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The liver plays a central role in glucose homeostasis in the whole-body by responding to environmental factors including nutrients, hormones, and oxygen. In conditions of metabolic overload such as diabetes mellitus and obesity, coordinated regulation between oxygen supply and consumption has been reported to be disrupted and subsequently cause tissue hypoxia, although pathological significance of the disease-related hypoxia remains elusive. To investigate the role of tissue hypoxia in the liver on systemic glucose homeostasis, mice lacking HIF-1α gene, a critical component of a master regulator of hypoxic response, in hepatocytes were exposed to high fat/sucrose diet (HFSD). Exposure to HFSD for 5 weeks elicited liver hypoxia with a transient increase in HIF-1α protein expression in the liver of control mice. Glucose disposal was marginally impaired in control mice when challenged oral glucose tolerance test, but such impairment was enhanced in the mutant mice. This alteration was accompanied by a complete inhibition of glucokinase induction with a significant reduction of hepatic glucose uptake. Mice fed HFSD for 20 weeks exhibited fasting hyperglycemia and glucose intolerance, whereas these metabolic phenotypes deteriorated considerably with severe insulin resistance in skeletal muscles and adipose tissues in the mutant mice. These findings suggest that HIF-1 in hepatocytes plays protective roles against the progression of diabetes mellitus.  相似文献   

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Regulation of energy metabolism is controlled by the brain, in which key central neuronal circuits process a variety of information reflecting nutritional state. Special sensory and gastrointestinal afferent neural signals, along with blood-borne metabolic signals, impinge on parallel central autonomic circuits located in the brainstem and hypothalamus to signal changes in metabolic balance. Specifically, neural and humoral signals converge on the brainstem vagal system and similar signals concentrate in the hypothalamus, with significant overlap between both sensory and motor components of each system and extensive cross-talk between the systems. This ultimately results in production of coordinated regulatory autonomic and neuroendocrine cues to maintain energy homeostasis. Therapeutic metabolic adjustments can be accomplished by modulating viscerosensory input or autonomic motor output, including altering parasympathetic circuitry related to GI, pancreas, and liver regulation. These alterations can include pharmacological manipulation, but surgical modification of neural signaling should also be considered. In addition, central control of visceral function is often compromised by diabetes mellitus, indicating that circuit modification should be studied in the context of its effect on neurons in the diabetic state. Diabetes has traditionally been handled as a peripheral metabolic disease, but the central nervous system plays a crucial role in regulating glucose homeostasis. This review focuses on key autonomic brain areas associated with management of energy homeostasis and functional changes in these areas associated with the development of diabetes.  相似文献   

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Diabetes mellitus, especially type 2 diabetes, remains the dominant metabolic disease worldwide, with an expected increase in prevalence of over 50% in the next 20 years. Our knowledge about the pathophysiology of type 2 diabetes continues to be incomplete, with unmet medical need for new therapies. The characterization of the fibroblast growth factor (FGF) family and the discovery of endocrine FGFs provided new information on the mechanisms of regulation and homeostasis of carbohydrate metabolism. More specifically, FGF19 and FGF21 signaling pathways have been linked to different glucose metabolic processes, including hepatic glucose synthesis, glycogen synthesis, glucose uptake, and insulin sensitivity, among others, and these molecules have been further related to the pathophysiology of diabetes mellitus. In-depth comprehension of these growth factors may bring to light new potential therapeutic targets for the treatment of diabetes mellitus.  相似文献   

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Healthy Atlantic bottlenose dolphins (Tursiops truncatus) have a sustained postprandial hyperglycemia, producing a prolonged glucose tolerance curve and a transient, diabetes mellitus-like state during 6 to 72 h of fasting. To further assess dolphins as comparative models for diabetes in humans, we hypothesized that a suite of hematological and clinical biochemistry changes during the fasting state may mimic those reported in humans with diabetes. We conducted a retrospective analysis of covariance to compare fasting and nonfasting hematologic and serum biochemical data, including 1161 routine blood samples from 52 healthy bottlenose dolphins (age, 1 to 49 y; male and female) collected during 1998 through 2005. Most changes found in dolphins during the fasting state--including significantly increased glucose, platelets, gamma-glutamyl transpeptidase, and alkaline phosphatase; significantly decreased serum uric acid; and shifts toward a metabolic acidodic state (significantly increased blood CO2)--have been previously associated with diabetes mellitus in humans. Therefore, healthy bottlenose dolphins may be the first complete and natural comparative animal model for diabetes mellitus in humans. Similarities between dolphins and humans, including metabolic changes associated with high-protein, low-carbohydrate diets; large brain-to-mass ratios; high central nervous system demands for glucose; and similarly unique blood glucose-carrying capacities should be further assessed to better understand the potential evolutionary paths of diabetes mellitus in these 2 species.  相似文献   

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A rare sugar, d-psicose has progressively been evaluated as a unique metabolic regulator of glucose and lipid metabolism, and thus represents a promising compound for the treatment of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine the underlying effector organs of d-psicose in lowering blood glucose and abdominal fat by exploiting a T2DM rat model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Rats were fed 5% d-psicose or 5% d-glucose supplemented in drinking water, and only water in the control for 13 weeks and the protective effects were compared. A non-diabetic Long-Evans Tokushima Otsuka (LETO), fed with water served as a counter control of OLETF. After 13 weeks feeding, d-psicose treatment significantly reduced the increase in body weight and abdominal fat mass. Oral glucose tolerance test (OGTT) showed the reduced blood glucose and insulin levels suggesting the improvement of insulin resistance in OLETF rats. Oil-red-O staining elucidated that d-psicose significantly reduced lipid accumulation in the liver. Immunohistochemical analysis showed d-psicose induced glucokinase translocation from nucleus to cytoplasm of the liver which enhances glucokinase activity and subsequent synthesis of glycogen in the liver. d-psicose also protected the pathological change of the β-cells of pancreatic islets. These data demonstrate that d-psicose controls blood glucose levels by reducing lipotoxicity in liver and by preserving pancreatic β-cell function.  相似文献   

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The hormones glucagon and insulin delicately regulate the concentration of blood glucose. When patients become resistant to the effects of insulin or produce too little of it to properly regulate glucose concentrations, then diabetes can result. Unfortunately, not all patients with insulin-resistant, type 2 diabetes mellitus respond to drugs that improve insulin sensitivity. However, there is reason to be hopeful. A new molecule that targets glucokinase (GK), the enzyme responsible for phosphorylating glucose in pancreatic beta cells and hepatic cells, acts to significantly reduce blood glucose concentrations in rodents. The GK activator RO-28-1675 increased the glucose affinity and Vmax of GK, and rats treated with RO-28-1675 had improved glucose tolerance and elevated glucose uptake in liver. These results provide the basis for improved drug design that may alleviate diabetes mellitus and the disorders that accompany it in patients.  相似文献   

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