Modulation Of Carbohydrate Metabolism Research Articles

Peripheral Metabolism of Thyroid Hormone and Glucose Homeostasis

Thyroid hormone action has long been recognized as an important determinant of glucose homeostasis. Recent advances in the knowledge of the physiology of the deiodinases indicate that through tissue-specific regulation of thyroid hormone metabolism, leading to local specificity of thyroid hormone action and target gene transcription patterns, they may have an important function in the modulation of carbohydrate metabolism. This review briefly addresses the role of thyroid hormone action on glucose homeostasis with a specific focus on the significance of the peripheral metabolism of thyroid hormone in the regulation of glucose homeostasis and insulin sensitivity.

Phytotherapies for diabetes

Plant medicines (phytotherapies) have a long history as treatments for diabetes. With a disturbing rise in the prevalence of this metabolic disease and associated healthcare costs, interest in alternative or complementary therapies has grown. Over the last 10-20 years, data from controlled investigations in animal models and patients have validated the therapeutic value of numerous phytotherapies for diabetes. Phytotherapies and their combinations demonstrate multiple beneficial antidiabetic mechanisms, including modulation of carbohydrate metabolism, restoration of β-cell integrity and function, insulin-releasing activity, improvements in glucose uptake/utilization, antioxidant properties and a reduction in the risk of cardiovascular disease. However, there is also a misconception that natural remedies are entirely safe. This article summarizes several of the most extensively studied phytotherapies for diabetes and its complications, indicating important associated adverse effects that should be considered when using natural therapies. More than 170 antidiabetic constitutents isolated from over 170 plants are presented.

BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis

Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.

Oxygen-Dependent Regulation of Hepatic Glucose Metabolism

This chapter discusses the oxygen-dependent regulation of hepatic glucose metabolism. Glucose is converted to glucose 6-phosphate by hexokinases, which exist in several isoforms. The glucokinase (GK) represents the major active form of the hexokinases in the liver, whereas hexokinases I–III are operative in the other majororgans. GK expression is restricted to hepatocytes, pancreatic β cells, and some neuroendocrine cells of the gastrointestinal tract. Contrary to other hexokinase family members, the GK has a lower affinity for glucose with sigmoidal kinetics and is not inhibited by its reaction product glucose 6-phosphate. In this study, protocols allowing the measurement of metabolic activities under the control of O 2 , as well as studying the modulatory role of O 2 for gene expression in primary hepatocytes are discussed. Degradation of glucose to acetyl-CoA, the synthesis and degradation of glycogen stores is analyzed. Metabolic zonation of liver, oxygen gradients, and modulation of carbohydrate metabolism by O 2 is elaborated. Preparation and culture of primary hepatocytes is discussed. Transfection of hepatocytes using the calcium-phosphate precipitation and luciferase assay is also described.

Naloxone decreases insulin secretion in hyperinsulinemic postmenopausal women and may positively affect hormone replacement therapy

Objective: To evaluate the influence of the opioid system on glyco-regulation in postmenopausal women before and after hormone replacement therapy (HRT). Design: Prospective nonrandomized clinical study. Setting: Academic research environment. Patient(s): Twenty-one healthy normo- or hyperinsulinemic postmenopausal women. Intervention(s): Oral glucose tolerance test (OGTT) (saline study), OGTT with IV injection of naloxone (naloxone study), and hyperinsulinemic euglycemic clamp performed before treatment, after 12 weeks of estrogen replacement therapy (ERT), and after 12 additional weeks of estro-progestin combined therapy (i.e., HRT). Main Outcome Measure(s): Glucose, insulin, and c-peptide plasma levels assessed in fasting condition and during the two OGTTs (area under the curve [AUC]). Evaluation of fractional hepatic insulin extraction (FHIE) and peripheral sensitivity to insulin. Result(s): At baseline, there is a greater increase of the FHIE and a more significant reduction of the insulin AUC in the hyperinsulinemic patients during the naloxone study compared with the saline study. In these women, ERT enhanced the c-peptide AUC and improved the FHIE; naloxone infusion mainly increased these two parameters. HRT did not induce any further change. Conclusion(s): Endogenous opioid peptides are involved in the modulation of carbohydrate metabolism in menopause in hyperinsulinemic patients more than in other patients. The favorable changes of the glyco-insulinemic metabolism induced by HRT may be partially due to the induction of the opioidergic activity.

Metabolic responses to fructose-1,6-diphosphate in healthy subjects

Fructose-1,6-diphosphate (FDP) is an important naturally occurring intracellular metabolite with a direct regulatory role in many metabolic pathways. The most important and widely studied of the FDP effects has been its regulation of glycolysis, particularly the enzyme that synthesizes FDP--phosphofructokinase (PFK). Since it was observed experimentally that FDP does indeed modulate carbohydrate metabolism, we investigated whether FDP would similarly enhance carbohydrate utilization in man. The study used indirect calorimetry and was open to healthy adults (N = 45) of either sex and above legal age. After a steady metabolic state was obtained, 5 g of FDP (10%) was infused into a brachial vein. In 10 subjects, glucose (5 g) or FDP (5 g) was sequentially infused. The rapid intravenous infusion of FDP produced a slight but significant decrease in heart and respiration rates (P < .05). A significant increase in the serum concentration of inorganic phosphate (P < .0001) and the intraerythrocytic concentration of adenosine triphosphate (ATP) (P < .01) was also observed. The FDP infusion produced a decrease in plasma cholesterol and triglycerides (P < .001 and P < .01, respectively). The indirect calorimetric data indicate that the infusion produced a highly significant increase in the respiratory quotient ([RQ] P < .0001) and the energy derived from carbohydrates (P < .0001) and a significant decrease in the energy derived from lipids (P < .0001). Glucose infusion did not cause changes in any of the parameters. These data indicate that carbohydrate metabolism is stimulated by FDP.

Intercellular signaling in neuronal-glial networks

Glial cells have recently been found to exhibit electrophysiological and metabolic responses to many neurotransmitters and neuromodulators. These findings have focused attention on the possibility that active signaling between neurons and glia could represent an important form of intercellular communication within the brain. Since glial and neuronal networks are both physically and metabolically interlinked, such intercellular signaling may represent a mechanism for inducing collective changes in the cellular physiology of neuronal and glial cell populations. Within the nervous tissue of both vertebrate and invertebrate organisms, glial cells are known to secrete extracellular signal molecules, modulate carbohydrate metabolism, and control the volume and ionic composition of extracellular space. In this paper, the roles that cytoplasmic [Ca2+] transients may play in regulating these glial cell functions are reviewed. Mechanisms by which intracellular Ca oscillations and intercellular Ca waves may be generated in neurotransmitter-stimulated glial cells are also discussed. In addition, it is proposed that rhythmic glial cell contractions and shape changes, which have been observed for many decades, are linked to Ca-induced secretion of ions, water, and neuroactive compounds. These activities represent mechanisms by which Ca-induced changes in glial cell physiology could potentially alter the excitability of neuronal networks.

In vitro autoradiographic localization of amylin binding sites in rat brain

Amylin is a recently discovered 37 amino acid peptide which is co-secreted from the pancreas with insulin and acts to modulate carbohydrate metabolism. Recently, high-affinity binding sites for [ 125I]rat amylin have been identified in the rat central nervous system. These sites also have high affinity for the structurally related peptides calcitonin gene-related peptide and salmon calcitonin. In the present study we have used in vitro autoradiography to map the distribution of these [ 125I]rat amylin binding sites in rat brain. High to moderate levels of binding were present in mid-caudal accumbens nucleus, fundus striati and parts of the bed nucleus of the stria terminalis and substantia inominata. This binding extended caudally into parts of the amygdalostriatal transition zone and the central and medial amygdaloid nuclei. High to moderate levels of binding also occurred in much of the hypothalamus including the medial preoptic, dorsomedial hypothalamic and medial tuberal nuclei as well as the ventrolateral subnucleus of the ventromedial hypothalamic nucleus. Other regions of high level binding included the subfornical organ, the vascular organ of the lamina terminalis, area postrema, locus coeruleus, dorsal raphe and caudal parts of the nucleus of the solitary tract. The subfornical organ, vascular organ of the lamina terminalis and area postrema, which display some of the highest binding densities, lack a patent blood-brain barrier and thus could be responsive to blood-borne amylin. In conclusion we have mapped, in detail, the distribution of amylin binding sites in rat brain. The location of binding is consistent with potential roles for these sites in appetite, fluid and electrolyte homeostasis, autonomie function and regulation of mood.

Effect of acute inhibition of lipolysis on operation of the glucose-fatty acid cycle in hepatic cirrhosis

Hepatic cirrhosis is frequently associated with glucose intolerance and insulin resistance, but the mechanisms underlying the insulin insensitivity are unknown. Plasma concentrations of nonesterified fatty acids (NEFA) are typically elevated in cirrhosis, and the glucose-fatty acid cycle provides a mechanism by which fatty acids may play a role in regulating glucose metabolism. We have therefore investigated the effect of acute inhibition of lipolysis, using the nicotinic acid analogue, acipimox, in 10 male patients with cirrhosis. All subjects were studied in the postabsorptive state after a 10- to 12-hour fast and were given either acipimox 250 mg or a placebo orally 2 hours before a 75-g oral glucose tolerance test (OGTT) and an infusion of insulin (50 mU/kg/h) and glucose (6 mg/kg/min) (insulin sensitivity tests [IST]). The drug was taken in a double-blind crossover design for each test. During the 2 hours following acipimox, there were rapid decreases in plasma NEFA, glycerol, and 3-hydroxybutyrate, confirming inhibition of lipolysis, while there were significant decreases in glucose, insulin, and C-peptide ( P < .001) compared with patients receiving the placebo. Acipimox blunted the increase in glucose after oral glucose loading and decreased incremental glucose concentration (from 579 ± 76 to 445 ± 65 mmol/min/L, P < .02) and incremental insulin concentration (from 13.4 ± 2.5 to 9.0 ± 1.4 U/min/L, P = .056) in the OGTT. Improvements in classification of glucose tolerance were seen in five subjects. During the IST, significant reductions occurred in steady-state blood glucose (to 8.8 ± 1 mmol/L, P < .02) and C-peptide (to 3.0 ± 0.5 nmol/L, P < .05). A significant correlation was seen between the change in NEFA incremental area in the basal period and the change in incremental glucose area of the OGTT, in response to acipimox. Although these findings support the operation of the glucose-fatty acid cycle in cirrhosis, the metabolic clearance for glucose and the insulin sensitivity index were not significantly improved when free fatty acid concentrations were fully suppressed, and thus gross insulin resistance persisted. The modulation of carbohydrate metabolism by short-term changes in NEFA is insufficient to account for the glucose intolerance of cirrhosis.

Co-secretion of amylin and insulin from cultured islet β-cells: Modulation by nutrient secretagogues, islet hormones and hypoglycemic agents

Amylin is a pancreatic islet β-cell peptide hormone which modulates carbohydrate metabolism in skeletal muscle and liver, and could contribute to impaired insulin sensitivity in Type II diabetes. Here we report the first description of amylin secretion from isolated β-cells. We measured amylin secretion from HIT T15 β-cells exposed to glucose, arginine, glucagon, somatostatin, tolbutamide, glyburide, or metformin. With the exception of glucagon at concentrations above 1μM, all compounds induced parallel, dose-dependent changes in secretion of amylin and insulin. We conclude that: 1) insulin and amylin are co-secreted from islet β-cells; (2) nutrient secretagogues and peptide modulators exert direct effects on β-cells to alter amylin and insulin secretion; (3) most modulators of islet β-cell secretion alter amylin and insulin in parallel, but differential secretion can occur; and (4) the HIT cell line is a useful model in which to study amylin metabolism.

Amylin activates glycogen phosphorylase in the isolated soleus muscle of the rat

The pancreatic beta-cell hormone amylin acts in isolated rat skeletal muscle to decrease insulin-stimulated incorporation of glucose into glycogen. It also increases blood levels of lactate and glucose in fasted rats in vivo. However, it remained uncertain whether amylin exerts direct effects to stimulate muscle glycogenolysis. We now report that amylin caused a dose-dependent increase in activity of muscle glycogen phosphorylase in isolated rat soleus muscle by stimulating phosphorylase a. Insulin inhibited amylin-stimulated activation of phosphorylase. Effects of amylin to stimulate muscle glycogenolysis are consistent with observed effects of amylin in vivo and could be a major mechanism whereby amylin modulates carbohydrate metabolism.

Modulation of carbohydrate metabolism in the selected tissues of marine prawn, Penaeus indicus (H. milne edwards), under phosphamidon-induced stress

Changes in carbohydrate metabolism were studied in midgut gland, muscle, and gill tissues of marine prawn Penaeus indicus exposed to a sublethal concentration (0.3 ppm) of phosphamidon. A significant decrease in glycogen and pyruvate and an increase in lactate content were observed in all phosphamidon-exposed prawn tissues after 96 hr. An increase in phosphorylase a and aldolase activity levels suggested the increased formation of triose sugars during phosphamidon toxicity. LDH activity was considerably decreased and an increment in lactate content was observed which indicates reduced mobilization of pyruvate into the citric acid cycle. Glucose-6-phosphate dehydrogenase activity was considerably increased, suggesting the enhanced oxidation of glucose in the hexose monophosphate shunt pathway. Krebs cycle enzymes such as NAD-isocitrate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase were found to be decreased, suggesting the impairment in mitochondrial oxidative metabolism due to the acute toxic impact of phosphamidon. Cytochrome- c oxidase and Mg 2+ ATPase activity levels were also decreased considerably, suggesting impaired energy synthesis and breakdown during phosphamidon toxicity, as a result of reduced oxidation of glucose aerobically. The increase in acid and alkaline phosphatase activities indicates the enhanced breakdown of phosphate to release energy in view of inhibition or impairment in the ATPase system during phosphamidon-induced stress. These results suggest that phosphamidon has a profound effect on the oxidative metabolism of prawn which results in the triggering of compensatory metabolic pathways for survivability.

Tryptophan hydroxylase and aromatic l-amino acid decarboxylase activities in the tissues of adult Ascaris suum

Serotonin (5-hydroxytryptamine, 5-HT) has been shown to modulate carbohydrate metabolism in adult female Ascaris suum. Two enzymes, l-tryptophan hydroxylase (TOH) and aromatic l-amino acid decarboxylase (AADC), which are responsible for the biosynthesis of 5-HT in mammalian systems, were demonstrated in isolated muscle and intestinal tissue of adult female A. suum. The specific activities of TOH in muscle and intestine were 0.22 nmol min −1 g −1 and 1.48 nmol min −1 g −1, respectively. The apparent Michaelis-Menten constant ( Km) and maximum initial velocity ( V max) of TOH for l-tryptophan (TRP) in the intestine were found to be 21.50 μm and 2.30 nmol min −1 g −1, respectively. The specific activities of AADC in the isolated muscle and intestinal tissues were 1.64 nmol mm −1 g −1 and 5.72 nmol min −1 g −1, respectively. The apparent Km and V max of the muscle AADC for l-5-hydroxy-tryptophan (5-HTP) were 10 μM and 3.40 nmol min −1 g −1. The apparent Km and V max of the intestinal AADC for 5-HTP were 1.08 μ M and 14.50 nmol min −1 g −1, respectively. The apparent inhibitor constant ( Ki) of TOH for p-chlorophenylalanine, an inhibitor of mammalian TOH activity, in isolated intestine of A. suum was 1.72 mM. The TOH activity from A. suum intestine was inactivated upon exposure to oxygen and this inactivation could be partially reversed by anaerobic incubation in the presence of dithiothreitol and ferrous sulfide at 25 ° C. Collectively, the data demonstrated the presence of TOH and AADC activities in adult A. suum isolated muscle and intestinal tissues.

Role of Exercise-Training in the Prevention of Hyperinsulinemia Caused by High Energy Diet

The present study was undertaken to determine whether exercise-training done in combination with feeding a high energy diet could modulate carbohydrate metabolism. Male rats were divided into exercise-trained or sedentary groups that received either a palatable high energy diet or merely standard laboratory diet. After 10 weeks of training, the animals were subjected to an intravenous glucose tolerance test. Body weight, epididymal fat pads, and adipocyte volume were reduced following training. The results also showed that exercise-training protects against deterioration of glucose tolerance produced by high energy diet. Training prevented the elevation of basal as well as glucose challenged insulin levels induced by the high energy diet in spite of a high fat as well as high overall energy intake. A highly significant coefficient of correlation (r = 0.78, P < 0.01) was observed between the size of adipocytes and the insulin response to glucose load and suggests that the prevention of hyperinsulinemia in rats fed high energy foods while training could be associated with the ability to prevent obesity.exercise-training high energy diet glucose tolerance insulin

122. Modulation of carbohydrate metabolism in rat uterus by estradiol-17β

122. Modulation of carbohydrate metabolism in rat uterus by estradiol-17β

Relationship of adenosine 3',5'-monophosphate to growth and metabolism of Tetrahymena pyriformis.

The concentration of adenosine 3',5'-monophosphate (cyclic AMP) and the activity of adenylate cyclase were determined for the first time in conjuncation with cyclic 3',5'-nucleotide phosphodiesterase (phosphodiesterase) during the growth cycle of Tetrahymena pyriformis. High levels of cyclic AMP observed during early exponential and late stationary phases were associated with elevated adenylate cyclase and decreased phosphodiesterase activities. Adenylate cyclase and cyclic AMP were decreased and phosphodiesterase was increased in cells grown in glucose-supplemented medium. In contrast to findings in mammalian liver, cyclic AMP was decreased during active gluconeogenesis in Tetrahymena. This suggests a different modulation of carbohydrate metabolism in the two species. The results illustrate that both the content of cyclic AMP and its action as a regulatory agent in Tetrahymena are uniquely suited to the metabolism of this organism.