Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although prostaglandin E2 (PGE2) is known to inhibit glucose-induced insulin secretion, it is uncertain whether PGE2 actions on the beta-cell are direct, whether they are equipotent for both phases of hormone secretion, and whether the same mechanism of action prevails throughout. Study of the HIT cell, a clonal line of pancreatic beta-cells, provides answers to these questions because perifusion with glucose and 3-isobutyl-1-methylxanthine stimulates biphasic insulin secretion. Perifusion with PGE2 decreased both the first and second phases of glucose-induced insulin release to 47 +/- 4% of controls. Pretreatment with pertussis toxin partly prevented PGE2 inhibition to 80 +/- 4% of controls for first phase and 79 +/- 4% of controls for second phase. To evaluate whether the partial prevention of PGE2 inhibition seen with pertussis toxin pretreatment was caused by Gi heterotrimer association between the preincubation period and the end of perifusion, PGE2 actions were also examined during continuous treatment with pertussis toxin. Under these conditions, PGE2 inhibition of both phases was totally prevented. However, no difference was observed in membrane protein ADP ribosylation when cells were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis after pretreatment or continuous treatment with pertussis toxin. Cyclic AMP (cAMP) accumulation was inhibited by PGE2 (from 3263 +/- 153 to 1549 +/- 158 fmol/10(6) cells) but less so after pretreatment with pertussis toxin (correlation between insulin release and cAMP accumulation during perifusion; n = 18, r = .85, P less than .001). Thus, PGE2 equally inhibits both phases of glucose-induced insulin secretion and cAMP generation through a pertussis toxin-sensitive G protein-mediated direct effect on the pancreatic beta-cell.
Diabetes 1989 Nov
PMID:Pertussis toxin-sensitive G protein mediation of PGE2 inhibition of cAMP metabolism and phasic glucose-induced insulin secretion in HIT cells. 248 18

Brief exposure of hepatocytes to glucagon, angiotensin or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate) caused the inactivation of the inhibitory guanine nucleotide regulatory protein Gi. Glucagon-mediated desensitization of glucagon-stimulated adenylate cyclase activity was seen in hepatocytes from both normal rats and those made diabetic with streptozotocin, where Gi is not functionally expressed. Normal glucagon desensitization was seen in hepatocytes from young animals, 6 weeks of age, which had amounts of Gi in their hepatocyte membranes which were some 45% of that seen in mature animals (3.4 pmol/mg of plasma-membrane protein). Streptozotocin-induced diabetes in young animals abolished the appearance of functional Gi in hepatocyte plasma membranes. Pertussis-toxin treatment of hepatocytes from both normal mature animals and those made diabetic, with streptozotocin, blocked the ability of glucagon or angiotensin or TPA to elicit desensitization of adenylate cyclase. The isolated B (binding)-subunit of pertussis toxin was ineffective in blocking desensitization. Neither induction of diabetes nor treatment of hepatocytes with pertussis toxin inhibited the ability of glucagon and angiotensin to stimulate the production of inositol phosphates in intact hepatocytes. Thus (i) Gi does not appear to play a role in the molecular mechanism of glucagon desensitization in hepatocytes, (ii) the G-protein concerned with receptor-stimulated inositol phospholipid metabolism in hepatocytes appears not to be a substrate for the action of pertussis toxin, (iii) in intact hepatocytes, treatment with glucagon and/or angiotensin can elicit the inactivation of the inhibitory G-protein Gi, and (iv) pertussis toxin blocks desensitization by a process which does not involve Gi.
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PMID:Glucagon desensitization of adenylate cyclase and stimulation of inositol phospholipid metabolism does not involve the inhibitory guanine nucleotide regulatory protein Gi, which is inactivated upon challenge of hepatocytes with glucagon. 249 30

Adenylate cyclase in liver plasma membranes from streptozotocin-diabetic (STZ) or BB/Wor spontaneously diabetic rats showed increased responsiveness to GTP, glucagon, fluoroaluminate, and cholera toxin. Basal or forskolin-stimulated activity was unchanged in STZ rats, but increased in BB/Wor rats. No change in the alpha-subunit of Gi (alpha i) was observed in STZ or BB/Wor rats using pertussis toxin-stimulated [32P]ADP-ribosylation. Immunodetection using antibodies against the COOH-terminal decapeptides of alpha T and alpha i-3 showed no change in alpha i in STZ rats and a slight decrease in BB/Wor rats. Angiotensin II inhibition of hepatic adenylate cyclase was not altered in either diabetic rat. In both models of diabetes, Gs alpha-subunits were increased as measured by cholera toxin-stimulated [32P]-ADP-ribosylation of 43-47.5-kD peptides, reconstitution with membranes from S49 cyc- cells or immunoreactivity using antibodies against the COOH-terminal decapeptide of alpha s. These data indicate that STZ-diabetes increases hepatic Gs but does not change Gi or adenylate cyclase catalytic activity. In contrast, BB/Wor rats show increased hepatic Gs and adenylate cyclase. These changes could explain the increase in hepatic cAMP and related dysfunctions observed in diabetes.
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PMID:Guanine nucleotide binding regulatory proteins and adenylate cyclase in livers of streptozotocin- and BB/Wor-diabetic rats. Immunodetection of Gs and Gi with antisera prepared against synthetic peptides. 249 95

Phosphatidic acid may be raised in glucose-stimulated islet cells through hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and de novo synthesis with glucose-derived trioses. The mechanism by which exogenous phosphatidic acid from egg yolk lecithin may augment insulin secretion was investigated in neonatal beta-cells. In whole cells labeled with [2,8-3H]-adenine, a dose-dependent increase in phosphatidic acid-stimulated adenylate cyclase activity was seen, and a small intracellular transient free-Ca2+ rise was seen in Fura 2AM-loaded cells. In [gamma-32P]ATP-labeled membranes from those beta-cells, phosphatidic acid effected PIP2 hydrolysis. These phosphatidic acid-stimulated effects were not sensitive to preincubation with Bordetella pertussis exotoxin. The findings are consistent with a stimulatory effect of exogenous phosphatidic acid on insulin release and indicate an effect at the plasma membrane. It is possible that newly synthesized phosphatidic acid may function similarly to amplify intracellular events in glucose-stimulated islet cells through both local Ca2+ concentration and cyclic AMP-sensitive mechanisms. The participation of newly synthesized phosphatidic acid derived from glucose could provide a link between the metabolism of glucose and insulin release.
Diabetes 1989 Sep
PMID:Effects of phosphatidic acid on islet cell phosphoinositide hydrolysis, Ca2+, and adenylate cyclase. 254 9

The administration of the Islet-Activating Protein (IAP) of pertussis toxin results in an increased insulin response to oral glucose in a dose- dependent manner. This response can be detected for up to 12 days after a single injection. In addition, IAP increases the number of peripheral blood leucocytes and lymphocytes. Inbred strains of rats differ in the magnitude of the leucocyte but not the insulin responses to IAP. Multiple injections of 1,000 ng of IAP to diabetes-prone BB rats at 50, 64 and 78 days of age caused an increased release in response to glucose challenge and a slight increase in peripheral blood leucocytes when compared to animals receiving saline injections. The prevalence of insulin-dependent diabetes in BB rats was increased in the IAP group as compared to controls. Histolgic examination of the pancreas at the time of detection of diabetes revealed a widespread intense insulitis. We speculate that the increased expression of disease observed in the BB rats receiving IAP may be secondary to the chronic increase in insulin release and/or to an effect on the cells of the immune system.
Diabetes Res 1989 Jun
PMID:The effect of islet-activating protein (IAP) of pertussis toxin on the spontaneous diabetic syndrome in the rat. 269 83

Adenylate cyclase activity and its modulation by guanine nucleotides and isoproterenol were assessed in adipocyte membranes of mice with mutations causing different genetic obesity syndromes. The object was to determine whether the defect in inhibitory modulation observed in the obese (ob/ob) mouse was also present in the diabetes (db/db) mouse. The data show that adipocyte adenylate cyclase in both the ob/ob and the db/db mouse is resistant to activation by isoproterenol. The response to guanosine triphosphate (GTP) differed between the two mutants, such that an inhibitory phase was visible in the db/db but not in the ob/ob membranes. Moreover, pertussis toxin attenuated the inhibitory effect of GTP and significantly stimulated cyclase activity in the db/db but not in the ob/ob membranes. The data show that the two mutations affect the expression of adenylate cyclase activity via different mechanisms.
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PMID:Effect of the genetic background and specific mutation on adenylate cyclase activity in obesity syndromes. 318 20

Of 22 immunomodulatory substances screened 12 were effective in modulating the course of hyperglycemia following low dose streptozotocin treatment. In this animal model diabetes is induced by administration of low doses of streptozotocin (30-40 mg/kg) body weight to male C57BL/6J/Bom, C57BL/KsJ and C3H/He/Bom mice on 5 consecutive days. Conventional immunosuppressants (azathioprine, cyclophosphamide) largely protected from diabetes development. Partial suppression of hyperglycemia was also seen after administration of B. pertussis, fetal tissue extracts, FTS, inosine pranobex, metronidazole and ADA 202-718. The majority of these substances, when applied with another regimen, and TP5 caused enhancement of diabetes. In conclusion, several substances with a therapeutic potential in experimental diabetes have been identified. Those with little risk of side-effects may deserve further analysis.
Diabetes Res 1987 Sep
PMID:Analysis of 22 immunomodulatory substances for efficacy in low-dose streptozotocin-induced diabetes. 331 52

Ethiopia is a country of 45 million people in northeast Africa. With a stagnant, agriculture-based economy and a per capita gross national product of $110 in 1984, it is one of the world's poorest nations. 70% of the children are mildly to severely malnourished, and 25.7% of children born alive die before the age of 5. Life expectancy is 41 years. The population is growing at the rate of 2.9%/year, but only 2% of the people use birth control. After the 1974 revolution, the socialist government nationalized land and created 20,000 peasant associations and kebeles (urban dwellers' associations), which are the units of local government. The government has set ambitious goals for development in all sectors, including health, but famine, near famine, forced resettlement programs, and civil war have prevented any real progress from being made. The government's approach to health care is based on an emphasis on primary health care and expansion of rural health services, but the Ministry of Health is allocated only 3.5% of the national budget. Ethiopia has 3 medical schools -- at Addis Ababa, Gondar, and the Jimma Institute of Health Sciences. Physicians are government employees but also engage in private practice. A major problem is that a large proportion of medical graduates emigrate. Ethiopia has 87 hospitals with 11,296 beds, which comes to 1 bed per 3734 people. There are 1949 health stations and 141 health centers, but many have no physician, and attrition among health workers is high due to lack of ministerial support. Health care is often dispensed legally or illegally by pharmacists. Overall, there is 1 physician for 57,876 people, but in the southwest and west central Ethiopia 1 physician serves between 200,000 and 300,000 people. In rural areas, where 90% of the population lives, 85% live at least 3 days by foot from a rural health unit. Immunization of 1-year olds against tuberculosis, diphtheria-pertussis-tetanus, poliomyelitis, and measles is 11, 6, 6, and 12% respectively. Infectious diseases dominate the medical scene in Ethiopia. In 1984, tuberculosis accounted for 11.2% of hospital admissions and 12.2% of deaths. The leading cause of childhood mortality in 1984 was diarrhea (45%). Malaria, trypanosomiasis, schistosomiasis, leishmaniasis, and meningococcal meningitis are endemic. Intestinal parasitism is rampant, and the nationwide prevalence of leprosy is 3/1000. Venereal diseases were the 9th most common cause of hospital outpatient visits in 1984, but AIDS is rare. The leading noninfectious diseases are rheumatic and syphilitic heart disease, hypertension, diabetes mellitus, hepatoma, and elephantiasis. Ethiopia has the highest number of cases of nonfilarial elephantiasis -- an estimated 350,000 cases -- in the world. Aside from a large influx of money, the most necessary changes to improve the health system are lowering the salaries of doctors and nurses, reorienting physician training toward primary health care, increasing the quality of existing health services, more efficient management, and better coordination between the Ministry of Health and the voluntary organizations.
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PMID:Health and medical care in Ethiopia. 271 Jan 85

Normally, the injection of streptozotocin (STZ) at a lower dose (60 mg/kg body weight) to young (45 days old) CD-1 male mice produces a sustained hyperglycemia with the concomitant development of hypoinsulinemia and immune insulitis in the pancreas, both of which lead to insulin-dependent diabetes (IDD). In an effort to abort the development of IDD, pertussis vaccine (PV) was administered either intraperitoneally (n = 12) or intravenously (n = 12) 3 days prior to STZ injection. In contrast to the control group (n = 12) which received only STZ resulting in the subsequent development of IDD after 16 weeks, none of the vaccinated group developed IDD. The complete protective effect was evidenced by normal insulin values, normoglycemia, the lack of the development of nucleic acid antibody and the absence of insulitis in the vaccinated animals. Under these experimental conditions, PV appeared to offer satisfactory protection of the beta cells of islets in pancreas against the inflammatory effect of STZ.
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PMID:Pertussis vaccine inhibits immune insulitis induced with streptozotocin. 621 27

Islet-activating protein (IAP) is a new active substance purified from the culture medium of Bordetella pertussis. The active protein possesses a molecular weight of 77,000 and an isoelectric point of pH 7.8. The nature of IAP-action is characterized by enhancement of insulin secretory response to glucose and other stimulants. A single injection of IAP into spontaneous diabetes rats resulted in normalization of their glucose intolerance over a period of a month. Acute and chronic animal toxicity tests showed that LD50 of IAP was 127 micrograms/kg in mice and 144 micrograms/kg in rats. After these animal experiments, phase 1 studies were designed and undertaken to establish dosage, duration of action and other factors. IAP of 0.5 micrograms/kg or 1.0 micrograms/kg did not bring about any serious toxic or adverse effects in five volunteers. On the 4th day of a single injection of IAP, insulin secretory response was proved to be enhanced. Follow-up studies showed that the IAP-action continued over a month or at most two months. Two features of IAP, i.e., the enhancement of insulin secretory response and the long duration of the action, was confirmed in healthy persons as well as in animals. As expected, IAP has a strong antigenic reaction resulting in formation of IgG antibody and possibly IgE antibody. The antigenicity of IAP causes some hindrance to clinical usefulness. For avoidance of anaphylactic reaction, IAP should be given repeatedly with care. The problem concerning antigen-antibody reaction should be overcome as soon as possible before the clinical use of IAP as a medicament.
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PMID:Effects of islet-activating protein (IAP) on blood glucose and plasma insulin in healthy volunteers (phase 1 studies). 624 81


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