malonyl-coenzyme-a and Diabetes-Mellitus--Type-2

It is widely held that although obesity and type 2 diabetes are polygenic in origin, the primary defect causing both conditions is insulin resistance, which in turn gives rise to a constellation of other abnormalities, including hyperinsulinemia, dyslipidemia, glucose intolerance, and (in the genetically predisposed) frank hyperglycemia. Explored here is an alternative, albeit speculative, scenario in which hyperinsulinemia and insulin resistance arise either simultaneously or sequentially from some preexisting defect within the leptin signaling pathway. In either case, a central component of the model is that the breakdown of glucose homeostasis that is characteristic of the condition of obesity with type 2 diabetes is secondary to disturbances in lipid dynamics. The possibility is raised that abnormally high concentrations of malonyl-CoA in liver and skeletal muscle suppress the activity of mitochondrial carnitine palmitoyltransferase I and thus fatty acid oxidation in both sites. It is suggested that the buildup of fat within the muscle cell (caused in part by excessive delivery of VLDLs from the liver) interferes with glucose transport or metabolism or both, producing insulin resistance. Elevated circulating concentrations of fatty acids are also implicated in the etiology of type 2 diabetes by virtue of 1) their powerful acute insulinotropic effect, 2) their ability to exacerbate insulin resistance in muscle, and 3) their long-term detrimental action on pancreatic beta-cell function.

Topics: Animals; Carnitine O-Palmitoyltransferase; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Energy Metabolism; Fatty Acids; Glucose; Humans; Islets of Langerhans; Liver; Malonyl Coenzyme A; Muscles; Obesity

Inhibition of fatty acid oxidation is well recognized as a potentially effective mechanism for controlling glycemia in non-insulin-dependent diabetes mellitus (NIDDM). However, a direct targeting of inhibition of the intramitochondrial beta-oxidation pathway or an indirect modulation of fatty acid oxidation by inhibition of substrate release from adipose stores has been fraught with lack of efficacy, unacceptable side-effects or both. Focus has therefore recently been directed towards the carnitine palmitoyltransferase (CPT) system, a three-component system necessary for the transfer of long-chain fatty acids into the intramitochondrial matrix. This article will briefly review the background for fatty acid oxidation inhibition in NIDDM and then focus on the progress in the biological understanding and drug discovery targeting of the CPT system for the treatment of NIDDM. Based upon the review, it is concluded that mechanism-based hepatic and myocardial toxicities in normal animals and a potential for a lack of human efficacy may pose insurmountable hurdles for the development of CPT inhibitors for the treatment of NIDDM.

Topics: Animals; Carnitine Acyltransferases; Carnitine O-Palmitoyltransferase; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Fatty Acids; Humans; Malonyl Coenzyme A; Mitochondria; Oxidation-Reduction

Widely held theories of the pathogenesis of obesity-associated NIDDM have implicated apparently incompatible events as seminal: 1) insulin resistance in muscle, 2) abnormal secretion of insulin, and 3) increases in intra-abdominal fat. Altered circulating or tissue lipids are characteristic features of obesity and NIDDM. The etiology of these defects is not known. In this perspective, we propose that the same metabolic events, elevated malonyl-CoA and long-chain acyl-CoA (LC-CoA), in various tissues mediate, in part, the pleiotropic alterations characteristic of obesity and NIDDM. We review the evidence in support of the emerging concept that malonyl-CoA and LC-CoA act as metabolic coupling factors in beta-cell signal transduction, linking fuel metabolism to insulin secretion. We suggest that acetyl-CoA carboxylase, which synthesizes malonyl-CoA, a "signal of plenty," and carnitine palmitoyl transferase 1, which is regulated by it, may perform as fuel sensors in the beta-cell, integrating the concentrations of all circulating fuel stimuli in the beta-cell as well as in muscle, liver, and adipose tissue. The target effectors of LC-CoA may include protein kinase C sub-types, complex lipid formation, genes encoding metabolic enzymes or transduction factors, and protein acylation. We support the concept that only under conditions in which both glucose and lipids are plentiful will the metabolic abnormality, which may be termed glucolipoxia, become apparent. If our hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC-CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds and for the fact that it has been difficult to determine whether one or the other is the primary event.

Topics: Acyl Coenzyme A; Animals; Cytosol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Malonyl Coenzyme A; Obesity; Signal Transduction

Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.

Topics: Acetyl-CoA Carboxylase; Adult; Animals; Area Under Curve; Cells, Cultured; Cross-Over Studies; Diabetes Mellitus, Type 2; Dogs; Double-Blind Method; Hepatocytes; Humans; Ketones; Lipogenesis; Male; Malonyl Coenzyme A; Microsomes; Middle Aged; Models, Molecular; Molecular Structure; Rats; Rats, Sprague-Dawley; Rats, Wistar; Structure-Activity Relationship; Young Adult

The molecular mechanisms by which thiazolidinediones improve insulin sensitivity in type 2 diabetes are not fully understood. We hypothesised that pioglitazone would activate the adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway and increase the expression of genes involved in adiponectin signalling, NEFA oxidation and mitochondrial function in human skeletal muscle.. A randomised, double-blind, parallel study was performed in 26 drug-naive type 2 diabetes patients treated with: (1) pioglitazone (n = 14) or (2) aggressive nutritional therapy (n = 12) to reduce HbA(1c) to levels observed in the pioglitazone-treated group. Participants were assigned randomly to treatment using a table of random numbers. Before and after 6 months, patients reported to the Clinical Research Center of the Texas Diabetes Institute for a vastus lateralis muscle biopsy followed by a 180 min euglycaemic-hyperinsulinaemic (80 mU m(-2) min(-1)) clamp.. All patients in the pioglitazone (n = 14) or nutritional therapy (n = 12) group were included in the analysis. Pioglitazone significantly increased plasma adiponectin concentration by 79% and reduced fasting plasma NEFA by 35% (both p < 0.01). Following pioglitazone, insulin-stimulated glucose disposal increased by 30% (p < 0.01), and muscle AMPK and acetyl-CoA carboxylase (ACC) phosphorylation increased by 38% and 53%, respectively (p < 0.05). Pioglitazone increased mRNA levels for adiponectin receptor 1 and 2 genes (ADIPOR1, ADIPOR2), peroxisome proliferator-activated receptor gamma, coactivator 1 gene (PPARGC1) and multiple genes involved in mitochondrial function and fat oxidation. Despite a similar reduction in HbA(1c) and similar improvement in insulin sensitivity with nutritional therapy, there were no significant changes in muscle AMPK and ACC phosphorylation, or the expression of ADIPOR1, ADIPOR2, PPARGC1 and genes involved in mitochondrial function and fat oxidation. No adverse (or unexpected) effects or side effects were reported from the study.. Pioglitazone increases plasma adiponectin levels, stimulates muscle AMPK signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes may represent an important cellular mechanism by which thiazolidinediones improve skeletal muscle insulin sensitivity.. NCT 00816218 FUNDING: This trial was funded by National Institutes of Health Grant DK24092, VA Merit Award, GCRC Grant RR01346, Executive Research Committee Research Award from the University of Texas Health Science Center at San Antonio, American Diabetes Association Junior Faculty Award, American Heart Association National Scientist Development Grant, Takeda Pharmaceuticals North America Grant and Canadian Institute of Health Research Grant.

Topics: Adiponectin; AMP-Activated Protein Kinases; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Diabetic; DNA Primers; Double-Blind Method; Fatty Acids, Nonesterified; Female; Gene Expression Regulation; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemic Agents; Male; Malonyl Coenzyme A; Middle Aged; Mitochondria, Muscle; Pioglitazone; Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones

Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D

Topics: Acetyl Coenzyme A; Adenosine Triphosphate; Animals; ATP Citrate (pro-S)-Lyase; Diabetes Mellitus, Type 2; Hepatocytes; Lipogenesis; Liver; Malonyl Coenzyme A; Mice; Mice, Obese; Palmitates; Sterol Regulatory Element Binding Protein 1

Topics: Adipose Tissue, Brown; Animals; Brain; Diabetes Mellitus, Type 2; Feeding Behavior; Gene Expression; Insulin; Leptin; Liver; Male; Malonyl Coenzyme A; Obesity; Rats, Zucker; Thermogenesis; Thinness

The carnitine palmitoyl transferase (CPT) system is a multiprotein complex with catalytic activity localized within a core represented by CPT1 and CPT2 in the outer and inner membrane of the mitochondria, respectively. Two proteins, the acyl-CoA synthase and a translocase also form part of this system. This system is crucial for the mitochondrial beta-oxidation of long-chain fatty acids. CPT1 has two well-known isoforms, CPT1a and CPT1b. CPT1a is the hepatic isoform and CPT1b is typically muscular; both are normally utilized by the organism for metabolic processes throughout the body. There is a strong evidence for their involvement in various disease states, e.g., metabolic syndrome, cardiovascular diseases, and in diabetes mellitus type 2. Recently, a new, third isoform of CPT was described, CPT1c. This is a neuronal isoform and is prevalently localized in brain regions such as hypothalamus, amygdala, and hippocampus. These brain regions play an important role in control of food intake and neuropsychiatric and neurological diseases. CPT activity has been implicated in several neurological and social diseases mainly related to the alteration of insulin equilibrium in the brain. These pathologies include Parkinson's disease, Alzheimer's disease, and schizophrenia. Evolution of both Parkinson's disease and Alzheimer's disease is in some way linked to brain insulin and related metabolic dysfunctions with putative links also with the diabetes type 2. Studies show that in the CNS, CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning.

Topics: Animals; Brain; Cardiovascular Diseases; Carnitine; Carnitine O-Palmitoyltransferase; Ceramides; Diabetes Mellitus, Type 2; Disease Progression; Eating; Endocannabinoids; Energy Metabolism; Fatty Acids; Humans; Hypoglycemia; Insulin; Learning; Lipid Metabolism, Inborn Errors; Malonyl Coenzyme A; Metabolic Syndrome; Mitochondria; Mitochondria, Liver; Mitochondria, Muscle; Multienzyme Complexes; Neurodegenerative Diseases; Oxidation-Reduction; Protein Isoforms

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an over-nutritioned patient population could be profound. If effective, the mitochondrial uncouple

Topics: Adipose Tissue, Brown; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Malonyl Coenzyme A; Mitochondria; Models, Biological

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.

Topics: Acetyl-CoA Carboxylase; Animals; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Drug Design; Enzyme Inhibitors; Fatty Acids; Humans; Liver; Male; Malonyl Coenzyme A; Mice; Mice, Inbred C57BL; Models, Molecular; Obesity; Rats; Rats, Zucker; Small Molecule Libraries; Structure-Activity Relationship

An elevated lipid content within skeletal muscle cells is associated with the development of insulin resistance and type 2 diabetes mellitus. We hypothesised that in subjects with type 2 diabetes muscle malonyl-CoA (an inhibitor of fatty acid oxidation) would be elevated at baseline in comparison with control subjects and in particular during physiological hyperinsulinaemia with hyperglycaemia. Thus, fatty acids taken up by muscle would be shunted away from oxidation and towards storage (non-oxidative disposal).. Six control subjects and six subjects with type 2 diabetes were studied after an overnight fast and during a hyperinsulinaemic (0.5 mU kg(-1) min(-1)), hyperglycaemic clamp (with concurrent intralipid and heparin infusions) designed to increase muscle malonyl-CoA and inhibit fat oxidation. We used stable isotope methods, femoral arterial and venous catheterisation, and performed muscle biopsies to measure palmitate kinetics across the leg and muscle malonyl-CoA.. Basal muscle malonyl-CoA concentrations were similar in control and type 2 diabetic subjects and increased (p<0.05) in both groups during the clamp (control, 0.14+/-0.05 to 0.24+/-0.05 pmol/mg; type 2 diabetes, 0.09+/-0.01 to 0.20+/-0.02 pmol/mg). Basal palmitate oxidation across the leg was not different between groups at baseline and decreased in both groups during the clamp (p<0.05). Palmitate uptake and non-oxidative disposal were significantly greater in the type 2 diabetic subjects at baseline and during the clamp (p<0.05).. Contrary to our hypothesis, the dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of muscle malonyl-CoA. However, elevated fatty acid uptake in type 2 diabetes may be a key contributing factor to the increase in fatty acids being shunted towards storage within muscle.

Topics: Adult; Blood Glucose; Carbon Isotopes; Case-Control Studies; Diabetes Mellitus, Type 2; Fatty Acids; Female; Glucose; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin Resistance; Lipid Metabolism; Male; Malonyl Coenzyme A; Muscles; Oxidation-Reduction; Palmitic Acid

Increased accumulation of fatty acids and their derivatives can impair insulin-stimulated glucose disposal by skeletal muscle. To characterize the nature of the defects in lipid metabolism and to evaluate the effects of thiazolidinedione treatment, we analyzed the levels of triacylglycerol, long-chain fatty acyl-coA, malonyl-CoA, fatty acid oxidation, AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), malonyl-CoA decarboxylase, and fatty acid transport proteins in muscle biopsies from nondiabetic lean, obese, and type 2 subjects before and after an euglycemic-hyperinsulinemic clamp as well as pre-and post-3-month rosiglitazone treatment. We observed that low AMPK and high ACC activities resulted in elevation of malonyl-CoA levels and lower fatty acid oxidation rates. These conditions, along with the basal higher expression levels of fatty acid transporters, led accumulation of long-chain fatty acyl-coA and triacylglycerol in insulin-resistant muscle. During the insulin infusion, muscle fatty acid oxidation was reduced to a greater extent in the lean compared with the insulin-resistant subjects. In contrast, isolated muscle mitochondria from the type 2 subjects exhibited a greater rate of fatty acid oxidation compared with the lean group. All of these abnormalities in the type 2 diabetic group were reversed by rosiglitazone treatment. In conclusion, these studies have shown that elevated malonyl-CoA levels and decreased fatty acid oxidation are key abnormalities in insulin-resistant muscle, and, in type 2 diabetic patients, thiazolidinedione treatment can reverse these abnormalities.

Topics: Acetyl-CoA Carboxylase; Acyl Coenzyme A; Adult; AMP-Activated Protein Kinases; Carboxy-Lyases; Diabetes Mellitus, Type 2; Fatty Acid Transport Proteins; Fatty Acids; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin Resistance; Lipids; Male; Malonyl Coenzyme A; Middle Aged; Mitochondria, Muscle; Multienzyme Complexes; Muscle, Skeletal; Obesity; Oxidation-Reduction; Protein Serine-Threonine Kinases; Rosiglitazone; Thiazolidinediones; Triglycerides

In obesity, skeletal muscle accumulates triglyceride. Recent work from Hulver and colleagues (2005) in the October issue of Cell Metabolism implicates stearoyl-CoA desaturase as part of the underlying molecular mechanism.

Topics: Carnitine O-Palmitoyltransferase; Diabetes Mellitus, Type 2; Fatty Acids; Glycogen; Humans; Insulin Resistance; Malonyl Coenzyme A; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Oxidation-Reduction; Stearoyl-CoA Desaturase; Triglycerides

Abdominal obesity and physical inactivity are associated with insulin resistance in humans and contribute to the development of type 2 diabetes. Likewise, sustained increases in the concentration of malonyl coenzyme A (CoA), an inhibitor of fatty-acid oxidation, have been observed in muscle in association with insulin resistance and type 2 diabetes in various rodents. In the present study, we assessed whether these factors are present in a defined population of slightly overweight (body mass index, 26.2 kg/m2), insulin-resistant patients with type 2 diabetes. Thirteen type 2 diabetic men and 17 sex-, age-, and body mass index-matched control subjects were evaluated. Insulin sensitivity was assessed during a two-step euglycemic insulin clamp (infusion of 0.25 and 1.0 mU/kg x min). The rates of glucose administered during the low-dose insulin clamp were 2.0 +/- 0.2 vs. 0.7 +/- 0.2 mg/kg body weight x min (P < 0.001) in the control and diabetic subjects, respectively; rates during the high-dose insulin clamp were 8.3 +/- 0.7 vs. 4.6 +/- 0.4 mg/kg body weight x min (P < 0.001) for controls and diabetic subjects. The diabetic patients had a significantly lower maximal oxygen uptake than control subjects (29.4 +/- 1.0 vs. 33.4 +/- 1.4 ml/kg x min; P = 0.03) and a greater total body fat mass (3.7 kg), mainly due to an increase in truncal fat (16.5 +/- 0.9 vs. 13.1 +/- 0.9 kg; P = 0.02). The plasma concentration of free fatty acid and the rate of fatty acid oxidation during the clamps were both higher in the diabetic subjects than the control subjects (P = 0.002-0.007). In addition, during the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in the diabetic patients (P < 0.05 vs. P < 0.001). Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the diabetic subjects. In conclusion, the results confirm that insulin sensitivity is decreased in slightly overweight men with mild type 2 diabetes and that this correlates closely with an increase in truncal fat mass and a decrease in physical fitness. Whether the unexpectedly high levels of malonyl CoA in muscle, together with the diminished suppression of plasma free fatty acid, explains the insulin resistance of the diabetic patients during the clamp remains to be determined.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin Resistance; Male; Malonyl Coenzyme A; Middle Aged; Obesity; Oxidation-Reduction; Physical Fitness