Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance

Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.

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In Utero Maternal Benzene Exposure Predisposes to the Metabolic Imbalance in the Offspring

Toxicological Sciences ◽

10.1093/toxsci/kfab010 ◽

2021 ◽

Author(s):

Lisa Koshko ◽

Lucas K Debarba ◽

Mikaela Sacla ◽

Juliana B M de Lima ◽

Olesya Didyuk ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Mass ◽

Beta Cell Mass ◽

Female Offspring ◽

Male Offspring ◽

Differential Sensitivity ◽

Model Assessment ◽

Male And Female ◽

Benzene Exposure ◽

Metabolic Imbalance

Abstract Environmental chemicals play a significant role in the development of metabolic disorders, especially when exposure occurs early in life. We have recently demonstrated that benzene exposure, at concentrations relevant to cigarette smoke, induces a severe metabolic imbalance in a sex-specific manner affecting male but not female mice. However, the roles of benzene in the development of aberrant metabolic outcomes following gestational exposure, remain largely unexplored. In this study, we exposed pregnant C57BL/6JB dams to benzene at 50 ppm or filtered air for 6 h/day from gestational day 0.5 (GD0.5) through GD21 and studied male and female offspring metabolic phenotypes in their adult life. While no changes in body weight or body composition were observed between groups, 4-month-old male and female offspring exhibited reduced parameters of energy homeostasis (VO2, VCO2, and heat production). However, only male offspring from benzene-exposed dams were glucose intolerant and insulin resistant at this age. By 6 months of age, both male and female offspring exhibited marked glucose intolerance however, only male offspring developed severe insulin resistance. This effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. In support, Homeostatic Model Assessment for Insulin Resistance, the index of insulin resistance was elevated only in male but not in female offspring. Regardless, both male and female offspring exhibited a considerable increase in hepatic gene expression associated with inflammation and endoplasmic reticulum stress. Thus, gestational benzene exposure can predispose offspring to increased susceptibility to the metabolic imbalance in adulthood with differential sensitivity between sexes.

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059. POOR GROWTH BEFORE BIRTH IMPAIRS INSULIN SECRETION - WHAT WE HAVE LEARNT ABOUT THE MECHANISMS FROM THE PLACENTALLY-RESTRICTED SHEEP

Reproduction Fertility and Development ◽

10.1071/srb09abs059 ◽

2009 ◽

Vol 21 (9) ◽

pp. 14

Author(s):

K. L. Gatford

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Beta Cell ◽

Insulin Action ◽

Cell Function ◽

Cell Mass ◽

Beta Cell Mass ◽

Poor Growth ◽

Impaired Insulin ◽

Impaired Insulin Action

Diabetes occurs when insulin secretion fails to increase sufficiently to compensate for developing insulin resistance. This implies that the increased risk of diabetes in adults who were small at birth reflects impaired insulin secretion as well as their well-known insulin resistance. More recently, direct evidence has been obtained that adults and children who were growth-restricted before birth secrete less insulin than they should, given their level of insulin resistance. Our research group is using the placentally-restricted (PR) sheep to investigate the mechanisms underlying impaired insulin action (sensitivity and secretion) induced by poor growth before birth. Like the intra-uterine growth-restricted (IUGR) human, the PR sheep develops impaired insulin action by adulthood, but has enhanced insulin sensitivity in infancy, associated with neonatal catch-up growth1, 2. Impaired insulin action begins to develop in early postnatal life, where although basal insulin action is high due to enhanced insulin sensitivity, maximal glucose-stimulated insulin action is already impaired in males3. Our cellular and molecular studies have identified impaired beta-cell function rather than mass as the likely cause of impaired insulin secretion, and we have reported a novel molecular defect in the calcium channels involved in the insulin secretion pathway in the pancreas of these lambs3. Upregulation of IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass in the PR lamb3. By adulthood, both basal and maximal insulin action are profoundly impaired in the male lamb who was growth-restricted at birth2. These studies suggest therapies to prevent diabetes in the individual who grew poorly before birth should target beta-cell function, possibly in addition to further increasing beta-cell mass, to improve insulin secretion capacity, and its ability to increase in response to development of insulin resistance. We are now using the PR sheep to test potential therapies, since the timing of pancreatic development and hence exposure to a growth-restricting environment, is similar to that of the human.

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Normal islet vascularization is dispensable for expansion of beta-cell mass in response to high-fat diet induced insulin resistance

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2009.03.138 ◽

2009 ◽

Vol 383 (3) ◽

pp. 303-307 ◽

Cited By ~ 13

Author(s):

Yukiko Toyofuku ◽

Toyoyoshi Uchida ◽

Shiho Nakayama ◽

Takahisa Hirose ◽

Ryuzo Kawamori ◽

...

Keyword(s):

Insulin Resistance ◽

Beta Cell ◽

High Fat Diet ◽

Cell Mass ◽

Beta Cell Mass ◽

High Fat

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p8 deficiency lead to elevated pancreas beta cell mass but does not contribute to insulin resistance in mice fed with high fat diet

Pancreatology ◽

10.1016/j.pan.2017.05.137 ◽

2017 ◽

Vol 17 (3) ◽

pp. S44

Author(s):

Marcus Hollenbach ◽

Matthias Blüher ◽

Nora Klöting ◽

Ines Sommerer ◽

Joachim Mössner ◽

...

Keyword(s):

Insulin Resistance ◽

Beta Cell ◽

High Fat Diet ◽

Cell Mass ◽

Beta Cell Mass ◽

High Fat

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Metabolic Reprogramming by In Utero Maternal Benzene Exposure

10.1101/2020.10.12.336313 ◽

2020 ◽

Author(s):

Lisa Koshko ◽

Lucas K. Debarba ◽

Mikaela Sacla ◽

Juliana M.B. de Lima ◽

Olesya Didyuk ◽

...

Keyword(s):

Cell Mass ◽

Adult Life ◽

Beta Cell Mass ◽

Female Offspring ◽

Male Offspring ◽

Metabolic Reprogramming ◽

Differential Sensitivity ◽

Male And Female ◽

Benzene Exposure ◽

Metabolic Imbalance

SummaryEnvironmental chemicals play a significant role in the development of metabolic disorders, especially when exposure occurs early in life. We have recently demonstrated that benzene exposure, at concentrations relevant to a cigarette smoke, induces a severe metabolic imbalance in a sex-specific manner affecting male but not female mice. However, the roles of benzene in the development of aberrant metabolic outcomes following gestational exposure, remain largely unexplored. In this study, we exposed pregnant C57BL/6JB dams to benzene at 50 ppm or filtered air for 5 days/week (6h/day from gestational day 1 to birth) and studied male and female offspring metabolic phenotypes in their adult life. While no changes in body weight or body composition were observed between groups, 4-month-old male and female offspring exhibited reduced parameters of energy homeostasis (VO2, VCO2, and heat production). However, only male offspring from benzene-exposed dams were glucose intolerant and insulin resistant at this age. By six months of age, both male and female offspring displayed glucose and insulin intolerance, associated with elevated expression of hepatic gluconeogenesis and inflammatory genes. Additionally, this effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. Thus, gestational benzene exposure can reprogram offspring for increased susceptibility to the metabolic imbalance in adulthood with differential sensitivity between sexes.

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BACE1, but not BACE2, function is critical for metabolic disorders induced by high-fat diets in C57BL/6N mice

10.1101/2021.12.20.473491 ◽

2021 ◽

Author(s):

Thomas W Rosahl ◽

Lynn A Hyde ◽

Patrick T Reilly ◽

Marie-France Champy ◽

Kristin J Belongie ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Glucose Tolerance ◽

Beta Cell ◽

Pancreatic Beta Cells ◽

Cell Mass ◽

Beta Cell Mass ◽

High Fat ◽

Modest Improvement ◽

Peripheral Tissues

Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of toxic amyloid peptides and is highly expressed in the brain, but also to a lesser extent in major peripheral organs such as muscle and liver. In contrast, BACE2 is mainly expressed in peripheral tissues and is enriched in pancreatic beta cells, where it regulates beta-cell function and mass. Previous reports demonstrated that loss of BACE1 function decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice, whereas mice lacking Bace2 exhibit reduced blood glucose levels, improved intraperitoneal glucose tolerance and increased beta-cell mass. Impaired glucose homeostasis and insulin resistance are hallmarks of type 2 diabetes and have been implicated in Alzheimers disease. Therefore, we tested the contribution of the individual BACE isoforms to those metabolic phenotypes by placing Bace1 knockout (KO), Bace2 KO, Bace1/2 double knockout (dKO) and wild-type (WT) mice on a high-fat high-cholesterol diet (HFD) for 16 weeks. Bace1 KO and Bace1/2 dKO mice showed decreased body weight and improved glucose tolerance and insulin resistance vs. WT mice. Conversely, Bace2 KO mice did not show any significant differences in body weight, glucose tolerance or insulin resistance under our experimental conditions. Finally, subchronic MBi-3 mediated BACE1/2 inhibition in mice in conjunction with a HFD resulted in a modest improvement of glucose tolerance. Our data indicate that lack of BACE1, but not BACE2, function contributes mainly to the metabolic phenotypic changes observed in Bace1/2 dKO mice, suggesting that inhibition of BACE1 has the greater role (vs. BACE2) in any potential improvements in metabolic homeostasis.

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The Eye as a Transplantation Site to Monitor Pancreatic Islet Cell Plasticity

Frontiers in Endocrinology ◽

10.3389/fendo.2021.652853 ◽

2021 ◽

Vol 12 ◽

Author(s):

Erwin Ilegems ◽

Per-Olof Berggren

Keyword(s):

Beta Cells ◽

Pancreatic Islet ◽

Islet Cell ◽

Molecular Mechanisms ◽

Cell Function ◽

Severe Disease ◽

Cell Mass ◽

Beta Cell Mass ◽

Cell Plasticity ◽

Pancreatic Islet Cell

The endocrine cells confined in the islets of Langerhans are responsible for the maintenance of blood glucose homeostasis. In particular, beta cells produce and secrete insulin, an essential hormone regulating glucose uptake and metabolism. An insufficient amount of beta cells or defects in the molecular mechanisms leading to glucose-induced insulin secretion trigger the development of diabetes, a severe disease with epidemic spreading throughout the world. A comprehensive appreciation of the diverse adaptive procedures regulating beta cell mass and function is thus of paramount importance for the understanding of diabetes pathogenesis and for the development of effective therapeutic strategies. While significant findings were obtained by the use of islets isolated from the pancreas, in vitro studies are inherently limited since they lack the many factors influencing pancreatic islet cell function in vivo and do not allow for longitudinal monitoring of islet cell plasticity in the living organism. In this respect a number of imaging methodologies have been developed over the years for the study of islets in situ in the pancreas, a challenging task due to the relatively small size of the islets and their location, scattered throughout the organ. To increase imaging resolution and allow for longitudinal studies in individual islets, another strategy is based on the transplantation of islets into other sites that are more accessible for imaging. In this review we present the anterior chamber of the eye as a transplantation and imaging site for the study of pancreatic islet cell plasticity, and summarize the major research outcomes facilitated by this technological platform.

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p8 deficiency lead to elevated pancreatic beta cell mass but does not contribute to insulin resistance in mice fed with high fat diet

10.1055/s-0037-1604898 ◽

2017 ◽

Author(s):

M Hollenbach ◽

N Klöting ◽

I Sommerer ◽

J Lorenz ◽

M Heindl ◽

...

Keyword(s):

Insulin Resistance ◽

Beta Cell ◽

High Fat Diet ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

High Fat ◽

Pancreatic Beta Cell Mass

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Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review

Nutrients ◽

10.3390/nu12123846 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3846

Author(s):

Jun Inaishi ◽

Yoshifumi Saisho

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Beta Cell ◽

Current Knowledge ◽

Cell Mass ◽

Beta Cell Mass ◽

Beta Cell Dysfunction ◽

Cell Dysfunction ◽

Pancreatic Fat

Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.

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