Special Issue "Type 2 Diabetes: Update on Pathophysiology and Treatment"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (15 April 2019).

Special Issue Editor

Dr. Tomoaki Morioka
E-Mail Website
Guest Editor
Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University, Osaka, Japan
Interests: type 2 diabetes; obesity; leptin; adipokines; atherosclerosis; beta-cell function

Special Issue Information

Dear Colleagues,

Type 2 diabetes and its complications are among the most important health problems in the world. Nowadays, it is widely recognized that type 2 diabetes is associated not only with cardiovascular mortality, but also with poor quality of life due, for example, to chronic kidney disease, sarcopenia, cancer, and dementia. To overcome these problems, it is important to better understand the disease process of type 2 diabetes and its complications with the goal of developing new treatment strategies.

This Special Issue of the Journal of Clinical Medicine aims to invite authors to contribute original research articles as well as review articles related to the pathophysiology and treatment of type 2 diabetes and its vascular and non-vascular complications.

Dr. Tomoaki Morioka
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • type 2 diabetes
  • insulin secretion
  • insulin resistance
  • glucagon
  • hypoglycemia
  • obesity
  • adipocytokines
  • atherosclerosis
  • cardiovascular diseases
  • diabetic kidney disease
  • cancer
  • sarcopenia
  • dementia
  • exercise
  • antidiabetic drugs
  • incretin hormones

Published Papers (25 papers)

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Open AccessArticle
Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes: Prescription According to Reimbursement Constraints and Guideline Recommendations in Catalonia
J. Clin. Med. 2019, 8(9), 1389; https://doi.org/10.3390/jcm8091389 - 05 Sep 2019
Abstract
To assess the clinical characteristics, the prescription pattern of GLP-1 receptor agonists (GLP-1RA) users, and HbA1c and weight change, we retrospectively assessed patients with type 2 diabetes by initiating GLP-1RA as an add-on to the standard of care in Catalonia. The mean change [...] Read more.
To assess the clinical characteristics, the prescription pattern of GLP-1 receptor agonists (GLP-1RA) users, and HbA1c and weight change, we retrospectively assessed patients with type 2 diabetes by initiating GLP-1RA as an add-on to the standard of care in Catalonia. The mean change from the baseline in glycated hemoglobin (HbA1c) and weight at 6 and 12 months of therapy was calculated, and we assessed the predictors of the HbA1c reduction of ≥1% and/or the weight reduction of ≥3% as recommended by the Catalan Health Service. In 2854 patients who initiated a GLP-1RA during 2014 and 2015, the overall mean HbA1c values were reduced from the baseline by −0.84% (SD = 1.66) (−9.2 mmol/mol) and lost on average 2.73 kg (SD = 6.2). About 44% percent of patients decreased their HbA1c by ≥1%; 44% decreased their weight by ≥3%; and only 22% met both of them together. The odds of achieving a reduction of ≥1% in initial HbA1c were two-fold higher for patients with higher baseline levels, and the likelihood of a reduction of ≥3% in the initial weight was associated with a higher BMI at the baseline, but they were independent of each other. The composite outcome (target 1% HbA1c reduction and 3% weight loss) to evaluate both the GLP-1RA clinical benefit and treatment withdrawal should be judged from a patient-centered approach. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Long Daytime Napping Is Associated with Increased Adiposity and Type 2 Diabetes in an Elderly Population with Metabolic Syndrome
J. Clin. Med. 2019, 8(7), 1053; https://doi.org/10.3390/jcm8071053 - 19 Jul 2019
Abstract
Research examining associations between objectively-measured napping time and type 2 diabetes (T2D) is lacking. This study aimed to evaluate daytime napping in relation to T2D and adiposity measures in elderly individuals from the Mediterranean region. A cross-sectional analysis of baseline data from 2190 [...] Read more.
Research examining associations between objectively-measured napping time and type 2 diabetes (T2D) is lacking. This study aimed to evaluate daytime napping in relation to T2D and adiposity measures in elderly individuals from the Mediterranean region. A cross-sectional analysis of baseline data from 2190 elderly participants with overweight/obesity and metabolic syndrome, in the PREDIMED-Plus trial, was carried out. Accelerometer-derived napping was measured. Prevalence ratios (PR) and 95% confidence intervals (CI) for T2D were obtained using multivariable-adjusted Cox regression with constant time. Linear regression models were fitted to examine associations of napping with body mass index (BMI) and waist circumference (WC). Participants napping ≥90 min had a higher prevalence of T2D (PR 1.37 (1.06, 1.78)) compared with those napping 5 to <30 min per day. Significant positive associations with BMI and WC were found in those participants napping ≥30 min as compared to those napping 5 to <30 min per day. The findings of this study suggest that longer daytime napping is associated with higher T2D prevalence and greater adiposity measures in an elderly Spanish population at high cardiovascular risk. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Body Weight Fluctuation as a Risk Factor for Type 2 Diabetes: Results from a Nationwide Cohort Study
J. Clin. Med. 2019, 8(7), 950; https://doi.org/10.3390/jcm8070950 - 30 Jun 2019
Abstract
We aimed to investigate how body weight fluctuation affects the risk of developing type 2 diabetes by conducting a nationwide cohort study. A total of 3,855,884 participants from the National Health Insurance System health check-up data from 2012 were included in this study, [...] Read more.
We aimed to investigate how body weight fluctuation affects the risk of developing type 2 diabetes by conducting a nationwide cohort study. A total of 3,855,884 participants from the National Health Insurance System health check-up data from 2012 were included in this study, and follow-up continued until 2016. Body weight was measured at least thrice between 2009 and 2012. Body weight variability (BWV) was estimated using average successive variability (ASV) indices. Cox proportional hazards regression models were used to evaluate the association of BWV with the risk of type 2 diabetes using hazard ratios (HRs) and 95% confidence intervals (CIs). Body weight fluctuation was associated with a higher risk of incident diabetes after adjustment for confounders (HR 1.10, 95% CI 1.07, 1.12 in the highest BWV quartile compared to the lowest). Regardless of the weight change status, the highest ASV quartile of BWV increased the risk for diabetes. Even subjects with a normal glucose tolerance status and those aged under 65 years had a higher risk of diabetes if their body weight highly fluctuated during the follow-up years. Our results suggest that body weight variability is an independent risk factor for diabetes. It is important to pay attention to frequent body weight fluctuations. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
1H Nuclear Magnetic Resonance (NMR)-Based Cerebrospinal Fluid and Plasma Metabolomic Analysis in Type 2 Diabetic Patients and Risk Prediction for Diabetic Microangiopathy
J. Clin. Med. 2019, 8(6), 874; https://doi.org/10.3390/jcm8060874 - 19 Jun 2019
Abstract
Insulin resistance and metabolic derangement are present in patients with type 2 diabetes mellitus (T2DM). However, the metabolomic signature of T2DM in cerebrospinal fluid (CSF) has not been investigated thus far. In this prospective metabolomic study, fasting CSF and plasma samples from 40 [...] Read more.
Insulin resistance and metabolic derangement are present in patients with type 2 diabetes mellitus (T2DM). However, the metabolomic signature of T2DM in cerebrospinal fluid (CSF) has not been investigated thus far. In this prospective metabolomic study, fasting CSF and plasma samples from 40 T2DM patients to 36 control subjects undergoing elective surgery with spinal anesthesia were analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy. NMR spectra of CSF and plasma metabolites were analyzed and correlated with the presence of T2DM and diabetic microangiopathy (retinopathy, nephropathy, and neuropathy) using an area under the curve (AUC) estimation. CSF metabolomic profiles in T2DM patients vs. controls revealed significantly increased levels of alanine, leucine, valine, tyrosine, lactate, pyruvate, and decreased levels of histidine. In addition, a combination of alanine, histidine, leucine, pyruvate, tyrosine, and valine in CSF showed a superior correlation with the presence of T2DM (AUC:0.951), diabetic retinopathy (AUC:0.858), nephropathy (AUC:0.811), and neuropathy (AUC:0.691). Similar correlations also appeared in plasma profiling. These metabolic alterations in CSF suggest decreasing aerobic metabolism and increasing anaerobic glycolysis in cerebral circulation of patients with T2DM. In conclusion, our results provide clues for the metabolic derangements in diabetic central neuropathy among T2DM patients; however, their clinical significance requires further exploration. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Circulating C1q/TNF-Related Protein 3, Omentin-1 and NGAL in Obese Patients with Type 2 Diabetes During Insulin Therapy
J. Clin. Med. 2019, 8(6), 805; https://doi.org/10.3390/jcm8060805 - 05 Jun 2019
Abstract
The aim of the study was to quantify the plasma concentration of omentin-1, neutrophil gelatinase-associated lipocalin (NGAL), and complement C1q tumor necrosis factor-related protein-3 (CTRP3) in obese patients with type 2 diabetes, before introducing insulin therapy, in relation to the plasma expression profiles [...] Read more.
The aim of the study was to quantify the plasma concentration of omentin-1, neutrophil gelatinase-associated lipocalin (NGAL), and complement C1q tumor necrosis factor-related protein-3 (CTRP3) in obese patients with type 2 diabetes, before introducing insulin therapy, in relation to the plasma expression profiles of these regulatory molecules in the same patients after a 6-month insulin mixture therapy and in obese controls. Elevated plasma NGAL concentrations were found in type 2 diabetic patients as compared with subjects with metabolically healthy obesity. In turn, a 6-month insulin mixture therapy has shown a marked increase in the plasma concentration of omentine-1 and a significant decrease in plasma CTRP3 concentration in obese patients with type 2 diabetes, in relation to the values found in these patients before the implementation of insulin therapy. Insulin mixture therapy has also proved to be an important factor modifying the plasma profile of NGAL, increasing the concentration of this bioactive molecule in the plasma of patients with type 2 diabetes, after 6 months of its use, in relation to the concentration before treatment. The significant changes in the plasma profile of omentin-1, NGAL and CTRP3 during insulin therapy suggest their potential diagnostic utility in monitoring metabolic changes associated with the introduction of insulin treatment in type 2 diabetic patients. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets
J. Clin. Med. 2019, 8(5), 674; https://doi.org/10.3390/jcm8050674 - 14 May 2019
Abstract
Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions [...] Read more.
Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in α-cells. In α-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in α-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic β-cells and improving glucose homeostasis. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Extracellular Vesicle Encapsulated MicroRNAs in Patients with Type 2 Diabetes Are Affected by Metformin Treatment
J. Clin. Med. 2019, 8(5), 617; https://doi.org/10.3390/jcm8050617 - 07 May 2019
Abstract
Recently, microRNAs (miRNAs) in circulating extracellular vesicles (EVs), have emerged as a source of potential biomarkers for various pathophysiological conditions, including metabolic disorders such as diabetes. Type 2 diabetes mellitus (T2DM), is the most prevalent form of diabetes in the USA, with 30 [...] Read more.
Recently, microRNAs (miRNAs) in circulating extracellular vesicles (EVs), have emerged as a source of potential biomarkers for various pathophysiological conditions, including metabolic disorders such as diabetes. Type 2 diabetes mellitus (T2DM), is the most prevalent form of diabetes in the USA, with 30 million diagnosed patients. Identifying miRNA biomarkers that can be used to assess response to glucose lowering treatments would be useful. Using patient plasma samples from a subset of the Danish Metagenomics of the Human Intestinal Tract (MetaHIT) cohort, we characterized miRNAs from whole plasma, plasma-derived EVs, and EV-depleted plasma by small RNA-sequencing to identify T2DM associated miRNAs. We identified several miRNAs that exhibited concentration changes between controls and non-metformin treated T2DM patients and we validated a subset of these by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The results showed that the concentrations of many T2DM-affected miRNAs in EV (but not in whole or EV-depleted plasma) decreased to levels close to those of healthy controls following metformin treatment. Among other potential uses of these differentially expressed miRNAs, some might be useful in assessing the response to metformin in T2DM patients. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessFeature PaperArticle
GLP-1 Limits Adipocyte Inflammation and Its Low Circulating Pre-Operative Concentrations Predict Worse Type 2 Diabetes Remission after Bariatric Surgery in Obese Patients
J. Clin. Med. 2019, 8(4), 479; https://doi.org/10.3390/jcm8040479 - 09 Apr 2019
Cited by 1
Abstract
Objective: Glucagon-like peptide (GLP)-1 has been proposed as a key candidate in glucose improvements after bariatric surgery. Our aim was to explore the role of GLP-1 in surgically-induced type 2 diabetes (T2D) improvement and its capacity to regulate human adipocyte inflammation. Methods: Basal [...] Read more.
Objective: Glucagon-like peptide (GLP)-1 has been proposed as a key candidate in glucose improvements after bariatric surgery. Our aim was to explore the role of GLP-1 in surgically-induced type 2 diabetes (T2D) improvement and its capacity to regulate human adipocyte inflammation. Methods: Basal circulating concentrations of GLP-1 as well as during an oral glucose tolerance test (OGTT) were measured in lean and obese volunteers with and without T2D (n = 93). In addition, GLP-1 levels were determined before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 77). The impact of GLP-1 on inflammation signalling pathways was also evaluated. Results: We show that the reduced (p < 0.05) circulating levels of GLP-1 in obese T2D patients increased (p < 0.05) after RYGB. The area under the curve was significantly lower in obese patients with (p < 0.01) and without (p < 0.05) T2D compared to lean volunteers while obese patients with T2D exhibited decreased GLP-1 levels at baseline (p < 0.05) and 120 min (p < 0.01) after the OGTT. Importantly, higher (p < 0.05) pre-operative GLP-1 concentrations were found in patients with T2D remission after RYGB. We also revealed that exendin-4, a GLP-1 agonist, downregulated the expression of inflammation-related genes (IL1B, IL6, IL8, TNF) and, conversely, upregulated the mRNA levels of ADIPOQ in human visceral adipocytes. Furthermore, exendin-4 blocked (p < 0.05) LPS-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Conclusions: Our data indicate that GLP-1 may contribute to glycemic control and exert a role in T2D remission after RYGB. GLP-1 is also involved in limiting inflammation in human visceral adipocytes. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Faecal Microbiota Are Related to Insulin Sensitivity and Secretion in Overweight or Obese Adults
J. Clin. Med. 2019, 8(4), 452; https://doi.org/10.3390/jcm8040452 - 04 Apr 2019
Abstract
Emerging evidence suggests a role for the gut microbiota in glucose metabolism and diabetes. Few studies have examined the associations between the faecal microbiome and insulin sensitivity and secretion using gold-standard methods in high-risk populations prior to diabetes onset. We investigated the relationships [...] Read more.
Emerging evidence suggests a role for the gut microbiota in glucose metabolism and diabetes. Few studies have examined the associations between the faecal microbiome and insulin sensitivity and secretion using gold-standard methods in high-risk populations prior to diabetes onset. We investigated the relationships between faecal microbiota composition (16S rRNA sequencing) and gold-standard measures of insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) and insulin secretion (intravenous glucose tolerance test) in 38 overweight or obese otherwise healthy individuals. Genus Clostridium was positively associated with insulin sensitivity, and genera Dialister and Phascolarctobacterium were related to both insulin sensitivity and secretion. Insulin sensitivity was associated with a higher abundance of Phascolarctobacterium and lower abundance of Dialister. Those with higher insulin secretion had a higher abundance of Dialister and lower abundance of Bifidobacterium, compared to those with lower insulin secretion. Body mass index (BMI) was positively correlated with Streptococcus abundance whereas Coprococcus abundance was negatively correlated to BMI and percent body fat. These results suggest that faecal microbiota is related to insulin sensitivity and secretion in overweight or obese adults. These correlations are distinct although partially overlapping, suggesting different pathophysiological pathways. Our findings can inform future trials aiming to manipulate gut microbiome to improve insulin sensitivity and secretion and prevent type 2 diabetes. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
H. pylori Eradication Treatment Alters Gut Microbiota and GLP-1 Secretion in Humans
J. Clin. Med. 2019, 8(4), 451; https://doi.org/10.3390/jcm8040451 - 04 Apr 2019
Cited by 2
Abstract
Changes in the intestinal microbial community and some metabolic disturbances, including obesity and type2 diabetes, are related. Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis. Microbiota have been linked to incretin secretion. Antibiotic use causes changes in microbial diversity and composition. Our aim was to [...] Read more.
Changes in the intestinal microbial community and some metabolic disturbances, including obesity and type2 diabetes, are related. Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis. Microbiota have been linked to incretin secretion. Antibiotic use causes changes in microbial diversity and composition. Our aim was to evaluate the relationship between microbiota changes and GLP-1 secretion. A prospective case-control study with a Helicobacter pylori-positive patient model involving subjects under eradication therapy (omeprazole, clarithromycin, and amoxicillin). Forty patients with H. pylori infection and 20 matched participants, but negative for H. pylori antigen. Patients were evaluated before and two months after treatment. We analyzed anthropometric measurements, carbohydrate metabolism, lipid profile, and C-reactive protein. Gut microbiota composition was analyzed through 16S rRNA amplicon sequencing (IlluminaMiSeq). Eradication treatment for H. pylori decreased bacterial richness (Chao1, p = 0.041). Changes in gut microbiota profiles were observed at phylum, family, genus and species levels. GLP-1 secretion and variables of carbohydrate metabolism were improved. Correlations were seen between GLP-1 changes and variations within microbial community abundances, specifically Bifidobacterium adolescentis, the Lachnobacterium genus, and Coriobacteriaceae family. A conventional treatment to eradicate H. pylori could improve carbohydrate metabolism possibly in relation with an increase in GLP-1 secretion. GLP-1 secretion may be related to alterations in intestinal microbiota, specifically Lachnobacterium, B. adolescentis and Coriobacteriaceae. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Data Independent Acquisition Mass Spectrometry Can Identify Circulating Proteins That Predict Future Weight Loss with a Diet and Exercise Programme
J. Clin. Med. 2019, 8(2), 141; https://doi.org/10.3390/jcm8020141 - 25 Jan 2019
Abstract
We investigated biological determinants that would associate with the response to a diet and weight loss programme in impaired glucose regulation (IGR) people using sequential window acquisition of all theoretical fragment ion spectra (SWATH) mass spectrometry (MS), a data acquisition method which complement [...] Read more.
We investigated biological determinants that would associate with the response to a diet and weight loss programme in impaired glucose regulation (IGR) people using sequential window acquisition of all theoretical fragment ion spectra (SWATH) mass spectrometry (MS), a data acquisition method which complement traditional mass spectrometry-based proteomics techniques. Ten women and 10 men with IGR underwent anthropometric measurements and fasting blood tests. SWATH MS was carried out with subsequent immunoassay of specific peptide levels. After a six-month intervention, 40% of participants lost 3% or more in weight, 45% of patients remained within 3% of their starting weight and 15% increased their weight by 3% or more. Hemoglobin A1c (HbA1C) level was reduced with weight loss with improvements in insulin sensitivity. SWATH MS on pre-intervention samples and subsequent principal component analysis identified a cluster of proteins associated with future weight loss, including insulin-like growth factor-II (IGF-II) and Vitamin D binding protein. Individuals who lost 3% in weight had significantly higher baseline IGF-II levels than those who did not lose weight. SWATH MS successfully discriminated between individuals who were more likely to lose weight and potentially improve their sensitivity to insulin. A higher IGF-II baseline was predictive of success with weight reduction, suggesting that biological determinants are important in response to weight loss and exercise regimes. This may permit better targeting of interventions to prevent diabetes in the future. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Deduction of Novel Genes Potentially Involved in Keratinocytes of Type 2 Diabetes Using Next-Generation Sequencing and Bioinformatics Approaches
J. Clin. Med. 2019, 8(1), 73; https://doi.org/10.3390/jcm8010073 - 10 Jan 2019
Cited by 2
Abstract
Keratinocytes constitute the major cell type of epidermis, which participates in re-epithelialization during wound repair and the immune defense response to pathogens. The aim of the current study was to explore the differentially expressed genes and novel microRNA (miRNA) regulations that are potentially [...] Read more.
Keratinocytes constitute the major cell type of epidermis, which participates in re-epithelialization during wound repair and the immune defense response to pathogens. The aim of the current study was to explore the differentially expressed genes and novel microRNA (miRNA) regulations that are potentially involved in diabetic keratinocytes through next-generation sequencing (NGS) and bioinformatics approaches. A total of 420 differentially expressed genes between normal and diabetic keratinocytes were identified, and systematic bioinformatics analyses indicated that these differentially expressed genes were functionally enriched in interferon-alpha signaling, viral defense response, and immune response. Additionally, the potential miR-340-3p-DTX3L interaction that has been systematically validated in miRNA prediction databases was proposed to participate in the disrupted skin homeostasis, altering the defense and immune response of diabetic skin. The findings may provide new insights into understanding the pathogenesis of epidermal pathologies in diabetic patients and targeting novel molecules to advance diabetic skin care in clinical practice. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Type 2 Diabetes Is Associated with a Different Pattern of Serum Polyamines: A Case–Control Study from the PREDIMED-Plus Trial
J. Clin. Med. 2019, 8(1), 71; https://doi.org/10.3390/jcm8010071 - 10 Jan 2019
Cited by 1
Abstract
Objective: Polyamines are naturally occurring cationic molecules present in all living cells. Dysregulation of circulating polyamines has been reported in several conditions, but little is known about the levels of serum polyamines in chronic metabolic disorders such as type 2 diabetes (T2D). Therefore, [...] Read more.
Objective: Polyamines are naturally occurring cationic molecules present in all living cells. Dysregulation of circulating polyamines has been reported in several conditions, but little is known about the levels of serum polyamines in chronic metabolic disorders such as type 2 diabetes (T2D). Therefore, the aim of this study was to evaluate the polyamine-related metabolome in a cohort of metabolic syndrome individuals with and without T2D. Design and methods: This was a nested case–control study within the PREDIMED-Plus trial that included 44 patients with T2D and 70 patients without T2D. We measured serum levels of arginine, ornithine, polyamines, and acetyl polyamines with an ultra-high performance liquid chromatography tandem mass spectrometry platform. Results: Our results showed that serum putrescine, directly generated from ornithine by the catalytic action of the biosynthetic enzyme ornithine decarboxylase, was significantly elevated in patients with T2D compared to those without T2D, and that it significantly correlated with the levels of glycosylated hemoglobin (HbA1c). Correlation analysis revealed a significantly positive association between fasting insulin levels and spermine. Multiple logistic regression analysis (adjusted for age, gender and body weight index) revealed that serum putrescine and spermine levels were associated with a higher risk of T2D. Conclusions: Our study suggests that polyamine metabolism is dysregulated in T2D, and that serum levels of putrescine and spermine are associated with glycemic control and circulating insulin levels, respectively. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Plasma Branched-Chain Amino Acids and Risk of Incident Type 2 Diabetes: Results from the PREVEND Prospective Cohort Study
J. Clin. Med. 2018, 7(12), 513; https://doi.org/10.3390/jcm7120513 - 04 Dec 2018
Cited by 3
Abstract
Plasma branched-chain amino acids (BCAAs) are linked to metabolic disease, but their relevance for prediction of type 2 diabetes development is unclear. We determined the association of plasma BCAAs with type 2 diabetes risk in the prevention of renal and vascular end-stage disease [...] Read more.
Plasma branched-chain amino acids (BCAAs) are linked to metabolic disease, but their relevance for prediction of type 2 diabetes development is unclear. We determined the association of plasma BCAAs with type 2 diabetes risk in the prevention of renal and vascular end-stage disease (PREVEND) cohort. The BCAAs were measured by means of nuclear magnetic resonance spectroscopy. We evaluated the prospective associations of BCAAs with type 2 diabetes in 6244 subjects. The BCAAs were positively associated with HOMA-IR after multivariable adjustment (p < 0.0001). During median follow-up for 7.5 years, 301 cases of type 2 diabetes were ascertained. The Kaplan-Meier plot demonstrated that patients in the highest BCAA quartile presented a higher risk (p log-rank < 0.001). Cox regression analyses revealed a positive association between BCAA and type 2 diabetes; the hazard ratio (HR) for the highest quartile was 6.15 (95% CI: 4.08, 9.24, p < 0.0001). After adjustment for multiple clinical and laboratory variables, the association remained (HR 2.80 (95% CI: 1.72, 4.53), p < 0.0001). C-statistics, Net reclassification improvement, and −2 log likelihood were better after adding BCAAs to the traditional risk model (p = 0.01 to <0.001). In conclusions, high concentrations of BCAAs associate with insulin resistance and with increased risk of type 2 diabetes. This association is independent of multiple risk factors, HOMA-IR and β cell function. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Factors Influencing Variations in Hospitalization for Diabetes with Hypoglycemia
J. Clin. Med. 2018, 7(10), 367; https://doi.org/10.3390/jcm7100367 - 18 Oct 2018
Cited by 1
Abstract
Many studies have explored risk factors associated with Hypoglycemia (HG) and examined the variation in healthcare utilization among HG patients. However, most of these studies failed to integrate a comprehensive list of personal risk factors in their investigations. This empirical study employed the [...] Read more.
Many studies have explored risk factors associated with Hypoglycemia (HG) and examined the variation in healthcare utilization among HG patients. However, most of these studies failed to integrate a comprehensive list of personal risk factors in their investigations. This empirical study employed the Behavioral Model (BM) of health care utilization as a framework to investigate diabetes’ hospitalizations with HG. The national inpatient sample with all non-pregnant adult patients admitted to hospitals’ emergency departments and diagnosed with HG from 2012 to 2014 was used. Personal factors were grouped as predictors of the length of stay and the total charges incurred for hospitalization. High-risk profiles of hospitalized HG patients were identified. The analysis shows the need for care factors are the most influential predictors for lengthy hospitalization. The predisposing factors have a limited influence, while enabling factors influence the variation in hospital total charges. The presence of renal disease and diabetes mellitus (DM) complications played a key role in predicting hospital utilization. Furthermore, age, socio-economic status (SES), and the geographical location of the patients were also found to be vital factors in determining the variability in utilization among HG patients. Findings provide practical applications for targeting the high-risk HG patients for interventions. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Inhibitory Effects of Intranasal Administration of Insulin on Fat Oxidation during Exercise Are Diminished in Young Overweight Individuals
J. Clin. Med. 2018, 7(10), 308; https://doi.org/10.3390/jcm7100308 - 28 Sep 2018
Abstract
It remains unknown whether the high insulin (INS) levels in the brain affect fat oxidation during exercise. We examined the effects of the intranasal administration of INS, which increases the INS concentration in the cerebrospinal fluid when peripheral effects are lacking, on the [...] Read more.
It remains unknown whether the high insulin (INS) levels in the brain affect fat oxidation during exercise. We examined the effects of the intranasal administration of INS, which increases the INS concentration in the cerebrospinal fluid when peripheral effects are lacking, on the maximum fat oxidation rate (maxFOR) and its intensity (FATmax) during exercise in 15 young normal-weight (N group) and eight young overweight (O group) individuals. On two separate days, either INS or placebo (PL) was randomly administered intranasally before a graded exercise test. Indirect calorimetry was used to assess maxFOR and FATmax during exercise. Blood INS and glucose levels did not change after INS administration. In the N group, maxFOR and FATmax were significantly smaller in the INS trial than in the PL trial. MaxFOR was significantly smaller in the O group than in the N group and was not influenced by INS administration. Exercise-induced elevation in blood epinephrine levels tended to be reduced by INS administration only in the N group. Intranasal INS administration reduces fat oxidation during exercise without any peripheral effects, possibly by suppressing sympathetic nerve activity. This inhibitory effect is diminished in overweight subjects, suggesting that cerebral insulin effects are attenuated in this population. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Pioglitazone Reduces Dementia Risk in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Analysis
J. Clin. Med. 2018, 7(10), 306; https://doi.org/10.3390/jcm7100306 - 27 Sep 2018
Cited by 4
Abstract
Background: The beneficial effect of pioglitazone on dementia requires confirmation. Methods: The database of Taiwan’s National Health Insurance was used to enroll a propensity score-matched-pair cohort of patients who had ever used pioglitazone and patients who had never used pioglitazone from Taiwanese patients [...] Read more.
Background: The beneficial effect of pioglitazone on dementia requires confirmation. Methods: The database of Taiwan’s National Health Insurance was used to enroll a propensity score-matched-pair cohort of patients who had ever used pioglitazone and patients who had never used pioglitazone from Taiwanese patients with newly diagnosed diabetes mellitus during 1999–2008. The patients were to be alive on 1 January 2009 and were followed up for dementia until 31 December 2011. Hazard ratios were estimated using the Cox proportional hazards model. Results: There were 11,011 never users and 11,011 ever users of pioglitazone, with respective numbers of incident dementia of 123 and 91. The overall hazard ratio was 0.716 (95% confidence interval: 0.545–0.940) for ever users versus never users. The hazard ratios for the first (<11.0 months), second (11.0–19.6 months) and third (>19.6 months) tertiles of cumulative duration were 0.806 (0.544–1.193), 0.654 (0.430–0.994) and 0.694 (0.469–1.026), respectively. When cumulative duration was treated as a continuous variable, the hazard ratio was 0.987 (0.976–0.998). In subgroup analyses, the beneficial effect was mainly observed in patients who had not been treated with metformin. Among metformin ever users, the hazard ratio for dementia for pioglitazone ever users versus never users was 0.802 (0.580–1.109); and was 0.494 (0.284–0.857) among never users of metformin. No interaction between pioglitazone and major risk factors of dementia (i.e., stroke, hypoglycemia, head injury and Parkinson’s disease) was observed. Conclusions: Pioglitazone use is associated with a lower risk of dementia, especially when it is used in never users of metformin and has been used for more than 20 months. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Development of a Prediction Model for Colorectal Cancer among Patients with Type 2 Diabetes Mellitus Using a Deep Neural Network
J. Clin. Med. 2018, 7(9), 277; https://doi.org/10.3390/jcm7090277 - 12 Sep 2018
Cited by 1
Abstract
Objectives: Observational studies suggested that patients with type 2 diabetes mellitus (T2DM) presented a higher risk of developing colorectal cancer (CRC). The current study aims to create a deep neural network (DNN) to predict the onset of CRC for patients with T2DM. Methods: [...] Read more.
Objectives: Observational studies suggested that patients with type 2 diabetes mellitus (T2DM) presented a higher risk of developing colorectal cancer (CRC). The current study aims to create a deep neural network (DNN) to predict the onset of CRC for patients with T2DM. Methods: We employed the national health insurance database of Taiwan to create predictive models for detecting an increased risk of subsequent CRC development in T2DM patients in Taiwan. We identified a total of 1,349,640 patients between 2000 and 2012 with newly diagnosed T2DM. All the available possible risk factors for CRC were also included in the analyses. The data were split into training and test sets with 97.5% of the patients in the training set and 2.5% of the patients in the test set. The deep neural network (DNN) model was optimized using Adam with Nesterov’s accelerated gradient descent. The recall, precision, F1 values, and the area under the receiver operating characteristic (ROC) curve were used to evaluate predictor performance. Results: The F1, precision, and recall values of the DNN model across all data were 0.931, 0.982, and 0.889, respectively. The area under the ROC curve of the DNN model across all data was 0.738, compared to the ideal value of 1. The metrics indicate that the DNN model appropriately predicted CRC. In contrast, a single variable predictor using adapted the Diabetes Complication Severity Index showed poorer performance compared to the DNN model. Conclusions: Our results indicated that the DNN model is an appropriate tool to predict CRC risk in patients with T2DM in Taiwan. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Short Course of Insulin Treatment versus Metformin in Newly Diagnosed Patients with Type 2 Diabetes
J. Clin. Med. 2018, 7(9), 235; https://doi.org/10.3390/jcm7090235 - 23 Aug 2018
Abstract
The ß-cell dysfunction of type 2 diabetes is partly reversible. The optimal time window to induce glycemic remission is uncertain; short courses of insulin treatment have been tested as a strategy to induce remission. In a pilot study in 38 newly-diagnosed patients, we [...] Read more.
The ß-cell dysfunction of type 2 diabetes is partly reversible. The optimal time window to induce glycemic remission is uncertain; short courses of insulin treatment have been tested as a strategy to induce remission. In a pilot study in 38 newly-diagnosed patients, we assessed the time-course of insulin sensitivity and ß-cell function (by repeat oral glucose tolerance tests) following a 6-week basal insulin treatment compared to metformin monotherapy in equipoised glycemic control. At 6 weeks, insulin secretion and sensitivity were increased in both groups whilst ß-cell glucose sensitivity was unchanged. From this time onwards, in the insulin group glycemia started to rise at 3 months, and was no longer different from baseline at 1 year. The initial improvement in insulin secretion and sensitivity dissipated. In the metformin group, fasting plasma glucose and HbA1c levels reached a nadir at 8 months, at which time insulin secretion, glucose and insulin sensitivity were significantly better than at baseline and higher than in the insulin group. A short course of basal insulin in newly-diagnosed patients does not appear to offer clinical advantage over recommended initiation with metformin. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
Open AccessArticle
Albuminuria Increases All-Cause Mortality in Japanese Patients with Type 2 Diabetes Mellitus
J. Clin. Med. 2018, 7(9), 234; https://doi.org/10.3390/jcm7090234 - 23 Aug 2018
Abstract
Previous studies have reported that diabetic kidney disease is associated with cardiovascular events and death. Little is known about the independent association of albuminuria and estimated glomerular filtration rate (eGFR), with mortality in Asian patients with type 2 diabetes mellitus (T2DM) without renal [...] Read more.
Previous studies have reported that diabetic kidney disease is associated with cardiovascular events and death. Little is known about the independent association of albuminuria and estimated glomerular filtration rate (eGFR), with mortality in Asian patients with type 2 diabetes mellitus (T2DM) without renal failure. We conducted a historical cohort study to clarify this issue in Japanese patients with T2DM. In this study, we recruited 385 patients with T2DM, who never had chronic renal failure (eGFR < 30 mL/min/1.73 m2 at baseline) and malignant diseases. With the end point of all-cause mortality, Cox regression analysis was performed. During the observational period of 7 years, 54 patients died. Cox regression analysis adjusted for confounding factors such as age, duration of diabetes, body mass index, and HbA1c, and showed that urinary albumin level was significantly associated with the mortality [hazard ratio (HR) = 1.32, 95% confidence interval (CI) = 1.03–1.70 per standard deviation (SD) increase, p = 0.031]. After additional adjustment for eGFR, the association remained significant (HR = 1.32, 95% CI = 1.02–1.70 per SD increase, p = 0.033). On the other hand, eGFR was not associated with the mortality. The present study showed that higher urinary albumin was associated with increased all-cause mortality in T2DM, independently of eGFR. These findings suggest that, regardless of eGFR, albuminuria is important for the increased risk of mortality in Japanese T2DM patients without chronic renal failure (eGFR < 30 mL/min/1.73 m2). However, because of several limitations, further large-scale longitudinal studies are necessary to confirm the present study. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
Open AccessArticle
Mitochondrial DNA Haplogroup JT is Related to Impaired Glycaemic Control and Renal Function in Type 2 Diabetic Patients
J. Clin. Med. 2018, 7(8), 220; https://doi.org/10.3390/jcm7080220 - 16 Aug 2018
Abstract
The association between mitochondrial DNA (mtDNA) haplogroup and risk of type 2 diabetes (T2D) is undetermined and controversial. This study aims to evaluate the impact of the main mtDNA haplogroups on glycaemic control and renal function in a Spanish population of 303 T2D [...] Read more.
The association between mitochondrial DNA (mtDNA) haplogroup and risk of type 2 diabetes (T2D) is undetermined and controversial. This study aims to evaluate the impact of the main mtDNA haplogroups on glycaemic control and renal function in a Spanish population of 303 T2D patients and 153 healthy controls. Anthropometrical and metabolic parameters were assessed and mtDNA haplogroup was determined in each individual. Distribution of the different haplogroups was similar in diabetic and healthy populations and, as expected, T2D patients showed poorer glycaemic control and renal function than controls. T2D patients belonging to the JT haplogroup (polymorphism m.4216T>C) displayed statistically significant higher levels of fasting glucose and HbA1c than those of the other haplogroups, suggesting a poorer glycaemic control. Furthermore, diabetic patients with the JT haplogroup showed a worse kidney function than those with other haplogroups, evident by higher levels of serum creatinine, lower estimated glomerular filtration rate (eGFR), and slightly higher (although not statistically significant) urinary albumin-to-creatinine ratio. Our results suggest that JT haplogroup (in particular, change at position 4216 of the mtDNA) is associated with poorer glycaemic control in T2D, which can trigger the development of diabetic nephropathy. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessArticle
Heat Shock Protein 70 Gene Single Nucleotide Polymorphism and Diabetic Foot Ulcer. Is There Any Relationship?
J. Clin. Med. 2018, 7(8), 187; https://doi.org/10.3390/jcm7080187 - 27 Jul 2018
Abstract
Objective: The study aims to investigate the potential role of C2437T (Met493Thr) single nucleotide polymorphism (SNP) of the heat shock protein (HSP) 70 in diabetic foot ulcer patients. Methods: In this prospective cohort study, SNP of the HSP70 hom gene, also called HSPA1L, [...] Read more.
Objective: The study aims to investigate the potential role of C2437T (Met493Thr) single nucleotide polymorphism (SNP) of the heat shock protein (HSP) 70 in diabetic foot ulcer patients. Methods: In this prospective cohort study, SNP of the HSP70 hom gene, also called HSPA1L, was studied among diabetic patients with an ulcer (Group A: n = 50), diabetic patients without an ulcer (Group B: n = 50), and healthy subjects (Group C: n = 50). Results: There was a higher frequency of T/T genotype in group A (76%) as compared to group B (44%) and group C (14%). Moreover, the frequency of T allele was 7.3% in group A, 5.5% in group B, and 3.9% in group C. C allele frequency was 2.6%, 4.4%, and 6.1% in group A, group B, and group C, respectively. In group A, the odds ratio and risk ratio were 19-fold and 5-fold, respectively, for the HSP70 hom T/T homozygous gene compared to B (OR 19.45; RR 5.42; X2 38.8, p < 0.0001). Moreover, 4-fold and 1.75-fold ratios have been compared with group C (OR 4.03; RR 1.72; X2 10.6, p < 0.001). No significant difference in genotype was observed in group B and group C. Conclusions: There is a significant and positive association of hspHSP70 hom polymorphism restricted to T allele in homozygous and heterozygous states among diabetic foot ulcer (DFU) patients. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)

Review

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Open AccessReview
Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome—Strategies for In Vivo Administration: Part-II
J. Clin. Med. 2019, 8(9), 1332; https://doi.org/10.3390/jcm8091332 - 28 Aug 2019
Abstract
Diabetes is a complex disease characterized by hyperglycemia, together with polyuria, polydipsia, and polyphagia. While Type 1 diabetes mellitus (T1DM) results from genetic, environmental, or immune dysfunction factors leading to pancreatic β-cell destruction depriving the organism from endogenous insulin, Type 2 diabetes mellitus [...] Read more.
Diabetes is a complex disease characterized by hyperglycemia, together with polyuria, polydipsia, and polyphagia. While Type 1 diabetes mellitus (T1DM) results from genetic, environmental, or immune dysfunction factors leading to pancreatic β-cell destruction depriving the organism from endogenous insulin, Type 2 diabetes mellitus (T2DM) is characterized by peripheral insulin resistance. Depending on the type of diabetes mellitus and drug mechanism to study, the animal model should be carefully selected among the wide variety of the currently available ones. This review discusses the most common animal models currently employed to study T1DM and T2DM. Moreover, an overview on the administration routes that could be used is also discussed. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessReview
Current Progress in Pharmacogenetics of Second-Line Antidiabetic Medications: Towards Precision Medicine for Type 2 Diabetes
J. Clin. Med. 2019, 8(3), 393; https://doi.org/10.3390/jcm8030393 - 21 Mar 2019
Cited by 1
Abstract
Precision medicine is a scientific and medical practice for personalized therapy based on patients’ individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic [...] Read more.
Precision medicine is a scientific and medical practice for personalized therapy based on patients’ individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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Open AccessReview
Combination Therapy with an SGLT2 Inhibitor as Initial Treatment for Type 2 Diabetes: A Systematic Review and Meta-Analysis
J. Clin. Med. 2019, 8(1), 45; https://doi.org/10.3390/jcm8010045 - 04 Jan 2019
Cited by 4
Abstract
Background: Guidelines differ with regard to indications for initial combination pharmacotherapy for type 2 diabetes. Aims: To compare the efficacy and safety of (i) sodium-glucose cotransporter 2 (SGLT2) inhibitor combination therapy in treatment-naïve type 2 diabetes adults; (ii) initial high and low dose [...] Read more.
Background: Guidelines differ with regard to indications for initial combination pharmacotherapy for type 2 diabetes. Aims: To compare the efficacy and safety of (i) sodium-glucose cotransporter 2 (SGLT2) inhibitor combination therapy in treatment-naïve type 2 diabetes adults; (ii) initial high and low dose SGLT2 inhibitor combination therapy. Methods: PubMed, Embase and Cochrane Library were searched for randomised controlled trials (RCTs) of initial SGLT2 combination therapy. Mean difference (MD) for changes from baseline (HbA1c, weight, blood pressure) after 24–26 weeks of treatment and relative risks (RR, safety) were calculated using a random-effects model. Risk of bias and quality of evidence was assessed. Results: In 4 RCTs (n = 3749) there was moderate quality evidence that SGLT2 inhibitor/metformin combination therapy resulted in a greater reduction in HbA1c (MD (95% CI); −0.55% (−0.67, −0.43)) and weight (−2.00 kg (−2.34, −1.66)) compared with metformin monotherapy, and a greater reduction in HbA1c (−0.59% (−0.72, −0.46)) and weight (−0.57 kg (−0.89, −0.25)) compared with SGLT2 inhibitor monotherapy. The high dose SGLT2 inhibitor/metformin combination resulted in a similar HbA1c but greater weight reduction; −0.47 kg (−0.88, −0.06) than the low dose combination therapy. The RR of genital infection with combination therapy was 2.22 (95% CI 1.33, 3.72) and 0.69 (95% CI 0.50, 0.96) compared with metformin and SGLT2 inhibitor monotherapy, respectively. The RR of diarrhoea was 2.23 (95% CI 1.46, 3.40) with combination therapy compared with SGLT2 inhibitor monotherapy. Conclusions: Initial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy. Full article
(This article belongs to the Special Issue Type 2 Diabetes: Update on Pathophysiology and Treatment)
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