of the DM patient. Host response modulation therapy involves the use of anti-inflammatory and anti-oxidant products aimed at resolving inflammation, stopping destructive processes, and promoting periodontal healing, all important aspects in patients with high tissue loss rates, such as diabetic patients. This paper reviews the data available in the literature on the relationship between DM and periodontitis, the main substances modulating the inflammatory response (nonsteroidal anti-inflammatory drugs, sub-antimicrobial doses of doxycycline, or omega-3 fatty acids and their products, specialized pro-resolving mediators), as well as their application in diabetic patients. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Review
New Strategies for Volume Control in Patients with Diabetes Mellitus, a Narrative Review
Pharmaceutics 2022, 14(8), 1569; https://doi.org/10.3390/pharmaceutics14081569 - 28 Jul 2022
Viewed by 1557
Abstract
Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in [...] Read more.
Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Review
Glucose-Lowering Therapy beyond Insulin in Type 1 Diabetes: A Narrative Review on Existing Evidence from Randomized Controlled Trials and Clinical Perspective
Pharmaceutics 2022, 14(6), 1180; https://doi.org/10.3390/pharmaceutics14061180 - 31 May 2022
Viewed by 1737
Abstract
Background: In Type 1 diabetes (T1D), according to the most recent guidelines, the everyday glucose-lowering treatment is still restricted to the use of subcutaneous insulin, while multiple therapeutic options exist for Type 2 diabetes (T2D). Methods: For this narrative review we unsystematically screened [...] Read more.
Background: In Type 1 diabetes (T1D), according to the most recent guidelines, the everyday glucose-lowering treatment is still restricted to the use of subcutaneous insulin, while multiple therapeutic options exist for Type 2 diabetes (T2D). Methods: For this narrative review we unsystematically screened PubMed and Embase to identify clinical trials which investigated glucose-lowering agents as an adjunct to insulin treatment in people with T1D. Published studies up to March 2022 were included. We discuss the safety and efficacy in modifying cardiovascular risk factors for each drug, the current status of research, and provide a clinical perspective. Results: For several adjunct agents, in T1D, the scientific evidence demonstrates improvements in HbA1c, reductions in the risk of hypoglycemia, and achievements of lower insulin requirements, as well as positive effects on cardiovascular risk factors, such as blood lipids, blood pressure, and weight. As the prevalence of obesity, the major driver for double diabetes, is rising, weight and cardiovascular risk factor management is becoming increasingly important in people with T1D. Conclusions: Adjunct glucose-lowering agents, intended to be used in T2D, bear the potential to beneficially impact on cardiovascular risk factors when investigated in the T1D population and are suggested to be more extensively considered as potentially disease-modifying drugs in the future and should be investigated for hard cardiovascular endpoints. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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