Disease relevance of GIP

• The insulinotropic effect of GLP-1 is maintained in patients with Type II (non-insulin-dependent) diabetes mellitus, whereas, for unknown reasons, the effect of GIP is diminished or lacking [1].
• METHODS: Ten healthy subjects (9 men, 1 woman; age 33+/-11; BMI 26.8+/-2.2 kg/m(2)) received three different doses of intravenous GIP (7, 20, and 60 pmol/kg body weight) and placebo [2].
• CONCLUSION: These studies exclude both GIP and GLP-1 as key mediators for the immediate reduction in bone resorption seen after a meal [3].
• We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing's syndrome [4].
• We conclude that GIP-dependent nodular hyperplasia can progress in an asynchronous manner and that GIPR overexpression is an early event in this syndrome [5].

Psychiatry related information on GIP

• CCK, GIP, and GLP-1 secretion were studied in 13 adolescent girls suffering from simple obesity, 13 girls with anorexia nervosa, and 10 healthy girls [6].
• The diurnal variations of serum gastric inhibitory polypeptide (GIP), serum insulin, plasma glucagon, plasma glucose and serum triglycerides were studied for 24 hr in 6 healthy young men, consuming three meals and performing their usual physical activities [7].
• The effect of dietary modification and hyperglycaemia on gastric emptying and gastric inhibitory polypeptide (GIP) secretion [8].
• PATIENTS: Ten patients, who met the criteria for dementia (DSM-IV) and motor restless behaviour (subscale 10 of the GIP), were included [9].
• Apathetic behaviour and consciousness disorders were measured with the Behaviour Rating Scale for Psychogeriatric Inpatients (GIP) [10].

High impact information on GIP

• Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin [11].
• The development of aberrant adrenal sensitivity to GIP can result in food-dependent adrenal hyperplasia and therefore in Cushing's syndrome [12].
• In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producting or aldosterone-producing adenomas responded to corticotropin but not to GIP [11].
• These include ectopic receptors for gastric inhibitory polypeptide (GIP), beta-adrenergic agonists, or LH/hCG; a similar outcome can result from altered activity of eutopic receptors, such as those for vasopressin (V1-AVPR), serotonin (5-HT4), or possibly leptin [13].
• The targeting of proteins to mitochondria involves the recognition of the precursor proteins by receptors on the mitochondrial surface followed by insertion of the precursors into the outer membrane at the general insertion site GIP [14].

Chemical compound and disease context of GIP

• Incubation of adrenal cells with GIP stimulates cortisol secretion in GIP-dependent, but not in normal fetal, adult, or non-food-dependent Cushing's syndrome, adrenals [4].
• The two hormones responsible for the incretin effect, glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loads and augment insulin secretion in response to hyperglycemia [15].
• In patients with unilateral adrenal adenoma, the abnormal expression or function of GIP or vasopressin receptor has been found, but the presence of ectopic or abnormal hormone receptors appears to be less prevalent than in macronodular adrenal hyperplasia [16].
• Oral administration of triphenyltin chloride (TPT) (60 mg/kg body weight) inhibits the insulin secretion by decreasing the cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) induced by glucose-dependent insulinotropic polypeptide (GIP) in pancreatic beta-cells of the hamster [17].
• The GIP binding sites of human insulinoma were coupled to adenylate cyclase stimulation [18].

Biological context of GIP

• The predicted amino acid sequence indicates that GIP is derived by proteolytic processing of a 153-residue precursor, preproGIP [19].
• This appears to be the first demonstration of a GIP-stimulated signal transduction pathway involved in increasing fat storage in adipocytes [20].
• In the present study, we identified a novel role for GIP in regulating K(V)1.4 channel endocytosis [21].
• Using mutant forms of K(V)1.4 with Ala-Ser/Thr substitutions in a potential PKA phosphorylation site, C-terminal phosphorylation was shown to be linked to GIP-mediated current amplitude decreases [21].
• The incretin hormone, glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion by potentiating events underlying membrane depolarization and exerting direct effects on exocytosis [21].

Anatomical context of GIP

• Complementary DNA clones encoding human GIP were isolated from a library prepared with RNA from duodenum [19].
• Cultured subcutaneous human adipocytes showed similar responses to GIP but with greater sensitivity [20].
• AIMS/HYPOTHESIS: In the isolated perfused pancreas, gastric inhibitory polypeptide (GIP) has been shown to enhance glucagon secretion at basal glucose concentrations, but in healthy humans no glucagonotropic effect of GIP has yet been reported [2].
• RESULTS: Human islet cells express transcripts encoding glucagon, GLP-1 and GIP receptors [22].
• In conclusion, amino acid variants in the GIP receptor are not associated with random Type II diabetes in patients of Danish Caucasian origin or with altered GIP binding and GIP-induced cAMP production when stably transfected in Chinese hamster fibroblasts [1].

Associations of GIP with chemical compounds

• Gastric inhibitory polypeptide (GIP) is a 42-amino acid hormone that stimulates insulin secretion in the presence of glucose [19].
• GIP is released from the precursor by processing at single arginine residues [19].
• The GIP moiety is flanked by polypeptide segments of 51 and 60 amino acids at its NH2 and COOH termini, respectively [19].
• Parenteral administration of GIP and GLP-1 did not result in a reduction of the s-CTX level, whereas GLP-2 caused a statistically significant and dose-dependent reduction in the s-CTX level from baseline compared with placebo (p < 0.05) [3].
• Three months after surgery, fasting plasma ACTH and cortisol were suppressed, but cortisol increased 3.6-fold after oral glucose, whereas ACTH remained suppressed; this was inhibited by octreotide pretreatment, suggesting that cortisol secretion by the left adrenal is also GIP dependent [5].

Physical interactions of GIP

• Concerning the nuclear compartment, GIP is capable of complexing with the estrogen receptor and binding estradiol, but does not affect estradiol-induced estrogen receptor transcription [23].

Regulatory relationships of GIP

• RESULTS: Gastric inhibitory polypeptide dose-dependently stimulated glucagon secretion ( p=0.019) with a maximal increment after 10 min [2].
• We studied 9.0kb upstream and 1.3kb downstream of the GIPR gene putative promoter (pProm) by sequencing leukocyte DNA from controls and from adrenal tissues of GIP- and non-GIP-dependent CS patients [24].
• CCK-8, CCK-33, and GIP (100 pmol/kg) all potentiated the meal-induced plasma responses of insulin and PP, whereas plasma levels of glucagon after the meal were not affected [25].
• In contrast, RGS2 expression inhibited the GIP-induced cAMP response by 50%, a response similar to that of cells desensitized by preincubation with 10(-7) M GIP [26].
• GIP-stimulated cAMP generation in control cells and in those coexpressing RGS1, -3, and -4 displayed a dose-dependent increase 10 min after GIP treatment [26].

Other interactions of GIP

• Therefore, we studied the effect of GIP on glucagon secretion under normoglycaemic conditions [2].
• New alternative spliced isoforms of the GIPR were found, but are identical in GIP-dependent and normal adrenal tissues [4].
• These results suggest a potential role for GRK2/beta-arrestin-1 system in modulating GIP-mediated insulin secretion in pancreatic islet cells [27].
• GIP maps distal to NGFR with an estimated distance of 250 kb [28].
• Infusion of the CCK receptor antagonist only slightly increased postprandial peak plasma glucose, insulin and C-peptide levels, whereas GIP and neurotensin levels were not significantly influenced [29].

Analytical, diagnostic and therapeutic context of GIP

• The finding of an association between homozygosity for the codon 354 variant and reduced fasting and post oral glucose tolerance test (OGTT) serum C-peptide concentrations, however, calls for further investigations and could suggest that GIP even in the fasting state regulates the beta-cell secretory response [1].
• Venous blood samples were drawn over 30 min for glucagon and GIP concentrations (specific radioimmunoassays) [2].
• METHODS: Expression of the glucagon, GLP-1 and GIP receptors in human islets was investigated by northern blots and reverse transcription-polymerase chain reaction analysis [22].
• Collectively these data demonstrate that (Pro(3))GIP is a novel and potent enzyme-resistant GIP receptor antagonist capable of blocking the ability of native GIP to increase cAMP, stimulate insulin secretion, and improve glucose homeostasis in a commonly employed animal model of type 2 diabetes [30].
• Plasma glucose, GIP, GLP-1, insulin and paracetamol concentrations were measured before and after a 100 g oral carhohydrate load containing 1.5 g of paracetamol for 6 h during intravenous infusion of either glucagon or saline [31].

References