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Molecular Metabolic Regulation in Diabetes

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 66043

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Prof. Dr. Adam Krętowski

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Guest Editor

Department of Endocrinology, Diabetology and Internal Medicine, Clinical Research Centre, and Clinical Research Support Centre of Medical University of Białystok, Białystok, Poland
Interests: diabetes; obesity; insulin resistance; endocrinology; genetics, diet
Special Issues, Collections and Topics in MDPI journals

Dr. Lukasz Szczerbinski

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Co-Guest Editor

Department of Endocrinology, Diabetology and Internal Medicine,Medical University of Białystok, Białystok, Poland
Interests: diabetes; insulin resistance; NAFLD; obesity; exercise; genetics; bariatric surgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetes is a complex disease characterized by elevation in plasma glucose which is caused by impaired insulin secretion, insulin resistance or a combination of both. The disease is highly heterogeneous and currently divided among types and subtypes. These include the most prevalent type of diabetes mellitus, type 2 diabetes (T2D), which accounts for over 90% of all diabetes cases, type 1 diabetes (T1D), gestational diabetes mellitus (GDM), and other more specific types like latent autoimmune diabetes in adults (LADA), maturity onset diabetes of the young (MODY), and neonatal diabetes. Diabetes is already a global epidemic whose extraordinary global burden, as estimated by the International Diabetes Federation (IDF) in 2017, was 425 million adults aged 20–79 years with diabetes, representing 8.8% of the global population. Diabetes emerges from a combination of both environmental and genetic factors which can interact to influence disease outcomes. Type 1 diabetes and LADA are pathophysiologically linked to the autoimmune process of insulin-producing β-cells. Type 2 diabetes, on the other hand, is caused by a combination of abnormalities in β-cell function and insulin sensitivity. In the literature, these cardinal abnormalities comprise the “ominous octet”, representing the most significant eight pathophysiological disturbances leading to β-cell dysfunction or insulin resistance. However, their underlying molecular basis and their complications are still not fully understood. Thus, there is a pressing need to elucidate these mechanisms whose identification may lead to the discovery of new therapies and to the reduction of complications and mortality related to diabetes.

This Special Issue will focus on reviews and original data manuscripts that concern (1) molecular mechanisms of diabetes development including insulin resistance and β-cell dysfunction; (2) studies on molecular mechanisms related to carbohydrate and lipid metabolism; (3) pathophysiology of diabetes complications; (4) genetics of diabetes; and (5) molecular targets for new therapeutics for diabetes.

Prof. Adam Krętowski
Dr. Lukasz Szczerbinski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

Diabetes
Obesity
Autoimmunity
Insulin resistance
β-cell function
NAFLD
Genetics
Metabolomics
Proteomics
Inflammation
Metabolic syndrome
Gene expression
Lipid metabolism
Lipidomics
Carbohydrates metabolism
Gut hormones

Published Papers (12 papers)

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Research

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19 pages, 2381 KiB

Open AccessArticle

Circulating microRNAs Signature for Predicting Response to GLP1-RA Therapy in Type 2 Diabetic Patients: A Pilot Study

by Caterina Formichi, Daniela Fignani, Laura Nigi, Giuseppina Emanuela Grieco, Noemi Brusco, Giada Licata, Claudia Sabato, Elisabetta Ferretti, Guido Sebastiani and Francesco Dotta

Int. J. Mol. Sci. 2021, 22(17), 9454; https://doi.org/10.3390/ijms22179454 - 31 Aug 2021

Cited by 11 | Viewed by 2029

Abstract

Type 2 diabetes (T2D) represents one of the major health issues of this century. Despite the availability of an increasing number of anti-hyperglycemic drugs, a significant proportion of patients are inadequately controlled, thus highlighting the need for novel biomarkers to guide treatment selection. MicroRNAs (miRNAs) are small non-coding RNAs, proposed as useful diagnostic/prognostic markers. The aim of our study was to identify a miRNA signature occurring in responders to glucagon-like peptide 1 receptor agonists (GLP1-RA) therapy. We investigated the expression profile of eight T2D-associated circulating miRNAs in 26 prospectively evaluated diabetic patients in whom GLP1-RA was added to metformin. As expected, GLP1-RA treatment induced significant reductions of HbA1c and body weight, both after 6 and 12 months of therapy. Of note, baseline expression levels of the selected miRNAs revealed two distinct patient clusters: “high expressing” and “low expressing”. Interestingly, a significantly higher percentage of patients in the high expression group reached the glycemic target after 12 months of treatment. Our findings suggest that the evaluation of miRNA expression could be used to predict the likelihood of an early treatment response to GLP1-RA and to select patients in whom to start such treatment, paving the way to a personalized medicine approach. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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14 pages, 1522 KiB

Open AccessArticle

The Obscure Effect of Tribulus terrestris Saponins Plus Inulin on Liver Morphology, Liver Fatty Acids, Plasma Glucose, and Lipid Profile in SD Rats with and without Induced Type 2 Diabetes Mellitus

by Kamila Misiakiewicz-Has, Dominika Maciejewska-Markiewicz, Sylwia Rzeszotek, Anna Pilutin, Agnieszka Kolasa, Paweł Szumilas, Ewa Stachowska and Barbara Wiszniewska

Int. J. Mol. Sci. 2021, 22(16), 8680; https://doi.org/10.3390/ijms22168680 - 12 Aug 2021

Cited by 8 | Viewed by 2963

Abstract

Diabetes is a predictor of nonalcoholic fatty liver disease (NAFLD). There are data suggesting that Tribulus terrestris (TT) saponins act as antidiabetic agents and protect against NAFLD. The effect of saponins may be increased by fermentable fibers such as inulin. The aim of the present study was to investigate the influence of TT saponins and TT saponins plus inulin on the plasma lipid profile and liver fatty acids of rats with induced diabetes mellitus type 2 (T2DM). The study was performed on 36 male Sprague–Dawley rats divided into two main groups: control and diabetic. Animals of the diabetic (DM) group were fed a high-fat diet and injected with streptozotocin (low doses). Animals of the control group (nDM) were on a regular diet and were injected with buffer. After the injections, the animals were split into subgroups: three non-diabetic (nDM): (i) control (c-C); (ii) saponin-treated rats (C-Sap); (iii) rats treated with saponins + inulin (C-Sap + IN), and three diabetic subgroups (DM): (iv) control (c-DM); (v) saponin-treated rats (DM-Sap); (vi) rats treated with saponins + inulin (DM-Sap + IN). Liver fatty acids were extracted and analyzed by gas chromatography, and plasma glucose and lipids were measured. The study showed significant changes in liver morphology, liver fatty acids, plasma lipid profile, and plasma glucose. In summary, supplementation with TT saponins or saponins with inulin for one month decreased the level of steatosis in rats with induced type 2 diabetes. Moreover, there were favorable effects on the plasma lipid profile in the rats. However, additional supplementation with inulin had a negative effect on liver morphology (with a microvesicular type of steatosis) in the non-diabetes group. Moreover, supplementation with inulin had a negative effect on plasma glucose in both diabetic and non-diabetic rats. These data show that a diet enriched with fermentable fibers reveals different effects in different organisms, and not all sources and forms of fiber are beneficial to health. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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25 pages, 5226 KiB

Open AccessArticle

Effect of Streptozotocin-Inducted Diabetes on the Pathophysiology of Enteric Neurons in the Small Intestine Based on the Porcine Diabetes Model

by Michał Bulc, Jarosław Całka and Katarzyna Palus

Int. J. Mol. Sci. 2020, 21(6), 2047; https://doi.org/10.3390/ijms21062047 - 17 Mar 2020

Cited by 6 | Viewed by 2322

Abstract

Hyperglycemia is one of the main causes of diabetes complications. Gastrointestinal (GI) disturbances are one of the most frequent complications during diabetes. The porcine digestive tract possesses physiological and pathological similarities to the human digestive tract. This also applies to the innervation of the gastrointestinal tract. In this study, the influence of experimentally-inducted hyperglycemia was examined on the expression of vesicular acetylcholine transporter (VAChT), cocaine- and amphetamine-regulated transcript (CART), galanin (GAL), vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP) in the enteric nervous system (ENS) neurons in the small intestine of the pig. During the current study, an increased number of neurons containing CART, VIP, GAL, and CGRP under streptozotocin injection were observed. The augmentation of expression included all enteric plexuses present in the small intestine. The same results were obtained in the case of VAChT; namely, chronic hyperglycemia led to an increase in the number of neurons utilizing VAChT in all investigated plexuses. The obtained results suggested that the function of neuropeptides studied in this experiment depended on their localization in the ENS structures, as well as part of the GI tract. Diabetes led to alterations in the neurochemical phenotype of small intestine enteric neurons. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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15 pages, 240 KiB

Open AccessArticle

Evaluation of Transcriptomic Regulations behind Metabolic Syndrome in Obese and Lean Subjects

by Magdalena Paczkowska-Abdulsalam, Magdalena Niemira, Agnieszka Bielska, Anna Szałkowska, Beata Anna Raczkowska, Sini Junttila, Attila Gyenesei, Edyta Adamska-Patruno, Katarzyna Maliszewska, Anna Citko, Łukasz Szczerbiński and Adam Krętowski

Int. J. Mol. Sci. 2020, 21(4), 1455; https://doi.org/10.3390/ijms21041455 - 20 Feb 2020

Cited by 11 | Viewed by 3966

Abstract

Multiple mechanisms have been suggested to confer to the pathophysiology of metabolic syndrome (MetS), however despite great interest from the scientific community, the exact contribution of each of MetS risk factors still remains unclear. The present study aimed to investigate molecular signatures in peripheral blood of individuals affected by MetS and different degrees of obesity. Metabolic health of 1204 individuals from 1000PLUS cohort was assessed, and 32 subjects were recruited to four study groups: MetS lean, MetS obese, “healthy obese”, and healthy lean. Whole-blood transcriptome next generation sequencing with functional data analysis were carried out. MetS obese and MetS lean study participants showed the upregulation of genes involved in inflammation and coagulation processes: granulocyte adhesion and diapedesis (p < 0.0001, p = 0.0063), prothrombin activation pathway (p = 0.0032, p = 0.0091), coagulation system (p = 0.0010, p = 0.0155). The results for “healthy obese” indicate enrichment in molecules associated with protein synthesis (p < 0.0001), mitochondrial dysfunction (p < 0.0001), and oxidative phosphorylation (p < 0.0001). Our results suggest that MetS is related to the state of inflammation and vascular system changes independent of excess body weight. Furthermore, “healthy obese”, despite not fulfilling the criteria for MetS diagnosis, seems to display an intermediate state with a lower degree of metabolic abnormalities, before they proceed to a full blown MetS. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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17 pages, 4532 KiB

Open AccessArticle

Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network

by Qi Kang, Mengyi Hu, Jianxin Jia, Xuanxuan Bai, Chengdong Liu, Zhiqiang Wu, Wenbiao Chen and Mingyu Li

Int. J. Mol. Sci. 2020, 21(3), 724; https://doi.org/10.3390/ijms21030724 - 22 Jan 2020

Cited by 6 | Viewed by 3710

Abstract

The glucagon receptor (GCGR) is a G-protein-coupled receptor (GPCR) that mediates the activity of glucagon. Disruption of GCGR results in many metabolic alterations, including increased glucose tolerance, decreased adiposity, hypoglycemia, and pancreatic α-cell hyperplasia. To better understand the global transcriptomic changes resulting from GCGR deficiency, we performed whole-organism RNA sequencing analysis in wild type and gcgr-deficient zebrafish. We found that the expression of 1645 genes changes more than two-fold among mutants. Most of these genes are related to metabolism of carbohydrates, lipids, and amino acids. Genes related to fatty acid β-oxidation, amino acid catabolism, and ureagenesis are often downregulated. Among gcrgr-deficient zebrafish, we experimentally confirmed increases in lipid accumulation in the liver and whole-body glucose uptake, as well as a modest decrease in total amino acid content. These results provide new information about the global metabolic network that GCGR signaling regulates in addition to a better understanding of the receptor’s physiological functions. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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17 pages, 2905 KiB

Open AccessArticle

High-Energy Diet and Shorter Light Exposure Drives Markers of Adipocyte Dysfunction in Visceral and Subcutaneous Adipose Depots of Psammomys obesus

by Joanne T.M. Tan, Victoria A. Nankivell, Carmel Bilu, Tomer Shemesh, Stephen J. Nicholls, Paul Zimmet, Noga Kronfeld-Schor, Alex Brown and Christina A. Bursill

Int. J. Mol. Sci. 2019, 20(24), 6291; https://doi.org/10.3390/ijms20246291 - 13 Dec 2019

Cited by 9 | Viewed by 3630

Abstract

Dysfunctional adipose tissue phenotype underpins type 2 diabetes mellitus (T2DM) development. The disruption of circadian rhythms contributes to T2DM development. We investigated the effects of high-energy diet and photoperiod length on visceral and subcutaneous adipose tissue phenotype. Psammomys obesus sand rats exposed to neutral (12 light:12 dark) or short (5 light:19 dark) photoperiod were fed a low- (LE) or high- (HE) energy diet. The HE diet and/or short photoperiod reduced subcutaneous expression of adipocyte differentiation/function markers C/ebpα, Pparδ, Pparγ and Adipoq. Visceral Pparα levels were elevated in the 5:19HE group; however, the HE diet and/or short photoperiod decreased visceral Pparγ and Adipoq expression. 5:19HE animals had elevated Ucp1 yet lower Pgc-1α levels. The HE diet increased visceral Tgf-β1, Ccl2 and Cd68 levels, suggestive of a pro-inflammatory state. Daily visceral rhythms of these genes were affected by a short photoperiod and/or HE diet. The 12:12HE, 5:19LE or 5:19HE animals had a higher proportion of larger adipocytes, indicating increased adipocyte hypertrophy. Collectively, the HE diet and/or shorter light exposure drives a dysfunctional adipose tissue phenotype. Daily rhythms are affected by a short photoperiod and HE diet in a site-specific manner. These findings provide mechanistic insight on the influence of disrupted circadian rhythms and HE diet on adipose tissue phenotype. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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16 pages, 3588 KiB

Open AccessArticle

The Protective Role of Calbindin-D_9k on Endoplasmic Reticulum Stress-Induced Beta Cell Death

by Changhwan Ahn, Eui-Man Jung, Beum-Soo An, Eui-Ju Hong, Yeong-Min Yoo and Eui-Bae Jeung

Int. J. Mol. Sci. 2019, 20(21), 5317; https://doi.org/10.3390/ijms20215317 - 25 Oct 2019

Cited by 1 | Viewed by 2683

Abstract

Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D_9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. In this study, we aimed to investigate the effect of CaBP-9k on cell survival in pancreatic beta cells. Six-month-old wildtype CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice were used to compare the pathological phenotypes of calcium-binding protein-deleted mice. Subsequently, the endoplasmic reticulum (ER) stress reducer tauroursodeoxycholic acid (TUDCA) was administered to wildtype and CaBP-9k KO mice. In vitro assessment of the role of CaBP-9k was performed following CaBP-9k overexpression and treatment with the ER stress inducer thapsigargin. Six-month-old CaBP-9k KO mice showed reduced islet volume and up-regulation of cell death markers resulting from ER stress, which led to pancreatic beta cell death. TUDCA treatment recovered islet volume, serum insulin level, and abdominal fat storage by CaBP-9k ablation. CaBP-9k overexpression elevated insulin secretion and recovered thapsigargin-induced ER stress in the INS-1E cell line. The results of this study show that CaBP-9k can protect pancreatic beta cell survival from ER stress and contribute to glucose homeostasis, which can reduce the risk of type 1 diabetes and provide the molecular basis for calcium supplementation to diabetic patients. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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15 pages, 3488 KiB

Open AccessArticle

Protective Effects and Mechanisms of Vaccarin on Vascular Endothelial Dysfunction in Diabetic Angiopathy

by Fei Xu, Yixiao Liu, Xuexue Zhu, Shuangshuang Li, Xuelin Shi, Zhongjie Li, Min Ai, Jiangnan Sun, Bao Hou, Weiwei Cai, Haijian Sun, Lulu Ni, Yuetao Zhou and Liying Qiu

Int. J. Mol. Sci. 2019, 20(18), 4587; https://doi.org/10.3390/ijms20184587 - 17 Sep 2019

Cited by 28 | Viewed by 3327

Abstract

Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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Review

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16 pages, 2141 KiB

Open AccessReview

Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease

by Thuy Trang Nguyen, Qui Thanh Hoai Ta, Thi Kim Oanh Nguyen, Thi Thuy Dung Nguyen and Vo Van Giau

Int. J. Mol. Sci. 2020, 21(9), 3165; https://doi.org/10.3390/ijms21093165 - 30 Apr 2020

Cited by 159 | Viewed by 22460

Abstract

The exact connection between Alzheimer’s disease (AD) and type 2 diabetes is still in debate. However, poorly controlled blood sugar may increase the risk of developing Alzheimer’s. This relationship is so strong that some have called Alzheimer’s “diabetes of the brain” or “type 3 diabetes (T3D)”. Given more recent studies continue to indicate evidence linking T3D with AD, this review aims to demonstrate the relationship between T3D and AD based on the fact that both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ are attributed to impaired insulin signaling, and that insulin resistance mediates the dysregulation of bioenergetics and progress to AD. Furthermore, insulin-related therapeutic strategies are suggested to succeed in the development of therapies for AD by slowing down their progressive nature or even halting their future complications. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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12 pages, 517 KiB

Open AccessReview

Can We Prevent Mitochondrial Dysfunction and Diabetic Cardiomyopathy in Type 1 Diabetes Mellitus? Pathophysiology and Treatment Options

by Aleksandra Cieluch, Aleksandra Uruska and Dorota Zozulinska-Ziolkiewicz

Int. J. Mol. Sci. 2020, 21(8), 2852; https://doi.org/10.3390/ijms21082852 - 19 Apr 2020

Cited by 19 | Viewed by 3803

Abstract

Type 1 diabetes mellitus is a disease involving changes to energy metabolism. Chronic hyperglycemia is a major cause of diabetes complications. Hyperglycemia induces mechanisms that generate the excessive production of reactive oxygen species, leading to the development of oxidative stress. Studies with animal models have indicated the involvement of mitochondrial dysfunction in the pathogenesis of diabetic cardiomyopathy. In the current review, we aimed to collect scientific reports linking disorders in mitochondrial functioning with the development of diabetic cardiomyopathy in type 1 diabetes mellitus. We also aimed to present therapeutic approaches counteracting the development of mitochondrial dysfunction and diabetic cardiomyopathy in type 1 diabetes mellitus. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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17 pages, 539 KiB

Open AccessReview

Systematic Review of Polygenic Risk Scores for Type 1 and Type 2 Diabetes

by Felipe Padilla-Martínez, Francois Collin, Miroslaw Kwasniewski and Adam Kretowski

Int. J. Mol. Sci. 2020, 21(5), 1703; https://doi.org/10.3390/ijms21051703 - 2 Mar 2020

Cited by 35 | Viewed by 6162

Abstract

Recent studies have led to considerable advances in the identification of genetic variants associated with type 1 and type 2 diabetes. An approach for converting genetic data into a predictive measure of disease susceptibility is to add the risk effects of loci into a polygenic risk score. In order to summarize the recent findings, we conducted a systematic review of studies comparing the accuracy of polygenic risk scores developed during the last two decades. We selected 15 risk scores from three databases (Scopus, Web of Science and PubMed) enrolled in this systematic review. We identified three polygenic risk scores that discriminate between type 1 diabetes patients and healthy people, one that discriminate between type 1 and type 2 diabetes, two that discriminate between type 1 and monogenic diabetes and nine polygenic risk scores that discriminate between type 2 diabetes patients and healthy people. Prediction accuracy of polygenic risk scores was assessed by comparing the area under the curve. The actual benefits, potential obstacles and possible solutions for the implementation of polygenic risk scores in clinical practice were also discussed. Develop strategies to establish the clinical validity of polygenic risk scores by creating a framework for the interpretation of findings and their translation into actual evidence, are the way to demonstrate their utility in medical practice. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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15 pages, 1523 KiB

Open AccessReview

Lessons from the Trials for the Desirable Effects of Sodium Glucose Co-Transporter 2 Inhibitors on Diabetic Cardiovascular Events and Renal Dysfunction

by Masanori Wakisaka, Masahiro Kamouchi and Takanari Kitazono

Int. J. Mol. Sci. 2019, 20(22), 5668; https://doi.org/10.3390/ijms20225668 - 12 Nov 2019

Cited by 15 | Viewed by 8248

Abstract

Recent large placebo-controlled trials of sodium glucose co-transporter 2 (SGLT2) inhibitors revealed desirable effects on heart failure (HF) and renal dysfunction; however, the mechanisms underlying these effects are unknown. The characteristic changes in the early stage of diabetic cardiomyopathy (DCM) are myocardial and interstitial fibrosis, resulting in diastolic and subsequent systolic dysfunction, which leads to clinical HF. Pericytes are considered to play crucial roles in myocardial and interstitial fibrosis. In both DCM and diabetic retinopathy (DR), microaneurysm formation and a decrease in capillaries occur, triggered by pericyte loss. Furthermore, tubulointerstitial fibrosis develops in early diabetic nephropathy (DN), in which pericytes and mesangial cells are thought to play important roles. Previous reports indicate that pericytes and mesangial cells play key roles in the pathogenesis of DCM, DR and DN. SGLT2 is reported to be functionally expressed in pericytes and mesangial cells, and excessive glucose and Na⁺ entry through SGLT2 causes cellular dysfunction in a diabetic state. Since SGLT2 inhibitors can attenuate the high glucose-induced dysfunction of pericytes and mesangial cells, the desirable effects of SGLT2 inhibitors on HF and renal dysfunction might be explained by their direct actions on these cells in the heart and kidney microvasculature. Full article

(This article belongs to the Special Issue Molecular Metabolic Regulation in Diabetes)

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