Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uncoupling protein (UCP) 3 and UCP2, mitochondrial carrier proteins dissipating electrochemical gradient across the mitochondrial inner membrane, have been implicated in the regulation of energy metabolism. The UCP3 gene is expressed abundantly in the skeletal muscle, while the UCP2 gene is detected in the white adipose tissue (WAT) with diffuse localization throughout the body. Uncoupling of electron transport and ATP synthesis has been reported to increase glucose uptake, suggesting that UCP may be involved in glucose metabolism. Thiazolidinediones (TZDs), which are insulin-sensitizing agents for NIDDM, have been reported to increase energy expenditure. To elucidate the pathophysiologic significance of UCP3 and UCP2 in the effect of TZDs on glucose metabolism and energy expenditure, we examined their basal mRNA levels in the WAT, brown adipose tissue (BAT), and skeletal muscle from Wistar fatty rats, a rat model of NIDDM and obesity with leptin receptor defect, and investigated expression of the genes encoding UCP3 and UCP2 in Wistar fatty rats and in Wistar lean rats with 2-week oral administration of 3 mg x kg(-1) x day(-1) pioglitazone, a TZD derivative. Basal UCP3 mRNA levels were significantly lower (38 +/- 8, 45 +/- 13, and 76 +/- 6%) in the retroperitoneal WAT, BAT, and skeletal muscle from Wistar fatty rats than in those from Wistar lean rats, while basal UCP2 mRNA levels were significantly higher by 2.1-, 1.8-, and 2.5-fold in the subcutaneous WAT, retroperitoneal WAT, and BAT from Wistar fatty rats, respectively, than in those from Wistar lean rats. In pioglitazone-treated Wistar fatty rats, UCP3 mRNA levels were significantly increased by 2.1-, 2.0-, and 1.6-fold in the epididymal WAT, retroperitoneal WAT, and BAT, respectively, as compared with those in nontreated fatty rats. In pioglitazone-treated lean rats, UCP3 mRNA levels were significantly increased by 1.3-fold in the BAT as compared with those in nontreated lean rats. No significant change of UCP2 mRNA levels was observed in pioglitazone-treated fatty and lean rats. In addition, to examine the direct effect of TZDs on adipocytes, we examined the regulation of UCP3 and UCP2 gene expression using the primary culture of rat mature adipocytes from Sprague-Dawley rats. In rat cultured mature adipocytes, UCP3 mRNA levels were increased in a dose-responsive manner by 10(-5) to 10(-4) mol/l pioglitazone, while there was no significant change of UCP2 mRNA levels. These results clearly demonstrate that UCP3 gene expression is upregulated by TZDs in the WAT and BAT in Wistar fatty rats, an obese model with leptin receptor defect, and that adipose UCP3 gene expression is increased in response to TZDs in vitro. The present study suggests the involvement of UCP3 in the effects of TZDs on energy and glucose metabolism.
 ...
PMID:Increased adipose expression of the uncoupling protein-3 gene by thiazolidinediones in Wistar fatty rats and in cultured adipocytes. 979 55

Noninsulin-dependent diabetes mellitus (NIDDM), a major health care problem in the Western world, is a disease typified by a relative deficiency of insulin, leading to vast derangements in glucose and lipid homeostasis with disastrous vascular complications. Despite immense research efforts aimed at a clear understanding of the etiology of this complex disease, the molecular mechanisms causing the disorder still remain elusive. This article reviews extant data from recent publications implicating novel signal transduction pathways as important regulators of the insulin stimulus-secretion coupling in the pancreatic beta-cell. The significance of nitric oxide and serine/threonine protein phosphatases, and their inactivation by insulin secretagogues, glucose metabolites, ATP, GTP, glutamate, and inositol hexaphosphate in this arena is scrutinized. Additionally, also presented is the growing concept that an important signal for insulin secretion may reside in the inextricable interplay between glucose and lipid metabolism, specifically the generation of malonyl-CoA, which inhibits carnitine palmitoyltransferase 1 with the attendant accumulation of long-chain acyl CoA esters. Moreover, attention is directed towards novel intracellular actions of hypoglycemic sulfonylureas in the beta-cell. Finally, the importance of "lipotoxicity" and aberrations in glucose uptake and metabolism in beta-cell dysfunction is given consideration. Future research efforts should aim at further characterization of effects of second messengers on protein phosphorylation elements in beta-cells. Additionally, long-term regulation by glucose and the diabetic state (e.g., fatty acids and ketones) on beta-cell protein phosphatases, pyruvate dehydrogenase, and carnitine palmitoyltransferase 1 needs to be explored in greater depth. Clearly, the detrimental impact of diabetic hyperlipidemia on beta-cell function has been a relatively neglected area, but futu re pharmacological approaches directed at preventing lipotoxicity may prove beneficial in the treatment of diabetes.
 ...
PMID:Aspects of novel sites of regulation of the insulin stimulus-secretion coupling in normal and diabetic pancreatic islets. 979 25

Leptin levels in subjects with android obesity with the insulin resistance syndrome (syndrome X, 5H) are in general elevated, as compared with non-obese subjects and correlate with the BMI, with the percentage of body fat, WHR, IRI levels and sex (they are higher in women), as it is the case in the general population. In the elevated leptin level in syndrome 5H (association of hyperinsulinism, hyperglycaemia-NIDDM, hyperlipoproteinaemia with android obesity, arterial hypertension and hirsutism in females with the polycystic ovaries syndrome) participate in a significant way also elevated basal IRI and cortisol levels as well as an elevated postprandial IRI response during oGTT despite the fact that leptin and endothelin-1 levels do not rise significantly during oGTT despite hyperinsulinaemia. Leptin levels were however higher in men (liminally significant in women) with an hyperinsulinaemic response during oGTT, as compared with probands with a normal insulin response. Optimal insulin and glucocorticoid levels are the prerequisite for a rise of leptin because proadipocytes in vitro begin to produce leptin as soon as insulin is added to the medium and this effect is trebled, if cortisol is added. It appears that the insulin and leptin resistance in syndrome 5H are parallel phenomena which potentiate each other. Elevated insulin and cortisol levels maintain elevated leptin levels which in turn enhances the insulin resistance in muscles and at the same time has an impact on the IRI response to postprandial hyperglycaemia. In the background of this insulin and leptin resistance in the majority of subjects with the 5H syndrome there is apparently no actual molecular defect of the hormone and its receptors in target tissues but a possible defect in mechanisms of postreceptor transduction of the hormonal signal. In the hormonal resistance participate moreover also two general and non-specific mechanisms such as: 1. increased consumption or uptake of hormonal receptors by elevated levels of the appropriate hormone ("down regulation" phenomenon), 2. disorders of paracrine endothelial mechanisms of the vascular wall which determine via the control of the inflow in the regional microcirculation the availability of insulin, leptin and metabolic substrates to target tissues. Impaired vasodilatation reserves and the development of paradoxical vascular spasms in response to stimuli which normally cause vasodilatation (strain, administration of acetylcholine, histamine, ATP etc.) are constant, associated phenomena in hyperlipoproteinaemias, arterial hypertension and in type 2 diabetics. These phenomena are the syndrome of insulin resistance and syndrome 5H-X resp. Endothelin-1 levels assessed in the systemic circulation are however due to their short biological half-life and the paracrine action of endothelin-1 not sensitive markers of endothelial dysfunction in syndrome X.
 ...
PMID:[Relation between levels of leptin, insulin and cortisol in persons with the 5H (X) syndrome]. 982 79

Hexosamines have been hypothesized to mediate aspects of glucose sensing and toxic effects of hyperglycemia. For example, insulin resistance results when the rate-limiting enzyme for hexosamine synthesis, glutamine:fructose-6-phosphate amidotransferase (GFA), is overexpressed in muscle and adipose tissue of transgenic mice. The glucose infusion rates required to maintain euglycemia at insulin infusion rates of 0.5, 2, 15, and 20 mU/kg x min were 39-90% lower in such transgenic mice, compared with their control littermates (P < or = 0.01). No differences were observed in hepatic glucose output, serum insulin levels, or muscle ATP levels. Uptake of 2-deoxyglucose, measured under conditions of hyperinsulinemia, was significantly lower in transgenic hindlimb muscle, compared with controls (85.9 +/- 17.8 vs. 166.8 +/- 15.1 pmol deoxyglucose/g x min). The decrease in glucose uptake by transgenic muscle was associated with a disruption in the translocation of the insulin-stimulated glucose transporter GLUT4. Fractionation of muscle membranes on a discontinuous sucrose gradient revealed that insulin stimulation of control muscle led to a 28.8% increase in GLUT4 content in the 25% fraction and a 61.2% decrease in the 35% fraction. In transgenic muscle, the insulin-stimulated shifts in GLUT4 distribution were inhibited by over 70%. Treatment of the transgenic animals with the thiazolidinedione troglitazone completely reversed the defect in glucose disposal without changing GFA activity or the levels of uridine 5'-diphosphate-N-acetylglucosamine. Overexpression of GFA in skeletal muscle thus leads to defects in glucose transport similar to those seen in type 2 diabetes. These data support the hypothesis that excess glucose metabolism through the hexosamine pathway may be responsible for the diminished insulin sensitivity and defective glucose uptake that are seen with hyperglycemia.
 ...
PMID:Mechanism of hexosamine-induced insulin resistance in transgenic mice overexpressing glutamine:fructose-6-phosphate amidotransferase: decreased glucose transporter GLUT4 translocation and reversal by treatment with thiazolidinedione. 1006 38

The incidence of diabetes mellitus has been increased year by year and now 5-6 millions are diabetic patients in Japan. Studies of DCCT and UKPDS concluded that tight control of diabetes was benefit for prevention of diabetic complications in type 1 and type 2 diabetes, respectively. New type of sulfonylurea (glimepiride) has been developed by Hoechst Marion Roussel company which continues clinical trials in Japan. Grimepiride is an insulin sparing sulfonylurea drug for the treatment of type 2 diabetes patients whose high blood glucose cannot be controlled by diet and exercise alone. In Europe and United State glimepiride has been used as a monotherapy or in combination with insulin. Glucose control was effectively observed in type 2 diabetics including obese and hypertensive patients by the drug. Mechanism of sulfonylurea which stimulates insulin release is supposed by binding to a regulatory subunit of plasma membrane ATP-sensitive K+ (KATP) channel. The consequent closure of KATP channel leads to depolarization, opening of voltage-dependent Ca2+ channels, Ca2+ influx, and a rise in intracellular [Ca2+], resulting in insulin secretion. However, it has been suggested that sulfonylurea may have an additional action on secretion, independent of changes in intracellular [Ca2+] but dependent on the activity of protein kinase C (PKC). It is controversial whether or not sulfonylurea is a risky drug to the process of diabetic macroangiopathy, by suppressing KATP channels in the heart.
 ...
PMID:[Sulfonylurea drug--a new sulfonylurea drug for type 2 diabetes]. 1019 56

The chemical structures, mechanisms of actions, bioavailabilities, insulinotrophic and hypoglycemic actions, and clinical trials of three novel oral hypoglycemic agents, NN-623, A-4166 and KAD-1229 are overviewed. They are non-SU insulin secretagogues and they induce quicker and shorter hypoglycemia than sulphonylureas do, presumably because they are rapidly absorbed into (Tmax: < 30 min) and excreted from blood (T 1/2: < 60 min). They bind to the SU-receptors and suppress K-ATP channels like sulphonylureas do. They stimulate mainly the initial phase of insulin release and evoke a decrease in postprandial rises in plasma glucose in several animals and humans. Clinical trials demonstrated they are efficacious and safe in the treatment of NIDDM subjects. They are useful as a first choice drug for the early stage of NIDDM.
 ...
PMID:[Non-SU, insulin secretagogues]. 1019 57

KATP channels are a newly defined class of potassium channels based on the physical association of an ABC protein, the sulfonylurea receptor, and a K+ inward rectifier subunit. The beta-cell KATP channel is composed of SUR1, the high-affinity sulfonylurea receptor with multiple TMDs and two NBFs, and KIR6.2, a weak inward rectifier, in a 1:1 stoichiometry. The pore of the channel is formed by KIR6.2 in a tetrameric arrangement; the overall stoichiometry of active channels is (SUR1/KIR6.2)4. The two subunits form a tightly integrated whole. KIR6.2 can be expressed in the plasma membrane either by deletion of an ER retention signal at its C-terminal end or by high-level expression to overwhelm the retention mechanism. The single-channel conductance of the homomeric KIR6.2 channels is equivalent to SUR/KIR6.2 channels, but they differ in all other respects, including bursting behavior, pharmacological properties, sensitivity to ATP and ADP, and trafficking to the plasma membrane. Coexpression with SUR restores the normal channel properties. The key role KATP channel play in the regulation of insulin secretion in response to changes in glucose metabolism is underscored by the finding that a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in KATP channel subunits that result in the loss of channel activity. KATP channels set the resting membrane potential of beta-cells, and their loss results in a constitutive depolarization that allows voltage-gated Ca2+ channels to open spontaneously, increasing the cytosolic Ca2+ levels enough to trigger continuous release of insulin. The loss of KATP channels, in effect, uncouples the electrical activity of beta-cells from their metabolic activity. PHHI mutations have been informative on the function of SUR1 and regulation of KATP channels by adenine nucleotides. The results indicate that SUR1 is important in sensing nucleotide changes, as implied by its sequence similarity to other ABC proteins, in addition to being the drug sensor. An unexpected finding is that the inhibitory action of ATP appears to be through a site located on KIR6.2, whose affinity for ATP is modified by SUR1. A PHHI mutation, G1479R, in the second NBF of SUR1 forms active KATP channels that respond normally to ATP, but fail to activate with MgADP. The result implies that ATP tonically inhibits KATP channels, but that the ADP level in a fasting beta-cell antagonizes this inhibition. Decreases in the ADP level as glucose is metabolized result in KATP channel closure. Although KATP channels are the target for sulfonylureas used in the treatment of NIDDM, the available data suggest that the identified KATP channel mutations do not play a major role in diabetes. Understanding how KATP channels fit into the overall scheme of glucose homeostasis, on the other hand, promises insight into diabetes and other disorders of glucose metabolism, while understanding the structure and regulation of these channels offers potential for development of novel compounds to regulate cellular electrical activity.
 ...
PMID:Molecular biology of adenosine triphosphate-sensitive potassium channels. 1020 14

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.
 ...
PMID:The Effect of Glibornuride on Plasma Atrial Natriuretic Factor Levels in Patients with Newly Diagnosed NIDDM. 1040 67

Glucokinase (GK) is expressed in the pancreatic beta-cells and liver, and plays a key role in the regulation of glucose homeostasis. The enzymatic activity and thermal stability of wild-type (WT) GK and several mutant forms associated with maturity-onset diabetes of the young type 2 (MODY-2) were determined by a steady-state kinetic analysis of the purified expressed proteins. The eight MODY-2 mutations studied were Ala53Ser, Val367Met, Gly80Ala, Thr168Pro, Arg36Trp, Thr209Met, Cys213Arg, and Val226Met. These missense mutations were shown to have variable effects on GK kinetic activity. The Gly80Ala and Thr168Pro mutations resulted in a large decrease in Vmax and a complete loss of the cooperative behavior associated with glucose binding. In addition, the Gly80Ala mutation resulted in a sixfold increase in the half-saturating substrate concentration (S0.5) for ATP, and Thr168Pro resulted in eight- and sixfold increases in the S0.5 values for ATP and glucose, respectively. The Thr209Met and Val226Met mutations exhibited three- and fivefold increases, respectively, in the S0.5 for ATP, whereas the Cys213Arg mutation resulted in a fivefold increase in the S0.5 for glucose. These mutations also led to a small yet significant reduction in Vmax. Of all the mutations studied, only the Cys213Arg mutation had reduced enzymatic activity and decreased thermal stability. Two mutants, Ala53Ser and Val367Met, showed kinetic and thermal stability properties similar to those of WT. These mutants had increased sensitivities to the known negative effectors of GK activity, palmitoyl-CoA, and GK regulatory protein. Taken together, these results illustrate that the MODY-2 phenotype may be linked not only to kinetic alterations but also to the regulation of GK activity.
 ...
PMID:Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype. 1042 85

The functional defect of the pancreatic beta cell represents one of the main therapeutic targets in type 2 diabetes mellitus. Among the currently available oral antidiabetic drugs, only hypoglycaemic sulfonylureas exhibit beta cell stimulating properties. However, their use has some limits, particularly those related to the risk of hypoglycaemia and the frequent secondary therapeutic failure. These drugs have largely contributed to the knowledge of the mechanisms of insulin secretion. Besides some galenic modifications of existing sulfonylureas and the development of new drugs of this family with original properties, like glimepiride, the research is essentially focused on drugs derived from the non sulfonylurea moiety of some sulfonylureas, particularly the meglitinide family, which will probably be available for the clinician in the near future. These drugs act however grossly by the same mechanism than sulfonylureas, even if their binding site on a protein coupled with the ATP sensitive K channel appears different. Among the other possible approaches suggested by the theoretical data concerning the mechanisms of insulin secretion, GLP-1 derivatives probably represent good candidates, if stable analogues are developed.
 ...
PMID:[Present status in the treatment of type 2 diabetes mellitus. Insulin-secreting agents]. 1048 Jan 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>