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Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders

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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 (10 August 2023) | Viewed by 21678

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Dr. Stephan Scherneck

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Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, 38106 Braunschweig, Germany
Interests: diabetes – pregnancy – medication safety

Special Issue Information

Dear Colleagues,

The prevalence of different types of diabetes, such as type 2 and gestational diabetes, is constantly increasing. This presents a significant challenge for health care systems worldwide. Although new targets have been identified and new therapeutic approaches developed in recent years, many processes in the pathogenesis of diabetes mellitus are still not understood. In this context, the definition of new diabetes subtypes represents an appropriate approach to close this gap. This applies in particular to type 2 diabetes, gestational diabetes, but also to pre-existing symptoms in form of prediabetes, which can be very different in their expression. Not every patient with prediabetes develops the manifest disease, and the disease itself can progress in quite different manners. Therefore, this Special Issue aims to better understand the transition from prediabetes to manifest diabetes and whether new subtypes of the disease can be defined within this process. Pathophysiological changes in the hormone secretion of the islets of Langerhans, the regulation of glucose metabolism by the liver, and the interactions between different tissues will be considered. The influence of different mechanisms on diabetic complications is also relevant. In this regard, pathological changes in the mitochondrial metabolism of the relevant tissues can also be addressed.

Dr. Stephan Scherneck
Guest Editor

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Keywords

subtypes of type 2 diabetes/prediabetes/gestational diabetes
pathophysiology of (pre)diabetes/gestational diabetes
regulation of insulin/glucagon secretion
mouse models of diabetic phenotypes
mitochondrial metabolism in (pre)diabetes
organ interplay in diabetes

Published Papers (9 papers)

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Research

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16 pages, 3106 KiB

Open AccessArticle

Fatty Acid Induced Hypermethylation in the Slc2a4 Gene in Visceral Adipose Tissue Is Associated to Insulin-Resistance and Obesity

by Jan H. Britsemmer, Christin Krause, Natalie Taege, Cathleen Geißler, Nuria Lopez-Alcantara, Linda Schmidtke, Alison-Michelle Naujack, Jonas Wagner, Stefan Wolter, Oliver Mann and Henriette Kirchner

Int. J. Mol. Sci. 2023, 24(7), 6417; https://doi.org/10.3390/ijms24076417 - 29 Mar 2023

Cited by 1 | Viewed by 1902

Abstract

De novo lipogenesis (DNL) in visceral adipose tissue (VAT) is associated with systemic insulin sensitivity. DNL in VAT is regulated through ChREBP activity and glucose uptake through Glut4 (encoded by Slc2a4). Slc2a4 expression, ChREBP activity, and DNL are decreased in obesity, the underlying cause however remains unidentified. We hypothesize that increased DNA methylation in an enhancer region of Slc2a4 decreases Slc2a4 expression in obesity and insulin resistance. We found that SLC2A4 expression in VAT of morbidly obese subjects with high HbA1c (>6.5%, n = 35) is decreased, whereas DNA methylation is concomitantly increased compared to morbidly obese subjects with low HbA1c (≤6.5%, n = 65). In diet-induced obese (DIO) mice, DNA methylation of Slc2a4 persistently increases with the onset of obesity and insulin resistance, while gene expression progressively decreases. The regulatory impact of DNA methylation in the investigated enhancer region on SLC2A4 gene expression was validated with a reporter gene assay. Additionally, treatment of 3T3 pre-adipocytes with palmitate/oleate during differentiation decreased DNA methylation and increased Slc2a4 expression. These findings highlight a potential regulation of Slc2a4 by DNA methylation in VAT, which is induced by fatty acids and may play a role in the progression of obesity and insulin resistance in humans. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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18 pages, 3964 KiB

Open AccessArticle

BCL-XL Overexpression Protects Pancreatic β-Cells against Cytokine- and Palmitate-Induced Apoptosis

by Atenea A. Perez-Serna, Reinaldo S. Dos Santos, Cristina Ripoll, Angel Nadal, Decio L. Eizirik and Laura Marroqui

Int. J. Mol. Sci. 2023, 24(6), 5657; https://doi.org/10.3390/ijms24065657 - 16 Mar 2023

Cited by 2 | Viewed by 1903

Abstract

Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca²⁺ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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17 pages, 3059 KiB

Open AccessArticle

Targeted Delivery of Butyrate Improves Glucose Homeostasis, Reduces Hepatic Lipid Accumulation and Inflammation in db/db Mice

by Signe Schultz Pedersen, Michala Prause, Christina Sørensen, Joachim Størling, Thomas Moritz, Eliana Mariño and Nils Billestrup

Int. J. Mol. Sci. 2023, 24(5), 4533; https://doi.org/10.3390/ijms24054533 - 25 Feb 2023

Cited by 7 | Viewed by 2064

Abstract

Butyrate produced by the gut microbiota has beneficial effects on metabolism and inflammation. Butyrate-producing bacteria are supported by diets with a high fiber content, such as high-amylose maize starch (HAMS). We investigated the effects of HAMS- and butyrylated HAMS (HAMSB)-supplemented diets on glucose metabolism and inflammation in diabetic db/db mice. Mice fed HAMSB had 8-fold higher fecal butyrate concentration compared to control diet-fed mice. Weekly analysis of fasting blood glucose showed a significant reduction in HAMSB-fed mice when the area under the curve for all five weeks was analyzed. Following treatment, fasting glucose and insulin analysis showed increased homeostatic model assessment (HOMA) insulin sensitivity in the HAMSB-fed mice. Glucose-stimulated insulin release from isolated islets did not differ between the groups, while insulin content was increased by 36% in islets of the HAMSB-fed mice. Expression of insulin 2 was also significantly increased in islets of the HAMSB-fed mice, while no difference in expression of insulin 1, pancreatic and duodenal homeobox 1, MAF bZIP transcription factor A and urocortin 3 between the groups was observed. Hepatic triglycerides in the livers of the HAMSB-fed mice were significantly reduced. Finally, mRNA markers of inflammation in liver and adipose tissue were reduced in mice fed HAMSB. These findings suggest that HAMSB-supplemented diet improves glucose metabolism in the db/db mice, and reduces inflammation in insulin-sensitive tissues. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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11 pages, 303 KiB

Open AccessCommunication

Serum Concentrations and Dietary Intake of Vitamin B₁₂ in Children and Adolescents on Metformin: A Case–Control Study

by Kyriaki Tsiroukidou, Eleni G. Paschalidou, Maria G. Grammatikopoulou, John Androulakis, Anastasios Vamvakis, Kalliopi K. Gkouskou, Christos Tzimos, Theodoros N. Sergentanis, Tonia Vassilakou, Emmanuel Roilides, Dimitrios P. Bogdanos and Dimitrios G. Goulis

Int. J. Mol. Sci. 2023, 24(4), 4205; https://doi.org/10.3390/ijms24044205 - 20 Feb 2023

Viewed by 1849

Abstract

The International Society of Pediatric and Adolescent Diabetes (ISPAD) recommends metformin (MET) use for metabolic disturbances and hyperglycemia, either in combination with insulin therapy or alone. A caveat of MET therapy has been suggested to be biochemical vitamin B₁₂ deficiency, as seen mainly in studies conducted in adults. In the present case–control study, children and adolescents of different weight status tiers on MET therapy for a median of 17 months formed the cases group (n = 23) and were compared with their peers not taking MET (n = 46). Anthropometry, dietary intake, and blood assays were recorded for both groups. MET group members were older, heavier, and taller compared with the controls, although BMI z-scores did not differ. In parallel, blood phosphorus and alkaline phosphatase (ALP) concentrations were lower in the MET group, whereas MCV, Δ₄-androstenedione, and DHEA-S were higher. No differences were observed in the HOMA-IR, SHBG, hemoglobin, HbA1c, vitamin B₁₂, or serum 25(OH)D₃ concentrations between groups. Among those on MET, 17.4% exhibited vitamin B₁₂ deficiency, whereas none of the controls had low vitamin B₁₂ concentrations. Participants on MET therapy consumed less energy concerning their requirements, less vitamin B₁₂, more carbohydrates (as a percentage of the energy intake), and fewer fats (including saturated and trans fats) compared with their peers not on MET. None of the children received oral nutrient supplements with vitamin B₁₂. The results suggest that, in children and adolescents on MET therapy, the dietary intake of vitamin B₁₂ is suboptimal, with the median coverage reaching 54% of the age- and sex-specific recommended daily allowance. This low dietary intake, paired with MET, may act synergistically in reducing the circulating vitamin B₁₂ concentrations. Thus, caution is required when prescribing MET in children and adolescents, and replacement is warranted. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

24 pages, 4703 KiB

Open AccessArticle

The Dynamics of Calcium Signaling in Beta Cells—A Discussion on the Comparison of Experimental and Modelling Data

by Michael Müller, Jonas Walkling, Nele Seemann and Ingo Rustenbeck

Int. J. Mol. Sci. 2023, 24(4), 3206; https://doi.org/10.3390/ijms24043206 - 06 Feb 2023

Cited by 1 | Viewed by 1432

Abstract

The stimulus–secretion coupling of the pancreatic beta cell is particularly complex, as it integrates the availability of glucose and other nutrients with the neuronal and hormonal input to generate rates of insulin secretion that are appropriate for the entire organism. It is beyond dispute however, that the cytosolic Ca²⁺ concentration plays a particularly prominent role in this process, as it not only triggers the fusion of insulin granules with the plasma membrane, but also regulates the metabolism of nutrient secretagogues and affects the function of ion channels and transporters. In order to obtain a better understanding of the interdependence of these processes and, ultimately, of the entire beta cell as a working system, models have been developed based on a set of nonlinear ordinary differential equations, and were tested and parametrized on a limited set of experiments. In the present investigation, we have used a recently published version of the beta cell model to test its ability to describe further measurements from our own experimentation and from the literature. The sensitivity of the parameters is quantified and discussed; furthermore, the possible influence of the measuring technique is taken into account. The model proved to be powerful in correctly describing the depolarization pattern in response to glucose and the reaction of the cytosolic Ca²⁺ concentration to stepwise increases of the extracellular K⁺ concentration. Additionally, the membrane potential during a KATP channel block combined with a high extracellular K⁺ concentration could be reproduced. In some cases, however, a slight change of a single parameter led to an abrupt change in the cellular response, such as the generation of a Ca²⁺ oscillation with high amplitude and high frequency. This raises the question as to whether the beta cell may be a partially unstable system or whether further developments in modeling are needed to achieve a generally valid description of the stimulus–secretion coupling of the beta cell. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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18 pages, 2835 KiB

Open AccessArticle

E96V Mutation in the Kdelr3 Gene Is Associated with Type 2 Diabetes Susceptibility in Obese NZO Mice

by Delsi Altenhofen, Jenny Minh-An Khuong, Tanja Kuhn, Sandra Lebek, Sarah Görigk, Katharina Kaiser, Christian Binsch, Kerstin Griess, Birgit Knebel, Bengt-Frederik Belgardt, Sandra Cames, Samaneh Eickelschulte, Torben Stermann, Axel Rasche, Ralf Herwig, Jürgen Weiss, Heike Vogel, Annette Schürmann, Alexandra Chadt and Hadi Al-Hasani

Int. J. Mol. Sci. 2023, 24(1), 845; https://doi.org/10.3390/ijms24010845 - 03 Jan 2023

Viewed by 2174

Abstract

Type 2 diabetes (T2D) represents a multifactorial metabolic disease with a strong genetic predisposition. Despite elaborate efforts in identifying the genetic variants determining individual susceptibility towards T2D, the majority of genetic factors driving disease development remain poorly understood. With the aim to identify novel T2D risk genes we previously generated an N2 outcross population using the two inbred mouse strains New Zealand obese (NZO) and C3HeB/FeJ (C3H). A linkage study performed in this population led to the identification of the novel T2D-associated quantitative trait locus (QTL) Nbg15 (NZO blood glucose on chromosome 15, Logarithm of odds (LOD) 6.6). In this study we used a combined approach of positional cloning, gene expression analyses and in silico predictions of DNA polymorphism on gene/protein function to dissect the genetic variants linking Nbg15 to the development of T2D. Moreover, we have generated congenic strains that associated the distal sublocus of Nbg15 to mechanisms altering pancreatic beta cell function. In this sublocus, Cbx6, Fam135b and Kdelr3 were nominated as potential causative genes associated with the Nbg15 driven effects. Moreover, a putative mutation in the Kdelr3 gene from NZO was identified, negatively influencing adaptive responses associated with pancreatic beta cell death and induction of endoplasmic reticulum stress. Importantly, knockdown of Kdelr3 in cultured Min6 beta cells altered insulin granules maturation and pro-insulin levels, pointing towards a crucial role of this gene in islets function and T2D susceptibility. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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14 pages, 329 KiB

Open AccessReview

Mouse Models of Gestational Diabetes Mellitus and Its Subtypes: Recent Insights and Pitfalls

by Katharina Grupe and Stephan Scherneck

Int. J. Mol. Sci. 2023, 24(6), 5982; https://doi.org/10.3390/ijms24065982 - 22 Mar 2023

Cited by 3 | Viewed by 2143

Abstract

Gestational diabetes mellitus (GDM) is currently the most common complication of pregnancy and is defined as a glucose intolerance disorder with recognition during pregnancy. GDM is considered a uniform group of patients in conventional guidelines. In recent years, evidence of the disease’s heterogeneity has led to a growing understanding of the value of dividing patients into different subpopulations. Furthermore, in view of the increasing incidence of hyperglycemia outside pregnancy, it is likely that many cases diagnosed as GDM are in fact patients with undiagnosed pre-pregnancy impaired glucose tolerance (IGT). Experimental models contribute significantly to the understanding of the pathogenesis of GDM and numerous animal models have been described in the literature. The aim of this review is to provide an overview of the existing mouse models of GDM, in particular those that have been obtained by genetic manipulation. However, these commonly used models have certain limitations in the study of the pathogenesis of GDM and cannot fully describe the heterogeneous spectrum of this polygenic disease. The polygenic New Zealand obese (NZO) mouse is introduced as a recently emerged model of a subpopulation of GDM. Although this strain lacks conventional GDM, it exhibits prediabetes and an IGT both preconceptionally and during gestation. In addition, it should be emphasized that the choice of an appropriate control strain is of great importance in metabolic studies. The commonly used control strain C57BL/6N, which exhibits IGT during gestation, is discussed in this review as a potential model of GDM. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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17 pages, 1877 KiB

Open AccessReview

Support Provided by Caregivers for Community-Dwelling Diabetic Hispanic Adults with Intellectual Disabilities and Comorbid Conditions

by Priyanka Rawat, Ujala Sehar, Jasbir Bisht and P. Hemachandra Reddy

Int. J. Mol. Sci. 2023, 24(4), 3848; https://doi.org/10.3390/ijms24043848 - 14 Feb 2023

Cited by 4 | Viewed by 2544

Abstract

Diabetes is an age-related chronic health condition and a major public health concern. Diabetes is one of the significant causes of morbidity and mortality and a major contributing factor to dementia. Recent research reveals that Hispanic Americans are at an increased risk of chronic conditions such as diabetes, dementia, and obesity. Recent research also revealed that diabetes develops at least ten years earlier in Hispanics and Latinos than in neighboring non-Hispanic whites. Furthermore, the management of diabetes and providing necessary/timely support is a challenging task for healthcare professionals. Caregiver support is an emerging area of research for people with diabetes, mainly family caregiver support work for Hispanic and Native Americans. Our article discusses several aspects of diabetes, factors associated with diabetes among Hispanics, its management, and how caregivers can support individuals with diabetes. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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13 pages, 2006 KiB

Open AccessReview

Role of Impaired Glycolysis in Perturbations of Amino Acid Metabolism in Diabetes Mellitus

by Milan Holeček

Int. J. Mol. Sci. 2023, 24(2), 1724; https://doi.org/10.3390/ijms24021724 - 15 Jan 2023

Cited by 8 | Viewed by 4112

Abstract

The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H⁺ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased. Full article

(This article belongs to the Special Issue Diabetes Mellitus (DM) - Endocrine and Metabolic Disorders)

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