Review Article

The Role of Organelle Stresses in Diabetes Mellitus and Obesity: Implication for Treatment

Table 1

Genetically modified mice model linking organelle stress to metabolic diseases.

ModelGene functionTissuePhenotypes

Xbp1UPRGlobal haploinsufficiencyWeight gain, glucose intolerance, and insulin resistance on HFD [11]
Xbp1UPRLiver-specific KODiminished hepatic cholesterol and triglyceride secretion and hepatic lipogenesis [22]
Xbp1UPRLiver-specific OEReducing serum glucose concentrations and increasing glucose tolerance [12] Fasting and postprandial hypoglycemia; increased hepatic triglyceride content [13]
Xbp1UPRβ-cell-specific KOHyperglycemia and glucose intolerance resulting from decreased insulin secretion [14]
PerkUPRMammary epithelium-specific KOReduced accumulation of lipid content and the milk produced [23]
PerkUPRβ-cell-specific KOHyperglycemia associated with loss of islet and β-cell architecture [29, 30]
eIF2αUPRPhosphorylation site mutationDefective gluconeogenesis and deficiency of pancreatic beta-cell [14]
Gadd34UPRLiver-specific OELower liver glycogen levels, fasting hypoglycemia, diminished hepatics steatosis [15]
Atf6UPRLiver-specific OE/silencing Increased hepatic glucose output/lowered hepatic glucose output [16]
Atf6UPRGlobal KOHepatic steatosis [24]
Atf6, eIF2α, Ire1UPRGlobal KO/phosphorylation site mutationHepatic steatosis [25]
ChopUPRGlobal KODelayed the onset of diabetes and beta-cell apoptosis [32]
Grp78ChaperoneLiver-specific OEReduced hepatic triglyceride and cholesterol contents and improved insulin sensitivity improved [17]
Orp150ChaperoneLiver-specific OE/SilencingImproved insulin resistance and ameliorated glucose tolerance/increased insulin resistance [18]
AifMitochondrion-localized flavoproteinMuscle and liver-specific KOImproved glucose tolerance, reduced fat mass, and increased insulin sensitivity [49]
Pgc-1αMitochondrial biogenesisGlobal KOResistance to diet-induced obesity and insulin resistance [50, 51]
TfamMitochondrial DNA transcription Muscle-specific and adipose-specific KOImproved glucose disposal [52, 53]
TfamMitochondrial DNA transcriptionβ-cell-specific KOReduced β-cell mass and insulin secretion [61]
Cisd1Mitochondrial iron transportGlobal and liver-specific OEMassive expansion of adipose tissue but improved insulin sensitivity [54]
FxnAssembly of iron-sulfur cluster in mitochondriaβ-cell-specific KOIncreased islet oxidative stress, reduced islet mass, and diabetes [62]
Atg5AutophagyAdipose-specific KOImpaired adipocyte differentiation [124]
Atg5AutophagyGlobal OELean, enhanced glucose tolerance, insulin sensitivity, and extended lifespan [125]
Atg7AutophagyGlobal KOIncreased hepatic ER stress and impaired insulin sensitivity [69]
Atg7Autophagyβ-cell-specific KOReduction of β-cells mass, reduced insulin secretion, mitochondria swelling, and lower ATP production [74, 75]
Atg7AutophagyAdipose-specific KOLean, browning of white adipose tissue, increased fatty acid oxidation, and improved insulin sensitivity [82, 83]
Atg7AutophagyMuscle-specific KOReduced weight and body fat, enhanced glucose tolerance and insulin sensitivity, enhanced lipolysis and fatty acid oxidation, and increased FGF21 level [85]
Atg7AutophagyAgRP neuron-specific KOLean with decreased food intake [126]
Atg7AutophagyPOMC neuron-specific KOIncreased body weight and food intake,
impaired glucose tolerance [127, 128]
Atg7AutophagyMyf5+ progenitors-specific KOImpaired brown adipose tissue and skeletal muscle differentiation, browning of white adipose tissue, increased energy expenditure, increased body temperature, impaired glucose tolerance [129]
Atg7Autophagyβ-cell-specific KO in hIAPP transgenicsDecreased β-cell mass and diabetes [7779]
Atg7AutophagyGlobal haploinsufficiency in ob/ob mice Reduces ER stress; improves insulin sensitivity and glucose tolerance ob/ob mice [84]
Atg7AutophagyLiver-specific OE in ob/ob miceImproved insulin sensitivity and glucose tolerance [69]
Atg12AutophagyPOMC neuron-specific KOWeight gain, adiposity, and impaired glucose tolerance under HFD [130]

KO: knockout; OE: overexpression; UPR: unfolded protein response; HFD: high-fat diet; AgRP: agouti-related peptide; POMC: proopiomelanocortin; hIAPP: human islet amyloid polypeptide.