The effect of Psidium guajava aqueous leaf extract on liver glycogen enzymes, hormone sensitive lipase and serum lipid profile in diabetic rats.

Diabetes mellitus is characterized by hyperglycaemia that results from defects in insulin secretion or insulin action and is accompanied by general disturbances metabolism. Psidium guajava (PG) leaf is known to have antidiabetic effects that include lowering of blood glucose. The aim of the study was to investigate the effect of PG leaf extract on tissue activity of glycogen synthase (GS) and glycogen phosphorylase (GP); tissue activity of hormone sensitive lipase (HSL); serum lipid profile; and serum enzyme biomarkers of tissue damage. Diabetes was induced in male Sprague-Dawley rats with a single dose of 40 mg/kg body weight streptozotocin. The aqueous extract of PG leaves was used to treat both normal and diabetic animals (400 mg/kg body weight) for 2 weeks while control animals were treated with the vehicle. At the end of the treatment period, blood, liver and adipose tissue samples were collected from the euthanized animals. The results show that PG extract significantly decreased (P < 0.05) HSL activity in adipose tissue and liver of diabetic animals which was accompanied by increased glycogen levels, reduced serum triglycerides, total cholesterol, LDL-cholesterol and increased HDL-cholesterol. This study demonstrates that P. guajava has significant anti-diabetic effects that include increased glycogen storage and reduced HSL activity in the liver and adipose tissue with an improved serum lipid profile.

Silibinin decreases hepatic glucose production through the activation of gut-brain-liver axis in diabetic rats.

Silibinin, a flavonolignan derived from milk thistle (Silybum marianum), has been revealed to have a beneficial effect on improving diabetes-impaired glycemic control. However, the underlying mechanism is still unclear. In the present study, to evaluate whether the gut-brain-liver axis, an important neural pathway for the control of hepatic glucose production, is involved in silibinin-regulated glucose homeostasis, the expression of glucagon-like peptide-1 receptor (GLP1R) in the duodenum, activation of neurons in the nucleus of the solitary tract (NTS), as well as glycogen accumulation and expression of gluconeogenic enzymes in the livers of diabetic SHRSP·Z-Leprfa/IzmDmcr (SP·ZF) rats with 4-week oral administration of silibinin (100 and 300 mg kg-1 day-1) were evaluated. Common hepatic branch vagotomy was further conducted in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic SD rats to confirm the role of the gut-brain-liver axis in silibinin-improved glycemic control. The results revealed a significant inhibition of fasting blood glucose after SP·ZF rats were administrated with silibinin for 4 weeks. The expression of GLP1R in the duodenum and the activation of neurons in the NTS increased, while hepatic glucose production decreased on silibinin administration. However, the hypoglycemic effect of silibinin was reversed by common hepatic branch vagotomy in diabetic SD rats. Our study suggested that silibinin may be useful as a potential functional food ingredient against diabetes by triggering the gut-brain-liver axis.

Effects of insulin deficiency or excess on hepatic gluconeogenic flux during glycogenolytic inhibition in the conscious dog.

The direct acute effects of insulin on the regulation of hepatic gluconeogenic flux to glucose-6-phosphate (G6P) in vivo may be masked by the hormone's effects on net hepatic glycogenolytic flux and the resulting changes in glycolysis. To investigate this possibility, we used a glycogen phosphorylase inhibitor (BAY R3401) to inhibit glycogen breakdown in the overnight-fasted dog, and the effects of complete insulin deficiency or a fourfold rise in the plasma insulin level were assessed during a 5-h experimental period. Hormone levels were controlled using somatostatin with portal insulin and glucagon infusion. After the control period, plasma insulin infusion 1) was discontinued, creating insulin deficiency; 2) increased fourfold; or 3) was continued at the basal rate. During insulin deficiency, glucose production and the plasma level and net hepatic uptake of nonesterified free fatty acids increased, whereas during hyperinsulinemia they decreased. Net hepatic lactate uptake increased sixfold during insulin deficiency and 2.5-fold during hyperinsulinemia. Net hepatic gluconeogenic flux increased more than fourfold during insulin deficiency but was not reduced by hyperinsulinemia. We conclude that in the absence of appreciable glycogen breakdown, an acute gluconeogenic effect of hypoinsulinemia becomes manifest, whereas inhibition of the process by a physiologic rise in insulin was not evident.

Glucagon-like peptide-1 inhibits glucagon-induced glycogenolysis in perivenous hepatocytes specifically.

Hepatocytes form the hepatic acinus as a unit of microcirculation. Following the bloodstream, at least two different zones can be discerned: the periportal (PPH) and the perivenous (PVH) zones. Recently, we found that insulin inhibits glucagon-induced glycogenolysis in PVH specifically. We therefore investigated the region-specific functional effects of glucagon-like peptide-1 (GLP-1), which is known to have an insulin-like activity, on glucagon-induced glycogenolysis in isolated PPH and PVH prepared by the digitonin-collagenase method. GLP-1 inhibited 0.1 nM glucagon-induced increase in glucose release from the PVH of fed rats specifically (p < 0.01) and had an additive effect with insulin. Insulin binding did not differ between PPH and PVH of fed rats. GLP-1 did not displace [125I]-glucagon binding to the purified hepatic cell membrane. Thus, it is directly confirmed that GLP-1 has an insulin-like activity in the liver.

Pharmacological activities of a new glycosaminoglycan, acharan sulfate isolated from the giant African snail Achatina fulica.

Acharan sulfate (AS) is a glycosaminoglycan (GAG) prepared from the giant African snail, Achatina fulica. In this study, some biological activities of AS were evaluated on the basis of structural similarities to heparin/heparan sulfate and the biological functions of GAGs. We demonstrated that it exhibited strong immunostimulating activities as measured by carbon clearance test in mice and in vivo phagocytosis. It also exhibited a significant hypoglycemic activity in epinephrine (EP)-induced hyperglycemia as well as antifatigue effects by weight-loaded forced swimming test. And it showed hypolipidemic activities in cholesterol-rich mixture induced hyperlipidemia in rats. The above results indicate that AS has diverse biological activities and suggest therapeutically important target molecules.

Glycogen phosphorylase inhibitor N-(3,5-dimethyl-Benzoyl)-N'-(ß-D-glucopyranosyl)urea improves glucose tolerance under normoglycemic and diabetic conditions and rearranges hepatic metabolism.

Glycogen phosphorylase (GP) catalyzes the breakdown of glycogen and largely contributes to hepatic glucose production making GP inhibition an attractive target to modulate glucose levels in diabetes. Hereby we present the metabolic effects of a novel, potent, glucose-based GP inhibitor (KB228) tested in vitro and in vivo under normoglycemic and diabetic conditions. KB228 administration enhanced glucose sensitivity in chow-fed and obese, diabetic mice that was a result of higher hepatic glucose uptake. Besides improved glucose sensitivity, we have observed further unexpected metabolic rearrangements. KB228 administration increased oxygen consumption that was probably due to the overexpression of uncoupling protein-2 (UCP2) that was observed in animal and cellular models. Furthermore, KB228 treatment induced mammalian target of rapamycin complex 2 (mTORC2) in mice. Our data demonstrate that glucose based GP inhibitors are capable of reducing glucose levels in mice under normo and hyperglycemic conditions. Moreover, these GP inhibitors induce accommodation in addition to GP inhibition--such as enhanced mitochondrial oxidation and mTORC2 signaling--to cope with the glucose influx and increased glycogen deposition in the cells, however the molecular mechanism of accommodation is unexplored.

[Evolution of liver and kidney gluconeogenesis during acute liver intoxication by carbon tetrachloride (author's transl)]. / Evolución de la gluconeogénesis hepática y renal durante la intoxicación aguda del hígado por tetracloruro de carbono.

Evolution of early renal metabolic adaptation to the rat liver intoxication by carbon tetrachloride is studied. Liver glycogen is very rapidly depleted (20% of initial values at 3 h) and liver gluconeogenic capacity is completely inhibited 7 h after carbon tetrachloride treatment. Contrariwise, a gradual enhancement of phosphoenolpyruvate carboxikinase activity and gluconeogenic capacity of kidney cortex takes place during this period. Accordingly, renal concentrations of aspartate, malate, and phosphoenolpyruvate indicate that the reaction catalysed by phosphoenolpyruvate carboxykinase is accelerated in vivo. These findings suggest that metabolic adaptation of kidney cortex in response to liver functional impairment plays an important role early after carbon tetrachloride administration.

Influence of glycogen on liver density: computed tomography from a metabolic perspective.

The liver is a metabolically active organ with a radiographic density that can be modified by its glycogen and fat content. In rhesus monkeys an increase in liver glycogen induced by glucose loading was accompanied by an increase in attenuation values on computed tomography and a decrease in total liver fat. Conversely, fasting depleted glycogen, increased fat, and decreased liver attenuation. Acute glycogen depletion without significant change in fat was induced by administration of glucagon and accompanied by a decrease in attenuation. These results along with in vitro measurements of glycogen solutions suggest that an increase of approximately 3 Hounsfield units can be expected for each percent increase in liver glycogen content.