UMLS:C0011860 - FACTA Search

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Query: UMLS:C0011860 (type 2 diabetes)
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This review is meant to give to the readers an overview of the pharmacokinetics, pharmacodynamics, mechanism(s) of action and therapeutical indications of the sulfonylurea compound glibenclamide, which is a cardinal drug in the treatment of type 2 diabetes mellitus. Data produced in our own laboratory over the past 15 years will be presented, along with reference to the main literature in the field. As pharmacokinetics is concerned, special emphasis will be placed on the detrimental effect of hyperglycemia in the intestinal absorption of this class of drugs. Both beta-cell and extrapancreatic effects of glibenclamide will be highlighted. The mechanism of action of the drug consists in the inhibition of the ATP-sensitive K+ channels, which leads to depolarization of the cells and insulin secretion. Based on the same mechanism are also the extrapancreatic action of the drug at the liver, skeletal muscle, heart muscle and smooth muscle sites. The newly discovered possible physiological actions of the C-peptide molecule [suggesting a stimulatory effect of C-peptide on the Na+, K+ (ATPase) pump and on diabetic complications], cast a new light on all therapeutic approaches (like sulfonylurea class of compounds and whole pancreas or islet of Langerhans transplantation), which induce/replace both insulin and C-peptide secretion.
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PMID:Glibenclamide: an old drug with a novel mechanism of action? 945 65

The aim of this study was to determine the ouabain receptor density, Na+,K(+)-ATPase function and contractile properties of cardiac muscle in insulin-dependent and non-insulin-dependent rat diabetes mellitus (IDDM and NIDDM, respectively) and the reversibility of the diabetes-induced changes by insulin or thyroxin substitution. IDDM and NIDDM were induced in Wistar rats by streptozotocin injection. Contractile parameters were measured in isolated left ventricular trabeculae. [3H]Ouabain binding to myocardium was measured in right and left ventricular strips obtained from diabetic animals and their age-matched controls. Both the maximum [3H]ouabain binding capacity (Bmax) and the Kd for [3H]ouabain binding, as well as maximum 86Rb+ uptake and rate of contraction, were decreased in IDDM myocardium compared with controls. Insulin or thyroxin substitution reversed the reduction in Bmax and contraction rate, but not the decrease in Kd. In young, but not old, control animals, both Bmax and maximum 86Rb+ uptake were higher in the right ventricular myocardium than in the left one. In contrast to changes observed in IDDM, both Bmax and Kd for [3H]oubain binding were increased in the left but not in the right ventricle of NIDDM animals. NIDDM caused no alterations in contractile properties. Prominent differences were observed in [3H]ouabain binding characteristics and myocardial contractility between young and old control animals. Bmax of [3H]ouabain binding and rate of contraction were inversely proportional in all preparations studied. It is concluded that IDDM and NIDDM induce different alterations in myocardial Na+,K(+)-ATPase, and these changes may influence the contractile properties of cardiac muscle.
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PMID:Altered [3H]ouabain binding to cardiac muscle in insulin-dependent and non-insulin-dependent diabetic rats. 948 20

The serum concentrations of digoxin-like immunoactivity (DLIA) were measured in 99 patients: 20 healthy volunteers (HV), 15 patients with insulin-dependent diabetes mellitus (IDDM), 14 patients with non-insulin-dependent diabetes mellitus without hypertension taking oral hypoglycemic (OHA) agents (NIDDM/-HT), 11 patients with NIDDM without hypertension taking insulin (NIDDM/-HT+INS), 12 NIDDM patients with hypertension taking OHA (NIDDM/+HT), nine NIDDM patients with hypertension taking insulin (NIDDM/+HT/+INS), 10 patients with essential hypertension with normal insulin levels (HT/-HI), and in eight patients with essential hypertension with hyperinsulinemia (HT/+HI). The numbers (%) of subjects with DLIA levels above the detection limit of the assay used (> 0.1 nmol/L) were, in the NIDDM/-HT group, 12/14 (85.7%) and in the NIDDM/+HT group, 9/12 (75%), significantly higher (P < .05) than in the HV (7/20; 35%), IDDM (3/15; 20%), and HT/-HI groups (2/10; 20%). The number and percentage of subjects with DLIA levels above the detection limit in the HT/+HI group was six of eight (75%), significantly (P < .05) higher than in the IDDM and HT/-HI groups, and tended to be higher than in the HV group (P < .055). Means and SD of serum DLIA levels (nmol/L) in the NIDDM/-EH (0.18/0.09) and NIDDM/+EH (0.19/0.15) groups were significantly higher (P < .05) than in the HV (0.09/0.07), IDDM (0.05/0.05), and EH/-HI (0.06/0.06) groups. DLIA levels in the HT/+HI group (0.15/0.12) were significantly higher (P < .05) than in the IDDM and HT/-HI groups. The percentage of DLIA levels above the detection limit, as well as the mean and SD of DLIA in the NIDDM group taking OHA, did not differ from those in subjects taking insulin. In all subjects studied (n = 99), DLIA correlated with C-peptide (r = 0.30; P < .01) and glomerular filtration (GF) (r = -0.21; P < .05). After exclusion of insulin-treated patients, DLIA correlated significantly with plasma glucose (PG; r = 0.25; P < .05), immunoreactive insulin (IRI; r = 0.41; P < .001), C-peptide (r = 0.27; P < .05), and GF (r = -0.26; P < .05) (n = 64). Correlation of DLIA with IRI (r = 0.33; P < .05; n = 38) also persisted after exclusion of patients taking insulin and those with DLIA levels below the detection limit. Similarly, DLIA also correlated with C-peptide (r = 0.64; P < .05) and IRI (r = 0.70; P < .05) in the subgroup of 10 patients with the highest levels of DLIA (> 0.25 nmol/L). None of the sera (n = 15) with different DLIA concentrations (0.0-0.38 nmol/L) exhibited K-pNPPase (Na+-K+-ATPase) inhibitory activity. In conclusion, this work demonstrated elevated serum DLIA in NIDDM and HT/+HI patients, and its correlation with IRI and GF. However, due to the fact that the chemical nature and biologic properties of DLIA are still a matter of debate, it is too early to speculate whether the elevation of DLIA is just a secondary result associated with HI and reduced GF, or whether it also has pathophysiologic consequences. Nevertheless, in both cases the elevated concentrations of substances with DLIA and their interference with antidigoxin antibodies may affect therapeutic monitoring of digitalization in NIDDM and HT/+HI patients. Also, the elevated DLIA could subclassify these patients. The significance of such subclassifications (pathophysiologic, therapeutic, or prognostic), however, will need further investigation.
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PMID:Endogenous digoxin-like immunoactivity in subjects with diabetes mellitus and hypertension. 965 25

Familial hypobetalipoproteinemia is caused by mutations in the apolipoprotein (apo) B gene. We identified a 57-year-old woman whose plasma total cholesterol and apoB levels were 2.17 mmol/L and 0.03 g/L, respectively. Separation of plasma lipoproteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the absence of apoB-100 and the presence of a faster-migrating form of apoB with an apparent Mr of 195 kDa. Direct sequencing of a polymerase chain reaction-amplified fragment of the patient's apoB gene DNA revealed a single C-->T transition at nucleotide 5472 that converts glutamine 1755 (CAA) to a stop codon (TAA). We predict this novel nonsense mutation of the apoB gene to produce a truncated protein that contains 1754 amino-terminal amino acid residues of apoB-100. We designated this mutant form of apoB apoB-38.7 by following the centile nomenclature of the apoB species. The same mutation was found in both of her children. The proband revealed clinical findings of retinitis pigmentosa, acanthocytosis, and loss of deep tendon reflexes that are characteristic of severe hypobetalipoproteinemia. In addition, the proband had type II diabetes mellitus with nephropathy, anemia, cholelithiasis, hepatic hemangioma, bronchiectasis, and extensive calcification of major arteries including, the celiac, splenic, and renal. In summary, we have found a novel truncated apoB, apoB-38.7, in a patient with an unusual presentation of hypobetalipoproteinemia that includes diabetes mellitus and extensive arterial calcification.
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PMID:A truncated species of apolipoprotein B (B-38.7) in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus. 971 41

The mechanisms responsible for hypertension in NIDDM patients are only partially understood. Increased sensitivity to dietary salt intake and to vasoconstrictor hormones are among the mechanisms proposed. We have studied 19 hypertensive NIDDM patients 7 salt-sensitive and 12 salt-resistant while they were ingesting a diet with 20 mEq/day of Na+ for 9 days and while they were ingesting a diet containing 250 mEq/day of Na+ for 14 days. During the last 4 days of each dietary regimen, they received 60 mg/day of slow-release nifedipine. Blood pressure response to increasing doses of norepinephrine and angiotensin II was studied at the end of each of the four phases of the study. High salt intake increased blood pressure and decreased heart rate in these patients. High salt intake also increased the vascular response to norepinephrine but not to angiotensin II in NIDDM hypertensive subjects. Glomerular filtration rate and renal blood flow were not different during the low and high salt diets. There were no differences in the blood pressure response to norepinephrine or angiotensin II, nor in renal hemodynamic changes among salt-sensitive and salt-resistant NIDDM patients. Nifedipine decreased blood pressure equally in salt-sensitive and salt-resistant hypertensive patients and during the high and the low salt intake. Nifedipine increased renal blood flow, both in salt-sensitive and in salt-resistant individuals, but the differences did not reach statistical significance. Nifedipine decreased the blood pressure response to both norepinephrine and angiotensin II. The studies indicate that an increased reactivity to the pressor action of norepinephrine may contribute to the maintenance of hypertension in NIDDM hypertensive subjects and high salt intake may aggravate the pressor responsiveness to norepinephrine in these patients. Nifedipine is an effective antihypertensive drug in NIDDM patients and its action may be in part related to a decrease in pressor response to norepinephrine and angiotensin II.
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PMID:Dietary salt intake, blood pressure and the kidney in hypertensive patients with non-insulin dependent diabetes mellitus. 1004 94

In diabetic nephropathy, heparan sulfate glycosaminoglycan side chains are reduced in glomerular basement membranes proportionally to the degree of proteinuria. Recently, it was demonstrated that additional therapy with danaparoid sodium, a mixture of sulfated glycosaminoglycans with mainly heparan sulfate, lowered proteinuria in type 1 diabetes patients with diabetic nephropathy. A randomized placebo-controlled parallel study was performed with 750 anti-Xa units of danaparoid sodium once daily in type 2 diabetes patients with severe proteinuria. The aim of the study was to evaluate the possible effects of danaparoid sodium on proteinuria, endothelial dysfunction, and hard exudates in the retina and to determine the safety/tolerability of this drug. Twenty-two patients completed the study, and one patient had to stop prematurely after 6 wk of danaparoid sodium treatment because of urticaria at the injection sites. Apart from a small decrease of hemoglobin and minor skin hematomas at the injection site in five patients in the danaparoid sodium group, no other safety parameters showed any clinically or statistically significant difference between and within groups. The relative change in time of both the urinary albumin and protein excretion rate corrected for creatinine did not differ between both treatment arms (P = 0.2 and 0.49, respectively). No retinal complications or changes of hard exudates occurred. von Willebrand factor was elevated in both groups, but was not influenced by either treatment modality. Contrary to the beneficial effects that occurred in type 1 diabetes patients with diabetic nephropathy, treatment for 8 wk with 750 anti-Xa units of danaparoid sodium gave no reduction of proteinuria, hard exudates, and von Willebrand factor.
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PMID:Effect of danaparoid sodium on proteinuria, von Willebrand factor, and hard exudates in patients with diabetes mellitus type 2. 1036 73

The discovery of opioid receptors and endogenous substances capable of specific binding to these receptors, i.e. endorphin and enkephalin, is one of the most spectacular indications suggesting that the presence of a receptor for a certain drug in the organism authenticates searching for an endogenous substances with high affinity at this receptor. Later, further studies were undertaken to detect other endogenous drug-like factors. Some experiments led to the discovery of digoxin-like factor in blood which could bind to a specific receptor on Na+, K(+)-ATPase subunit, showing also the affinity for cardiac glucosides. Digoxin-like factor was detected in blood of healthy people who did not receive any drug treatments. It has been estimated to be present in 15% of the population but in some diseases this value is much higher, e.g. digoxin-like factor was detected in 90% of patients with IDDM, and it can be used as a risk factor of the occurrence of vascular complications. In cases with NIDDM, the digoxin-like factor was detected in patients with insulin-resistance. The presence of digoxin-like factor was ascertained in patients with heart failure who did not take digitalis preparations. Endogenous digoxin-like factor can contribute to the detection of falsely increased digoxin blood concentrations during the monitoring of drug level in the course of the therapy. In our studies we ascertained the presence of the quinidine-, cyclosporin-, theophylline- and phenytoin-like substances in the blood of the healthy people who did not receive any drugs. It seems that these endogenous substances resembling drugs are synthesized in human organism when they are needed for maintaining the physiological equilibrium. We can suggest that stimulation of the production of drug-like factors in the organism can be used in the future in the therapy of some diseases.
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PMID:Endogenous drug-like factors. 1038 21

The aim of this clinical trial was to study the participation of plasma atrial natriuretic factor (ANF) in the risk of developing diabetic nephropathy by increasing the intraglomerular pressure. The effect of glibornuride on the plasma ANF levels and natriuresis was estimated in 10 newly diagnosed NIDDM patients and 10 control subjects. At base line, plasma ANF levels (15.05+/-2.32 pg/ml and 11.13+/-0.85 pg/ml) and the urinary sodium and potassium excretion rates were similar in patients and control subjects, respectively. Similarly, intravenous saline infusion (2 mmol/kg/60 min) resulted in remarkable elevation of plasma ANF levels in patients and in controls (28.89+/-4.72 pg/ml and 20.18+/-2.48 pg/ml, respectively) and in increased urinary sodium and potassium excretion rates in both groups. In contrast, after a single dose of 50 mg glibornuride p.o. the saline infusion did not increase ANF levels (15.13+/-1.00 pg/ml), while natriuresis but not kaliuresis persisted. All tests were performed during euglycemic clamp. It was suggested that glibornuride, with its natriuretic effect through the ATP sensitive potassium channels on the apical membrane of the thick ascending limb of loop of Henle and cortical collecting duct cells might inhibit the elevation of plasma ANF levels in response to extracellular fluid volume expansion. Similarly, with its natriuretic effect, it protects the diabetic patients against possible sodium retention. This result is considered noteworthy, since the inhibition of plasma ANF elevation in early diabetes by glibornuride may prevent glomerular hypertension and subsequent development of nephropathy.
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PMID:The Effect of Glibornuride on Plasma Atrial Natriuretic Factor Levels in Patients with Newly Diagnosed NIDDM. 1040 67

Sodium fluorescein angiography is a widely used technology in ophthalmology, which allows us to visualise the chorioretinal microcirculation. Previous reports showed a prolongation of the retinal circulation time along with erythrocyte hyperaggregation and a decrease of erythrocyte acetylcholinesterase activity and a possible interference with the erythrocyte's membrane fluidity. The aim of the present work is to investigate the influence of sodium fluorescein on the hemorheological profile of a group of 23 non-insulin dependent diabetes mellitus (NIDDM) patients undergoing routine retinal angiography. Thirty minutes after the endovenous administration of the fluorescein there was: (I) an increase of whole blood viscosity (p = 0.015), erythrocyte elongation index (EEI, p < 0.05), whole blood pH (p < 0.001), methemoglobin (p < 0.001) and carboxyhemoglobin (p < 0.001) concentrations; (II) no variation of plasma osmolality and erythrocyte aggregation index (EAI); (III) a decrease of the erythrocyte acetylcholinesterase activity, p < 001; (IV) no variation in membrane lipid fluidity, although 1,6-diphenyl-1,3,5-hexatriene (DPH) correlated directly with the EEI, while 1,4-trimethyl-phenyl-1,3,5-hexatriene (TMA-DPH) and EAI correlated inversely, suggesting that the decreasing EEI (lower erythrocyte deformablity) might be associated with an increased rigidity of the external polar region and fluidification of the hydrophobic region of the erythrocyte membrane, with an increasing EAI. In conclusion, the endovenous administration of sodium fluorescein in NIDDM patients during the retinal angiography procedure interferes with the erythrocyte membrane and possibly with the microcirculatory blood flow.
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PMID:Sodium fluorescein influence on the hemorheological profile of non-insulin dependent diabetes mellitus patients. 1041 8

Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about changes in vascular reactivity in those at risk for developing type 2 diabetes. To address this situation, the vascular reactivity in both the micro- and macrocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degree relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impaired glucose tolerance (IGT), and 42 patients with type 2 diabetes without vascular complications (diabetes). Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent) and 1% sodium nitroprusside (SNP) (endothelium-independent), whereas high-resolution ultrasound images were used to measure brachial artery diameter changes during reactive hyperemia. Plasma concentrations of endothelin-1 (ET-1), von Willebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The vasodilatory responses to Ach, expressed as percent increase of blood flow over baseline, were reduced in relatives (98 +/- 48, mean +/- SD), IGT (94 +/- 52), and diabetes (74 +/- 45) compared with controls (126 +/- 67) (P < 0.001 controls versus relatives, IGT, and diabetes). The responses to SNP were similarly reduced: controls (123 +/- 46), relatives (85 +/- 46), IGT (83 +/- 48), and diabetes (65 +/- 31) (P < 0.001 controls versus relatives, IGT, and diabetes) as were the responses in the brachial artery diameter during reactive hyperemia: controls (13.7 +/- 6.1), relatives (10.5 +/- 6.7), IGT (9.8 +/- 4.5), and diabetes (8.4 +/- 5.0) (P < 0.01 controls versus relatives, IGT, and diabetes). Women had greater responses than men in both the micro- and macrovascular circulatory tests, but a similar progressive reduction was observed in both sexes with increasing degrees of glucose intolerance. A significant inverse correlation was found between microvascular reactivity and systolic blood pressure, fasting plasma glucose, HDL cholesterol, fasting plasma insulin, and homeostasis model assessment (HOMA) values, an index of insulin resistance. BMI and diastolic blood pressure had a significant inverse correlation only with endothelium-dependent vasodilation. In the macrocirculation, systolic blood pressure, HbA1c, HDL cholesterol, and HOMA had significant correlation with brachial artery diameter changes. Compared with control subjects, ET-1 was significantly higher in all groups, vWF was higher only in the diabetic group, sICAM levels were higher in the IGT and diabetic groups, while sVCAM concentrations were higher in the relatives and those with diabetes (P < 0.05). On stepwise multivariate analysis, age, sex, fasting plasma glucose, and BMI were the most important contributing factors to the variation of vascular reactivity. Addition of all clinical and biochemical measures explained only 32-37% of the variation in vascular reactivity. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes, even at a stage when normal glucose tolerance exists, and that factors in addition to insulin resistance may be operative.
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PMID:Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. 1048 Jun 19

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