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Zykov VA, Tuchina TP, Lebedev DA, Krylova IB, Babenko AY, Kuleshova EV, Grineva EN, Bayramov AA, Galagudza MM. Effects of glucagon-like peptide 1 analogs in combination with insulin on myocardial infarct size in rats with type 2 diabetes mellitus. World J Diabetes 2018; 9:149-156. [PMID: 30254724 PMCID: PMC6153122 DOI: 10.4239/wjd.v9.i9.149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 07/03/2018] [Accepted: 07/10/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the effects of glucagon-like peptide-1 analogs (GLP-1a) combined with insulin on myocardial ischemia-reperfusion injury in diabetic rats.
METHODS Type 2 diabetes mellitus (T2DM) was induced in male Wistar rats with streptozotocin (65 mg/kg) and verified using an oral glucose tolerance test. After anesthesia, the left coronary artery was occluded for 40 min followed by 80 min reperfusion. Blood glucose level was measured during surgery. Rats were randomized into six groups as follows: (1) control rats; (2) insulin (0.1 U/kg) treated rats prior to ischemia; (3) insulin (0.1 U/kg) treated rats at reperfusion; (4) GLP-1a (140 mg/kg) treated rats prior to ischemia; (5) GLP-1a (140 mg/kg) treated rats at reperfusion; and (6) rats treated with GLP-1a (140 mg/kg) prior to ischemia plus insulin (0.1 U/kg) at reperfusion. Myocardial area at risk and infarct size was measured planimetrically using Evans blue and triphenyltetrazolium chloride staining, respectively.
RESULTS There was no significant difference in the myocardial area at risk among groups. Insulin treatment before ischemia resulted in a significant increase in infarct size (34.7% ± 3.4% vs 18.6% ± 3.1% in the control rats, P < 0.05). Post-ischemic administration of insulin or GLP-1a had no effect on infarct size. However, pre-ischemic administration of GLP-1a reduced infarct size to 12% ± 2.2% (P < 0.05). The maximal infarct size reduction was observed in the group treated with GLP-1a prior to ischemia and insulin at reperfusion (8% ± 1.6%, P < 0.05 vs the control and GLP-1a alone treated groups).
CONCLUSION GLP-1a pre-administration results in myocardial infarct size reduction in rats with T2DM. These effects are maximal in rats treated with GLP-1a pre-ischemia plus insulin at reperfusion.
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Affiliation(s)
- Vladislav A Zykov
- Almazov National Medical Research Centre, St-Petersburg 197341, Russia
| | - Taisiia P Tuchina
- Almazov National Medical Research Centre, St-Petersburg 197341, Russia
| | - Denis A Lebedev
- Almazov National Medical Research Centre, St-Petersburg 197341, Russia
| | - Irina B Krylova
- Institute of Experimental Medicine, St-Petersburg 197376, Russia
| | - Alina Y Babenko
- Almazov National Medical Research Centre, St-Petersburg 197341, Russia
| | | | - Elena N Grineva
- Almazov National Medical Research Centre, St-Petersburg 197341, Russia
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Romero-Nava R, Rodriguez JE, Reséndiz-Albor AA, Sánchez-Muñoz F, Ruiz-Hernandéz A, Huang F, Hong E, Villafaña S. Changes in protein and gene expression of angiotensin II receptors (AT1 and AT2) in aorta of diabetic and hypertensive rats. Clin Exp Hypertens 2015; 38:56-62. [PMID: 26268856 DOI: 10.3109/10641963.2015.1060984] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT1 and AT2 receptors. For that reason, the aim of this work was to study the gene and protein expression of AT1 and AT2 receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60 mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT1 receptors than normotensive rats while the AT2 expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT1 and AT2 receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT1 and AT2 receptors. However, the overexpression of AT2 could be associated with the reduction in the response to Ang II in the early stage of diabetes.
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Affiliation(s)
- R Romero-Nava
- a Laboratorio de Señalización Intracelular , Sección de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, México D.F. , México
| | - J E Rodriguez
- a Laboratorio de Señalización Intracelular , Sección de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, México D.F. , México
| | - A A Reséndiz-Albor
- a Laboratorio de Señalización Intracelular , Sección de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, México D.F. , México
| | - F Sánchez-Muñoz
- b Departamento de Inmunología , Instituto Nacional de Cardiología Ignacio Chávez, México D.F. , México
| | - A Ruiz-Hernandéz
- a Laboratorio de Señalización Intracelular , Sección de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, México D.F. , México
| | - F Huang
- c Departamento de Farmacología y Toxicología , Hospital Infantil de México Federico Gómez (HIMFG), México D.F. , México , and
| | - E Hong
- d Departamento de Neurofarmacobiología , Centro de Investigación y de Estudios Avanzados, México D.F. , México
| | - S Villafaña
- a Laboratorio de Señalización Intracelular , Sección de Posgrado, Escuela Superior de Medicina del Instituto Politécnico Nacional, México D.F. , México
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Al-Abdullah ES, Al-Tuwaijri HM, Hassan HM, Al-Alshaikh MA, Habib EE, El-Emam AA. Synthesis, Antimicrobial and Hypoglycemic Activities of Novel N-(1-Adamantyl)carbothioamide Derivatives. Molecules 2015; 20:8125-43. [PMID: 25955889 PMCID: PMC6272754 DOI: 10.3390/molecules20058125] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 05/01/2015] [Accepted: 05/05/2015] [Indexed: 12/26/2022] Open
Abstract
The reaction of 1-adamantyl isothiocyanate 4 with the various cyclic secondary amines yielded the corresponding N-(1-adamantyl)carbothioamides 5a–e, 6, 7, 8a–c and 9. Similarly, the reaction of 4 with piperazine and trans-2,5-dimethylpiperazine in 2:1 molar ratio yielded the corresponding N,N'-bis(1-adamantyl)piperazine-1,4-dicarbothioamides 10a and 10b, respectively. The reaction of N-(1-adamantyl)-4-ethoxycarbonylpiperidine-1-carbothioamide 8c with excess hydrazine hydrate yielded the target carbohydrazide 11, in addition to 4-(1-adamantyl)thiosemicarbazide 12 as a minor product. The reaction of the carbohydrazide 11 with methyl or phenyl isothiocyanate followed by heating in aqueous sodium hydroxide yielded the 1,2,4-triazole analogues 14a and 14b. The reaction of the carbohydrazide 11 with various aromatic aldehydes yielded the corresponding N'-arylideneamino derivatives 15a–g. The compounds 5a–e, 6, 7, 8a–c, 9, 10a, 10b, 14a, 14b and 15a–g were tested for in vitro antimicrobial activity against certain strains of pathogenic Gram-positive and Gram-negative bacteria and the yeast-like fungus Candida albicans. The compounds 5c, 5d, 5e, 6, 7, 10a, 10b, 15a, 15f and 15g showed potent antibacterial activity against one or more of the tested microorganisms. The oral hypoglycemic activity of compounds 5c, 6, 8b, 9, 14a and 15b was determined in streptozotocin (STZ)-induced diabetic rats. Compound 5c produced significant reduction of serum glucose levels, compared to gliclazide.
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Affiliation(s)
- Ebtehal S Al-Abdullah
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
| | - Hanaa M Al-Tuwaijri
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
| | - Hanan M Hassan
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia.
| | - Monirah A Al-Alshaikh
- Department of Chemistry, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia.
| | - Elsayed E Habib
- Department of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
- Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah 11344, Saudi Arabia.
| | - Ali A El-Emam
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
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4
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Antimicrobial and hypoglycemic activities of novel N-Mannich bases derived from 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thiones. Int J Mol Sci 2014; 15:22995-3010. [PMID: 25514407 PMCID: PMC4284750 DOI: 10.3390/ijms151222995] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 11/26/2014] [Accepted: 12/08/2014] [Indexed: 11/16/2022] Open
Abstract
The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).
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5
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Degirmenci I, Ustuner MC, Kalender Y, Kalender S, Gunes HV. The effects of acarbose and Rumex patientia L. on ultrastructural and biochemical changes of pancreatic B cells in streptozotocin-induced diabetic rats. JOURNAL OF ETHNOPHARMACOLOGY 2005; 97:555-559. [PMID: 15740895 DOI: 10.1016/j.jep.2005.01.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2004] [Revised: 01/03/2005] [Accepted: 01/14/2005] [Indexed: 05/24/2023]
Abstract
This study was performed to observe the effects of acarbose and Rumex patientia on morphological change of pancreatic B cells in streptozotocin (STZ)-induced diabetic (type 2) rats. Two-day-old Wistar albino rats were intraperitoneally injected with 100mg/kg of STZ or vehicle alone for control. Vehicle and STZ given rats were divided into six groups (1st, 2nd and the 3rd groups are control; the 4th, 5th and 6th groups are STZ groups). The 1st and the 4th groups received water, the 2nd and the 5th groups received 40 mg acarbose/100 g feed, the 3rd and the 6th groups received 2% decoction of Rumex patientia grain. During experimentation period, blood glucose levels were checked periodically, and HbA1c level was measured from cardiac blood at the end of the experiment. Pancreas tissues were examined by electron microscope. Glucose and HbA1c levels increased by STZ were decreased by acarbose and Rumex patientia. Morphologically, we found a mitochondrial vacuolization and swelling as well as dilatation of the endoplasmic reticulum in the B cells of STZ-induced diabetic rats. Also, a decrease in the secretory granules of B cells was observed in the STZ-induced diabetic group. No pathological changes were observed in the STZ+acarbose group. In the STZ+Rumex patientia group, a weak swelling in the B cells was observed in the some of the mitochondria.
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Affiliation(s)
- Irfan Degirmenci
- Department of Medical Biology, Osmangazi University, Faculty of Medicine, Eskisehir, Turkey
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6
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Dachicourt N, Bailbé D, Gangnerau MN, Serradas P, Ravel D, Portha B. Effect of gliclazide treatment on insulin secretion and beta-cell mass in non-insulin dependent diabetic Goto-Kakisaki rats. Eur J Pharmacol 1998; 361:243-51. [PMID: 9865514 DOI: 10.1016/s0014-2999(98)00718-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The Goto-Kakisaki rat is a genetic non-overweight model of non-insulin-dependent diabetes mellitus. Adult Goto-Kakisaki rats exhibit a mild basal hyperglycaemia (11 mmol/l) with impaired glucose tolerance, elevated basal plasma insulin level, a failure of insulin release in response to glucose together with a 50% depletion of the total pancreatic beta-cell mass and insulin stores. We have examined the effects of long-term (4 weeks) gliclazide treatment on the severity of diabetes in adult male Goto-Kakisaki rats (10-12 weeks of age). Gliclazide was administered orally (10 mg/kg per day). Gliclazide-treated Goto-Kakisaki rats were evaluated against Wistar and untreated Goto-Kakisaki rats. In the gliclazide-treated Goto-Kakisaki rats, basal plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of treatment, and their basal insulin levels decreased to values similar to those in non-diabetic Wistar rats. Despite their total pancreatic beta-cell remaining unaffected, their pancreatic insulin stores were twice increased, with a similar improvement of the insulin content per individual beta-cell. Furthermore, the glucose-stimulated insulin release as evaluated in vivo during an intravenous glucose tolerance-test was significantly improved (twice increased) in the gliclazide-treated Goto-Kakisaki rats. This was correlated with a modest but significant enhancement of the early phase of insulin release in vitro (isolated perfused pancreas), in response to glucose. However, the overall insulin response in vitro remained clearly defective with no reappearance of the late phase of insulin release. The in vitro response to arginine (which was basically amplified in the Goto-Kakisaki model) or to gliclazide were kept unchanged after the gliclazide treatment. In conclusion, chronic gliclazide does not exert any beta-cytotrophic effect, but improves beta-cell function in the adult Goto-Kakisaki rat as far as it lowers basal insulin release, increases beta-cell insulin stores, and increases the glucose-induced insulin release.
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Affiliation(s)
- N Dachicourt
- Lab. Physiopathology of Nutrition, CNRS ESA 7059, Université Paris 7/D. Diderot, France
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7
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Cam MC, Li WM, McNeill JH. Partial preservation of pancreatic beta-cells by vanadium: evidence for long-term amelioration of diabetes. Metabolism 1997; 46:769-78. [PMID: 9225830 DOI: 10.1016/s0026-0495(97)90121-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Streptozotocin (STZ)-diabetic rats treated with vanadium can remain euglycemic for up to 20 weeks following withdrawal from vanadium treatment. In this study, we examined the effects of short-term vanadium treatment in preventing or reversing the STZ-induced diabetic state. Male Wistar rats were untreated (D) or treated (DT) with vanadyl sulfate for 1 week before administering STZ. Treatment was subsequently maintained for 3 days (DT3) or 14 days (DT14) post-STZ, after which vanadium was withdrawn. At 4 to 5 weeks post-STZ and following long-term withdrawal from vanadium, DT14 rats demonstrated levels of food and fluid intake and glucose tolerance that were not significantly different from those of age-matched untreated nondiabetic rats, and had significantly reduced glycemic levels in the fed state compared with D and DT3 groups. The proportion of animals that were euglycemic (fed plasma glucose < 9.0 mmol/L) was significant in DT14 (five of 10) relative to D (one of 10) and DT3 (one of 10) (P = .01). All euglycemic animals had an improved pancreatic insulin content that, albeit low (12% of control), was strongly linked to euglycemia in the fed state (r = -.91, P < .0001). Moreover, the highly significant correlation persisted with the analysis of untreated STZ-rats alone (r = -.95, P < .0001). Similarly, improvements in glucose tolerance and insulin secretory function in euglycemic rats were strongly correlated with small changes in residual insulin content. Hence, as vanadium pretreatment did not prevent STZ-induced beta-cytotoxicity, the vanadium-induced amelioration of the diabetic state appears to be secondary to the preservation of a functional portion of pancreatic beta cells that initially survived STZ toxicity. The partial preservation of pancreatic beta cells, albeit small in proportion to the total insulin store, was both critical and sufficient for a long-term reversal of the diabetic state. These results suggest that apparently modest effects in preserving residual pancreatic insulin content can have profound consequences on glucose homeostasis and may bear important implications for interventions that have "limited" protective effects on beta cells.
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Affiliation(s)
- M C Cam
- Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
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8
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Ohnota H, Kitamura T, Kinukawa M, Hamano S, Shibata N, Miyata H, Ujiie A. A rapid- and short-acting hypoglycemic agent KAD-1229 improves post-prandial hyperglycemia and diabetic complications in streptozotocin-induced non-insulin-dependent diabetes mellitus rats. JAPANESE JOURNAL OF PHARMACOLOGY 1996; 71:315-23. [PMID: 8886929 DOI: 10.1254/jjp.71.315] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
We investigated therapeutic effects of a rapid- and short-acting non-sulfonylurea hypoglycemic agent, calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229), on streptozotocin (STZ)-induced non-insulin-dependent diabetes mellitus (NIDDM) rats. The effects exerted by KAD-1229 on the post-prandial plasma glucose rise in STZ-induced mild NIDDM (mNIDDM) rats were different from those of sulfonylureas. When KAD-1229 with liquid meal (10 kcal/kg) was given to the mNIDDM rats, the plasma glucose migration was similar to that of normal healthy rats. On the contrary, glibenclamide had little or no effect on the plasma glucose rise 0.5-1 hr after oral administration, and its effect was only evident 2-5 hr after dosing. Tolbutamide showed similar hypoglycemia to that induced by glibenclamide at 2-5 hr with insufficient efficacy at 0.5 hr. Gliclazide sufficiently suppressed the level of post-prandial plasma glucose. However, its complete inhibition of post-prandial plasma glucose was associated with the extra-hypoglycemia 1-5 hr after oral administration. We also tested the efficacy of KAD-1229 in more severe STZ-induced NIDDM (sNIDDM) rats to elucidate the effects of the drug on the long-term glycemic controls and diabetic complications. When the sNIDDM rats were treated with 10 mg/kg KAD-1229 twice a day for about 17 weeks, increases in fasting plasma glucose and hemoglobin A1c were inhibited. Furthermore, treatment with KAD-1229 suppressed the development of microalbuminuria and cortical cataract. We conclude that the rapid- and short-acting insulinotropic agent KAD-1229 is able to improve the deterioration in the glycemic controls and inhibit the development of diabetic complications in STZ-induced NIDDM rats.
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Affiliation(s)
- H Ohnota
- Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan
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9
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Nakayama K, Murakami N, Ohta M, Kato K, Notsu T, Mizota M, Miwa I, Okuda J. Effects of M16209 on insulin secretion in isolated, perfused pancreases of normal and diabetic rats. Eur J Pharmacol 1995; 276:85-91. [PMID: 7781699 DOI: 10.1016/0014-2999(95)00016-e] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
We investigated the stimulatory effect of M16209 (1-(3-bromobenzo[b]furan-2-yl-sulfonyl)hydantoin), a novel aldose reductase inhibitor, on insulin secretion using isolated, perfused pancreases of rats. In the pancreases from normal rats, M16209 (100 microM) greatly augmented glucose-stimulated insulin secretion, but showed no effect on unstimulated insulin secretion at 2.8 mM glucose. In contrast, gliclazide (10 microM), a sulfonylurea, strongly enhanced both glucose-stimulated and unstimulated insulin secretion. Sorbinil and epalrestat, potent aldose reductase inhibitors, had no stimulatory effect on insulin secretion. M16209 (100 microM) improved appreciably the decreased insulin response to 22.2 mM glucose and enhanced slightly unstimulated insulin secretion in the pancreases of rats with neonatally streptozotocin-induced, non-insulin-dependent diabetes mellitus (NIDDM). Gliclazide (10 microM), however, failed to affect the pancreases of NIDDM rats. Furthermore, M16209 showed no appreciable effect on ATP-sensitive K(+)-channels in pancreatic beta-cells. These results suggest that M16209, unlike sulfonylureas, selectively enhances glucose-stimulated insulin secretion in both normal and NIDDM rats through a direct action on the pancreas. The site of action remains unknown, but the inhibition of aldose reductase or the ATP-sensitive K+ channels is unlikely to be involved.
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Affiliation(s)
- K Nakayama
- Department of Pharmacology, Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Tokyo, Japan
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10
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Ohnota H, Koizumi T, Kobayashi M, Momose Y, Sato F. Normalization of impaired glucose tolerance by the short-acting hypoglycemic agent calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229) in non-insulin-dependent diabetes mellitus rats. Can J Physiol Pharmacol 1995; 73:1-6. [PMID: 7600439 DOI: 10.1139/y95-001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We have investigated the hypoglycemic effects of the newly synthesized short-acting nonsulphonylurea hypoglycemic agent calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)-propionate dihydrate (KAD-1229) in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM rats that were given a neonatal injection of 60 mg/kg streptozotocin showed a dose-dependent but attenuated response to oral administration of KAD-1229 and gliclazide, and their impaired glucose tolerance was improved but not normalized. We next produced, using a neonatal injection of 30 mg/kg streptozotocin, a mild type of NIDDM rat with less impaired glucose tolerance. These rats responded well to these insulinotropic hypoglycemic agents. Their impaired glucose and meal tolerance were completely normalized by oral administration of 3 mg/kg KAD-1229. The efficacy of KAD-1229 in this NIDDM rat model 1-3 h after oral glucose administration was comparable with similar doses of gliclazide, despite its shorter hypoglycemic action (compared with gliclazide), in fasting normal rats. In meal tolerance tests (20 kcal/kg; 1 cal = 4.2 J), KAD-1229 reduced abnormally enhanced plasma glucose levels 1-3 h after administration. This effect disappeared by 5 h. In contrast, gliclazide showed sustained hypoglycemic effects until 5 h after oral administration, with a lower postprandial (0.5-1 h) effect. These data indicated that the rapid- and short-acting efficacy of KAD-1229 would be beneficial and sufficient to control postprandial plasma glucose in NIDDM rats.
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Affiliation(s)
- H Ohnota
- Creative Products Research Laboratory, Kissei Pharmaceutical Co., Ltd., Nagano-ken, Japan
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11
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Vicent D, Villanueva-Peñacarrillo ML, Valverde I, Malaisse WJ. Impaired in vivo insulin secretion in response to non-glucidic secretagogues in adult rats after neonatal streptozotocin. Acta Diabetol 1994; 31:133-7. [PMID: 7827350 DOI: 10.1007/bf00570366] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
In the perfused pancreas of adult rats that were injected with streptozotocin (STZ) during the neonatal period, the release of insulin caused by glucose is more severely affected than that evoked by other secretagogues. We have now examined whether a comparable situation prevails in vivo. In anesthetised rats, the 0-10 min plasma insulin incremental area recorded after intravenous glucose administration (2.8 mumol/g body wt) was severely decreased in STZ rats, with a K value for glucose utilization of 1.9 +/- 0.2 x 10(-2)/min, as compared with control rats, with a K value of 4.4 +/- 0.4 x 10(-2)/min. At the 2nd min of the test, the plasma insulin increment was about 5 times lower in STZ than control rats. After glibenclamide administration (0.1 nmol/g body wt), the insulin incremental area was 3 times lower in STZ than control rats. Relative to the post-prandial readings, the plasma glucose concentration was decreased to the same extent, however, in control and STZ rats injected with glibenclamide. The secretory response to succinic acid methyl ester (SAM; 1.0 mumol/g body wt) was virtually abolished in the STZ rats. In the latter animals, SAM also failed to enhance the hypoglycemic action of glibenclamide in contrast to the situation found in control rats. Iterative intraperitoneal administration of SAM (1.0 mumol/g body wt) thrice daily for 7-10 days failed to improve significantly the insulin secretory response to glucose or glibenclamide, whether in control or STZ rats. These findings indicate that the altered metabolism of glucose in the B cell of STZ rats coincides with an impaired secretory response to glibenclamide and SAM, as possibly attributable, in part at least, to a loss of the modulating action of glucose upon the secretory response to the hypoglycemic sulfonylurea and succinate ester.
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Affiliation(s)
- D Vicent
- Fundacion Jimenez Diaz, Madrid, Spain
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12
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Inoue K, Cetkovic-Cvrlje M, Eizirik DL, Grill V. Irreversible loss of normal beta-cell regulation by glucose in neonatally streptozotocin diabetic rats. Diabetologia 1994; 37:351-7. [PMID: 8063034 DOI: 10.1007/bf00408470] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Animals with NIDDM display abnormal glucose regulation of insulin secretion and biosynthesis. We tested reversibility of abnormal regulation by normoglycaemia using an islet transplantation technique. Inbred non-diabetic and neonatally STZ diabetic rats (n-STZ) were used. Transplantations insufficient to normalize the blood glucose levels (200 islets under kidney capsule) were performed from diabetic to normal (D-N) and from diabetic to diabetic (D-D), as well as from normal to normal (N-N) and from normal to diabetic (N-D) rats. Four weeks after transplantation, graft bearing kidneys were isolated and perfused with Krebs-Henseleit bicarbonate buffer to measure insulin secretion in response to 27.8 mmol/l glucose and 10 mmol/l arginine. Four weeks of normoglycaemia failed to restore glucose-induced insulin secretion from n-STZ islets (glucose induced increment: -1.7 +/- 2.5 fmol/min in D-N, 1.2 +/- 7.1 fmol/min in D-D). In contrast to normal islets, normoglycaemia reduced insulin mRNA contents (60 +/- 24 in D-N, 496 +/- 119 in D-D; O.D.-arbitrary units). However, arginine-induced secretion was markedly enhanced by diabetic environment in both normal and n-STZ islet grafts. These results indicate that selected aspects of glucose recognition are irreversibly damaged by a long-term diabetic state or, alternatively, by a lasting effect of STZ administration.
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Affiliation(s)
- K Inoue
- Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden
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13
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Gregorio F, Ambrosi F, Cristallini S, Pedetti M, Filipponi P, Santeusanio F. Therapeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose levels: in vitro effects on pancreatic A- and B-cell function. Diabetes Res Clin Pract 1992; 18:197-206. [PMID: 1289021 DOI: 10.1016/0168-8227(92)90146-i] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In the classical model of isolated perfused rat pancreas four commonly used sulfonylureas--tolbutamide, glibenclamide, gliquidone and gliclazide--were investigated at therapeutical concentrations at three different glucose levels (with 0, 2.22 and 5 mmol/l glucose surrounding) and in the presence of a metabolic stimulus with glucose at 8.33 mmol/l. All the sulfonylureas stimulated the B-cell function. Tolbutamide, gliquidone and gliclazide produced a prompt biphasic hormone release while glibenclamide induced a delayed monophasic insulin secretion. In all cases the amount of insulin released depended on the metabolic condition. As the environmental glucose levels fell, the sulfonylureas' stimulatory effect on the B-cell function decreased. At the therapeutical concentrations we tested, no sulfonylurea influenced A-cell activity whether directly or indirectly via an insulin-mediated paracrine inhibition of glucagon release.
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Affiliation(s)
- F Gregorio
- Istituti di Clinica Medica I, Università di Perugia, Italy
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14
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Hillaire-Buys D, Gross R, Chapal J, Ribes G, Loubatières-Mariani MM. P2y purinoceptor responses of beta cells and vascular bed are preserved in diabetic rat pancreas. Br J Pharmacol 1992; 106:610-5. [PMID: 1504744 PMCID: PMC1907575 DOI: 10.1111/j.1476-5381.1992.tb14383.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
1. To investigate the effect of experimental diabetes on the P2y purinoceptor responses of pancreatic beta-cells and vascular bed, we used adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), a potent and stable P2y agonist. This work was performed in the isolated perfused pancreas of the rat. 2. Diabetes was induced by streptozotocin (66 mg kg-1, i.p.). Five weeks after the induction of diabetes, on the day of pancreas isolation, the animals displayed marked hyperglycaemia (37.6 +/- 2.7 mM). Age-matched rats were used as controls. 3. Insulin response to a glucose stimulation from 5 to 10 mM was completely lost and stimulation of insulin release by the sulphonylurea, tolbutamide (185 microM), was drastically impaired in the diabetic pancreas (maximum responses were 1.5 +/- 0.4 and 7.0 +/- 1.4 ng min-1 for diabetic and age-matched rats respectively). 4. In contrast, in the diabetic pancreas ADP beta S (15 microM), infused in the presence of glucose 5 mM, elicited an immediate and significant insulin release similar to that observed in the age-matched pancreas (maximum responses were 7.6 +/- 1.5 and 6.7 +/- 1.3 ng min-1 respectively). This ADP beta S stimulating effect occurred independently of the glucose concentration (5, 8.3 and 28 mM) in the diabetic pancreas. On pancreatic vascular resistance, ADP beta S induced a similar vasodilatation in diabetic and age-matched rats. 5. In conclusion, ADP beta S retains its insulin stimulatory and vasodilator effects in experimental diabetes; P2y purinoceptors could therefore be considered as a new target for the development of antidiabetic drugs.
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Affiliation(s)
- D Hillaire-Buys
- Faculté de Médecine, Laboratoire de Pharmacologie, CNRS, URA 599, Montpellier, France
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15
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Campbell DB, Lavielle R, Nathan C. The mode of action and clinical pharmacology of gliclazide: a review. Diabetes Res Clin Pract 1991; 14 Suppl 2:S21-36. [PMID: 1794262 DOI: 10.1016/0168-8227(91)90005-x] [Citation(s) in RCA: 77] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Gliclazide is a sulphonylurea drug with an intermediate half-life of around 11 hours. It is extensively metabolised, and renal clearance accounts for only 4% of total drug clearance. The molecule contains an azabicyclo-octyl group which confers special properties on the basic sulphonylurea moiety. Gliclazide stimulates insulin secretion through the beta cell sulphonylurea receptor, and possibly through a direct effect on intracellular calcium transport. It specifically improves the abnormal first phase insulin release in type 2 diabetes, and also has an effect on the second phase. This pattern of insulin release is thought to explain the lower incidence of hypoglycaemic episodes and weight gain compared with some other sulphonylureas. There is also a reduction in hepatic glucose production and improvement in glucose clearance, without changes in insulin receptors. This suggests a possible post-receptor effect on insulin action, perhaps by stimulation of hepatic fructose-2,6-bisphosphatase and muscle glycogen synthase. Gliclazide reduces platelet adhesion, aggregation and hyperactivity and increases fibrinolysis. These actions, thought to be independent of its hypoglycaemic activity, may make gliclazide useful in halting the progression of diabetic microangiopathy.
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Affiliation(s)
- D B Campbell
- Servier Research and Development, Fulmer, Slough, U.K
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