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

The electrical activity of pancreatic beta-cells in 48-h fasted mice has been recorded in vivo. Their electrical activity is exceedingly high at low levels of blood glucose when compared with control animals. For example, at a blood glucose concentration of 4.5 mmol/l, at which beta-cells are permanently hyperpolarized in control animals, fasted animals show continuous spiking activity. In fasted animals, hyperpolarization only occurs at glycemias below 2.2 mmol/l. As in fed animals, the electrical activity in fasted mice can be decreased or suppressed by the injection of diazoxide, indicating the participation of K(ATP) channels. The treatment of fasted animals with nicotinic acid, an inhibitor of lipolysis, produces a decrease in the levels of free fatty acids (FFAs) and a decrease in electrical activity, thereby restoring the dose-response curve for glucose in fasted animals to values close to those found in fed animals. Conversely, the injection of palmitic acid produces an increase in electrical activity without a change in blood glucose. These results point to FFAs as important regulators of electrical activity during fasting in vivo. They also indicate a dissociation of electrical activity and insulin release in fasted animals, since an increase in electrical activity is not associated with increased insulin secretion.
Diabetes 1998 Nov
PMID:Increased levels of free fatty acids in fasted mice stimulate in vivo beta-cell electrical activity. 979 39

We investigated the biological activity of a novel thiazolidinedione (TZD) derivative, KRP-297, and the molecular basis of this activity. When administered to obese Zucker fatty rats (obese rats) at 10 mg/kg for 2 weeks, KRP-297, unlike BRL-49,653, restored reduced lipid oxidation, that is, CO2 and ketone body production from [14C]palmitic acid, in the liver by 39% (P < 0.05) and 57% (P < 0.01), respectively. KRP-297 was also significantly more effective than BRL-49,653 in the inhibition of enhanced lipogenesis and triglyceride accumulation in the liver. To understand the molecular basis of the biological effects of KRP-297, we examined the effect on peroxisome proliferator-activated receptor (PPAR) isoforms, which may play key roles in lipid metabolism. Unlike classical TZD derivatives, KRP-297 activated both PPAR-alpha and PPAR-gamma, with median effective concentrations of 1.0 and 0.8 micromol/l, respectively. Moreover, radiolabeled [3H]KRP-297 bound directly to PPAR-alpha and PPAR-gamma with dissociation constants of 228 and 326 nmol/l, respectively. Concomitantly, KRP-297, but not BRL-49,653, increased the mRNA and the activity (1.5-fold [P < 0.01] and 1.8-fold [P < 0.05], respectively) of acyl-CoA oxidase, which has been reported to be regulated by PPAR-alpha, in the liver. By contrast, KRP-297 (P < 0.05) was less potent than BRL-49,653 (P < 0.01) in inducing the PPAR-gamma-regulated aP2 gene mRNA expression in the adipose tissues. These results suggest that PPAR-alpha agonism has a protective effect against abnormal lipid metabolism in liver of obese rats.
Diabetes 1998 Dec
PMID:A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. 983 14

To explore the role of chronically elevated free fatty acids (FFAs) in the pathogenesis of the hyperproinsulinemia of type 2 diabetes, we have investigated the effect of FFAs on proinsulin processing and prohormone convertases PC2 and PC1/PC3 in MIN6 cells cultured in Dulbecco's modified Eagle's medium with or without 0.5 mmol/l FFA mixture (palmitic acid:oleic acid = 1:2). After 7 days of culture, the percent of proinsulin in FFA-exposed cells was increased (25.9 +/-0.3% intracellular and 75.4 +/- 1.2% in medium vs. 13.5 +/-0.2 and 56.2 +/- 4.1%, respectively, in control cells). The biosynthesis and secretion of proinsulin and insulin were analyzed by comparing the incorporation of [3H]Leu and [35S]Met. In pulse-chase studies, proinsulin-to-insulin conversion was inhibited, and proinsulin in the medium was increased by 50% after 3 h of chase, while insulin secretion was decreased by 50% after FFA exposure. Levels of cellular PC2 and PC3 analyzed by Western blotting were decreased by 23 and 15%, respectively. However, PC2, PC3, proinsulin, and 7B2 mRNA levels were not altered by FFA exposure. To test for an effect on the biosynthesis of PC2, PC3, proinsulin, and 7B2, a protein required for PC2 activation, MIN6 cells were labeled with [35S]Met for 10-15 min, followed by a prolonged chase. Most proPC2 was converted after 6 h of chase in control cells, but conversion was incomplete even after 6 h of chase in FFA-exposed MIN6 cells. Media from chase incubations showed that FFA-exposed cells secreted more proPC2 than controls. Similar inhibitory effects were noted on the processing of proPC3, proinsulin, and 7B2. In conclusion, prolonged exposure of beta-cells to FFAs may affect the biosynthesis and posttranslational processing of proinsulin, PC2, PC3, and 7B2, and thereby contribute to the hyperproinsulinemia of type 2 diabetes. The mechanism of inhibition of secretory granule processing by FFAs may be through changes in Ca2+ concentration, the pH in the secretory granules, and/or other factors that may influence the activation and function of the convertases.
Diabetes 1999 Jul
PMID:Long-term elevation of free fatty acids leads to delayed processing of proinsulin and prohormone convertases 2 and 3 in the pancreatic beta-cell line MIN6. 1038 44

The reasons for the rapidly increasing prevalence of diabetes (NIDDM) among Alaskan Eskimos are only partly understood. This study examines the association of fatty acid metabolism in 68 Alaskan Eskimos with NIDDM or impaired glucose tolerance (IGT) and 386 with normal glucose tolerance > 24 years old. The prevalence of NIDDM was 12% and IGT was 18% in those > 54 years of age and in those < 55 years of age was 3.7% and 3.0%, respectively. Those with abnormal glucose tolerance had lower concentrations of some omega-3 fatty acids (FAs 18:3 omega-3, 20:5 omega-3) and some omega-6 FAs (18:3 omega-6, 20:3 omega-6, 22:4 omega-6) and higher concentrations of palmitic acid (16:0) and oleic acid (18:1 omega-9) than the normo-glycemic participants. These data provide evidence that glucose intolerance and insulin resistance are associated with a deviation from a traditional diet of fish and marine mammals (high in omega-3 FAs and low in saturated fats) to commercial foods (low in omega-3 FAs and high in saturated fats). The low plasma concentrations of the long-chain omega-6 FAs in the glucose impaired may reflect a defect in desaturase activity.
 ...
PMID:Diabetes is related to fatty acid imbalance in Eskimos. 1042 40

The high cytotoxicity of linoleic acid (LA) to cultured bovine lens epithelial cells is correlated with high uptake rates for the fatty acid (FA). Both, LA uptake and LA cytotoxicity strongly increase with the increasing LA-to-albumin molar ratio in the culture medium. Cellular uptake and cytotoxicity of LA can be competitively inhibited with the noncytotoxic palmitic acid. The findings may be of interest in view of the low albumin concentration in aqueous humor, resulting in extremely low buffering capacities for free FAs including LA, oleic acid and other cytotoxic cis-unsaturated free FAs, which are strongly raised in pathological situations like diabetes mellitus.
 ...
PMID:Linoleic acid cytotoxicity to bovine lens epithelial cells: influence of albumin on linoleic acid uptake and cytotoxicity. 1075 40

The aim of the present study was to examine the effect of acute streptozotocin diabetes on the content of different phospholipids and the incorporation of blood-borne 14C-palmitic acid into the phospholipid moieties in the rat liver nuclei. Diabetes was produced by intravenous administration of streptozotocin, and determinations were carried out two and seven days thereafter. Phospholipids were extracted from isolated nuclei and separated into the following fractions: sphingomyelin, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine and cardiolipin. Following that, they were quantified and radioactivity was measured. It was found that, in comparison to non-diabetic controls, two-day diabetes reduced the total content of phospholipids in the nuclei by 9.6%. The content of phospholipids in the nuclei by 9.6%. The content of phosphatidylcholine and phosphatidylserine was reduced and the content of the remaining phospholipids was stable. The specific activity of phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine and cardiolipin, based on radioactivity incorporated from 14C-palmitic acid, was elevated. Seven-day diabetes resulted in a reduction of the total phospholipid content in the nuclei by 39.4%. This was accounted for by a reduction in the content of each phospholipid fraction with the exception of cardiolipin. The specific activity of each phospholipid fraction, was elevated in this group. It is concluded that insulin is involved in the regulation of the nuclear phospholipid content.
 ...
PMID:Diabetes affects phospholipid content in the nuclei of the rat liver. 1106 2

The effects of long-term exposure of a pancreatic beta cell line, INS-1, to major free fatty acids (FFA; palmitic acid, oleic acid and linoleic acid) and leptin on insulin secretion and cell viability by C,N-diphenyl-N'-4,5 dimethylthiazol 2-yl tetrazolium bromide (MTT) assay were examined. The cells were incubated with 1 mmol/l of each FFA and 25 or 100 ng/ml leptin, alone or in combination, for 4, 24 or 48 h before the insulin secretion experiments. Palmitic acid (C 16:0) significantly suppressed cell viability, and suppressed insulin secretion at 24 h. Treatment with oleic acid (C 18:1) or linoleic acid (C 18:2) enhanced basal insulin secretion and diminished glucose-stimulated insulin secretion (GSIS) at 48 h. In these groups, there were no differences in cell viability as compared to cells treated without FFA. Leptin did not affect insulin secretion at 4, 24 and 48 h, and in the cells co-treated with FFA and leptin, leptin did not ameliorate lipotoxicity. These results suggest that, in INS-1 cells, different FFA have different patterns of lipotoxicity with chronic exposure, and leptin has little direct effect on insulin secretion.
Diabetes Res Clin Pract 2001 Jan
PMID:Chronic effects of different fatty acids and leptin in INS-1 cells. 1113 76

Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function observed in type 2 diabetes. Here we examine the effect of saturated and unsaturated fatty acids at different glucose concentrations on beta-cell proliferation and apoptosis. Adult rat pancreatic islets were cultured onto plates coated with extracellular matrix derived from bovine corneal endothelial cells. Exposure of islets to saturated fatty acid (0.5 mmol/l palmitic acid) in medium containing 5.5, 11.1, or 33.3 mmol/l glucose for 4 days resulted in a five- to ninefold increase of beta-cell DNA fragmentation. In contrast, monounsaturated palmitoleic acid alone (0.5 mmol/l) or in combination with palmitic acid (0.25 or 0.5 mmol/l each) did not affect DNA fragmentation. Increasing concentrations of glucose promoted beta-cell proliferation that was dramatically reduced by palmitic acid. Palmitoleic acid enhanced the proliferation activity in medium containing 5.5 mmol/l glucose but had no additional effect at higher glucose concentrations (11.1 and 33.3 mmol/l). The cell-permeable ceramide analog C2-ceramide mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on beta-cell viability. Additionally, palmitic acid but not palmitoleic acid decreased the expression of the mitochondrial adenine nucleotide translocator and induced release of cytochrome c from the mitochondria into the cytosol. Finally, palmitoleic acid improved beta-cell-secretory function that was reduced by palmitic acid. Taken together, these results suggest that the lipotoxic effect of the saturated palmitic acid involves an increased apoptosis rate coupled with reduced proliferation capacity of beta-cells and impaired insulin secretion. The deleterious effect of palmitate on beta-cell turnover is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid does not affect beta-cell apoptosis, yet it promotes beta-cell proliferation at low glucose concentrations, counteracting the negative effects of palmitic acid as well as improving beta-cell function.
Diabetes 2001 Jan
PMID:Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function. 1114 97

Atherosclerosis is a major complication of type 2 diabetes. The pathogenesis of this complication is poorly understood, but it clearly involves production in the vascular wall of macrophage (Mo) lipoprotein lipase (LPL). Mo LPL is increased in human diabetes. Peripheral factors dysregulated in diabetes, including glucose and free fatty acids (FAs), may contribute to this alteration. We previously reported that high glucose stimulates LPL production in both J774 murine and human Mo. In the present study, we evaluated the direct effect of FAs on murine Mo LPL expression and examined the involvement of peroxisome proliferator-activated receptors (PPARs) in this effect. J774 Mo were cultured for 24 h with 0.2 mmol/l unsaturated FAs (arachidonic [AA], eicosapentaenoic [EPA], and linoleic acids [LA]) and monounsaturated (oleic acid [OA]) and saturated FAs (palmitic acid [PA] and stearic acid [SA]) bound to 2% bovine serum albumin. At the end of this incubation period, Mo LPL mRNA expression, immunoreactive mass, activity, and synthetic rate were measured. Incubation of J774 cells with LA, PA, and SA significantly increased Mo LPL mRNA expression. In contrast, exposure of these cells to AA and EPA dramatically decreased this parameter. All FAs, with the exception of EPA and OA, increased extra- and intracellular LPL immunoreactive mass and activity. Intracellular LPL mass and activity paralleled extracellular LPL mass and activity in all FA-treated cells. In Mo exposed to AA, LA, and PA, an increase in Mo LPL synthetic rate was observed. To evaluate the role of PPARs in the modulatory effect of FAs on Mo LPL gene expression, DNA binding assays were performed. Results of these experiments demonstrate an enhanced binding of nuclear proteins extracted from all FA-treated Mo to the peroxisome proliferator-response element (PPRE) consensus sequence of the LPL promoter. PA-, SA-, and OA-stimulated binding activity was effectively diminished by immunoprecipitation of the nuclear proteins with anti-PPAR-alpha antibodies. In contrast, anti-PPAR-gamma antibodies only significantly decreased AA-induced binding activity. Overall, these results provide the first evidence for a direct regulatory effect of FAs on Mo LPL and suggest a potential role of PPARs in the regulation of Mo LPL gene expression by FAs.
Diabetes 2001 Mar
PMID:Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. 1124 88

Several studies support the concept of a diabetic cardiomyopathy in the absence of discernible coronary artery disease, although its mechanism remains poorly understood. We investigated the role of glucose and palmitic acid on cardiomyocyte apoptosis and on the organization of the contractile apparatus. Exposure of adult rat cardiomyocytes for 18 h to palmitic acid (0.25 and 0.5 mmol/l) resulted in a significant increase of apoptotic cells, whereas increasing glucose concentration to 33.3 mmol/l for up to 8 days had no influence on the apoptosis rate. However, both palmitic acid and elevated glucose concentration alone or in combination had a dramatic destructive effect on the myofibrillar apparatus. The membrane-permeable C2-ceramide but not the metabolically inactive C2-dihydroceramide enhanced apoptosis of cardiomyocytes by 50%, accompanied by detrimental effects on the myofibrils. The palmitic acid-induced effects were impaired by fumonisin B1, an inhibitor of ceramide synthase. Sphingomyelinase, which activates the catabolic pathway of ceramide by metabolizing sphingomyeline to ceramide, did not adversely affect cardiomyocytes. Palmitic acid-induced apoptosis was accompanied by release of cytochrome c from the mitochondria. Aminoguanidine did not prevent glucose-induced myofibrillar degeneration, suggesting that formation of nitric oxide and/or advanced glycation end products play no major role. Taken together, these results suggest that in adult rat cardiac cells, palmitic acid induces apoptosis via de novo ceramide formation and activation of the apoptotic mitochondrial pathway. Conversely, glucose has no influence on adult cardiomyocyte apoptosis. However, both cell nutrients promote degeneration of myofibrils. Thus, gluco- and lipotoxicity may play a central role in the development of diabetic cardiomyopathy.
Diabetes 2001 Sep
PMID:Glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in rat adult cardiomyocytes. 1152 78


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