Regulation of glucose metabolism from a liver-centric perspective

Glucose homeostasis is tightly regulated to meet the energy requirements of the vital organs and maintain an individual's health. The liver has a major role in the control of glucose homeostasis by controlling various pathways of glucose metabolism, including glycogenesis, glycogenolysis, glycolysis and gluconeogenesis. Both the acute and chronic regulation of the enzymes involved in the pathways are required for the proper functioning of these complex interwoven systems. Allosteric control by various metabolic intermediates, as well as post-translational modifications of these metabolic enzymes constitute the acute control of these pathways, and the controlled expression of the genes encoding these enzymes is critical in mediating the longer-term regulation of these metabolic pathways. Notably, several key transcription factors are shown to be involved in the control of glucose metabolism including glycolysis and gluconeogenesis in the liver. In this review, we would like to illustrate the current understanding of glucose metabolism, with an emphasis on the transcription factors and their regulators that are involved in the chronic control of glucose homeostasis.

Skeletal Muscle Glycogen Breakdown According to Duration of Endurance Training / 대한스포츠의학회지

Endurance exercise training such as marathon can increase the ability of exercise performance. Muscle glycogen is associated with an exercise performance, because glycogen depletion is primary causes of muscle fatigue. This review summarizes the glycogen saving effect according to duration of endurance exercise training. Long-term endurance exercise-induced mitochondrial biogenesis contributes to glycogen saving effect that is reduced glycogen breakdown and lactate accumulation. Glycogen sparing is due to a smaller decrease in adenosine triphosphate and phosphocreatine and a smaller increase in inorganic phosphate in the working muscles. It takes required endurance exercise training for about 4 weeks or more. Single bout or short-term endurance exercise is not sufficient to bring an increase in functional mitochondria. But peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) increases rapidly after single bout of endurance exercise. PGC-1α downregulates glycogenolytic and glycolytic enzymes to reduce muscle glycogen breakdown and lactic acid accumulation after short-term endurance exercise.

Glucose Homeostasis during Fetal and Neonatal Period / 대한주산의학회잡지

Glucose is essential for energy metabolism in human, especially in brain, and is a source of energy storage in the form of glycogen, fat and protein. During fetal life, the predominant source of energy is also glucose, which crosses the placenta by facilitated diffusion. There is very little endogenous glucose production under normal circumstances during fetal life. During labor, the fetus is exposed to physiological challenges that require metabolic adaptation. A healthy infant successfully manages the postnatal transition by mobilizing and using alternative. After birth, there is a rapid surge in catecholamine and glucagon levels, and a steady decrease in insulin, as blood glucose levels decline. These hormonal changes induce enzyme activities that lead to glycogenolysis and gluconeogenesis. During the first 24-48 hours of life, plasma glucose concentrations of neonates are typically lower than later in life. Distinguishing between transitional neonatal glucose regulation in normal neonates and hypoglycemia that persists or occurs for the first time beyond the first 72 hours of life is important for prompt diagnosis and treatment to avoid serious consequences.

A Case of Hepatocellular Carcinoma in a Patient with Crohn's Disease / 대한내과학회지

Hepatocellular carcinomas (HCCs) in patients with Crohn's disease (CD) without underlying chronic hepatitis or liver cirrhosis are extremely rare. Previously reported cases occurred in patients who had developed CD at a young age and had been treated with immunosuppressive agents long-term. We herein report the first case of HCC in a 34-year-old patient with CD in Korea. The patient was treated with azathioprine for 14 years and had undergone repeated surgeries for CD. During the follow-up period, the patient was hospitalized for colon perforation and pericolic abscess formation. Computed tomography showed a liver mass, and HCC was diagnosed based on liver biopsy. The patient underwent right hemicolectomy for colon perforation and transcatheter arterial chemoembolization followed by radiofrequency ablation for the HCC. The present case is similar to previously reported cases with the exception of the liver pathology findings, which exhibited neither primary sclerosing cholangitis nor focal hepatic glycogenolysis.

A Case of Adult Onset Glycogen Storage Myopathy / 대한임상신경생리학회지

Primary metabolic myopathy as a type of congenital myopathies was first described by McArdle in 1951. Glycogen storage disease is a disease caused by genetic mutations involved in glycogen synthesis, glycogenolysis or glycolysis. Several types of glycogen storage disease are known to cause metabolic myopathies. We report a case of adult onset metabolic myopathy with glycogen storage.

The Impacts of Alcohol Consumption on Glucose Metabolism / 임상당뇨병

The relationship between alcohol consumption and carbohydrate metabolism is complex and is not fully understood. Alcohol not only increases oxidative stress during metabolism, but also inhibits both gluconeogenesis and glycogenolysis in liver. Thus, acute alcohol intake can lead to hypoglycemia, particularly when glycogen stores are depleted or when alcohol is taken without meals. In addition, carbohydrate-rich food taken together with alcohol exaggerates insulin secretion and can cause reactive hypoglycemia about 2 to 3 hours after the meal. It is well established that mild to moderate alcohol consumption (3 drinks/day) is associated with reduced cardiovascular mortality through improvements in insulin sensitivity, lipid profiles, and blood pressure. These beneficial effects of alcohol may also be responsible for a decreased incidence of type 2 diabetes mellitus (T2DM) and a reduced risk of coronary heart disease (CHD) in patients with T2DM. However, excessive alcohol consumption causes higher insulin resistance and increases the risk of T2DM, and even reverses the favorable effects of moderate alcohol intake on CHD.

Arginine vasopressin (AVP) expressional changes in the hypothalamic paraventricular and supraoptic nuclei of stroke-prone spontaneously hypertensive rats / 대한해부학회지

Arginine vasopressin (AVP) is a neuropeptide with vasoconstrictive, antidiuretic, cardiovascular regulative and hepatic glycogenolysis effects, that also affects other behaviors including modulating learning. A number of studies on AVP regulation have been conducted in various metabolic diseases (disorders). In this study, the immunoreactivities of AVP in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) and mRNA expressions in the hypothalamus were investigated by immunohistochemistry and quantitative real-time PCR (RT-qPCR) in stroke-prone spontaneously hypertensive rats at different ages (i.e., at postnatal months [PM] 1, 8, and 12). Blood glucose levels in the PM 8 group were higher than in the other groups. However, cresyl violet positive neurons were detected in the PVN and SON of all animals, and numbers of cresyl violet positive neurons were similar in all aged groups. In addition, AVP immunoreactivity was detected in the PVN and SON of all age groups, and AVP immunoreactivity and mRNA expression levels were found to be increased in proportion to age by immunohistochemistry and RT-qPCR. These results suggest that the diabetic condition is temporally generated after hypertension has developed. Furthermore, our findings suggest that increased AVP expressions in the hypothalamic PVN and SON are associated with hypertension by age.

Effects of different general anesthetics on serum hemolysis and hepatic and muscular glycogenolysis in rats

Anesthetics can affect the structure and biological function of tissues and systems differentially. The aim of the present study was to compare three injectable anesthetics generally used in experiments with animals in terms of the degree of hemolysis and glycogenolysis occurring after profound anesthesia. Twenty-four male Wistar rats (330-440 g) were divided into three groups (N = 8): chloral hydrate (CH), ketamine + xylazine (KX), Zoletil 50® (zolazepam and tiletamine) + xylazine (ZTX). After deep anesthesia, total blood was collected. The liver and white (WG) and red gastrocnemius (RG) muscles were also immediately removed. The degree of serum hemolysis was quantified on the basis of hemoglobin concentration (g/L). Hepatic and muscular glycogen concentrations (mmol/kg wet tissue) were quantified by the phenol-sulfuric method. The CH and KX groups exhibited serum hemolysis (4.0 ± 2.2 and 1.9 ± 0.9 g/L, respectively; P < 0.05) compared to the ZTX group, which presented none. Only KX induced elevated glycogenolysis (mmol/kg wet tissue) in the liver (86.9 ± 63.2) and in WG (18.7 ± 9.0) and RG (15.2 ± 7.2; P < 0.05). The CH and ZTX groups exhibited no glycogenolysis in the liver (164.4 ± 41.1 and 176.8 ± 54.4, respectively), WG (28.8 ± 4.4, 32.0 ± 6.5, respectively) or RG (29.0 ± 4.9; 25.3 ± 8.6, respectively). Our data indicate that ZTX seems to be an appropriate general anesthetic for studies that seek to simultaneously quantify the concentration of glycogen and serum biochemical markers without interferences. ZTX is reasonably priced, found easily at veterinary markets, quickly induces deep anesthesia, and presents a low mortality rate.

Hepatic glycogenosis in a patient with poorly controlled type 1 diabetes mellitus / 소아과

Hepatomegaly and liver dysfunction might develop in patients with diabetes mellitus due to glycogen deposition or nonalcoholic steatohepatitis. We experienced a case of hepatic glycogenosis in a patient with type 1 diabetes mellitus who presented with recurrent hypoglycemia, suggesting impairment of glycogenolysis and gluconeogenesis. A 10-year-old girl with a 4-year history of type 1 diabetes mellitus was admitted because of recurrent hypoglycemia and abdominal pain in the right upper quadrant. She had Cushingoid features and hepatomegaly that extended 6 cm below the right costal margin. Laboratory data and radiologic examination revealed elevated liver enzyme levels due to fatty liver. Periodic acid-Schiff (PAS) staining revealed intense glycogen deposition in the cytoplasm of the hepatocytes and PAS reactivity was lost with diastase treatment. At 2 months after administration of glucagon injection and uncooked cornstarch between meals and at bedtime, the hypoglycemic episodes and liver dysfunction improved. It is important to distinguish hepatic glycogenosis from steatohepatitis, because it is possible to prevent excessive hepatic glycogen storage in hepatic glycogenosis cases by strictly controlling blood glucose level and by glucagon administration. To prevent severe hypoglycemic symptoms accompanied by hepatic glycogenosis, we suggest that uncooked cornstarch, which is effective in maintaining blood glucose level, can also be administered.

Hepatic glycogenosis in a patient with poorly controlled type 1 diabetes mellitus / 소아과

Hepatomegaly and liver dysfunction might develop in patients with diabetes mellitus due to glycogen deposition or nonalcoholic steatohepatitis. We experienced a case of hepatic glycogenosis in a patient with type 1 diabetes mellitus who presented with recurrent hypoglycemia, suggesting impairment of glycogenolysis and gluconeogenesis. A 10-year-old girl with a 4-year history of type 1 diabetes mellitus was admitted because of recurrent hypoglycemia and abdominal pain in the right upper quadrant. She had Cushingoid features and hepatomegaly that extended 6 cm below the right costal margin. Laboratory data and radiologic examination revealed elevated liver enzyme levels due to fatty liver. Periodic acid-Schiff (PAS) staining revealed intense glycogen deposition in the cytoplasm of the hepatocytes and PAS reactivity was lost with diastase treatment. At 2 months after administration of glucagon injection and uncooked cornstarch between meals and at bedtime, the hypoglycemic episodes and liver dysfunction improved. It is important to distinguish hepatic glycogenosis from steatohepatitis, because it is possible to prevent excessive hepatic glycogen storage in hepatic glycogenosis cases by strictly controlling blood glucose level and by glucagon administration. To prevent severe hypoglycemic symptoms accompanied by hepatic glycogenosis, we suggest that uncooked cornstarch, which is effective in maintaining blood glucose level, can also be administered.

A Case Report of Genetically Confirmed Glycogen Storage Disease type Ia / 대한소아신경학회지

Glycogen storage disease(GSD) type Ia is an autosomal recessive disease, caused by the absence or deficiency of glucose-6-phosphatase activity in the liver, kidney, and intestinal mucosa. Glucose-6-phosphatase is an essential enzyme necessary for gluconeogenesis and glycogenolysis. GSD type Ia is characterized by hypoglycemia, lactic acidosis, hepatomegaly, seizures, doll-like faces with fat cheeks, thin extremities, short stature, protuberant abdomen, easy bruising and epistaxis, delayed puberty, early gout, pancreatitis, kidney stone, and other metabolic derangements such as hyperlipidemia. The most important complications of GSD-Ia are focal segmental glomerulosclerosis and hepatic adenomas. Various mutations have been reported. The most common mutation sites are g727t, G122D, and T255I and also P178A and Y128X muations have been reported. We experienced a female patient showing typical clinical characteristics, laboratory findings such as hypoglycemia, hyperuricemia, and hyperlipidemia, and g727t mutation confirmed by DNA analysis. We present this case with a brief review of related articles

Identification of cDNAs of Genes Suppressed during the Process of Atrophy in Rat Skeletal Muscle / 대한정형외과연구학회지

PURPOSE: To elucidate the molecular basis of muscle atrophy in cellular adaptation point of view, gene expression profiling in rat muscle atrophy model was performed. The functions changed by muscle atrophy were analyzed. MATERIAL AND METHODS: Sciatic nerve and femoral nerve were resected in right leg to make muscle atrophy model in rat. The left leg was considered as a compensatory hypertrophy model. The suppression subtractive hybridization (SSH) was done to identify the profile of differential gene expression during muscle atrophy followed by nerve injury in rat. The DNA fragments obtained in SSH were labeled with biotin and used as cDNA tags for isolation of full-length cDNA from cDNA library. Differentially expressed genes were confirmed by reverse dot blot hybridization. RESULTS: Down regulation of genes were much more predominant than up regulation. The profile of down regulated genes were composed of genes coding muscle contractile proteins, enzymes involving carbohydrate metabolism including glycolysis and glycogenolysis, enzymes in oxidative phoshorylation, and proteins related with calcium release. The target genes were isolated by enrichment using cDNA tags from cDNA library for further functional studies. We identified some novel genes related with muscle atrophy by nerve injury. CONCLUSION: During the process of muscle atrophy, genes coding muscle contractile proteins, enzymes in carbohydrate metabolism, enzymes in oxidative phosphorylation, and proteins related with calcium release were down regulated.

Glycogenolysis response to adrenergic agonists in the liver of rats treated with monosodium glutamate (MSG)

Administração de glutamato monossódico (MSG) em ratos neonatos causa lesão no núcleo arqueado (NA), seguido por uma síndrome de disfunção neuroendócrina caracterizada por obesidade e reduzida atividade simpática. O objetivo da presente investigação foi examinar a resposta da glicogenólise hepática a agonistas adrenérgico em ratos tratados com MSG. Ratos Wistar machos receberam injeções subcutâneas de MSG (4 mg g-1 de peso corporal) ou salina equimolar (controles) durante cinco dias após o nascimento. Noventa dias após o tratamento, os fígados de ratos-MSG ou controles foram perfundidos in situ com epinefrina e agonistas alfa- e beta-adrenérgico. Isoproterenol, fenilefrina e epinefrina aumentaram a glicogenólise em ratos-MSG, comparados aos controles (50 ± 2,8 Vs 17 ± 0,89 µmol min-1 g-1 de fígado, p < 0,0001; 64 ± 0,15 Vs 37 ± 0,39, p < 0,0001; 35 ± 2,48 Vs 27 ± 0,98, p < 0,05, respectivamente). Concluiu-se que a lesão do NA aumentou o catabolismo do glicogênio aos agonistas adrenérgicos, possivelmente devido à reduzida atividade do eixo simpático - medula adrenal.

Administration of MSG to neonate rats causes lesions in the arcuate nucleus (AN), followed by a syndrome of neuroendocrine dysfunction characterized by obesity and decreased sympathetic activity. The aim of the present investigation was to examine the responses of hepatic glycogenolysis to alpha and beta-adrenergic agonists in rats? treatment with MSG. Male Wistar rats received subcutaneous injections of MSG (4 mg g-1 body weight) or hyperosmotic saline (controls) during five days after birth. Ninety days after treatment, the livers of the MSG or controls rats were perfused in situ with epinephryne and alpha- and beta-adrenergic agonists. Epinephryne, Isoproterenol and phenylephrine increased glycogenolysis in the MSG-treated rats, compared to the controls (50 ± 2.8 Vs 17 ± 0.89 µmol min-1 g-1 of liver, p < 0.0001; 64 ± 0.15 Vs 37 ± 0.39, p < 0.0001; 35 ± 2.48 Vs 27 ± 0.98, p < 0.05, respectively). Results indicated that the lesion in the AN increased glycogen catabolism to adrenergic agonists, possibly, due to the reduced activity of the sympathetic-adrenal axis.

Sleep-Disordered Breathing and Metabolic Dysfunction / 수면정신생리

Sleep-disordered breathing (SDB) is associated with increased cardiovascular and cerebrovascular morbidity. Epidemiological and clinic-based studies have shown that SDB is related to impaired glucose tolerance and increased insulin resistance, independent of obesity. Despite of a consistent association between SDB and impaired glucose-insulin metabolism, the mechanism underlying this relationship has not been fully elucidated. It is recognized that hypoxemia and hypercapnia that occur in SDB provoke sympathetic nervous activity and catecholamine, epinephrine and norepinephrine, and cortisol are released. Sympathetic hyperactivity and increased catecholamines can impair glucose homeostasis by increasing glycogenolysis and gluconeogenesis, which can result in increased circulating insulin levels and increased risk of insulin resistance. A prospective study is needed to investigate the causal relationship between SDB and impaired glucose-insulin metabolism in a healthy population without diabetes, hypertension and obesity as etiologic risk factors.

A Case of Acromegaly with Diabetic Ketoacidosis and Hypertriglyceridemia-Induced Acute Pancreatitis / 대한내분비학회지

Secondary diabetes mellitus caused by increased growth hormone secretion (GH) has well been known. There is a close association between glucose intolerance and GH secretion, and increased GH level itself probably worsens the blood glucose control and lipid profile by increasing glycogenolysis and / or gluconeogenesis and by suppressing lipase activity. We report a case of acromegaly with diabetic ketoacidosis as and hypertriglyceridemia-induced acute pancreatitis. A 38 year old male, previously diagnosed to have acromegaly and diabetes, presented with nausea, vomiting, diffuse abdominal pain and altered mentality. There was no history of drug or alcohol consumption, blood gas analysis showed severe acidosis and urinanalysis for ketone was positive. His serum blood glucose, amylase and lipase levels were 494 mg/dL, 331 U/L, and 1288 U/L, respectively (reference values: 70~110 mg/dL, 13~100 U/L and 13~190 U/L, respectively). The patient was diagnosed as having diabetic ketoacidosis and acute pancreatitis. With the serum concentration of triglyceride being 1488 mg/dL and the absence of any obvious precipitating factors, we considered hypertriglyceridemia to be the cause of acute pancreatitis. He was treated with continuous intravenous insulin infusion, lipid lowering agent, and fluid replacement. After conservative management, general condition gradually improved and his serum amylase, lipase and triglyceride levels were all normalized. GH level was not suppressed under 2 ng/mL during oral glucose loading test, and basal GH and IGF levels were 231 ng/mL and 29.5 ng/mL, respectively. Sella MRI showed a 3.7 cm sized pituitary mass. On the 55th day of admission, transsphenoidal surgery was performed. In immunohistochemical staining, the pathologic tumor specimen was proved to be GH positive pituitary adenoma. This is the first case reported in the English literature of an acromegaly presenting with diabetic ketoacidosis and acute pancreatitis