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)

Cells take up long chain free fatty acids (FFA) in vivo from the non-protein bound ligand pools in extracellular fluid and plasma, which contain approximately 100 and 600 microM albumin, respectively. The physiologic range of unbound FFA concentrations in such fluids has traditionally been calculated at <1 microM. Studies of [3H]-oleate uptake by hepatocytes, adipocytes, cardiac myocytes and other cell types demonstrate that FFA uptake within this range is saturable, and exhibits many other kinetic properties indicative of facilitated transport. Within this range, the uptake kinetics of the acidic (pKa = 0.5) FFA analog alpha2,beta2,omega3-heptafluorostearate are similar to those of stearate. Thus, uptake of physiologic concentrations of FFA involves facilitated transport of the FFA anion (FA). Over a much wider range of unbound FFA concentrations hepatocellular [3H]-oleate uptake exhibits both saturable and non-saturable components. Oleate binding to liver plasma membranes (LPM) also demonstrates such components. Comparing the two components of FFA uptake to the corresponding components of binding permits estimates of trans-membrane transport rates. T1/2 for saturable uptake (approximately 1 sec) is less than for non-saturable uptake (approximately 14 sec). Others have determined the flip-flop rates of protonated FFA (FAH) across small and large unilamellar vesicles (SUV, LUV) and across cellular plasma membranes. These reported flip-flop rates, measured by the decrease in pH resulting from the accompanying proton flux, exhibit a highly significant inverse correlation with cell and vesicle diameter (r = 0.99). Although T1/2's in vesicles are in the msec range, those in cells are >10 sec, and thus comparable to the rates of non-saturable uptake we determined. Thus, under physiologic conditions, the predominant mechanism of cellular FFA uptake is facilitated transport of FA ; at much higher, non-physiologic FFA concentrations, passive flip-flop of FAH predominates. Several plasma membrane proteins have been identified as potential mediators of facilitated FFA transport. Studies in animal models of obesity and non-insulin dependent diabetes mellitus demonstrate that tissue-specific regulation of facilitated FFA transport has important pathophysiologic consequences.
 ...
PMID:Mechanisms of cellular uptake of long chain free fatty acids. 1033 55

Non-insulin-dependent diabetes mellitus is associated with, in addition to impaired insulin release, elevated levels of free fatty acids (FFA) in the blood. Insulin release is stimulated when beta-cells are acutely exposed to FFA, whereas chronic exposure may inhibit glucose-induced insulin secretion. In the present study we investigated the direct effects of long chain acyl-CoA (LC-CoA), the active intracellular form of FFA, on insulin exocytosis. Palmitoyl-CoA stimulated both insulin release from streptolysin-O-permeabilized HIT cells and fusion of secretory granules to the plasma membrane of mouse pancreatic beta-cells, as measured by cell capacitance. The LC-CoA effect was chain length-dependent, requiring chain lengths of at least 14 carbons. LC-CoA needed to be present to stimulate insulin release, and consequently there was no effect following its removal. The stimulatory effect was observed after inhibition of protein kinase activity and in the absence of ATP, even though both kinases and ATP, themselves, modulate exocytosis. The effect of LC-CoA was inhibited by cerulenin, which has been shown to block protein acylation. The data suggest that altered LC-CoA levels, resulting from FFA or glucose metabolism, may act directly on the exocytotic machinery to stimulate insulin release by a mechanism involving LC-CoA protein binding.
 ...
PMID:Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin-secreting cells (HIT T-15 and NMRI beta-cells). 1073 79

In view of the importance of long chain fatty acids (LCFAs) to many cellular processes, it may be desirable to regulate the LCFA disposition in the cell. Such regulation may be present at the level of the plasma membrane, since a number of putative LCFA transport proteins have been cloned. The development of a model system of giant vesicles has proven to be important in identifying the metabolic role of the LCFA transport system. LCFA transport rates and transporters (FABPpm and FAT/CD36) are scaled with oxidative capacity of heart and muscle. FAT/CD36 is a critical LCFA transport protein in muscle. With chronic contraction the increase in this protein also results in an increase in LCFA transport. Most importantly, LCFA transport is also increased acutely by muscle contraction, involving the translocation of FAT/CD36 from intracellular depots to the surface of the muscle cell. The acute (minutes) and chronic (days) regulation of LCFA transporters and transport by muscle may be an important mechanism for LCFA utilization during exercise and adaptable with training and with a metabolic disease such as type 2 diabetes.
 ...
PMID:Fatty acid transport proteins facilitate fatty acid uptake in skeletal muscle. 1107 69

This review considers evidence for, and putative mechanisms of, lipid-induced muscle insulin resistance. Acute free fatty acid elevation causes muscle insulin resistance in a few hours, with similar muscle lipid accumulation as accompanies more prolonged high fat diet-induced insulin resistance in rodents. Although causal relations are not as clearcut in chronic human insulin resistant states such as obesity and type 2 diabetes, it is now recognised that muscle lipids also accumulate in these states. The classic Randle glucose-fatty acid cycle is only one of a number of mechanisms by which fatty acids might influence muscle glucose metabolism and insulin action. A key factor is seen to be accumulation of muscle long chain acyl CoAs, which could alter insulin action via several mechanisms including chronic activation of protein kinase C isoforms or ceramide accumulation. These interactions are fundamental to understanding metabolic effects of new insulin "sensitizers", e.g. thiazolidinediones, which alter lipid metabolism and improve muscle insulin sensitivity in insulin resistant states. Recent work has also pointed to a possible role of lipids in beta cell deterioration ("lipotoxicity") associated with type 2 diabetes.
 ...
PMID:The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity. 1146 May 70

ATP sensitive potassium (K(ATP)) channels reside in the plasma membrane of many excitable cells such as pancreatic beta-cells, heart, skeletal muscle and brain, where they link cellular metabolic energy to membrane electrical activity. They are composed of two subunits, K+ ion selective pore (Kir) and sulfonylurea receptor (SUR). In addition to the central role of pancreatic beta-cell K(ATP) channels in glucose-mediated insulin secretion, several lines of evidence support the hypothesis that K(ATP) channels modulate glucose transport in the insulin target tissues. Inhibition of K(ATP) channels by glibenclamide or gliclazide or an increase in intracellular ATP during hyperglycemia (glucose effect) or exercise facilitates glucose utilization, while activation of the channels by potassium channel openers, hypothermia (cardiac surgery), or ischemic damage (myocardial and brain infarction) reduces glucose uptake induced by insulin or hyperglycemia. Because insulin action has been known to depend on the energy level of the target cells, K(ATP) channel may function as an effector in this respect. It is now evident that long chain acyl-CoA esters, metabolically active forms of fatty acids, are the most potent and physiologically important activator of K(ATP) channels. Thus, I suppose that the sustained activation of K(ATP) channels by long chain fatty acyl-CoA seems to be a missing link between lipotoxicity and insulin resistance in obesity and type 2 diabetes mellitus.
 ...
PMID:Adenosine triphosphate-sensitive potassium (K(ATP)) channel activity is coupled with insulin resistance in obesity and type 2 diabetes mellitus. 1186 13

Fatty acid uptake into 3T3 L1 adipocytes is predominantly transporter mediated. Here we show that, during 3T3 L1 adipocyte differentiation, expression of fatty acid transport proteins (FATPs) 1 and 4 is induced. Using subcellular membrane fractionation and immunofluorescence microscopy, we demonstrate that, in adipocytes, insulin induces plasma membrane translocation of FATPs from an intracellular perinuclear compartment to the plasma membrane. This translocation was observed within minutes of insulin treatment and was paralleled by an increase in long chain fatty acid (LCFA) uptake. In contrast, treatment with TNF-alpha inhibited basal and insulin-induced LCFA uptake and reduced FATP1 and -4 levels. Thus, hormonal regulation of FATP activity may play an important role in energy homeostasis and metabolic disorders such as type 2 diabetes.
 ...
PMID:Insulin causes fatty acid transport protein translocation and enhanced fatty acid uptake in adipocytes. 1197 Aug 97

As knowledge of the fatty acid functions has increased, so has the complexity of making dietary fat recommendations to people with type 2 diabetes. Oleic acid seems to offer a slight advantage over linoleic acid in reducing plasma glucose, insulin levels, total cholesterol, low-density lipoproteins (LDLs), and triglycerides, but may also have atherogenic properties through another mechanism. A diet containing a higher proportion of polyunsaturated fatty acids (PUFAs) may require a concomitant increase in antioxidant intake because PUFAs oxidize easily and are then converted to oxidized LDL, which is more atherogenic. In addition to raising total and LDL cholesterol, long chain saturated free fatty acids may interact with plasma glucose to increase insulin secretion. Omega-3 fatty acids decrease triglycerides and reduce the risk of fatal cardiac arrhythmias. Glycemic control does not appear to be adversely affected by omega-3 fatty acids at amounts of up to 3 g/d.
 ...
PMID:Dietary fats and diabetes mellitus: is there a good fat? 1264 12

Insulin resistance in skeletal muscle is present in humans with type 2 diabetes (noninsulin-dependent diabetes mellitus) and obesity and in rodents with these disorders. Malonyl CoA is a regulator of carnitine palmitoyl transferase I (CPT I), the enzyme that controls the transfer of long chain fatty acyl CoA into mitochondria where it is oxidized. In rat skeletal muscle, the formation of malonyl CoA is regulated acutely (in minutes) by changes in the activity of acetyl CoA carboxylase (ACC), the enzyme that catalyzes malonyl CoA synthesis. ACC activity can be regulated by changes in the concentration of citrate which is both an allosteric activator of ACC and a source of its precursor, cytosolic acetyl CoA. Increases in cytosolic citrate leading to an increase in the concentration of malonyl CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation. In contrast, exercise lowers the concentration of malonyl CoA, by activating an AMP activated protein kinase (AMPK), which phosphorylates and inhibits ACC. Recently we have shown that the activity of malonyl CoA decarboxylase (MCD), an enzyme that degrades malonyl CoA, is also regulated by phosphorylation. The concentration of malonyl CoA in liver and muscle in certain circumstances correlates inversely with changes in MCD activity. This review will describe the current literature on the regulation of malonyl CoA/AMPK mechanism and its physiological function.
 ...
PMID:Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. 1461 57

We examined whether, in human obesity and type 2 diabetes, long chain fatty acid (LCFA) transport into skeletal muscle is upregulated and contributes to an excess intramuscular triacylglycerol accumulation. In giant sarcolemmal vesicles prepared from human skeletal muscle, LCFA transport rates were upregulated approximately 4-fold and were associated with an increased intramuscular triacylglycerol content in obese individuals and in type 2 diabetics. In these individuals, the increased sarcolemmal LCFA transport rate was not associated with an altered expression of FAT/CD36 or FABPpm. Instead, the increase in the LCFA transport rate was associated with an increase in sarcolemmal FAT/CD36 but not sarcolemmal FABPpm. Rates of fatty acid esterification were increased threefold in isolated human muscle strips obtained from obese subjects, while concomitantly rates of fatty acid oxidation were not altered. Thus, the increased rate of fatty acid transport may contribute to the increased rates of triacylglycerol accumulation in human skeletal muscle. The altered FAT/CD36 trafficking in muscle from obese subjects and type 2 diabetics juxtaposes the known alterations in GLUT4 trafficking, i.e., GLUT4 is known to be retained in its intracellular depots while FAT/CD36 is retained at the sarcolemma. This redistribution of FAT/CD36 to the sarcolemma may contribute to the etiology of insulin resistance in human muscle, and hence, FAT/CD36 provides another potential therapeutic target for the prevention and/or treatment of insulin resistance.
 ...
PMID:Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. 1513 77

n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFA), mainly eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3), are present in mammal tissues both from endogenous synthesis from desaturation and elongation of 18:3 n-3 and/or from dietary origin (marine products and fish oils). In rodents in vivo, n-3 LC-PUFA have a protective effect against high fat diet induced insulin resistance. Such an effect is explained at the molecular level by the prevention of many alterations of insulin signaling induced by a high fat diet. Indeed, the protective effect of n-3 LC-PUFA results from the following: (a) the prevention of the decrease of phosphatidyl inositol 3' kinase (PI3 kinase) activity and of the depletion of the glucose transporter protein GLUT4 in the muscle; (b) the prevention of the decreased expression of GLUT4 in adipose tissue. In addition, n-3 LC-PUFA inhibit both the activity and expression of liver glucose-6-phosphatase which could explain the protective effect with respect to the excessive hepatic glucose output induced by a high fat diet. n-3 LC-PUFA also decrease muscle intramyofibrillar triglycerides and liver steatosis. This last effect results on the one hand, from a decreased expression of lipogenesis enzymes and of delta 9 desaturase (via a depleting effect on sterol response element binding protein 1c (SREBP-1c). On the other hand, n-3 LC-PUFA stimulate fatty acid oxidation in the liver (via the activation of peroxisome proliferator activated receptor alpha (PPAR-alpha)). In patients with type 2 diabetes, fish oil dietary supplementation fails to reverse insulin resistance for unclear reasons, but systematically decreases plasma triglycerides. Conversely, in healthy humans, fish oil has many physiological effects. Indeed, fish oil reduces insulin response to oral glucose without altering the glycaemic response, abolishes extraggression at times of mental stress, decreases the activation of sympathetic activity during mental stress and also decreases plasma triglycerides. These effects are encouraging in the perspective of prevention of insulin resistance but further clinical and basic studies must be designed to confirm and complete our knowledge in this field.
 ...
PMID:N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? 1546 Jan 68


1 2 3 4 5 Next >>