J Korean Med Sci.  2022 Sep;37(37):e276. 10.3346/jkms.2022.37.e276.

Role of Autophagy in the Pathogenesis of Diabetes and Therapeutic Potential of Autophagy Modulators in the Treatment of Diabetes and Metabolic Syndrome

• Oh SJ
• Lee MS

• KMID: 2533555
• DOI: http://doi.org/10.3346/jkms.2022.37.e276

Abstract

Autophagy is critically involved in the maintenance of intracellular nutrient homeostasis and organelle function. Dysregulated autophagy is likely to play a role in the development of metabolic disorders and diabetes because autophagy is critical in the rejuvenation of dysfunctional or stressed endoplasmic reticulum and mitochondria that play a crucial role in the development of diabetes. Indeed, systemic autophagy insufficiency led to the increased tissue lipid content, aggravated metabolic and finally more severe diabetes when metabolic stress was imposed, suggesting that autophagy insufficiency of dysfunction of lysosome, an effector organelle of autophagy, due to aging, genetic predisposition or environmental factors could be an underlying cause of diabetes. Conversely, autophagy enhancer could improve metabolic profile of obese mice by reducing tissue lipid content and ameliorating metabolic inflammation. Furthermore, clearance of human islet amyloid polypeptide (hIAPP) oligomer and amyloid that accumulate in pancreatic islets of > 90% of diabetes patients was also dependent on autophagy. Consistently, autophagy enhancer could improve glucose profile and β-cell function of transgenic mice expressing amyloidogenic hIAPP in pancreatic β-cells, which was accompanied by reduced accumulation of hIAPP oligomer or amyloid, ameliorated β-cell apoptosis and increased β-cell mass. These results suggest that autophagy enhancer could be a novel therapeutic modality against diabetes associated with lipid overload and human diabetes characterized by islet amyloid accumulation.

Keyword

Autophagy; ER; Mitochondria; Metabolic Inflammation; Islet Amyloid; IAPP

Figure

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  Fig. 1 Aggravated metabolic profile and inflammasome activation in obese mice with autophagy haploinsufficiency. (A) Monitoring of non-fasting blood glucose level showed more severe and persistent diabetes in autophagy-haploinsufficient Atg7+/--ob/ob mice compared to autophagy-competent Atg7+/+-ob/ob mice. (B) Intraperitoneal glucose tolerance test showed more severe glucose intolerance in Atg7+/--ob/ob mice compared to Atg7+/+-ob/ob mice. (C) Lipid content in the liver tissue assessed by ORO staining was higher in Atg7+/--ob/ob mice compared to Atg7+/+-ob/ob mice, showing aggravated fatty liver. (D) Immunoblot showed increased maturation of pro-IL-1β to IL-1β in stromal vascular fraction of adipose tissue from Atg7+/--ob/ob mice compared to that from Atg7+/+-ob/ob mice.IL = interleukin.Reproduced from Lim et al. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat Commun 2014;5:4934.

• 

  Fig. 2 Improved glucose profile and fatty liver of obese mice by autophagy enhancer. (A) Monitoring of non-fasting blood glucose levels showed improved glucose profile after administration of MSL-7, an autophagy enhancer, to ob/ob (upper) and HFD-fed mice (lower). (B) Intraperitoneal glucose tolerance test showed improved glucose tolerance after administration of MSL-7 to ob/ob (upper) and HFD-fed mice (lower). (C) Hematoxyling and eosin staining showed ameliorated fatty liver after administration of MSL-7 to ob/ob mice.HFD = high-fat diet.Reproduced from Lim et al. A novel autophagy enhancer as therapeutic agent against metabolic syndrome and diabetes. Nat Commun 2018;9:1483.

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  Fig. 3 Reduced metabolic inflammation and inflammasome activation by autophagy enhancer. (A) Immunohistochemistry of adipose tissue sections from ob/ob mice using F4/80 antibody showed decreased number of CLS after administration of MSL for 8 weeks. (B) Real-time reverse transcription polymerase chain reaction using mRNA from adipose tissue showed reduced expression of inflammatory cytokines after administration of MSL for 8 weeks. (C) Content of IL-1β in the culture supernatant of primary peritoneal macrophages treated with 200 mM PA and/or 500 ng/mL LPS was reduced by MSL or MSL-7, as determined by enzyme-linked immunosorbent assay. (D) Mitochondrial ROS in primary peritoneal macrophages treated with 200 mM PA and/or 500 ng/mL LPS was reduced by MSL, as determined by MitoSox Red staining followed by FACS analysis.CLS = crown-like structure, TNF = tumor necrosis factor, IL = interleukin, PA = palmitic acid, LPS = lipopolysaccharide.Reproduced from Lim H et al. A novel autophagy enhancer as therapeutic agent against metabolic syndrome and diabetes. Nat Commun 9:1483, 2018

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  Fig. 4 Proposed model for improved metabolic profile in obesity-induced diabetes and human-type diabetes by an autophagy enhancer (MSL-7). Autophagy enhancer can reduce tissue lipid accumulation through activation of lipophagy in the presence of metabolic stress or lipid overload (left axis). Autophagy enhancer can also expedite rejuvenation of stressed or dysfunctional mitochondria which plays an important role in inflammasome activation, and, thereby, reduce metabolic inflammation (middle axis). Lipids such as palmitic acid can induce mitochondrial stress and activate inflammasome (gray arrow). Autophagy enhancer can accelerate clearance of hIAPP oligomer in pancreatic β-cells and protect β-cells from hIAPP oligomer-mediated apoptosis since hIAPP clearance is predominantly cleared by autophagy or lysosomal degradation rather than proteasomal degradation (right axis). Combined effects of these three axes and their interaction finally lead to the improvement of metabolic profile of obesity-induced diabetes and human-type diabetes characterized by islet amyloid accumulation through amelioration of insulin resistance and improvement of β-cell function.hIAPP = human islet amyloid polypeptide.

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  Fig. 5 Metabolic effect of autophagy enhancer on human-type diabetes of hIAPP+ mice. (A) Monitoring of non-fasting blood glucose in hIAPP+ mice during HFD feeding showed amelioration of diabetes in HFD-fed hIAPP+ mice by MSL-7, an autophagy enhancer. (B) Fasting blood glucose of HFD-fed hIAPP+ mice was also reduced by MSL-7 treatment for 8 weeks. (C) Intraperitoneal glucose tolerance test showed improved glucose tolerance by MSL-7 administration to HFD-fed hIAPP+ mice for 8 weeks. (D) Insulinogenic index representing β-cell function was also improved by MSL-7 administration to HFD-fed hIAPP+ mice for 8 weeks.hIAPP = human islet amyloid polypeptide, HFD = high-fat diet.Reproduced from Kim et al. An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer. Nat Commun 2021;12:183..

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  Fig. 6 Pancreatic islets of human-type diabetes of hIAPP+ mice treated with autophagy enhancer. (A) Immunostaining with A11 antibody showed that accumulation of hIAPP oligomer in pancreatic islets of HFD-fed hIAPP+ mice was significantly reduced by treatment with MSL-7, an autophagy enhancer for 8 weeks. (B) FSB staining showed that accumulation of islet amyloid in pancreatic islets of HFD-fed hIAPP+ mice was significantly reduced by treatment with MSL-7 for 8 weeks. (C) TUNEL staining combined with insulin immunohistochemistry showed that the number of apoptotic β-cells in pancreatic islets of HFD-fed hIAPP+ mice was significantly reduced by treatment with MSL-7 for 8 weeks. (D) Relative β-cell mass estimated by insulin immunohistochemistry and subsequent point counting was reduced in HFD-fed hIAPP+ mice, which was significantly improved by MSL-7 treatment for 8 weeks.hIAPP = human islet amyloid polypeptide, HFD = high-fat diet.Reproduced from Kim et al. An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer. Nat Commun 2021;12:183.

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