You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
incretins are hormones that stimulate insulin secretion from pancreatic cells , which are responsive to the difference of insulin levels after oral and intravenous ingestion of glucose .
gastric inhibitory polypeptide ( gip ) was originally isolated as a 42aminoacid hormone from the duodenum , inhibiting gastric acid secretion and gastric motility1 , 2 .
subsequently , gip was shown to be released from intestinal k  cells and to stimulate insulin secretion from pancreatic cells directly , and was renamed glucosedependent insulinotropic polypeptide3 , 4 .
glucagonlike peptide1 ( glp1 ) was originally identified as a glucagonlike polypepetide from the glucagon precursor5 .
glp1(737 ) and glp1(736 ) amide were shown to be released from intestinal l  cells , and stimulate insulin secretion from pancreatic cells directly6 .
amino acid sequences of human gip and glp17 , 8 were shown to be highly homologous , belonging to the glucagon / secretin family .
receptors for glp1 and gip were cloned and shown to be coupled with the stimulatory g  protein , belonging to the glucagon / secretin receptor family9 , 10 .
genetic deficiency of glp1 receptor ( glp1r ) and gip receptor ( gipr ) in mice was developed11 , 12 , 13 .
as shown in figure  1 , glp1rdeficent mice and giprdeficient mice showed higher blood glucose levels with impaired initial insulin response after oral glucose loading .
simultaneous ablation of glp1r and gipr further increased the blood glucose levels and decreased initial insulin response after glucose loading , showing that glp1 and gip can not compensate adequately for each other .
glucagonlike peptide1 ( glp1 ) receptordeficient ( left , blue ) , gastric inhibitory polypeptide ( gip ) receptordeficient ( middle , red ) and double receptordeficient mice ( right , green ) in the c57bl/7 background were challenged with oral glucose , and levels of glucose and insulin levels were measured .
* p  =  0.05 versus wildtype mice . original mice are described in references11 , 12 , 13 .
receptors for glp1 and gip are expressed not only in pancreatic cells , but also in several extrapancreatic tissues .
figure  2 shows the tissuespecific expression patterns of glp1 and gip receptors in mice .
glp1r is highly expressed in the lung and duodenum of mice , and gipr is highly expressed in the testis of mice .
the expression patterns of glp1r and gipr are quite different , suggesting that glp1 and gip have their own physiological activities .
gene expression of ( a ) glucagonlike peptide1 receptor and ( b ) gastric inhibitory polypeptide receptor was examined using reverse transcription polymerase chain reaction .
complementary deoxyribonucleic acid templates from various mouse tissues ( genostaff , tokyo , japan ) were amplified 25 cycles ( lane  1 ) , 30 cycles ( lane  2 ) and 35 cycles , and fractionated on 1.5% agarose gels with polymerase chain reaction products of glyceraldehyde3phosphate dehydrogenase as controls .
heart , lung , liver , stomach , small intestine ( s.int . ) , large intestine ( l.int . ) , pancreas , skin , skeletal muscle , kidney , spleen , testis , placenta , ovary , uterus , duodenum , ileum , jejunum , brown adipose ( b.a ) , white adipose ( w.a ) , eye , spinal cord ( s.c ) , bone marrow ( b.m ) , prostate , thymus , adrenal gland ( a.g ) , rectum , pituitary gland ( p.g ) , cerebral cortex ( c.c ) , cerebellum , olfactory bulb ( o.b ) , hippocampus , medulla oblongate ( m.o ) , striatum and thalamus  +  hypothalamus  +  pons ( t.h.p ) were examined .
the second amino acid from the nh3terminal of glp1 and gip is the alanine residue , and in  vitro and in  vivo studies showed that both glp1 and gip are substrates of dipeptidyl peptidase  iv ( dpp4 ) , and that active peptides are degraded to inactive peptides14 , 15 .
mice separately deficient in glp1r or gipr could augment insulin secretion after treatment with dpp4 inhibitors , one class of antihyperglycemic agents widely used for treatment of diabetes , but the mice simultaneously deficient in glp1r and gipr could not respond to the treatment , showing that both glp1 and gip signaling can be augmented by treatment with dpp4 inhibitors .
these results suggest that the extrapancreatic effects of glp1 and gip might be stimulated by treatment with dpp4 inhibitors , in addition to the increased pancreatic effects .
furthermore , dpp4resistant glp1r agonists , another class of antihyperglycemic agents , stimulate the pancreatic and extrapancreatic effects of glp1 .
therefore , comprehensively understanding the pancreatic and extrapancreatic effects of glp1 and gip is essential .
as aforementioned , gip was shown to have an activity to inhibit gastric acid secretion and was known as gastric inhibitory polypeptide .
subsequent studies showed that gip has an activity to stimulate insulin secretion in a glucosedependent manner , thus it was renamed glucosedependent insulinotropic polypeptide .
second , several peptides , including glp1 , can stimulate insulin secretion in a glucosedependent manner .
as gipr is expressed in white adipose tissues , and gip increases glucose uptake and heparinreleasable lipoprotein lipase activity of the differentiated 3t3l1 adipose cell line16 , we hypothesized that dietinduced gip is responsive for promoting nutrient uptake into the adipose tissues . a highfat diet or overeating induces obesity in mice as well as humans , compared with the control diet ( figure  3 ) .
we bred gip receptordeficient mice fed a highfat diet or induced by leptin deficiency to overeat , and found that mice lacking the gipr were protected from obesity .
the giprdeficient mice had a lower respiratory quotient , suggesting that fat was used as the preferred energy substrate instead of storing it in the adipose tissues .
next , we examined the effects of aging on obesity , as aging is associated with increased fat mass and decreased lean mass
. aged giprdeficient mice on the normal diet showed significantly reduced fat mass with conserved lean mass .
furthermore , giprdeficient mice showed higher heart rate , lower body temperature and increased physical activity17 .
these phenotypic characterizations of genetic inactivation of gip signaling showed similarity with those of caloricrestricted mice .
indeed , the gipdeficient mice showed lower adiposity18 . from these results and other studies ,
diabetic patients might develop microvascular complications , such as retinopathy , nephropathy , and neuropathy ; and macrovascular complications , such as cerebral infarction , myocardial infarction and peripheral arterial diseases , which are the major causes of morbidity and mortality . because poor glucose control is the major risk factor for diabetic complications , antihyperglycemic agents , such as sulfonylureas , biguanides and insulin ,
although glp1 receptor messenger ribonucleic acid was detected in the kidney , its precise localization was controversial because of the poor specificity of antiglp1r antibodies19 . using in  situ hybridization
, we have shown that glp1 receptor messenger ribonucleic acid was expressed in glomerular capillary and vascular walls in the mouse kidney20 . in  vivo examination
akita diabetic mice on c57bl/6 background are nephropathyresistant , and genetic ablation of glp1r showed higher urinary albumin levels and more advanced mesangial expansion with increased glomerular superoxide and upregulated renal nicotinamide adenine dinucleotide phosphate oxidase , despite comparable levels of hyperglycemia .
by contrast , nephropathyprone akita diabetic mice on kk / ta background treated with liraglutide , a glp1r agonist , showed reduced albuminuria and mesangial expansion .
these results showed that glp1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia .
although it has not been defined as the primary endpoint of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus  thrombolysis in myocardial infarction 53 trial21 , patients treated with saxagliptin , a dpp4 inhibitor , were significantly more likely to have an improved albumintocreatinine ratio , consistent with our animal studies .
abstractthe hormonal factors implicated as transmitters of signals from the gut to pancreatic cells are referred to as incretins . 
 gastric inhibitory polypeptide ( gip ) and glucagonlike peptide1 ( glp1 ) are incretins . 
 in addition to the insulinotropic effects , we have shown , using the gip receptor and glp1 receptordeficient mice , that gip and glp1 have direct actions on adipocytes and the kidney , respectively . because gip receptors and glp1 receptors are differentially expressed in a tissuespecific manner , gip and glp1 have specific physiological activities , and further comprehensive characterization of the extrapancreatic actions of gip and glp1 is anticipated , as dipeptidyl peptidase  iv inhibitors activate both gip and glp1 signaling .