Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is a 16 kDa adipocyte-secreted hormone that regulates weight centrally and links nutritional status with neuroendocrine and immune function. Since its cloning in 1994, leptin's role in regulating immune and inflammatory response has become increasingly evident. Actually, the increase of leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokines loop which governs the inflammatory-immune response and the host defence mechanism. Indeed, leptin stimulates the production of pro-inflammatory cytokines from cultured monocytes and enhances the production of Th1 type cytokines from stimulated lymphocytes. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as type 1 diabetes, rheumatoid arthritis and chronic bowel disease. Obesity is characterized by elevated circulating leptin levels which might contribute significantly to the so called low-grade systemic inflammation, making obese individuals more susceptible to the increased risk of developing cardiovascular diseases, type II diabetes or inflammatory articular degenerative disease such as osteorathritis (OA). As a matter of fact, a key role for leptin in OA has been recently demonstrated since leptin exhibits, in synergy with other pro-inflammatory cytokines, a detrimental effect on articular cartilage cells by promoting nitric oxide synthesis. This review will focus prevalently on the complex relationships existing among leptin, inflammatory response and immunity, trying to provide surprising insights into leptin's role and to discuss challenges and prospects for the future.
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PMID:Towards a pro-inflammatory and immunomodulatory emerging role of leptin. 1672 Jun 37

Hypogonadotropism is a common feature of uncontrolled diabetes, for which the ultimate mechanism remains to be elucidated. Kisspeptins, ligands of G protein-coupled receptor 54 (GPR54) encoded by the KiSS-1 gene, have recently emerged as major gatekeepers of the gonadotropic axis. Alteration in the hypothalamic KiSS-1 system has been reported in adverse metabolic conditions linked to suppressed gonadotropins, such as undernutrition. However, its potential contribution to defective gonadotropin secretion in diabetes has not been evaluated. We report herein analyses of luteinizing hormone (LH) responses to kisspeptin and hypothalamic expression of the KiSS-1 gene in streptozotocin (STZ)-induced diabetic male rats. In addition, functional studies involving kisspeptin replacement or continuous administration of leptin and insulin to diabetic male rats are presented. Kisspeptin administration evoked robust LH and testosterone bursts and enhanced postgonadectomy LH concentrations, despite prevailing attenuation of gonadotropic axis in diabetic animals. In addition, hypothalamic KiSS-1 mRNA levels were unambiguously decreased in diabetic male rats, and the postorchidectomy rise in KiSS-1 mRNA was severely blunted. Repeated administration of kisspeptin to diabetic rats evoked persistent LH and testosterone responses and partially rescued prostate and testis weights. In addition, central infusion of leptin, but not insulin, was sufficient to normalize hypothalamic KiSS-1 mRNA levels, as well as LH and testosterone concentrations. In summary, we provide evidence for altered expression of the hypothalamic KiSS-1 system in a model of uncontrolled diabetes. This observation, together with the ability of exogenous kisspeptin to rescue defective LH responses in diabetic rats, unravel the physiopathological implication, and potential therapeutic intervention, of the KiSS-1 system in altered gonadotropin secretion of type 1 diabetes.
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PMID:Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. 1693 10

Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocin-induced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice ( approximately 11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable ( approximately 78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with fidarestat (16 mg . kg(-1) . d(-1)), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)-positive nuclei in sciatic nerve, spinal cord, and DRGs of fidarestat-treated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes.
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PMID:The leptin-deficient (ob/ob) mouse: a new animal model of peripheral neuropathy of type 2 diabetes and obesity. 1713 Apr 77

The incidence of type 1 and type 2 diabetes mellitus in the pediatric population has increased over the past decade. The practitioner is often faced with the challenge of differentiating between type 1 and type 2 diabetes at the time of initial diagnosis because of the overlap of clinical and laboratory characteristics between these two entities. Adipokines are proteins secreted by the adipose tissue. Leptin and adiponectin are two adipokines that have been extensively studied in vitro, in animal studies, and in human subjects with type 1 and type 2 diabetes. Leptin and adiponectin play a significant role in the regulation of lipid and carbohydrate metabolism. Adiponectin increases insulin sensitivity in both the liver and skeletal muscle. Leptin decreases appetite, increases energy expenditure, suppresses insulin synthesis and secretion and increases insulin sensitivity. Changes in the secretion or sensitivity to leptin and adiponectin may contribute to the development of type 1 and type 2 diabetes. Adiponectin is higher in adult and pediatric patients with type 1 diabetes compared to those with type 2 diabetes. Data regarding leptin levels are contradictory. Most studies report decreased serum leptin at the time of diagnosis in type 1 diabetes compared to type 2 diabetes subjects and non-diabetic controls. This paper will review basic research and clinical evidence supporting the role of adiponectin and leptin in the development of type 1 and type 2 diabetes and discuss their potential use as tools in the differential diagnosis of pediatric diabetes.
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PMID:Adiponectin and leptin: potential tools in the differential diagnosis of pediatric diabetes? 1713 Dec 5

Population-based studies have shown strong relationship between inflammatory markers and metabolic disturbances, obesity, and atherosclerosis, whereas inflammation has been considered as a "common soil" between these clinical entities and type 2 diabetes (T2D). The accumulation of macrophages in adipose tissue (AT), the common origin of macrophages and adipocytes, the prevalent presence of peripheral mononuclear cells, and apoptotic beta cells by themselves seem to be the sources of inflammation present in T2D, since they generate the mediators of the inflammatory processes, namely cytokines. The main cytokines involved in the pathogenesis of T2D are interleukin-1beta (IL-1beta), with an action similar to the one present in type 1 diabetes, tumor necrosis factor-alpha (TNF-alpha), and IL-6, considered as the main regulators of inflammation, leptin, more recently introduced, and several others, such as monocyte chemoattractant protein-1, resistin, adiponectin, with either deleterious or beneficial effects in diabetic pathogenesis. The characterization of these molecules targeted diabetes treatment beyond the classical interventions with lifestyle changes and pharmaceutical agents, and toward the determination of specific molecular pathways that lead to low grade chronic inflammatory state mainly due to an immune system's unbalance.
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PMID:Inflammatory process in type 2 diabetes: The role of cytokines. 1715 Dec 95

Type I diabetes mellitus (T1D) is due to a loss of immune tolerance to islet antigen and thus, there is intense interest in developing therapies that can re-establish it. Tolerance is maintained by complex mechanisms that include inhibitory molecules and several types of regulatory T cells (Tr). A major historical question is whether gene therapy can be employed to generate Tr cells. This review shows that gene transfer of immunoregulatory molecules can prevent T1D and other autoimmune diseases. In our studies, non-viral gene transfer is enhanced by in vivo electroporation (EP). This technique can be used to perform DNA vaccination against islet cell antigens and when combined with appropriate immune ligands results in the generation of Tr cells and protection against T1D. In vivo EP can also be applied for non-immune therapy of diabetes. It can be used to deliver protein drugs such as glucagon-like peptide 1 (GLP-1), leptin or transforming growth factor beta (TGF-beta). These act in T1D or type II diabetes (T2D) by restoring glucose homeostasis, promoting islet cell survival and growth or improving wound healing and other complications. Furthermore, we show that in large animals EP can deliver peptide hormones, such as growth hormone releasing hormone (GHRH). We conclude that the non-viral gene therapy and EP represent a safe and efficacious approach with clinical potential.
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PMID:Plasmid-based gene therapy of diabetes mellitus. 1721 47

One of the most common symptoms of diabetes is extreme hunger, but the brain mechanism underlying this hyperphagia is unknown. The endocannabinoid system has emerged as one of the main food intake regulators in the brain. However, the effects of type 1 diabetes on the endocannabinoid system are not completely known. Thus, the aim of the present work is to establish the possible alterations induced by type 1 diabetes on the brain endocannabinoid system in rats. Western blot and immunocytochemistry were used to measure CB1 and phosphorylated CB1 receptor expression in several prosencephalic regions in streptozotocin-induced type 1 diabetic rats. Serum leptin levels were measured by ELISA. CB1 receptor expression was increased in striatum and hypothalamus of diabetic animals, with no changes in other brain areas studied. CB1 receptor phosphorylation was also increased in the same brain areas. Type 1 diabetes induced significant weight loss, and serum leptin levels were severely decreased. These results reinforce the possible role of the CB1 receptor as a pharmacological target for the clinical management of appetite in diabetic patients.
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PMID:Type 1 diabetes alters brain cannabinoid receptor expression and phosphorylation status in rats. 1840 37

Studies investigating the effect of leptin on bone mass were inconsistent and some related it to the effect of insulin. We intend in this cross-sectional study to investigate the effect of leptin on bone mass in type 1 diabetic patients. We recruited 42 patients with type 1 diabetes for which we determined weight, height, HbA1c, microalbuminuria, serum leptin, bone mineral content (BMC) and density (BMD), and body composition. The patients had an average age of 20.1 +/- 0.6 years, an average body mass index (BMI) of 23.6 +/- 0.5 kg/cm(2) and an average duration of diabetes of 9.1 +/- 1.0 years. The Z-score was not correlated with HbA1c or duration of the disease, and the average Z-score was not different in patients with microalbuminuria as compared to patients with no reported microalbuminuria. On the other hand, Z-score and BMC correlated negatively with leptin (r = -0.31; p = 0.04 and -0.60, p < 0.01, respectively). These correlations persisted after adjustment for fat mass. We conclude that not metabolic control of diabetes, but serum leptin has a negative effect on bone density in young patients with type 1 diabetes. This negative effect of leptin on bone density maybe, in part, due to deficiency of endogenous insulin secretion in these patients.
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PMID:Negative effect of leptin on bone mass in type 1 diabetes. 1869 Apr 7

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of beta-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within approximately 10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for approximately 175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-gamma-coactivator-1alpha may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.
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PMID:Making insulin-deficient type 1 diabetic rodents thrive without insulin. 1877 78

Diabetes mellitus induces alterations in bone and mineral metabolism. Diabetic bone disorder causes an increase in bone fractures, delays healing of fractures, and affects the quality of life. There are few optimal therapies for these disorders and the mechanisms responsible for their complications have not been clearly identified. Bone histology studies in humans and animals have demonstrated that decreased bone formation is a critical mechanism of bone mass reduction in diabetes. A major hypothesis about the mechanisms of diabetic complications is a diabetes-induced increase in oxidative stress, because reactive oxygen species (ROS) are increased under diabetic conditions and are known to induce cellular dysfunction in a wide variety of cell types. Oxidative stress is induced by a variety of mechanisms including formation of increased advanced glycation end-products (AGEs), increased polyol pathway flux, activation of protein kinase C isoforms, glucose autoxidation, and mitochondrial overproduction of superoxide under diabetic conditions. Other circulating factors that are elevated in diabetes, such as free fatty acids and leptin, also contribute to increased ROS generation. It is now widely accepted that ROS can cause severe damage to DNA, proteins, and lipids. Concerning bone metabolism, in vitro studies have shown that oxidative stress inhibits osteoblastic differentiation and induces osteoblast insults and apoptosis. Moreover, we have demonstrated that both streptozotocin-induced diabetic mice, an animal model of type 1 diabetes, and spontaneously diabetic Torii (SDT) rats, an animal model of type 2 diabetes, have low-turnover osteopenia associated with increased oxidative stress and that markers of oxidative stress are inversely associated with the histomorphometric parameters of bone formation. Growing evidence suggests that the increase in oxidative stress may at least partly contribute to the development of diabetic osteopenia. This review focuses on the impact of diabetes-induced oxidative stress in the development of diabetic bone disorder.
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PMID:Role of oxidative stress in diabetic bone disorder. 1923 2


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