Defects In Carbohydrate Metabolism Research Articles

Roles of PINK1 in regulation of systemic growth inhibition induced by mutations of PTEN in Drosophila

The maintenance of mitochondrial homeostasis requires PTEN-induced kinase 1 (PINK1)-dependent mitophagy, and mutations in PINK1 are associated with Parkinson's disease (PD). PINK1 is also downregulated in tumor cells with PTEN mutations. However, there is limited information concerning the role of PINK1 in tissue growth and tumorigenesis. Here, we show that the loss of pink1 caused multiple growth defects independent of its pathological target, Parkin. Moreover, knocking down pink1 in muscle cells induced hyperglycemia and limited systemic organismal growth by the induction of Imaginal morphogenesis protein-Late 2 (ImpL2). Similarly, disrupting PTEN activity in multiple tissues impaired systemic growth by reducing pink1 expression, resembling wasting-like syndrome in cancer patients. Furthermore, the re-expression of PINK1 fully rescued defects in carbohydrate metabolism and systemic growth induced by the tissue-specific pten mutations. Our data suggest a function for PINK1 in regulating systemic growth in Drosophila and shed light on its role in wasting in the context of PTEN mutations.

Bacoside-A diminishes liver functional enzymes and improves carbohydrate metabolic key enzymes in streptozotocin a rat model of T2DM

Abstract Type 2 diabetes mellitus (T2DM) is a global alarming predominant metabolic disease than other diabetes and incurs substantial burden to public and healthcare systems. Our study is designed to endeavor the valuable effect of bacoside-A on hepatic key enzymes of carbohydrate metabolism in streptozotocin (STZ) induced diabetic rats. A single intraperitoneal (i.p) injection of STZ (40 mg/kg body weight [BW]) is administered to adult male Wistar rats for the attainment of diabetes. Diabetic rats were orally treated with bacoside-A of various doses (5, 10 and 20 mg/kg BW) for 45 days. Bacoside-A (10 mg/kg BW) showed more pronounced effect than the other doses and thus resulted in a significant reduction in the level of plasma glucose, glycosylated hemoglobin (HbA1c) and an rise in insulin and hemoglobin levels. Administration of bacoside-A showed significant elevated in the activity of glycolytic enzyme (hexokinase) and hepatic shunt enzyme (glucose-6-phophate dehydrogenase) whereas significant decline in the activity of gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) in diabetic rats. Further, bacoside-A administration to diabetic rats enhanced body weight, liver glycogen content and modulating its metabolizing enzymes (glycogen synthase and glycogen phosphorylase) demonstrated the antihyperglycemic potential of bacoside-A in diabetic rats. Furthermore, hepatic marker enzymes such as aspartate transaminases (AST) and alanine transaminases (ALT) activities significantly decreased in diabetic rats and tend to normalcy in bacoside-A treated diabetic rats. Glibenclamide, a reference drug. In conclusion, our data explicated the bacoside-A, a promising antidiabetic agent which infers in modulating hepatic key enzymes by preventing defect in carbohydrate metabolism against T2DM.

Antihyperglycemic effect of syringic acid on attenuating the key enzymes of carbohydrate metabolism in experimental diabetic rats

Diabetes mellitus is one of the most common endocrine entities, which coexist with defect in carbohydrate metabolism. The Indian traditional system of medicine prescribed plant phytochemical therapies for diseases including diabetes mellitus. The present study was aimed to evaluate the therapeutic potential of syringic acid (SA) by assaying the activities of key enzymes of carbohydrate metabolism in experimental diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitoneal administration of alloxan (150mg/kg). SA was administered to diabetic rats intragastrically at 25, 50 and 100mg/kg b.w daily once for 30days. The levels of plasma glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA1c) and glycogen, levels of carbohydrate metabolic enzymes, liver and kidney markers were evaluated. Oral administration of SA (50mg/kg) for 30days, dose dependently improved the glycemic status in diabetic rats. The levels of insulin, Hb and glycogen increased with significant decrease in glucose and HbA1c levels in SA treated rats. The altered activities of carbohydrate metabolic enzymes, hepatic and renal marker were restored to near normal. Histopathological analysis of pancreas revealed that treatment with SA reduced the pancreatic damage induced by alloxan and stimulated β-cell regeneration in diabetic rats. The present findings suggest the antihyperglycemic effect of SA and its therapeutic potential for the management of diabetes.

Role of genetic modifiers in Lafora progressive myoclonus epilepsy-a neurodegenerative disorder with defects in carbohydrate metabolism

Lafora progressive myoclconus epilepsy, also known as Lafora disease (LD), is the most severe and fatal form of progressive myoclonus epilepsy with its typical onset during the late childhood or early adolescence. LD is characterised by the presence of abnormal glycogen inclusions – called the polyglucosan bodies – in the neurons and various other affected tissues. Therefore defects in the glycogen metabolism have been suspected to underlie neuropathology in LD. The two genes known for LD have been extensively characterized; these are the EPM2A and NHLRC1 genes, coding for a protein phosphatase (named laforin) and an E3 ubiquitin ligase (named malin) respectively. Laforin and malin interact with each other and as a complex participate in diverse cellular pathways. The pathways include glycogen metabolism, endoplasmic reticulum (ER) stress, ubiquitin-proteasome pathways and in heat shock response. A number of disease causing mutations, more than 100 of them, are known in EPM2A and NHLRC1and several studies have looked at possible genotype-phenotype correlations in the LD families. The factors other than the defective LD gene could possibly be involved in modifying the disease onset or the progression in some cases. Indeed, a recent study demonstrates that a sequence variant in the PPP1R3C gene coding for the protein targeting to glycogen (PTG) contributes to the milder course of LD. It would be therefore important to check possible contributions of sequence variations in critical regulators of these pathways which interact with laforin and/or malin and test their possible role as modifiers in LD. Here we have extensively reviewed the literature and list potential modifier genes for LD, their cellular functions, and propose their possible effect in LD. Validating these hypothesis will help us in identifying “druggable targets” for delaying the onset and/or the severity of LD if not its treatment.

Mutation analysis of the GLUT2 gene in three unrelated Egyptian families with Fanconi–Bickel syndrome: revisited gene atlas for renumbering

Fanconi-Bickel syndrome (FBS) is an autosomal recessive disorder caused by defects in the facilitative glucose transporter 2 (GLUT2 or SLC2A2) gene which codes for the glucose transporter protein 2 expressed in hepatocytes and renal tubular cells causing a defect in carbohydrate metabolism, hepatomegaly, severe hypophosphatemic rickets and failure to thrive. Among 17 unrelated Egyptian families with heritable renal tubular acidosis, three families clinically suspected as FBS were enrolled for this study after providing written informed consent. The three families had positive consanguinity and index cases with characteristic clinical features of FBS (hepatorenal glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy). Laboratory work-up included urinalysis, renal and liver function tests, fasting and postprandial blood sugar, serum calcium, phosphorus, alkaline phosphatase, sodium and potassium, lipid profile and arterial blood gas analysis. Imaging studies included bone survey and abdominal ultrasound. Liver biopsy was performed to confirm pathological diagnosis of the liver enlargement. Molecular analysis was performed for all family members-polymerase chain reaction followed by direct sequencing of the coding segments as well as the flanking introns. Three different mutations were detected, one specific for each family, including two new mutations. In the first family, exon 3, two bases (GA) were deleted (c.253_254delGA causing a frameshift mutation (p. Glu85fs); the patient presented with early symptoms but unfortunately died despite adequate treatment. In the second family, a mutation was found in exon 6, in the splicing acceptor site with intron 5 (c.776-1G>C or IVS5-1G>A). The third family showed a missense mutation C-to-T substitution at c.1250 (c.1250C>T) causing change of codon 417 (CCG) for proline to CTG for leucine (p. P417L); this is a well-known mutation in the Arab population previously localized in exon 9; however, it is currently renumbered to exon 10. Neither the new mutations nor the reported one were particularly more frequent; however, the third mutation (c.1250C>T) needs more attention in survey studies especially if performed in Arab patients as it has been renumbered because of the 'change' of gene structure since the initial reports.

The Δ9 Fatty Acid Desaturation Index as a Predictor of Metabolic Disease

There is a tremendous need for improved biomarkers that can be used in the clinical setting to aid in the early detection of metabolic diseases. Of particular interest is the metabolic syndrome, or insulin resistance syndrome, a condition that is often clinically diagnosed as a cluster of risk factors including abdominal obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, impaired glucose tolerance, and increased fasting glucose (1)(2). This constellation of phenotypes greatly increases the risk for the development of chronic conditions such as diabetes and several cardiovascular diseases. The root cause of the metabolic syndrome is insulin resistance, a condition in which the pancreas increases insulin secretion to compensate for the decreased ability of insulin-sensitive tissues to perform insulin-stimulated glucose uptake to maintain euglycemia (1). Therefore, the development of new tests that focus on the early detection of insulin resistance could help identify at-risk patients so that the benefits of lifestyle and pharmacological interventions can be maximized and progression to overt metabolic disease can be prevented. Insulin resistance is not limited to defects in carbohydrate metabolism, but is also associated with major perturbations in lipid metabolism (2). For example, adipocytes increase the release of free fatty acids (FFA)1 into the circulation, resulting in subsequent FFA uptake by the liver and other peripheral tissues, processes that may further exacerbate insulin resistance (2)(3). Although hepatic insulin resistance contributes to hyperglycemia by causing an inappropriate elevation in hepatic glucose production, the branch of insulin signaling responsible for stimulating de novo fatty acid biosynthesis in the liver remains intact (2)(4). Additionally, high-carbohydrate diets, especially those enriched in rapidly absorbed refined carbohydrates such as glucose and fructose, are able to potently stimulate de novo lipogenesis (DNL) (5). The effects of insulin and dietary carbohydrate occur via the transcriptional activation of …

Index of Suspicion

Index of Suspicion

Letters to the Editor

Letters to the Editor

A defect in carbohydrate metabolism ameliorates symptom severity in virus-infected Arabidopsis thaliana

Altered starch accumulation is a characteristic biochemical symptom of virus infection in plants. To assess its biological importance, infection of Arabidopsis thaliana with Turnip vein-clearing virus, Cucumber mosaic virus or Cauliflower mosaic virus was investigated in plants grown under continuous illumination (under which there is no net breakdown of starch) and in pgm1 mutant plants lacking chloroplastic phosphoglucomutase, an enzyme required for starch biosynthesis. Virus-infected wild-type plants grown under continuous light exhibited more severe leaf symptoms, but no reduction in growth compared with plants grown under diurnal illumination. Comparing lines grown in perpetual light, pgm1 mutant plants displayed less severe symptoms than the wild-type controls. However, accumulation of all three viruses was similar in wild-type and mutant plants and was unaffected by the light regime. The results show that, although changes in starch accumulation during infection are not required for successful viral infection, carbohydrate metabolism does influence symptom development.

MENSTRUAL DISORDERS IN ADOLESCENTS: Excess Androgens and the Polycystic Ovary Syndrome

The fundamental clinical features of PCOS include hirsutism and menstrual irregularities from the time of menarche. Obesity is present in approximately 50% of these patients, some of whom also carry a diagnosis of NIDDM. The biochemical abnormalities associated with the clinical picture include LH hypersecretion, hyperandrogenism, acyclic estrogen production, subnormal SHBG levels, and hyperinsulinemia. Hirsutism usually progresses slowly in patients with PCOS; however, the clinical presentation can resemble virilizing tumors, late-onset CAH, or Cushing syndrome. Virilization or rapidly progressive hirsutism requires immediate investigation to rule out a virilizing tumor. Goals of therapy for teenage patients include decreasing levels of bioavailable androgen, blockade of androgen action at target tissues, stabilization of the endometrium, and reduction of insulin resistance. Although the original description of PCOS by Stein and Leventhal was published in 1935, the cause of PCOS remains unknown. This reason, coupled with the fact that PCOS-related insulin resistance is an important cause of NIDDM in women, has caused this disorder to become one of interest and active investigation. Future research will likely be able to delineate mechanisms behind the defects of carbohydrate metabolism and ascertain large multigeneration kindreds for linkage analyses to identify affected genes. Future studies are also likely to confirm whether young women with PCOS are at increased risk for cardiovascular disease and other long-term health complications. As new pathophysiologic mechanisms are identified, the promise of new therapies arises, including treatments that could potentially reduce the long-term incidence of adverse health consequences.

Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis*

It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose. To date, no underlying enzymatic defect in carbohydrate metabolism has been identified. Therefore, and because of the impairment of both glucose and galactose metabolism, a primary defect of monosaccharide transport across membranes has been suggested. Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel. Homozygous mutations were found in affected individuals, whereas all parents tested were heterozygous for the respective mutation. Because all detected mutations (delta T446-449, C1251T and C1405T) predict truncated translation products that cannot be expected to have functional monosaccharide transport activity, GLUT2 mutations are probably the cause of FBS.

Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors

Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors

O-linked carbohydrate of recombinant von Willebrand factor influences ristocetin-induced binding to platelet glycoprotein 1b.

By transfecting the full-length cDNA for human von Willebrand factor (vWf) into a line of Chinese hamster ovary cells with a defect in carbohydrate metabolism, we have prepared recombinant vWf specifically lacking O-linked carbohydrates. We have compared this under-glycosylated protein to fully glycosylated recombinant vWf with respect to several structural and binding properties. vWf deficient in O-linked glycans was synthesized, assembled into multimers, and secreted in an apparently normal manner and was not prone to degradation in the extracellular milieu. It did not differ from fully glycosylated vWf in ability to bind to heparin or to collagen type I but did interact less well with glycoprotein 1b on formalin-fixed platelets. This decreased interaction was evidenced in both a lessened overall binding to platelets and in diminished capacity to promote platelet agglutination, in the presence of ristocetin. In contrast, no difference was seen in platelet binding in the presence of botrocetin. These data indicate a possible role for O-linked carbohydrates in the vWf-glycoprotein 1b interaction promoted by ristocetin and suggest that abnormalities in carbohydrate modification might contribute to the altered ristocetin-dependent reactivity between vWf and platelets described for some variant forms of von Willebrand disease.

The role of chemicals in the etiology of diabetes mellitus.

Diabetes mellitus is a collection of diseases that culminate in defects in carbohydrate metabolism and result in inappropriate hyperglycemia. Most individuals with this disease can be categorized into 1 of 2 groups, depending upon their insulin requirements. Individuals who require insulin therapy to maintain life have been designated as having insulin-dependent diabetes mellitus (IDDM), while individuals who can live without insulin treatment have been classified as having noninsulin-dependent diabetes mellitus (NIDDM). The single most important pathological finding in IDDM is a substantial reduction in the number of insulin-secreting pancreatic beta cells. Compelling experimental and epidemiological evidence indicates that, at least in some forms of IDDM, environmental factors, such as chemical toxins, play an important role in the etiology of this disease. Chemical toxins can precipitate IDDM through a variety of mechanisms. They can poison beta cells directly and cause the destruction of a critical mass of beta cells; alternatively, they can trigger autoimmune processes directed against beta cells; or, finally, they can augment the diabetogenic properties of another agent, such as a virus, to hasten the onset of clinical manifestations. In NIDDM, impaired beta cell function appears to be the initial event observed at the onset of this syndrome. Functional defects similar to those seen in NIDDM can be produced in laboratory animals using a specific beta cell toxin. These animals develop permanent glucose intolerance and insulin resistance as a consequence of beta cell alteration. A variety of other chemicals also have been found to produce glucose intolerance; however, this condition is transient and is resolved when the chemical is removed.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal expression of a lethal genetic defect in carbohydrate metabolism in mice.

Mouse fetuses homozygous for the lethal cab (cardiac abnormal) mutation are characterized by pleiotropic effects that lead to immediate postnatal death. Mutant fetuses have only 4% of the normal amount of hepatic glycogen and 39% of the normal cardiac glycogen reserve, coupled with lower specific activities of glycogen synthase and phosphorylase. Analysis with the periodic acid-Schiff reagent histochemical stain demonstrated that cab homozygotes also have reduced amounts of structural polysaccharides. One of the most distinctive mutant phenotypic traits is severe prenatal hypoglycemia, with average (+/-SEM) plasma glucose concentrations of 0.35 +/- 0.14 mM in late fetuses compared to 3.47 +/- 0.69 mM in normal littermates. Compromise of glucose transport from dam to fetus or altered cellular glucose utilization was considered as a possible basis for the low extracellular and intracellular (hepatic) levels of glucose in mutants. Transport of the glucose analogue alpha-methyl[14C]glucoside by the placenta of cab homozygotes is normal. However, metabolism of [14C]glucose by mutant cells yields only 20% of the normal amount of 14CO2. This reduced efficiency of glucose metabolism is correlated with lower ATP concentrations in mutant organs. Aberrant glucose utilization may account for the pleiotropic features of the cab syndrome.

The lectin binding affinity of Reed-Sternberg cells.

Reed-Sternberg cells from ten cases of Hodgkin's disease were examined by the direct immunofluorescence technique, for their affinity for nine lectins. The surrounding lymphocytes and monocytes of HD tissue were also assessed for their ability to bind lectins. RS cells showed considerable heterogeneity of reaction. Overall, there was a marked decrease in the binding of most of the lectins studied in HD cases as compared to normal peripheral blood mononuclear cells. This was particularly evident for RCA, PHA and PNA binding. It is suggested that there is a defect in carbohydrate metabolism, with fewer lectin-binding sites on both RS cells and on the mononuclear cell populations in Hodgkin's disease. Further quantitative work is required to verify this.

Stoffwechselstörungen und Hornhautveränderungen

The following inborn errors of metabolism may show corneal changes: A. Inborn errors of metabolism affecting the corneal epithelium: (1) familial dysautonomia, (2) tyrosinaemia type II, (3) Fabry's glycolipidosis. B. Inborn errors of metabolism affecting the corneal stroma: I. Localized amyloidosis (lattice dystrophy of the cornea), II. Defects in carbohydrate metabolism: (1) localized mucopolysaccharidosis (macular dystrophy of the cornea), (2) systemic mucopolysaccharides, (3) glycogen storage disease. III. Defects in lipid metabolism: (1) localized from (Schnyder's crystalline dystrophy), (2) systemic forms (hyperlipoproteinaemia, hypolipoproteinaemia, Lecithin-cholesterol acyl transferase deficiency, Wolman's disease, Gaucher's disease). IV. Combined defects in lipid and carbohydrate metabolism (mucolipidoses). V. Other inherited metabolic disorders: (1) aminoacidopathies (cystinosis, Wilson's disease, ochronosis, Chediak-Higashi syndrome), (2) hemochromatosis.

FAMILIAL HEMOCHROMATOSIS

Ffty asymptomatic members of a kindred with familial hemochromatosis were studied in an effort to clarify some of the physiologic abnormalities present in the pre-cirrhotic or latent stage of the disease. Using excess hepatic iron as a marker for inheritance of hemochromatosis, results of liver biopsies on 31 family members suggest an auto-somal dominant mode of inheritance with incomplete expressivity. In addition to a relationship between alcohol intake and excess liver iron, there was a strong association between the level of alcohol intake and the presence of hepatic fibrosis in those subjects with excess iron stores. Both serum iron and transferrin saturation were significantly higher in family members with iron overload than in those who were not affected. Only transferrin saturation was significantly correlated with the severity of hepatic iron deposition. Studies of glucose tolerance (OGTT, IVITT, glucose clamp studies) demonstrated a defect in carbohydrate metabolism associated with deficient insulin secretion and insulin resistance, both of which were related to the degree of hepatic iron depostion. In this kindred we have found no evidence for a contribution of inheritance to the carbohydrate intolerance of hemochromatosis. Iron overload was not related to activity of hepatic collagen proline hydroxylase or urinary excretion of peptide-bound hydroxyproline. Serum ferritin, previously thought to be a reliable marker of reticuloendothelial iron stores, was normal in 19 of 20 family members with iron overload.

Renal cortical and hepatic phosphoenolpyruvate carboxylase in the diabetic rat: Effect of acid-base status

Phosphoenolpyruvate (PEP) carboxylase activity was determined in renal cortex and liver from diabetic rats given NaCl (acidotic) or NaHCO 3 (nonacidotic) and in normal animals given ammonium chloride or NaHCO 3. When compared with control animals, diabetic acidosis increased PEP carboxylase activity in both liver and renal cortex. Sodium bicarbonate administration to diabetic animals returned renal cortical enzyme activity to control levels, but failed to influence enzyme activity in liver. The increase in renal cortical PEP carboxylase activity following induction of acidosis with ammonium chloride in normal animals or in insulin-treated diabetic animals was similar, for any given reduction in plasma carbon dioxide, to that found during spontaneous diabetic acidosis. It is concluded that the increase in hepatic PEP carboxylase present during diabetes is secondary to the defect in carbohydrate metabolism and independent of the changes in acid-base status. In renal cortex, on the other hand, the increase in PEP carboxylase during diabetes is secondary to the associated acidosis and independent of the defect in carbohydrate metabolism.