glucagon - like peptide-1 ( glp-1 ) is produced by posttranslational proteolytic cleavage of the proglucagon gene product and mainly secreted from the enteroendocrine l cells in the distal intestine in response to nutrient ingestion .
glp-1 is an incretin hormone , which increases glucose - stimulated insulin secretion [ 1 , 2 ] .
glp-1 is quickly degraded by dipeptidyl peptidase-4 ( dpp-4 ) , and inhibition of this proteolytic enzyme enhances its biological half - life .
glp-1 has many beneficial effects on the control of blood glucose levels including stimulation of insulin secretion and inhibition of glucagon secretion , expansion of the beta - cell mass by stimulating beta - cell proliferation and differentiation and inhibiting beta - cell apoptosis , delay of gastric emptying , and reduction of food intake [ 46 ] .
therefore , glp-1 has been extensively studied as a possible treatment of type 2 diabetes , and glp-1 analogues and dpp-4 inhibitors are now widely in clinical use in these patients [ 711 ] .
expression of the glp-1 receptor is widely detected in various cells and organs including the kidney , lung , heart , hypothalamus , endothelial cells , neurons , astrocytes , and microglia as well as pancreatic beta - cells [ 1217 ] , suggesting that glp-1 might have additional roles other than glucose - lowering effects .
it was reported that glp-1 shows anti - inflammatory effects on pancreatic islets and adipose tissue , contributing to lowering glucose levels in diabetes [ 1820 ] .
in addition to these tissues , emerging data suggest that glp-1-based therapies also showed anti - inflammatory effects on the liver , vascular system including aorta and vein endothelial cells , brain , kidney , lung , testis , and skin by reducing the production of inflammatory cytokines and infiltration of immune cells in the tissues [ 17 , 2125 ] .
thus , glp-1 therapy may be beneficial for the treatment of chronic inflammatory diseases including nonalcoholic steatohepatitis , atherosclerosis , neurodegenerative disorders , diabetic nephropathy , asthma , and psoriasis [ 14 , 2632 ] .
drugs which are glp-1 receptor agonists or dpp-4 inhibitors are shown in table 1 . in this review
, we will introduce some of the chronic inflammatory diseases and then discuss evidence for beneficial effects of glp-1-based therapies focusing on its anti - inflammatory actions .
type 1 diabetes is caused by autoimmune - mediated destruction of pancreatic beta - cells , and type 2 diabetes is caused by both insulin resistance and relative deficiency of insulin [ 3436 ] .
inflammation can be a mediator of insulin resistance and beta - cell damage by high glucose , fatty acids , or adipokines released from adipose tissues [ 3739 ] .
thus , inflammation is an important factor for the pathogenesis of both type 1 and type 2 diabetes , and inhibition of inflammation can be a therapeutic strategy for treatment of diabetes .
the proinflammatory cytokines , such as interleukin-1 beta ( il-1 ) , interferon gamma ( ifn- ) , and tumor necrosis factor alpha ( tnf- ) , inhibit glucose - stimulated insulin secretion and proliferation of beta - cells [ 4042 ] .
treatment of isolated mouse islets with palmitate induced the expression of proinflammatory cytokines tnf- , il-1 , and il-6 .
liraglutide ( 100  nm ) , a long - acting glp-1 analogue , inhibited the palmitate - induced expression of these inflammatory factors and p65 expression . treatment of cultured human islets with exendin-4 ( 50  nm ) , a glp-1 receptor agonist , suppressed the expression of inflammatory genes such as nfb1(p105 ) , nfb2(p100 ) , rela ( also termed p65 ) , tnf receptor superfamily member 1a , and receptor - interacting serine / threonine kinase 2 . as well , exendin-4 ( 50  nm ) and cyclic adenosine monophosphate ( camp ) response element - binding protein overexpression additively protected transplanted human islets in streptozotocin- ( stz- ) induced diabetic nude mice .
treatment of nonobese diabetic mice with the dpp-4 inhibitor , nvp - dpp728 ( 30  mg / kg ) , significantly increased the levels of plasma transforming growth factor beta-1 ( tgf-1 ) , an anti - inflammatory cytokine , and increased cd4+cd25+foxp3 + regulatory t cells , contributing to the remission of diabetes .
treatment of diet - induced obese mice with sitagliptin ( 4  g / kg ) , a dpp-4 inhibitor , significantly reduced the expression of inflammatory genes including monocyte chemotactic protein- ( mcp- ) 1 , il-6 , il-12(p40 ) , il-12(p35 ) , and ifn--induced protein 10 ( ip-10 ) in pancreatic islets and improved glucose - stimulated insulin secretion in isolated islets .
treatment of stz - induced diabetic rats with another dpp-4 inhibitor , vildagliptin ( 10  mg / kg ) , significantly reduced plasma tnf- concentration and decreased nitric oxide concentration in serum and pancreatic homogenates compared with untreated diabetic rats .
treatment with sitagliptin ( 20  mg / kg ) increased serum glp-1 levels in stz - induced diabetic monkeys and showed significantly protective effects on stz - induced islet injury in vivo and in vitro via activation of the insulin - like growth factor receptor ( igfr)/akt / mammalian target of rapamycin ( mtor ) signaling pathways .
these results suggest that glp-1-based therapies suppress inflammatory cytokines and increase anti - inflammatory mediators in the pancreas .
c - x - c motif chemokine 10 ( cxcl10/ip10 ) , which is induced by ifn- , has an important role in recruiting activated t cells into the islets in type 1 diabetes . exendin-4 ( 100  nm ) decreased ifn--induced signal transducer and activator of transcription-1 ( stat1 ) , which is important for cxcl10 expression in the pancreatic beta - cell line , min6 cells , and human islets .
therefore , suppression of cxcl10 production by exendin-4 could reduce islet inflammation by decreasing cytotoxic t lymphocyte recruitment into the islets in autoimmune type 1 diabetes .
serine proteinase inhibitor-9 plays an important role in the survival of cells against attack by natural killer cells and cytotoxic t lymphocytes , which play a direct role in the destruction of pancreatic beta - cells in type 1 diabetes .
the glp-1 receptor agonist , exenatide ( a synthetic form of exendin-4 ) ( 10  nm ) , induces the expression of serine protease inhibitor-9 in human islets .
these results suggest that glp-1-based therapies not only directly regulate the expression of inflammatory mediators , but also regulate the recruitment of immunocytes and protect from immunocyte attack , contributing to the preservation of pancreatic islets .
the abundance of proinflammatory cytokines and chemokines in adipose tissue is a key contributor to insulin resistance in type 2 diabetes , and blocking of inflammatory signaling pathways or immune cell infiltration in adipose tissue improves insulin sensitivity [ 5052 ] .
administration of a recombinant adenovirus producing glp-1 ( 4  10  pfu / mouse ) to ob / ob mice reduced the macrophage population and production of tnf- , mcp-1 , and il-6 in adipose tissue via inhibition of nuclear factor - kappa b ( nf-b ) activation and phosphorylation of erk1/2 and c - jun n - terminal kinases .
sitagliptin ( 4  g / kg ) also showed similar effects and reduced the expression of mrna for inflammatory cytokine genes and macrophage infiltration in adipose tissue of high fat diet- ( hfd- ) induced obese mice . in patients with type 2 diabetes , sitagliptin ( 100  mg / day )
therapy significantly reduced the plasma levels of c - reactive protein ( crp ) , il-6 , il-18 , secreted phospholipase - a2 , soluble intracellular adhesion molecule- ( icam- ) 1 , and e - selectin compared with placebo .
the inflammatory score and the homeostatic model assessment index for insulin resistance were significantly reduced in sitagliptin - treated type 2 diabetes patients .
therefore , suppression of inflammatory mediators in adipose tissue by glp-1-based therapies might contribute to the improvement of insulin sensitivity .
glp-1-based therapies for diabetes contribute to reduce inflammation and have additional beneficial effects such as islet preservation and improvement of insulin sensitivity in addition to glucose - lowering effects .
however , some rare cases of acute pancreatitis and neoplasms have been reported [ 5355 ] ; thus the establishment of safety of glp-1-based therapy should be validated by sufficient further studies .
atherosclerotic cardiovascular disease is caused by proinflammatory stimuli in the vascular endothelial cells and is associated with increased plasma levels of tnf- , il-6 , crp , and circulating endotoxin ( i.e. , lipopolysaccharide ( lps ) ) [ 56 , 57 ] .
atherosclerosis is a chronic inflammatory condition resulting from the invasion and accumulation of white blood cells ( foam cells ) in the walls of arteries and therefore is a syndrome affecting arterial blood vessels .
glp-1 ( 5.0  m ) perfusion attenuates lps - induced microvascular permeability via the camp protein kinase a ( pka ) pathway .
liraglutide ( 100  m ) reduced the mrna expression of adhesion molecules such as vascular cell adhesion molecule- ( vcam- ) 1 , icam-1 , and e - selectin in tnf-- or lps - stimulated human aortic endothelial cells and human umbilical vein endothelial cells [ 6062 ] .
liraglutide ( 100  nm ) induced phosphorylation of calcium / calmodulin - dependent protein kinase i and 5 adenosine monophosphate - activated protein kinase ( ampk ) , and inhibition of calcium / calmodulin - dependent protein kinase kinase  ( camkk ) abolished the inhibitory effect of liraglutide on the expression of vcam-1 and e - selectin .
in addition , knockdown of ampk with short hairpin ampk rna abolished the liraglutide activation of ampk and anti - inflammatory effects .
these results demonstrate that the anti - inflammatory effects of liraglutide in human aortic endothelial cells is dependent on activation of camkk and ampk , which are camp / ca signaling pathways .
in addition , it was reported that liraglutide ( 100  nm ) inhibited tnf-- or hyperglyceamia - mediated induction of plasminogen activator inhibitor type-1 in human vascular endothelial cells .
exendin-4 ( 50  g / kg / day ) treatment resulted in a reduction of atherosclerosis development and the number of monocytes adhering to the endothelium wall in the aortic root in western - type diet - fed apoe3-leiden.cetp(e3l.cetp ) mice .
sitagliptin ( 25  m ) , nvp - dpp728 ( 270  m ) , or liraglutide ( 1000  ng / ml ) treatment significantly reduced oxidized - low - density lipoprotein - induced or pkc activator - induced protein expression of nucleotide - binding domain - like receptor with a pyrin domain 3 ( nlrp3 ) , toll - like receptor 4 ( tlr4 ) , and il-1 in a human monocytic cell line , thp-1 , by decreasing phosphorylated - protein kinase c ( pkc ) .
administration of linagliptin ( 10  mg / kg / day ) , a dpp-4 inhibitor , to apoe mice , an animal model of atherosclerosis , decreased inflammatory molecule expression and macrophage infiltration in the atherosclerotic aorta .
another report showed that sitagliptin ( 576  mg / kg ) reduced plaque macrophage infiltration and matrix metallopeptidase-9 ( mmp-9 ) levels in apoe mice   and increased activation of ampk and akt signaling pathway but inhibited mapk and erk1/2 signaling in aorta of apoe mice .
this suggests that sitagliptin has protective actions against atherosclerosis through ampk and mapk - dependent mechanisms .
in addition , sitagliptin ( 30  mg / kg / day ) and exenatide ( 3  g / kg/12  h ) significantly inhibited advanced glycation end products - induced oxidative stress in aortic endothelials in high fat diet ( hfd)/stz diabetic rats by reducing endothelin-1 ( et-1 ) and inflammatory cytokine via rhoa / rho - associated protein kinase ( rock)/nf-b signaling pathways and ampk activation . des - fluoro - sitagliptin ( 200  mg / kg / day ) treatment reduced atherosclerotic lesion formation , infiltration of macrophage and t lymphocytes , and the expression of proinflammatory cytokines within plaques in apoe mice .
as well , treatment with alogliptin ( 20  mg / kg / day ) , a selective dpp-4 inhibitor , showed similar anti - inflammatory effects in the injured arteries of low - density lipoprotein receptor - deficient mice .
interestingly , metabolite ( 9 - 37 ) of glp-1 as well as the c - terminal glp-1 split product ( 28 - 37 ) also reduced plaque inflammation and stabilized atherosclerotic lesions in apoe mice .
these suggest that glp-1-based therapies have protective effects in atherosclerosis by decreasing macrophage infiltration in atherosclerotic lesions via inhibition of the expression of adhesion molecules .
the loss of sirtuin 6 ( sirt6 ) , which regulates proinflammatory mediators , in human umbilical vein endothelial cells is associated with upregulation of the expression of proinflammatory genes .
liraglutide ( 100  nm ) treatment increased sirt6 expression and reduced nf-b expression compared with only high glucose - treated endothelial cells . in diabetic patients treated with glp-1-based therapy ,
the protein level of sirt6 in asymptomatic plaques was significantly increased and tnf- and mmp-9 levels in lesions were significantly reduced compared with diabetic patients without treatment .
this result suggests that glp-1-based therapy has anti - inflammatory effects by induction of sirt6 expression in endothelial cells .
cardiovascular disease is increased in type 2 diabetes , and hyperglyceamia is a critical promoter during the development of cardiovascular diseases .
exendin-4 ( 5  g / kg or 1 and 10  nm ) inhibited high mobility group box i protein expression , a proinflammatory mediator , in myocardial ischemia and reperfusion in rats   and in high glucose - induced myocardial cell injury .
sitagliptin ( 30 and 50  mg / kg / day ) reduced the expression of tnf- and il-6 in the diabetic heart and had a myocardial protective effect in stz / hfd - induced diabetic rats .
therefore , glp-1-based therapy have anti - inflammatory effects on vascular disease and may explain the vasoprotective properties .
epidemiological and clinical studies have suggested a link between type 2 diabetes and alzheimer 's disease . in patients with alzheimer 's disease ,
insulin receptors and insulin signaling in the brain are desensitized and impaired as found in type 2 diabetes patients .
therefore , drugs used for treatment of diabetes are expected to have a preventive effect against alzheimer 's disease .
glp-1 is known to be produced in the brain   and has many functions including neuroprotection [ 8082 ] .
in addition , glp-1 and glp-1 analogues enter the brain through blood brain barrier [ 8386 ] .
the glia may play a critical role in the central nervous system inflammatory responses including alzheimer 's disease , and glp-1 receptor was observed in astrocytes and microglia [ 17 , 87 ] . in astrocytes ,
glp-1 ( 1  m ) prevented the lps - induced il-1 expression by increase of camp .
models of alzheimer 's disease include intracerebroventricular injection of stz , intracerebral injection of lps , and the appswe / ps1e9 mouse .
exenatide ( 20  g / kg / day ) treatment inhibited brain tnf- levels , which were induced by intracerebroventricular injection of stz .
glp-1 ( 7 - 36 ) amide ( 50  nm ) protected the synaptic impairments induced by intracerebral injection of lps in the rat hippocampus .
liraglutide ( 25  nmol / kg / day ) treatment significantly reduced the inflammatory response in the cortex as measured by the number of activated microglia and prevented degenerative processes in a 7-month - old appswe / ps1e9 mouse model of alzheimer 's disease .
in addition , in the 14-month - old appswe / ps1e9 mouse , inflammation was also markedly reduced and restorative effects were improved by liraglutide treatment .
the glp-1 receptor agonist , lixisenatide , exerted neuroprotective effects via reduction of oxidative stress and the chronic inflammation response in the brain of appswe / ps1e9 mouse .
in addition , sitagliptin ( 10 and 20  mg / kg ) also showed similar anti - inflammatory effects in appswe / ps1e9 mouse .
this suggests that glp-1-based therapies could have a preventive and restorative effect on the pathophysiology of alzheimer 's disease progression .
x - ray irradiation of the brain significantly increased il-6 , il-1 , and il-12p70 cytokine protein expression .
liraglutide ( 25  nmol / kg / day ) treatment reduced the mrna expression of proinflammatory cytokine genes , which was induced by x - ray irradiation .
parkinson 's disease is a chronic and neurodegenerative brain disorder , and inflammatory activity is one of important features of parkinson 's disease .
microglial activation plays a critical role in the pathogenesis of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyidine- ( mptp- ) induced parkinson 's disease model and human parkinson 's disease .
exendin-4 ( 10  g / kg ) treatment significantly decreased mptp - induced microglial activation and suppressed mptp - induced expression of tnf- and il-1 .
the inhibitory effect of exendin-4 on microglial activation may have therapeutic potential for the treatment of parkinson 's disease .
these anti - inflammatory effects of glp-1-based therapies on the brain may protect against neurodegenerative central nervous system disorders .
nonalcoholic steatohepatitis is associated with an inflammation of the liver by an aberrant accumulation of fat in the liver .
glp-1 receptor agonists reduced alanine aminotransferase and aspartate aminotransferase levels in patients with nonalcoholic fatty liver disease ( or type 2 diabetes ) and improved lipid metabolism and reduced fat mass .
liraglutide ( 50 , 100 , and 200  g / kg/12  h ) treatment protected against nonalcoholic fatty liver disease by inhibition of er stress - associated apoptosis in hfd - fed rats .
liraglutide or exendin-4 ( 1  nmol / kg / day ) treatment dose - dependently reduced steatosis and lobular inflammation in hfd - fed rats or mice compared with the saline - injected group [ 28 , 95 ] , probably due to an increase of sirt1 . as a matter of fact , exendin-4 ( 50  g / kg / day )
treatment increased the expression of sirt1 and its downstream factor , ampk , in exendin-4 treated mouse livers and hepatocytes .
exendin-4 treatment reduced hepatic expression of the inflammatory markers tnf- , il-1 , and il-6 and macrophage markers , cluster of differentiation 68 ( cd68 ) , and f4/80 in the liver of mice fed a western - type diet . in nonalcoholic steatohepatitis patients with glucose intolerance , liraglutide ( 0.9  mg / person / day ) therapy for 96 weeks resulted in improvement of histological indicators of inflammation in seven subjects out of ten subjects .
crp is produced by the liver and is a marker of inflammation . in a retrospective analysis of 110 obese patients with type 2 diabetes treated with liraglutide ,
the mean concentration of crp declined after treatment with liraglutide for a mean duration of 7.5 months .
in addition , exenatide plus metformin resulted in a significant reduction in crp and tnf- compared with baseline .
these reports suggest that glp-1-based therapies improve fatty liver disease by ameliorating inflammation in rodents and humans .
diabetic nephropathy is associated with a state of low - grade inflammation in the microvasculature of the kidney 's glomeruli [ 99 , 100 ] .
the glp-1 receptor is expressed in glomerular capillaries and vascular walls of the mouse kidney [ 14 , 101 ] and in the glomerulus and proximal convoluted tubules of the rat and pig [ 29 , 102 ] .
glp-1 receptor deficiency in the diabetic nephropathy - resistant c57bl/6-akita mouse contributes to the development of diabetic nephropathy , and liraglutide treatment suppressed the progression of nephropathy of the kk / ta - akita mouse , which shows high susceptibility to diabetic nephropathy , suggesting that glp-1 action might play an important role in prevention of diabetic nephropathy .
various studies have shown that glp-1-based therapies can reduce macrophage infiltration and inflammatory molecules in models of diabetic nephropathy .
exendin-4 ( 3 and 10  g / kg / day ) treatment significantly downregulated the gene expression of cd14 , icam-1 , and tgf1 in the renal cortex , prevented glomerular macrophage infiltration in glomeruli , and reduced oxidative stress and inflammation in tubular cells in stz - induced diabetic animals [ 101 , 103 ] .
treatment with the dpp-4 inhibitor , saxagliptin ( 10  mg / kg / day ) , reduced renal tubulointerstitial inflammation by nf-bp65-mediated macrophage infiltration in stz - induced diabetic enos mice .
administration of the dpp-4 inhibitor , pkf275 - 055 ( 3  mg / kg / day ) , or linagliptin in stz - induced diabetic rats inhibited macrophage infiltration , inflammatory molecules , and nf-b activity in the glomeruli   and significantly reduced glomerular leukocyte infiltration .
sitagliptin ( 10  mg / kg / day ) treatment decreased the expression of proinflammatory cytokine genes il-1 and tnf- in kidney of diabetic zdf rat .
glp-1-based therapies are also effective in nondiabetic models of kidney injury . in a nondiabetic glomerular injury model , alogliptin ( 20  mg / kg / day ) , anagliptin ( 300  mg / kg / day ) , or exendin-4 ( 10  mg / kg ) significantly reduced infiltration of cd68-positive inflammatory macrophages in the kidney . in the mouse cisplatin - induced renal injury model , treatment with alogliptin ( 10  mg / kg / day ) significantly decreased cisplatin - induced renal injury via antiapoptotic effects .
in addition , after ischemia - reperfusion injury , the expression of proinflammatory cytokines , nf-b and icam-1 , as well as macrophage infiltration in the kidney was significantly decreased by exendin-4 ( 10  g / kg ) or sitagliptin ( 600  mg / kg ) treatment .
therefore , glp-1-based therapies might be beneficial for nephropathy by reducing glomerular leukocyte infiltration and proinflammatory mediators .
liraglutide ( 2  mg / kg ) reduced immune cell infiltration and protein expression of e - selectin , tnf- , il-4 , il-5 , and il-13 in the lung tissue or bronchoalveolar lavage fluid in an ovalbumin - induced chronic asthma model .
liraglutide treatment decreased nf-b activation , which was reversed by pka inhibitor , h-89 , suggesting that the camp - pka pathway is involved in inhibition of nf-b activation , and subsequently the inhibition of inflammation .
in addition , in mice with bleomycin - induced pulmonary fibrosis , liraglutide treatment inhibited infiltration of immune cells and decreased the content of tgf-1 .
these results suggest that glp-1-based therapies might have beneficial effects on asthma but need to be validated by clinical studies .
obesity can reduce the quality and count of men 's sperm [ 111 , 112 ] .
the expression of tnf- , mcp-1 , and f4/80 mrna levels is increased in the testis and significantly decreased the sperm motility and activity in diet - induced obesity mice , and exenatide ( 24  nmol / kg / day ) treatment suppressed the expression of tnf- , mcp-1 , and f4/80 mrna levels in testis and improved sperm quality in diet - induced obesity mice . in type 2
diabetes patients , glp-1 and liraglutide also improve clinical symptoms of psoriasis , a skin inflammatory disease , by downregulation of invariant natural killer t cells [ 31 , 113 , 114 ] .
glp-1 ( 100  nm ) or exendin-4 ( 10  nm ) treatment inhibited tnf--induced expression of receptor for advanced glycation end products ( rage ) , icam-1 , and vcam-1 in human retinal pigment epithelial cells , suggesting that glp-1-based therapies might have beneficial effects on diabetic retinopathy .
treatment with the dpp-4 inhibitors , linagliptin ( 5  mg / kg / day ) and sitagliptin ( 50  mg / kg / day ) , and the glp-1 analogue , liraglutide ( 200  g / kg / day ) , significantly reduced inflammatory markers such as inducible no synthase , cyclooxygenase , and vcam-1 via the ampk pathway in lps - induced endotoxemic shock in rats as a model of human sepsis .
these reports suggest that glp-1-based therapies have anti - inflammatory effects in the lung , testis , skin , and eye .
inflammation is a protective process including immune system , vascular system , and molecular mediators . however out - of - control inflammation and chronic inflammation can cause pathological disease .
inflammation is a risk factor for diabetes , atherosclerosis , cardiovascular disease , neurodegenerative central nervous system disorders , nonalcoholic steatohepatitis , and nephropathy .
glp-1-based therapies have many attractive and beneficial effects including their antidiabetic actions on pancreatic beta - cells .
however , beyond their metabolic effects , glp-1-based therapies have been shown to have anti - inflammatory effects via several molecular pathways ( figure 1 ) in several organs , tissues , and cells ( figure 2 ) .
thus glp-1 , glp-1r agonists , and dpp-4 inhibitors might have important roles as mediators of inflammation .
 glucagon - like peptide-1 ( glp-1 ) is an incretin hormone mainly secreted from intestinal l cells in response to nutrient ingestion . 
 glp-1 has beneficial effects for glucose homeostasis by stimulating insulin secretion from pancreatic beta - cells , delaying gastric emptying , decreasing plasma glucagon , reducing food intake , and stimulating glucose disposal . 
 therefore , glp-1-based therapies such as glp-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 , which is a glp-1 inactivating enzyme , have been developed for treatment of type 2 diabetes . 
 in addition to glucose - lowering effects , emerging data suggests that glp-1-based therapies also show anti - inflammatory effects in chronic inflammatory diseases including type 1 and 2 diabetes , atherosclerosis , neurodegenerative disorders , nonalcoholic steatohepatitis , diabetic nephropathy , asthma , and psoriasis . 
 this review outlines the anti - inflammatory actions of glp-1-based therapies on diseases associated with chronic inflammation in vivo and in vitro , and their molecular mechanisms of anti - inflammatory action . 
1. Introduction
2. Diabetes
3. Vascular Disease
4. Neurodegenerative Brain Disorder
5. Nonalcoholic Steatohepatitis
6. Nephropathy
7. Other Diseases
8. Conclusion