Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?

2022 ◽  
Vol 62 (1) ◽  
pp. 55-84
Author(s):  
Zaman Mirzadeh ◽  
Chelsea L. Faber ◽  
Michael W. Schwartz
Keyword(s):  
Type 2 Diabetes ◽  
Central Nervous System ◽  
Nervous System ◽  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Integrative Model ◽  
Glucose Disposal ◽  
System Control ◽  
Normal Glucose

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.

Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis

2005 ◽  
Vol 288 (4) ◽  
pp. E707-E714 ◽  
Author(s):  
Marcela Brissova ◽  
Michael Blaha ◽  
Cathi Spear ◽  
Wendell Nicholson ◽  
Aramandla Radhika ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Glucose Disposal ◽  
Β Cell ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic β-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX-1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated (PDX-1+/−, resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated (GLUT4+/−, resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 (GLUT4+/−;PDX-1+/−). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. GLUT4+/−;PDX-1+/− mice developed β-cell hyperplasia but failed to increase their β-cell insulin content. These results indicate that PDX-1 heterozygosity (∼60% of normal protein levels) abrogates the β-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.

scholarly journals METABOLIC PHENOTYPING GUIDELINES: Assessing glucose homeostasis in rodent models

2014 ◽  
Vol 222 (3) ◽  
pp. G13-G25 ◽  
Author(s):  
James E Bowe ◽  
Zara J Franklin ◽  
Astrid C Hauge-Evans ◽  
Aileen J King ◽  
Shanta J Persaud ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Β Cells ◽  
Advantages And Disadvantages ◽  
Autoimmune Destruction ◽  
Normal Glucose

The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic β-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the β-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasisin vivohas become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designingin vivoexperiments for the measurement of glucose homeostasis are also discussed.

scholarly journals High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Tsuyoshi Okura ◽  
Etsuko Ueta ◽  
Risa Nakamura ◽  
Yohei Fujioka ◽  
Keisuke Sumi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Advanced Glycation End Products ◽  
Glucose Disposal ◽  
Sensitivity Index ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Glucose Disposal Rate

Objective. Advanced glycation end products (AGEs) are important in the pathophysiology of type 2 diabetes mellitus (T2DM). They directly cause insulin secretory defects in animal and cell culture models and may promote insulin resistance in nondiabetic subjects. We have developed a highly sensitive liquid chromatography-tandem mass spectrometry method for measuring AGEs in human serum. Here, we use this method to investigate the relationship between AGEs and insulin secretion and resistance in patients with T2DM. Methods. Our study involved 15 participants with T2DM not on medication and 20 nondiabetic healthy participants. We measured the AGE carboxyethyllysine (CEL), carboxymethyllysine (CML), and methyl-glyoxal-hydro-imidazolone (MG-H1). Plasma glucose and insulin were measured in these participants during a meal tolerance test, and the glucose disposal rate was measured during a euglycemic-hyperinsulinemic clamp. Results. CML and CEL levels were significantly higher in T2DM than non-DM participants. CML showed a significant negative correlation with insulin secretion, HOMA-%B, and a significant positive correlation with the insulin sensitivity index in T2DM participants. There was no correlation between any of the AGEs measured and glucose disposal rate. Conclusions. These results suggest that AGE might play a role in the development or prediction of insulin secretory defects in type 2 diabetes.

scholarly journals The long non-coding RNA Pax6os1/PAX6-AS1 modulates pancreatic β-cell identity and function

2020 ◽  
Author(s):  
Livia Lopez-Noriega ◽  
Rebecca Callingham ◽  
Aida Martinez-Sánchez ◽  
Grazia Pizza ◽  
Nejc Haberman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucose Homeostasis ◽  
High Glucose ◽  
High Fat Diet ◽  
High Fat ◽  
Β Cell ◽  
And Function

AbstractLong non-coding RNAs (lncRNAs) are emerging as crucial regulators of β-cell development and function. Consequently, the mis-expression of members of this group may contribute to the risk of type 2 diabetes (T2D). Here, we investigate roles for an antisense lncRNA expressed from the Pax6 locus (annotated as Pax6os1 in mice and PAX6-AS1 in humans) in β-cell function. The transcription factor Pax6 is required for the development of pancreatic islets and maintenance of a fully differentiated β-cell phenotype. Pax6os1/PAX6-AS1 expression was increased in pancreatic islets and β-cell lines at high glucose concentrations, in islets from mice fed a high fat diet, and in those from patients with type 2 diabetes. Silencing or deletion of Pax6os1/PAX6-AS1 in MIN6 cells and EndoC-βH1cells, respectively, upregulated β-cell signature genes, including insulin. Moreover, shRNA-mediated silencing of PAX6-AS1 in human islets not only increased insulin mRNA, but also enhanced glucose-stimulated insulin secretion and calcium dynamics. In contrast, inactivation of Pax6os1 in mice was largely without effect on glucose homeostasis, though female Pax6os1 null mice on high fat diet (HFD) showed a tendency towards enhanced glucose clearance. Together, our results suggest that increased expression of PAX6-AS1 at high glucose levels may contribute to β-cell dedifferentiation and failure in some forms of type 2 diabetes. Thus, targeting PAX6-AS1 may provide a promising strategy to enhance insulin secretion and improve glucose homeostasis in type 2 diabetes.

scholarly journals Sex differences in the effects of androgens acting in the central nervous system on metabolism

2016 ◽  
Vol 18 (4) ◽  
pp. 415-424 ◽  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Central Nervous System ◽  
Nervous System ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Sexually Dimorphic ◽  
Metabolic Homeostasis ◽  
The Central Nervous System

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose and energy homeostasis by testosterone in males and females. Testosterone deficiency predisposes men to metabolic dysfunction, with excess adiposity, insulin resistance, and type 2 diabetes, whereas androgen excess predisposes women to insulin resistance, adiposity, and type 2 diabetes. This review discusses how testosterone acts in the central nervous system, and especially the hypothalamus, to promote metabolic homeostasis or dysfunction in a sexually dimorphic manner. We compare the organizational actions of testosterone, which program the hypothalamic control of metabolic homeostasis during development, and the activational actions of testosterone, which affect metabolic function after puberty. We also discuss how the metabolic effect of testosterone is centrally mediated via the androgen receptor.

scholarly journals Type 2 diabetes mellitus: A central nervous system etiology

2010 ◽  
Vol 1 (1) ◽  
pp. 31 ◽  
Author(s):  
PeterJ Jannetta ◽  
LynnH Fletcher ◽  
PeterM Grondziowski ◽  
KennethF Casey ◽  
RaymondF Sekula
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Central Nervous System ◽  
Nervous System ◽  
Type 2 Diabetes Mellitus

scholarly journals Cyanidin-3-O-glucoside inhibits different enzymes involved in central nervous system pathologies and type-2 diabetes

2019 ◽  
Vol 120 ◽  
pp. 241-246 ◽  
Author(s):  
Guillermo Cásedas ◽  
Francisco Les ◽  
Elena González-Burgos ◽  
Maria Pilar Gómez-Serranillos ◽  
Carine Smith ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Central Nervous System ◽  
Nervous System

scholarly journals Perinatal changes in plasma of type 2 diabetes mellitus pregnancies who delivered newborns with cardiomyopathy, depression of the central nervous system, or hepatomegaly

2020 ◽  
Author(s):  
Arthur T. Kopylov ◽  
Olga Papysheva ◽  
Iveta Gribova ◽  
Anna L. Kaysheva ◽  
Galina Kotaysch ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Central Nervous System ◽  
Nervous System ◽  
Type 2 Diabetes Mellitus ◽  
Maternal Diabetes ◽  
Controlled Study ◽  
Cross Sectional ◽  
Peripheral Blood Plasma

Abstract Background Maternal diabetes either pregestational or gestational is the main risk factor contributing in development of diabetic fetopathy (DF) in newborns. There are no generalized signs of DF up to late gestational age due to insufficient sensitivity of the currently employed instrumental methods for diagnosis. Methods This is a cross-sectional prospective controlled study. Here, we reported proteomic investigation for several cases of severe types of diabetic fetopathy (cardiomyopathy (CRDM, n = 37), central nervous system depression (CNSD, n = 35) and hepatomegaly (HPMG, n = 35)) diagnosed during 30–35 gestational weeks and confirmed upon delivery by from patients with type 2 diabetes mellitus (T2DM). Control groups were comprised from women in whom T2DM had been ruled out (n = 40) and group of pregnancies with T2DM who delivered healthy newborns (n = 40). Results We found a composition of serum-based non-trivial markers capable that are strongly associated with the certain type of fetopathy or anatomical malfunctions in the affected newborns. Significant impact on mRNA splicing and DNA reparation has been determined by emerging alterations in CDCL5. Patients of CNSD groups were characterized by utmost depletion (ca. 7% of baseline) of DFP3 neurotrophic factor needed for the proper specialization of cardiomyocytes and oligodendrocytes. Corrupted regulation of non-canonical Wnt-signaling guided by PEDF (in CNSD and HPMG groups) and DAAM2 (in CRDM and HPMG groups) was also proposed. In addition, deficiency in retinoic acid and thyroxine transport was revealed by dramatic increase of TTHY in CNDS group. Conclusions We examined peripheral blood plasma and determined a small proportion of proteins indicating the pre-existing signs of DF. Most of the examined markers are participants of critical processes at different stages of embryogenesis and regulate various phases of morphogenesis. There are proteins regulating splicing and DNA repair, differentiation of neurons and their switching to the post-mitotic state. Therefore, reconstruction of the molecular interplay between the defined in proteins is decisive to appreciate cryptic violations in fetal development on the background of diabetic conditions

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