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1.
Trends Endocrinol Metab ; 34(10): 583-585, 2023 10.
Article in English | MEDLINE | ID: mdl-37625920

ABSTRACT

Increasing evidence suggests that the brain plays a key role in glucose homeostasis, making it a potential target for the treatment of type 2 diabetes (T2D). Sun et al. recently reported that intracerebroventricular (ICV) administration of a single dose of fibroblast growth factor 4 (FGF4) can induce sustained T2D remission in mouse models in the absence of any risk of hypoglycemia.


Subject(s)
Diabetes Mellitus, Type 2 , Hyperglycemia , Hypoglycemia , Animals , Mice , Diabetes Mellitus, Type 2/drug therapy , Fibroblast Growth Factor 4 , Hyperglycemia/drug therapy , Obesity/drug therapy
2.
Int J Mol Sci ; 24(10)2023 May 15.
Article in English | MEDLINE | ID: mdl-37240109

ABSTRACT

Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.


Subject(s)
Macular Degeneration , Retinal Pigment Epithelium , Humans , Aged , Retinal Pigment Epithelium/metabolism , Proteostasis , Autophagy/genetics , Oxidative Stress/genetics , Macular Degeneration/pathology , Mitochondria/metabolism
3.
Nat Rev Endocrinol ; 18(1): 23-42, 2022 01.
Article in English | MEDLINE | ID: mdl-34703027

ABSTRACT

Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.


Subject(s)
Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Insulin Resistance , Adaptive Immunity , Adipose Tissue/metabolism , Diabetes Mellitus, Type 2/metabolism , Female , Humans , Inflammation , Male , Obesity/metabolism
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