Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastases of breast cancer are a major cause of treatment failure. To evaluate the therapeutic efficacy of suicide gene therapy in metastatic breast cancer, we used the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) administration to treat breast cancer, generated by an adenocarcinoma cell line MOD in syngeneic mice. The bystander effect of HSV-tk + GCV on tumor cell killing was illustrated by demonstrating complete regression of subcutaneous tumors consisting of 90% parental tumor cells and 10% HSV-tk transformed tumor cells. To establish a model of breast cancer metastases in the liver, tumors were generated by intra-hepatic implantation of MOD cells in syngeneic animals. Two weeks after tumor cell implantation, replication defective adenoviral vectors expressing HSV-tk (ADV.tk), or beta-galactosidease (ADV. beta-Gal) were injected intratumorally, followed by buffer or GCV administration. Treatment with ADV.tk + GCV resulted in significant regression of tumor (P < .001), as assessed by computerized morphometric analysis of residual tumor. This was reflected as a significant prolongation of survival in treated animals (P < .001). These results demonstrate that ADV-mediated suicide gene therapy in vivo can be incorporated in a comprehensive treatment strategy for liver metastases of breast cancer.
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PMID:Adenoviral-mediated suicide gene therapy for hepatic metastases of breast cancer. 889 53

Brown adipose tissue (BAT) has been proposed to play an important role in the regulation of energy balance. The unique presence of uncoupling protein (UCP) permits BAT to expend calories unrelated to the performance of work with the net result being the generation of heat. The role of BAT in mediating diet-induced thermogenesis had led to the suggestion that BAT activity contributes to metabolic inefficiency and, as such, might provide a cellular and molecular explanation for protection from obesity. In order to directly test this hypothesis, we recently created mice with isolated BAT deficiency by using a suicide DNA transgenic vector in which regulatory elements of the UCP gene were used to drive brown fat specific expression of diptheria toxin A-chain (DTA). Transgenic mice are characterized by reduced energy expenditure and marked obesity, associated with insulin resistance and NIDDM with both receptor and post-receptor components. Feeding of a "Western diet" which derives 41% of its calories from fat leads to a synergistic effect on the development of obesity and its accompanying disorders in transgenics. The results of our studies support a critical role for BAT in the nutritional homeostasis of mice and suggest that the intact thermogenic function of BAT is required for protection from diet induced obesity. Obese UCP-DTA mice have many features in common with obesity as it appears in most humans, and should therefore be a useful model that may aid studies of the pathogenesis and treatment of human obesity, NIDDM and their complications.
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PMID:Obesity after genetic ablation of brown adipose tissue. 955 22

We present a case of a 47-year-old man with Type 2 diabetes mellitus who attempted suicide with 2,100 U of insulin injected subcutaneously. Administration of dextrose intravenously was required to maintain the blood glucose concentration normally for 5 days. Moreover, hypokalemia, hypophosphatemia, and hypomagnesemia were also seen for 24 hours after insulin injection. The serum phosphorus and magnesium concentrations decreased to nadirs of 1.6 mg/dl and 1.6 mg/dl respectively 7 hours after insulin injection. Electrolyte disorders other than hypokalemia may be induced in hypoglycemic patients by massive insulin overdose.
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PMID:Electrolyte disorders following massive insulin overdose in a patient with type 2 diabetes. 1067 50

The beta-isoform of group VIA calcium-independent phospholipase A(2) (iPLA(2)beta) does not require calcium for activation, is stimulated by ATP, and is sensitive to inhibition by a bromoenol lactone suicide substrate. Several potential functions have been proposed for iPLA(2)beta. Our studies indicate that iPLA(2)beta is expressed in beta-cells and participates in glucose-stimulated insulin secretion but is not involved in membrane phospholipid remodeling. If iPLA(2)beta plays a signaling role in glucose-stimulated insulin secretion, then conditions that impair iPLA(2)beta functions might contribute to the diminished capacity of beta-cells to secrete insulin in response to glucose, which is a prominent characteristic of type 2 diabetes. Our recent studies suggest that iPLA(2)beta might also participate in beta-cell proliferation and apoptosis and that various phospholipid-derived mediators are involved in these processes. Detailed characterization of the iPLA(2)beta protein level reveals that beta-cells express multiple isoforms of the enzyme, and our studies involve the hypothesis that different isoforms have different functions.
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PMID:Islet complex lipids: involvement in the actions of group VIA calcium-independent phospholipase A(2) in beta-cells. 1474 85

Metformin is widely used in the treatment of type 2 diabetes, though it is recognized to be associated with the risk of lactic acidosis. A case of pronounced lactic acidosis with cardiac arrest (pH 6.60, lactate 17.5 mmol/l, base excess - 30, standard bicarbonate 2.5 mmol/l, core body temperature 27.8 degrees C) is presented in a 61-year-old woman under metformin therapy. The key laboratory abnormalities observed during the intensive care treatment including repeated hemodialysis are described. The patient showed a complete recovery with residually reduced mental capabilities. Furthermore, an explorative data analysis of our poison center database from 1995 until 2003 concerning metformin was performed. In 109 inquiries for metformin a lactic acidosis (mean pH 6.87 +/- 0.11, mean lactate 20.9 +/- 8.1 mmol/l) was present in 14 cases (9 female, 5 male, average age 57.7 years) with 8 patients under regular metformin therapy and 6 patients who ingested large amounts of metformin to attempt suicide. 4 patients did not survive the severe metabolic disturbance. The present report demonstrates that metformin-associated lactic acidosis is a rare but critical complication of metformin therapy of type 2 diabetes as well as in acute suicidal ingestion of metformin. Early diagnosis and rapid correction of the metabolic acidosis using hemodialysis provides the possibility of a positive outcome even in severe cases. If metformin-associated lactic acidosis is suspected we recommend early involvement of a poison center.
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PMID:Experiences of a poison center with metformin-associated lactic acidosis. 1512 22

Schizophrenia is a life-threatening disease associated with mortality rates that are two to three times higher than those expected/observed in the general population. It is associated with high levels of suicide, particularly in young male patients soon after diagnosis. Delays in treating schizophrenia could contribute to the high number of suicides during this period. However, approximately two-thirds of the excess mortality is caused by natural deaths. Patients with schizophrenia die from the same diseases as people in the general population. The number of deaths caused by cardiovascular disease, as in the general population, is high and could be reduced by the modification of certain lifestyle factors, such as diet and exercise. Careful monitoring of patients' weight, blood pressure, blood glucose levels and serum lipid levels will not only provide an opportunity to educate patients about lifestyle choices that contribute to cardiovascular disease but will also give them a better chance of receiving early treatment for disorders that contribute to cardiovascular disease, such as obesity, type 2 diabetes, hypertension and dyslipidaemia. Careful selection of antipsychotic drugs, some of which are associated with side effects such as weight gain and cardiac disorders, will also help reduce co-morbidity and mortality among patients with schizophrenia.
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PMID:Mortality in schizophrenia. 1794

Metformin is an oral hypoglycemic agent used in the management of type 2 diabetes mellitus. Limited information exists on adult metformin ingestions reported to poison control centers. The distribution of adult metformin ingestions reported to Texas poison control centers during 2000-2006 was determined for various factors. In addition, triage guidelines for the management of isolated ingestions were drafted. Of 1528 total metformin ingestions, 58% involved coingestants. Of the 264 ingestions of metformin alone, where the final medical outcome was known, dose ingested was reported for 66%. The mean reported dose was 4739 mg (range 500-60,000 mg). Ingestions of < or =2500 mg and >5000 mg reported doses differed with respect to the proportion involving suspected attempted suicide (6% versus 81%), serious final medical outcome (3% versus 19%), and referral to a health care facility (3% versus 83%). Using 5000 mg as a threshold dose for referral to a health care facility, 91% of cases not already at or en route to a health care facility were managed according drafted triage guidelines.
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PMID:Adult metformin ingestions reported to Texas poison control centers, 2000-2006. 1882 34

Metformin-associated lactic acidosis is a very rare but critical condition. It is seen in patients with type 2 diabetes mellitus who take metformin and attempt suicide with a metformin overdose. Here, we report a 43-year-old woman with type 2 diabetes mellitus and chronic renal insufficiency who developed hypoglycemia, hypothermia, tachycardia and lactic acidosis after a suicide attempt with a metformin overdose. She was successfully treated by continuous venovenous hemofiltration, and adequate hemodynamic and ventilatory support. Although metformin does not usually cause hypoglycemia when administered as monotherapy, hypoglycemia can occur in a condition coexistent with lactic acidosis secondary to metformin overdose. Metformin intoxication should be suspected when patients present with high anion gap metabolic acidosis after attempting suicide by ingesting drugs, particularly when comorbidities such as renal failure are present. Early diagnosis and rapid correction of the metabolic acidosis using hemodialysis or hemofiltration, together with concomitant cardiovascular support, and maintenance of blood glucose and core body temperature, provide the possibility of a positive outcome.
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PMID:Successful treatment of severe lactic acidosis caused by a suicide attempt with a metformin overdose. 1932 13

Pancreatic beta-cell mass is dynamic and is regulated by beta-cell proliferation, neogenesis, and apoptosis. Under physiological conditions, apoptosis is tightly regulated with a slow, net rise in beta-cell mass over time. Excessive beta-cell apoptosis is an important contributor to both type 1 and type 2 diabetes development. Therefore, much effort has been given recently to better understand the mechanisms of apoptosis that occur both during physiological homeostasis and during the course of both types of diabetes. Caspases are the executioners of apoptosis that ultimately result in cell suicide. In mammals, there are 14 caspases, of which many participate in the apoptotic pathways. Genetic mouse models have been important tools for elucidation of the specific apoptotic pathways that play an essential role in beta-cell apoptosis under physiological and pathological conditions. This review focuses on the diverse roles of each of the specific caspases and their regulators, unveiling both the classical apoptotic roles as well as emerging nonapoptotic roles.
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PMID:Executioners of apoptosis in pancreatic {beta}-cells: not just for cell death. 2002 68

Activation of phospholipases A(2) (PLA(2)s) leads to the generation of biologically active lipid mediators that can affect numerous cellular events. The Group VIA Ca(2+)-independent PLA(2), designated iPLA(2)beta, is active in the absence of Ca(2+), activated by ATP, and inhibited by the bromoenol lactone suicide inhibitor (BEL). Over the past 10-15 years, studies using BEL have demonstrated that iPLA(2)beta participates in various biological processes and the recent availability of mice in which iPLA(2)beta expression levels have been genetically-modified are extending these findings. Work in our laboratory suggests that iPLA(2)beta activates a unique signaling cascade that promotes beta-cell apoptosis. This pathway involves iPLA(2)beta dependent induction of neutral sphingomyelinase, production of ceramide, and activation of the intrinsic pathway of apoptosis. There is a growing body of literature supporting beta-cell apoptosis as a major contributor to the loss of beta-cell mass associated with the onset and progression of Type 1 and Type 2 diabetes mellitus. This underscores a need to gain a better understanding of the molecular mechanisms underlying beta-cell apoptosis so that improved treatments can be developed to prevent or delay the onset and progression of diabetes mellitus. Herein, we offer a general review of Group VIA Ca(2+)-independent PLA(2) (iPLA(2)beta) followed by a more focused discussion of its participation in beta-cell apoptosis. We suggest that iPLA(2)beta-derived products trigger pathways which can lead to beta-cell apoptosis during the development of diabetes.
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PMID:Group VIA Ca2+-independent phospholipase A2 (iPLA2beta) and its role in beta-cell programmed cell death. 2008 51


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