Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thiazolidinedione derivatives are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the molecular basis for this adipogenic effect has remained unclear. Here, we report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPAR gamma with a Kd of approximately 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPAR gamma is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPAR gamma is a target for the therapeutic actions of this class of compounds.
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PMID:An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). 776 81

The thiazolidinediones are a unique class of compounds that exert direct effects on the mechanisms of insulin resistance and result in improved insulin action and reduced hyperinsulinemia. Troglitazone is the first of these compounds to be approved for use in humans and has the potential not only to reduce glycemia and insulin requirements in type II diabetes but to improve other components of the insulin resistance syndrome including dyslipidemia, hypertension, and accelerated cardiovascular disease. Such compounds also hold promise for the prevention of type II diabetes and for the treatment of other insulin-resistant states including polycystic ovary disease. In addition to the novel mechanism of action through binding and activation of PPARs, troglitazone has other unique advantages, including once-a-day administration, a low incidence of minor side effects, no known drug interactions, hepatic metabolism and secretion, and potent antioxidant properties. Thiazolidinedione compounds such as troglitazone provide an important additional resource for the health care provider in the management of type II diabetes and other components of the insulin resistance syndrome.
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PMID:Thiazolidinediones. 931 15

Macrophage infiltration into pancreatic islets is thought to be an initial event inducing insulitis in the development of type 1 diabetes. Thiazolidinedione is a direct ligand for peroxisome proliferator-activated receptor-gamma, recently reported to inhibit macrophage activation, including cytokine production and type 2 nitric oxide synthase expression. We investigated the effect of pioglitazone, a thiazolidinedione compound, on the development of multiple low-dose streptozotocin (MLDS)-induced autoimmune diabetes in mice. CD-1 mice intraperitoneally injected with five daily sub-diabetogenic doses (30 or 40 mg/kg body weight) of streptozotocin developed mononuclear cell infiltration in and around islets, followed by hyperglycemia. Oral administration of pioglitazone (0.01% food admixture) from 7 days before the first streptozotocin injection prevented or delayed the development of diabetes induced by MLDS. Histologically, pioglitazone blocked the infiltration of mononuclear cells into islets in MLDS mice. Peritoneal macrophages from MLDS mice at day-7 produced significantly large amount of nitric oxide compared with those from control mice. Such activation of peritoneal macrophages was not observed in pioglitazone-treated MLDS mice. These findings suggest that pioglitazone blocks the autoimmune process in the development of MLDS diabetes, partly by inhibiting the macrophage activation.
Diabetes Res Clin Pract 1999 May
PMID:Pioglitazone prevents mice from multiple low-dose streptozotocin-induced insulitis and diabetes. 1041 29

Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent glomerular dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent glomerular dysfunction through the inhibition of the DAG-PKC-ERK pathway.
Diabetes 2000 Jun
PMID:Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats. 1086 56

The lipoatrophy syndromes are a heterogeneous group of syndromes characterized by a paucity of adipose tissue. Severe lipoatrophy is associated with insulin-resistant diabetes mellitus (DM). The loss of adipose tissue can have a genetic, immune, or infectious/drug-associated etiology. Causative mutations have been identified in patients for one form of partial lipoatrophy--Dunnigan-type familial partial lipodystrophy. Experiments using lipoatrophic mice demonstrate that the diabetes results from the lack of fat and that leptin deficiency is a contributing factor. Thiazolidinedione therapy improves metabolic control in lipoatrophic patients; the efficacy of leptin treatment is currently being investigated.
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PMID:Lipoatrophy revisited. 1109 Nov 18

Diabetic nephropathy is characterized functionally by glomerular hyperfiltration and albuminuria and histologically by the expansion of glomerular mesangium. We and others have found that protein kinase C (PKC) is activated through an increase in de novo synthesis of diacylglycerol (DAG) from glucose in glomerular mesangial cells cultured under high glucose conditions and in glomeruli of diabetic rats. The activation of PKC could activate further various intracellular signal transduction systems, such as extracellular regulated kinase (ERK). The activation of the DAG-PKC-ERK pathway is considered to be one of the important molecular mechanisms of the development and progression of diabetic nephropathy. To prove this hypothesis, we examined whether the inhibition of the DAG-PKC-ERK pathway could prevent the development of glomerular dysfunction in diabetic animals. First, we found that thiazolidinedione compounds could inhibit PKC activation by activating DAG kinase. Thiazolidinedione compounds were able to prevent glomerular hyperfiltration, albuminuria, and excessive production of extracellular matrix proteins in glomeruli in streptozotocin-induced diabetic rats, a model for type 1 diabetes. Second, we tried to inhibit PKC directly by oral administration of PKC beta inhibitor. PKC beta inhibitor could prevent albuminuria and mesangial expansion in db/db mice, a model for type 2 diabetes. These results confirmed the importance of the activation of the DAG-PKC-ERK pathway in the development of glomerular dysfunction in diabetes.
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PMID:Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway. 1157 50

Type 2 diabetes is characterized by decreased secretion of insulin and insulin resistance. Thiazolidinediones are drugs to ameliorate insulin resistance. At present, only pioglitazone is available in Japan. The first drug of this category, troglitazone, has been withdrawn from market because of its liver toxicity in a few patients. The decrease in fasting plasma glucose begins within 2 weeks and reaches the nadir in 8-12 weeks. Plasma insulin levels usually decrease together with plasma glucose. Thiazolidinedione drugs are effective in about 50% of type 2 diabetic patients. The efficacy is higher in patients with obesity, high insulin levels and in aged people and females. The mechanism is thought to be mediated by activation of a nuclear receptor, PPAR-gamma, which is most abundantly expressed in the adipose tissue. Current concept is that, when PPAR-gamma is activated by these drugs, the number of small adipocytes is increased to replace large adipocytes, thereby decreasing the release of TNF-alpha and FFA from adipose tissue. However, there seems to be a complex relationship between the activity of PPAR-gamma and insulin sensitivity. The effect of these new category drugs should be monitored carefully on a long-term basis.
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PMID:[Insulin sensitizer drugs, thiazolidinediones: current state and prospect]. 1171 93

The National Cholesterol Education Program recognizes the importance of the metabolic syndrome and has published guidelines for its diagnosis. Weight loss, physical activity, and treatment of the individual risk factors constitute the main strategies for treatment. For now, the goals and methods of treating hypertension and dyslipidemia are the same in people with the metabolic syndrome as in the general population. Thiazolidinedione drugs increase insulin sensitivity, but their use in the metabolic syndrome is only speculative at present. We recommend they be used only as indicated to treat diabetes mellitus.
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PMID:A truly deadly quartet: obesity, hypertension, hypertriglyceridemia, and hyperinsulinemia. 1254 72

The development and progress of antidiabetic drugs (e.g., insulin preparations and hypoglycemic drugs) are retrospectively investigated in Japan. Their influences on the treatment of diabetes mellitus (DM) and its epidemiological aspects are also discussed. 1) Insulin preparations: Insulin was introduced for DM therapy in 1925, two or three years after its discovery in Canada. The preparations were raw extracts of bovine or porcine pancreas. These did not prevail widely in Japan because of the low incidence of DM before World Wan II. After the war, a shortage of mammalian materials compelled the use of fish pancreatic tissues such as bonito and/or tuna for insulin production. Insulin infection, so-called regular insulin, was first promoted in the 6th "Pharmacopoeia Japonica" (JP6) in 1951 and has been maintained to the present edition (JP14, 2001). Although depot-type insulin preparations were developed in the USA and Europe during the war, the introduction of those preparations to Japan was delayed until 1951, when Protamine zinc insulin appeared. Globin zinc insulin and Isophane insulin were introduced for clinical use in 1952 and 1955, respectively. These were also adopted for JP7 (1961). Biphasic-type insulin, which has a rapid onset and long duration of activity, appeared in 1965. Purified preparations from bovine or porcine sources have been available since 1980, which might be a strong reason for the decrease in insulin allergy. Insulin from animal origin has been supplied for almost 60 years since its discovery. Amino acid sequences of insulins from various species of animals were determined by the pioneering studies of Sanger and his associates. Human insulin, which differs from porcine insulin by only one amino acid, was produced by Novo researchers in 1982 using a semi-synthetic method. Then the Lilly group soon succeeded in obtaining human insulin by recombinant DNA technology in the same year. Both products were introduced to Japan in 1985, and the recombinant products prevailed throughout the 1990s. Human insulin analogues (i.e., Insulin lispro and Insulin aspart) appeared in 2001. These are applied for after-meal glycosmia owing to their ultrarapid onset of activity. Self-injection by DM patients was legalized in 1981. To make the infection technique sure and easy, cartridge (pen-type) and disposable kit-type needles were devised in the 1990s. 2) Oral hypoglycemic drugs: Instead of the exclusive parenteral usage of insulins, there was also demand for oral dosage forms. The first of the sulfonyrlurea (SU) group, BZ-55, was used for DM clinically in 1955 in Germany. But it was soon withdrawn because of its antibacterial action. This led to the development of various SU groups. Tolbutamide (1956), chlorpropamide (1959), acetohexamide (1964) and tolazamide (1961) were introduced to Japan as first-generation SUs. Then glyclopyramide (Kyorin, 1965), glybenclamide (1971), gliclazide (1984) and glimepiride (1999) appeared as the second-generation SUs. These were used orally for Type 2 diabetes. Biguanide (BG) group, phenformin HC1 (1959), metformin HC1 (1961) and buformin HC1 (1961) had also been in use by oral treatment of Type 2 diabetes. SU appears to act by increasing the sensitivity of b-cells, which secrete insulin. BG probably exerts by increasing glucose transport across the membranes of target organs. 3) New types of antidiabetic drugs: a-Glucosidase inhibitors (i.e., acarbose: Bayer, 1993; and voglibose: Takeda, 1994) act on hyperglycemia after meals by decreasing glucose absorption. Thiazolidinedione compounds, such as troglitazone (Sankyo, 1995) and pioglitazone HC1 (Takeda, 1994) act by increasing the insulin sensitivity of the target tissues. These are useful for Type 2 DM patients when SUs are ineffective. Nevertheless, troglitazone was discontinued in 2000 due to severe liver damage. Nateglinide (Ajinomoto Co., 1999), which is a D-phenylalanine derivative acting similar to SUs, is useful orally for after-meal hyperglycemia of Type 2 diabetes. Epalrestat (Ono Yakuhin Co., 1992) is effective for diabetic neuropathy by reducing the formation of sorbitol. These anti-DM drugs were recently studied and developed in Japan. 4) The Japan Diabetes Society proposed a guideline on diagnostic criteria and treatment of diabetes mellitus (DM) in 1999 and revised it in 2002. DM is classified as insulin-dependent DM (Type l) and non-insulin dependent DM (Type 2). Type 1, juvenile onset DM, requires insulin therapy to prevent ketosis and to sustain life. Treatment of type 2, adult onset DM, is recommended as a step-by-step method, starting with dietary-exercise therapy, followed by oral hypoglycemic drugs and then insulin therapy. DM patients with complications should have a therapy devised to match their circumstances. 5) Epidemiological aspects: The mortality rate of DM compared to the time of drug appearance was traced from 1920 to 2000. The curve goes down slowly in the time frame of World War II, but rises from 1950 to 1970. The elevation could not be suppressed by the appearance of SUs, BGs or improved insulin preparations. The curve runs flat from 1980 to 1990, which might be related to the use of purified insulin or human insulin therapy. The mortality rate of DM indicates that death by hyperglycemic coma and other deaths resulting from complications are excluded. The survey of the principal cause of death by DM during the period of 1981-1990 indicates that the death rate due to hyperglycemic coma is only 1.7% of the total deaths caused by DM. The effect of drug therapy on all of the death resulting from DM is not detected. Hospital visitation and admission rates of the DM patients have been recorded since 1952 in Japan. This curve is rising continuously, and none of the antidiabetic drugs has been able to suppress it. These data show that the antidiabetic drugs relieve DM symptoms through their effective hypoglycemic actions, but that they cannot suppress the mortality rate of DM. It is possible that none of the drugs currently available can suppress the increasing tendency of DM patients.
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PMID:[A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus]. 1457 54

Diabetic nephropathy is a common complication in diabetes mellitus (DM). Thiazolidinedione (TZD) is thought to ameliorate diabetic nephropathy, however, the mechanism has not been elucidated. We hypothesized that VEGF participates in the pathogenesis of diabetic nephropathy and that TZD may be beneficial for the treatment of diabetic nephropathy through its effect on VEGF. Increased VEGF expression was demonstrated in the glomeruli of DM rats and rat mesangial cells (RMC) incubated with high medium glucose. It was also demonstrated that VEGF promoted mesangial cell proliferation, which was inhibited by TZD. It was shown that a rapid fall and rise of ambient glucose concentration induces more VEGF production and cell proliferation in RMC than in cells with continuously high glucose medium, which was also inhibited by TZD. Prostaglandin J2 and protein C kinase inhibitors significantly inhibited [3H]thymidine incorporation in RMC incubated with VEGF, which was inhibited by TZD. These findings indicate that a rapid change of glucose concentration promotes RMC proliferation by the increased production of VEGF. TZD has an inhibitory action through, at least in part, PPAR-gamma.
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PMID:Rapid change of glucose concentration promotes mesangial cell proliferation via VEGF: inhibitory effects of thiazolidinedione. 1504 43


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