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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with an increased risk of macro- and microvascular degenerative complications. Gliclazide is a second generation sulfonylurea that is widely used in the treatment of type II diabetes mellitus. Its hypoglycemic activity is well documented. In addition to its metabolic effects, gliclazide has beneficial effects on the hemobiological abnormalities of NIDDM. These effects are mediated by the azabicyclo-octyl ring grafted on to its aulfonylurea core. Numerous studies have demonstrated that gliclazide reduces platelet hyperadhesion and platelet hyperaggregability. These actions have been extensively confirmed in diabetic patients over periods of up to 3 years. With regard to platelet functions, several groups have demonstrated a significant reduction in serum and intraplatelet beta thromboglobulin and thromboxane B2. In animal models, in-vitro and in-vivo gliclazide stimulates endothelial prostacyclin synthesis. The beneficial effects of the compound on thromboxane/prostacyclin balance have been recently confirmed in type II diabetic patients after a 3-month treatment period. Concerning fibrinolysis, gliclazide restores low plasminogen activity to normal in NIDDM patients previously treated with first-generation sulfonyl-ureas. Gliclazide increases fibrinolytic potential by increasing endothelial cell tissue plasminogen activator and pre-kallikrein activity. More recent studies suggest that gliclazide may have effects on fibrin network structure, rendering the fibrin more amenable to fibrinolysis. Finally, it has been shown that gliclazide has a potent free-radical-scavenging activity in vitro. This property has been recently confirmed in vivo in type II diabetic patients and may suggest that platelet reactivity and oxidative stress are related in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
J Diabetes Complications
PMID:Hemobiological properties of gliclazide. 783

Renal kallikrein is increased in diabetic patients and streptozotocin (STZ)-induced diabetic rats with hyperfiltration. Chronic inhibition of renal kallikrein reduces glomerular filtration rate (GFR) and renal plasma flow (RPF) in hyperfiltering STZ-induced diabetic rats. To investigate whether these actions of kallikrein and its inhibition are kinin-mediated, we used a B2-kinin receptor antagonist (BKA). In STZ-induced diabetic rats with hyperfiltration, renal kallikrein excretion rate was significantly increased (P < or = 0.01), and kinin excretion rate was increased 57%, as compared with control rats. Left kidney GFR and RPF were measured before and during a 40-min infusion of BKA (0.5 micrograms.kg-1.min-1) or vehicle. Infusion of the kinin receptor antagonist reduced the GFR and RPF significantly. GFR was reduced by 18%, from an average baseline value of 2.07 +/- 0.11 to 1.70 +/- 0.06 ml/min, P < or = 0.001 (means +/- SE). RPF was reduced by 25%, from 6.74 +/- 0.38 to 5.06 +/- 0.17 ml/min, P < or = 0.001. Total renal vascular resistance was significantly increased during BKA infusion, P < or = 0.001. Vehicle infusion for the same period had no significant effect on GFR, RPF, or renal vascular resistance. These findings further support the hypothesis that increased renal production of kinins contributes to the renal vasodilation of diabetes.
Diabetes 1995 Feb
PMID:Kinin, a mediator of diabetes-induced glomerular hyperfiltration. 785 34

To assess possible roles of the renal kallikrein-kinin system in the development of renal impairments in diabetes mellitus, we determined daily excretion of urinary total and active kallikrein in uninephrectomized Wistar-Kyoto rats made diabetic by streptozotocin (45 mg/kg) as a bolus injection. We also evaluated the effect of captopril (50 mg/kg/day) administered orally on the development of diabetic renal impairments in the streptozotocin-treated rats. Active kallikrein was determined by its kininogenase activity, and generated kinins were radioimmunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in streptozotocin-treated rats whereas urinary total kallikrein excretion was unchanged, resulting in the decreased ratio of active to total kallikrein compared to that in the controls. These reductions were preceded by the increased excretion of urine protein measured as an index of renal impairments. The administration of captopril for 12 weeks attenuated the development of diabetic renal impairments evaluated by urine protein excretion in streptozotocin-treated rats, although it did not induce significant changes in urinary total and active kallikrein excretion, and the ratio of active to total kallikrein. Thus the results of this study indicate that the renal kallikrein-kinin system might not play major roles in the development of diabetic renal impairments in the rat, although the pathophysiological relevance of impaired activation of renal kallikrein system to the development of diabetic renal impairments remains to be determined. In addition, they suggest that the renoprotective effects of captopril may be independent of the activation of renal kallikrein system in streptozotocin-treated rats.
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PMID:Urinary active kallikrein excretion and diabetic renal impairments in streptozotocin-treated rats. 812 82

The mechanisms responsible for the increase in blood pressure response to high salt intake in salt-sensitive patients with essential hypertension are complex and only partially understood. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for such patients to retain salt and develop salt-dependent hypertension. The possible role of vasodilator and natriuretic agents, such as the prostaglandins, endothelium-derived relaxing factor, atrial natriuretic factor, and kinin-kallikrein system, requires further investigation. An association between salt sensitivity and a greater propensity to develop renal failure has been described in certain groups of hypertensive patients, such as blacks, the elderly, and those with diabetes mellitus. Salt-sensitive patients with essential hypertension manifest a deranged renal hemodynamic adaptation to a high dietary salt intake. During a low salt diet, salt-sensitive and salt-resistant patients have similar mean arterial pressure, glomerular filtration rate, effective renal plasma flow, and filtration fraction. On the other hand, during a high salt intake glomerular filtration rate does not change in either group, and effective renal blood flow increases in salt-resistant but decreases in salt-sensitive patients; filtration fraction and glomerular capillary pressure decrease in salt-resistant but increase in salt-sensitive patients. Salt-sensitive patients are also more likely than salt-resistant patients to manifest left ventricular hypertrophy, microalbuminuria, and metabolic abnormalities that may predispose them to cardiovascular diseases. In conclusion, salt sensitivity in hypertension is associated with substantial renal, hemodynamic, and metabolic abnormalities that may enhance the risk of cardiovascular and renal morbidity.
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PMID:Salt sensitivity in hypertension. Renal and cardiovascular implications. 814 22

Early renal manifestations of type I diabetes include kidney enlargement, increased glomerular filtration rate, and renal plasma flow. These hemodynamic changes may be caused by a number of factors, including growth hormone and/or insulin-like growth factor-I (IGF-I). Streptozotocin-induced insulinopenic diabetes in rats represents a model of human type I diabetes and is associated with the early hemodynamic changes in the kidney seen in poorly controlled type I diabetic patients. These changes are preceded by an accumulation of IGF-I peptide in the kidney. Insulin-like growth factor-I is not locally produced, but rather accumulates from circulating IGF-I, trapped by increased levels of IGF-binding proteins, particularly IGF-binding protein-1. The hemodynamic effects, reproduced by infusions of recombinant human IGF-I in normal rats, may be blocked by co-infusion of a kinin-receptor antagonist, suggesting that at least one of the mechanisms involved is the kallikrein-kinin system. These studies strongly support the notion that the IGF system may play a role in early hemodynamic manifestations of the diabetic kidney. Whether these effects lead to long-term diabetic renal disease remains to be studied.
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PMID:The role of insulin-like growth factors in diabetic kidney disease. 823 20

The genetic and environmental determinants of hypertension, lipid abnormalities, and coronary artery disease (CAD) have been studied for 15 years in Utah in population-based multigenerational pedigrees (2500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships), siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type II diabetes (271 subjects among 16 pedigrees), lipoprotein lipase deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids. A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several 'intermediate phenotypes' associated with hypertension (erythrocyte sodium-lithium countertransport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion, and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for low-density lipoprotein (LDL) cholesterol, lipoprotein (a) (Lp[a]), low high-density lipoprotein (HDL) cholesterol, and high apolipoprotein (apo) B. Deoxyribonucleic acid (DNA) markers of lipid abnormalities or hypertension have included LDL-receptor defects, lipoprotein lipase deficiency, high Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen, and 'glucocorticoid remediable aldosteronism (GRA) hypertension.' Also tested in Utah studies, but not found to be DNA markers for hypertension, were the genetic loci for the structural genes for renin and angiotensin-converting enzyme, and the sodium antiport system. In addition, important gene-gene interactions (LDL receptor with apo E2) and gene-environment interactions (kallikrein with potassium intake) were found.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah. 829 39

Kidney haemodynamics appear to change after the early phases of diabetic nephropathy: increases in glomerular filtration rate and in renal plasma flow have been widely reported, while kidney size is increased. As the renal kallikrein-kinin system has been demonstrated to regulate kidney blood circulation, we have evaluated the excretion of urinary kallikrein in 87 Type 1 (insulin-dependent) diabetic patients with and without hyperfiltration. Urinary kallikrein excretion was measured in 24-h urine collections. The esterolytic activity was determined by fluorimetric assay. The excretion of urinary kallikreins was significantly higher in hyperfiltering patients (472 +/- 125 esterase units/24 h) than in normofiltering (168 +/- 77 esterase units/24 h) and control subjects (151 +/- 39 esterase units/24 h), p < 0.001. Furthermore, we observed a positive correlation between urinary kallikrein excretion and glomerular filtration rate (r = 0.785). These data suggest that variations of kallikrein and kinin concentrations may play a role in the alteration of renal haemodynamics in Type 1 diabetes. It is possible that the kinin-kallikrein system, the renin-angiotensin system and the prostaglandins may interact to determine the haemodynamic alterations which are present in the diabetic disease.
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PMID:Urinary kallikrein excretion in type 1 (insulin-dependent) diabetes mellitus. 831 46

The levels of tissue kallikrein, tonin, and other kallikrein-like proteinases were determined in extracts of rat submandibular glands 3 mo after the induction of diabetes with STZ (65 mg/kg i.v.). Total kallikrein-like proteinase activity was assayed catalytically with the fluorogenic substrate DVLR-AFC. Tissue kallikrein was assayed by using the same substrate in the presence of SBTI. Activity of other kallikrein-like proteinases was defined as the difference between the total kallikrein-like activity and that of tissue kallikrein. Tonin was assayed by using the substrate ZVKKR-AFC in the presence of aprotinin. Results were compared with age-matched controls and with diabetic rats that had received daily insulin injections for the last week of the test period. The results showed that all activities were significantly reduced in diabetic glands compared with controls. Insulin treatment restored concentrations of tissue kallikrein activity, whereas the activities of tonin and other kallikrein-like proteinases were unchanged. RIA supported these findings. The results indicate that in rat submandibular glands, insulin affects the synthesis of kallikrein-like proteinases in different ways and, allowing for the slowness of the processes involved, insulin may exert a direct influence on the regulation of tissue kallikrein synthesis but only have indirect effects on the synthesis of tonin and the closely related kallikrein-like proteinases.
Diabetes 1993 Jan
PMID:Tissue kallikrein and tonin levels in submandibular glands of STZ-induced diabetic rats and the effects of insulin. 838 May 62

Using the euglycemic-hyperinsulinemic glucose clamp and the human forearm technique, we have demonstrated that the improved glucose disposal rate observed after the administration of an angiotensin-converting enzyme (ACE) inhibitor such as captopril may be primarily due to increased muscle glucose uptake (MGU). These results are not surprising because ACE, which is identical to the bradykinin (BK)-degrading kininase II, is abundantly present in muscle tissue, and its inhibition has been observed to elicit the observed metabolic actions via elevated tissue concentrations of BK and through a BK B2 receptor site in muscle and/or endothelial tissue. These findings are supported by several previous studies. Exogenous BK applied into the brachial artery of the human forearm not only augmented muscle blood flow (MBF) but also enhanced the rate of MGU. In another investigation, during rhythmic voluntary contraction, both MBF and MGU increased in response to the higher energy expenditure, and the release of BK rose in the blood vessel, draining the working muscle tissue. Inhibition of the activity of the BK-generating protease in muscle tissue (kallikrein) with aprotinin significantly diminished these functional responses during contraction. Applying the same kallikrein inhibitor during the infusion of insulin into the brachial artery significantly reduced the effect of insulin on glucose uptake into forearm muscle. This is of interest, because in recent studies insulin has been suggested to elicit its actions on MBF and MGU via the accelerated release of endothelium-derived nitric oxide, the generation of which is also stimulated by BK in a concentration-dependent manner. This new evidence obtained from in vitro and in vivo studies sheds new light on the discussion of whether BK may play a role in energy metabolism of skeletal muscle tissue.
Diabetes 1996 Jan
PMID:Potential role of bradykinin in forearm muscle metabolism in humans. 852 90

Kallikrein-kininogen-kinin systems are now topics of widespread interest. The long-standing appreciation of their diverse pharmacological properties and biochemical characteristics is being supplemented by modern definitions of their cellular receptors' signal-transduction mechanisms and physiological and pathological roles. The assignment of important homeostatic responsibilities for kinins, including those in autocrine and paracrine signaling for skeletal and cardiac muscle energy metabolism, is now subject to definitive experimental evaluation via the availability of better kallikrein inhibitors, specific kinin receptor antagonists, and techniques of genetic manipulation.
Diabetes 1996 Jan
PMID:Kallikreins and kinins. Molecular characteristics and cellular and tissue responses. 852 94


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