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http://www.sciencedaily.com/releases/2009/05/ 090514153136.htm

Old Diabetes Drug Teaches Experts New Tricks

ScienceDaily (May 20, 2009) — Research from the Johns Hopkins Children's Center reveals that the drug most commonly used in type 2 diabetics who don't need insulin works on a much more basic level than once thought, treating persistently elevated blood sugar — the hallmark of type 2 diabetes — by regulating the genes that control its production.
Reporting in the May 15 issue of Cell, investigators say they have zeroed in on a specific segment of a protein called CBP made by the genetic switches involved in overproduction of glucose by the liver that could present new targets for drug therapy of the disease.
In healthy people, the liver produces glucose during fasting to maintain normal levels of cell energy production. After people eat, the pancreas releases insulin, the hormone responsible for glucose absorption. Once insulin is released, the liver should turn down or turn off its glucose production, but in people with type 2 diabetes, the liver fails to sense insulin and continues to make glucose. The condition, known as insulin resistance, is caused by a glitch in the communication between liver and pancreas.
Metformin, introduced as frontline therapy for uncomplicated type 2 diabetes in the 1950s, up until now was believed to work by making the liver more sensitive to insulin. The Hopkins study shows, however, that metformin bypasses the stumbling block in communication and works directly in the liver cells.
"Rather than an interpreter of insulin-liver communication, metformin takes over as the messenger itself," says senior investigator Fred Wondisford, M.D., who heads the metabolism division at Hopkins Children's. "Metformin actually mimics the action of CBP, the critical signaling protein involved in the communication between the liver and the pancreas that's necessary for maintaining glucose production by the liver and its suppression by insulin."
To test their hypothesis, researchers induced insulin resistance in mice by feeding them a high-fat diet over several months. Mice on high-fat diets developed insulin resistance, and their high blood glucose levels did not drop to normal after eating. Once treated with metformin, however, CBP was activated to the levels of nondiabetic mice, and their blood glucose levels returned to normal. However, when given to diabetic mice with defective copies of CBP, metformin had no effect on blood glucose levels, a proof that metformin works through CBP.
Researchers further were able to determine that metformin worked on one particular section of CBP by studying the drug's effects in mice with normal CBP and in mice missing this section of their CBP. The mice with normal CBP responded to metformin with a drop in their fasting blood glucose — much like diabetes patients do — while the mice missing that section in their CBP had no decrease in their blood sugar.
Because CBP is involved in growth and development and a variety of metabolic processes in other organs, this newly discovered pathway may hold therapeutic promise for conditions like growth retardation, cancer and infertility, investigators say.
Another important finding in the study: Investigators have discovered a biomarker that can predict how well a person will respond to treatment with metformin and help doctors determine the optimal therapeutic dose, which can vary widely from person to person. The Hopkins team has found that in mice, metformin changes CBP in white bloods cells — just as it does in liver cells — creating a molecular marker that is easily measured via a standard blood test.
"This is the quintessence of individualized medicine: We have found an easily obtainable biomarker with great predictive power that can tell us whether and how well an individual will respond to treatment and help us determine the best dose right away instead of trying to do it by trial and error," Wondisford says.
Researchers caution that, while promising, their findings must be first replicated in humans.
Diabetes (type 1 and type 2) is a leading cause of kidney failure, eye disease and amputations, and one of the main causes of heart disease and stroke. Nearly 24 million Americans have type 2 diabetes, according to the U.S. Centers for Disease Control.
Lead author of the paper is Ling He.
Other investigators in the study include Amin Sabet, Stephen Djedjos, Ryan Miller, Mehboob Hussain and Sally Radovick, all of Hopkins, and Xiaojian Sun, of the University of Chicago.
The research was funded by the National Institutes of Health and by the Baltimore Diabetes Research and Training Center, a joint endeavor between Johns Hopkins and the University of Maryland for basic science, clinical research and community outreach on diabetes and obesity in both adults and children.

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Adapted from materials provided by Johns Hopkins Medical Institutions, via EurekAlert!, a service of AAAS.
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Johns Hopkins Medical Institutions (2009, May 20). Old Diabetes Drug Teaches Experts New Tricks. ScienceDaily. Retrieved June 3, 2009, from http://www.sciencedaily.com* /releases/2009/05/090514153136.htm

J Nucl Med. 2007; 48 (Supplement 2):184P

Oncology: Clinical Diagnosis-Solid Tumors Miscellaneous Tumors and Clinical Problems

Alteration of FDG uptake associated with metformin: Pitfall and opportunity

Bahar Dasgeb¹ and Eliot Siegel^{1 1} Radiology/Nuclear Medicine, University of Maryland, Baltimore, Maryland
627
Objectives: Metformin, a biguanide molecule with 15 hour half life, is commonly utilized in the treatment of non-insulin-dependent diabetes mellitus. The major effect of metformin is postulated to be enhanced glucose utilization. In vivo and in vitro studies have demonstrated that metformin stimulates the insulin-induced glucose uptake into skeletal muscle and adipocytes in both diabetic individuals and animal models. It has also been shown that insulin-mediated visceral fat glucose uptake (VFGU) is enhanced by metformin monotherapy which is believed to be related to enhanced VF insulin sensitivity. Administration of metformin is routinely discontinued prior to administration of contrast for a CT study. The purpose of the study was to demonstrate and quantify the alteration in FDG uptake in subcutaneous tissue and peripheral striated muscle associated with the use of metformin. Methods: PET images were obtained on fifteen patients who had taken metformin either within four hours prior to an FDG PET examination, between four and twelve hours, or more than twelve hours prior to the study. Subjective and quantitative analysis was made of the distribution and ratio of uptake in the striated muscles and subcutaneous tissue. Results: Patients who received metformin within 12 hours of a PET study were found to have significantly increased uptake in their peripheral musculature and in their subcutaneous fat diffusely as judged subjectively and utilizing ratios of uptake with that in the liver and lungs in comparison to those that did not receive metformin within that time period. Conclusions: Metformin should be discontinued at least 12 hours prior to performing a PET study regardless of whether intravenous CT contrast material is administered. PET may also help quantify the impact of metformin therapy on diabetic patients which could have treatment selection implications.




Free Radic Biol Med. 2010 Jan 15. [Epub ahead of print]
Paclitaxel Combined with Inhibitors of Glucose and Hydroperoxide Metabolism Enhances Breast Cancer Cell Killing Via H(2)O(2)-Mediated Oxidative Stress.

Hadzic T, Aykin-Burns N, Zhu Y, Coleman MC, Leick K, Jacobson GM, Spitz DR.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA.
Cancer cells (relative to normal cells) demonstrate alterations in oxidative metabolism characterized by increased steady-state levels of reactive oxygen species [i.e. hydrogen peroxide, H(2)O(2)] that may be compensated for by increased glucose metabolism but the therapeutic significance of these observations is unknown. In the current study, inhibitors of glucose [i.e., 2-deoxy-D-glucose, 2DG] and hydroperoxide [i.e., L-buthionine-S, R-sulfoximine, BSO] metabolism were utilized in combination with a chemotherapeutic agent paclitaxel [PTX], thought to induce oxidative stress, to treat breast cancer cells. 2DG+PTX were found to be more toxic than either agent alone in T47D and MDA-MB231 human breast cancer cells, but not in normal human fibroblasts or normal human mammary epithelial cells. Increases in parameters indicative of oxidative stress, including steady-state levels of H(2)O(2), total glutathione, and glutathione disulfide accompanied the enhanced toxicity of 2DG+PTX in cancer cells. Antioxidants, including N-acetyl-cysteine [NAC], polyethylene glycol-conjugated catalase [PEG-CAT] and superoxide dismutase [PEG-SOD], inhibited the toxicity of 2DG+PTX and suppressed parameters indicative of oxidative stress in cancer cells, while inhibition of glutathione synthesis using BSO further sensitized breast cancer cells to 2DG+PTX. These results show that combining inhibitors of glucose [2DG] and hydroperoxide [BSO] metabolism with PTX selectively (relative to normal cells) enhances breast cancer cell killing via H(2)O(2)-induced metabolic oxidative stress, and suggests that this biochemical rationale may be effectively utilized to treat breast cancers. Copyright © 2010. Published by Elsevier Inc.

PMID: 20083194 [PubMed - as supplied by publisher]





A treatment that capitalizes on the PET/Glucose mechanism:

http://www.antiagingmedicine.com/procedures_insulin.htm

Controlling Cancer Growth
At the Nevada Center we use a form of chemotherapy called Insulin Potentiation Therapy (IPT). IPT is a simple, safe medical treatment that exploits the fact that cancer cells, unlike healthy cells, are not able to metabolize fat for energy. They rely completely on glucose (sugar/carbohydrates) for their energy supply. This is a weakness of cancer cells, and we use this weakness to control them. We use the hormone insulin to do this.
When insulin is injected it has the effect of causing the patient’s blood sugar to drop. As the blood sugar drops, the patient’s healthy cells simply shift over to fat metabolism, but the patient’s cancer cells become seriously compromised. Since they rely entirely on sugar metabolism, they go into an emergency mode and open all of their membranes in an effort to get sugar. In this state they are very vulnerable to chemotherapy drugs.
Once the blood sugar has reached a low enough level for the treatment to be effective, we then inject the chemotherapy drugs. This is immediately followed by an intravenous infusion of large amounts of sugar. What happens next is that the cancer cells, weakened and starved for sugar, take up the chemotherapy drugs in large amounts as they take up the sugar they so desperately need.
The effect of this technique is two-fold. First, the cancer cells will take up much larger amounts of chemotherapy medications than they ordinarily would without the insulin application. Secondly, since they are in such a weakened and vulnerable state from the lack of sugar, they are much more sensitive to the toxic effects of the drugs. The result is a level of cancer cell death and growth control comparable to standard chemotherapy. But there is one very big difference.
IPT Is Gentle
Because the IPT technique results in a higher concentration of the chemo-therapeutic drugs in the cancer cells, we are able to use much lower chemo-therapy doses than are normally used to get the same intracellular levels. In general, we usually use about one tenth of the standard dose. A recent soon to be published review of patients treated with IPT shows that the cancer growth controlling effect of IPT is equal to that of standard chemotherapy.
The fact that we can use a lower dose of medication and yet have the same results leads to two very important advantages to IPT. First, the lower dose means that there are little to no side effects. Our patients typically feel as good as ever – even immediately after the treatments. Secondly, and perhaps more importantly, because the doses are so low, IPT treatments can be used as long as they are needed without the concern of long-term toxicity to healthy cells and tissues.



Cancer Res. 2009 Aug 15;69(16):6539-45.
Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth.

Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E.
Departments of Medicine, CURE, Digestive Diseases Research Center, Molecular Biology Institute, University of California at Los Angeles, 90095-1786, USA.
Recently, we identified a novel crosstalk between insulin and G protein-coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTOR. Here, we determined whether metformin disrupts the crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, and BxPC-3) with insulin (10 ng/mL) for 5 minutes markedly enhanced the increase in intracellular [Ca(2+)] induced by GPCR agonists (e.g., neurotensin, bradykinin, and angiotensin II). Metformin pretreatment completely abrogated insulin-induced potentiation of Ca(2+) signaling but did not interfere with the effect of GPCR agonists alone. Insulin also enhanced GPCR agonist-induced growth, measured by DNA synthesis, and the number of cells cultured in adherent or nonadherent conditions. Low doses of metformin (0.1-0.5 mmol/L) blocked the stimulation of DNA synthesis, and the anchorage-dependent and anchorage-independent growth induced by insulin and GPCR agonists. Treatment with metformin induced striking and sustained increase in the phosphorylation of AMPK at Thr(172) and a selective AMPK inhibitor (compound C, at 5 micromol/L) reversed the effects of metformin on [Ca(2+)](i) and DNA synthesis, indicating that metformin acts through AMPK activation. In view of these results, we tested whether metformin inhibits pancreatic cancer growth. Administration of metformin significantly decreased the growth of MIAPaCa-2 and PANC-1 cells xenografted on the flank of nude mice. These results raise the possibility that metformin could be a potential candidate in novel treatment strategies for human pancreatic cancer.

PMID: 19679549 [PubMed - indexed for MEDLINE]



Clin Cancer Res. 2010 Apr 13. [Epub ahead of print]
Crosstalk between Insulin/Insulin-like Growth Factor-1 Receptors and G Protein-Coupled Receptor Signaling Systems: A Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer.

Rozengurt E, Sinnett-Smith J, Kisfalvi K.
Authors' Affiliation: Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles California.
Abstract

Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine-paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between insulin/IGF-1 receptors and GPCR signaling systems in pancreatic cancer cells, leading to enhanced signaling, DNA synthesis, and proliferation. Crosstalk between these signaling systems depends on mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTORC1. Recent results show that metformin-induced activation of AMPK disrupts crosstalk between insulin/IGF-1 receptor and GPCR signaling in pancreatic cancer cells and inhibits the growth of these cells in xenograft models. Given that insulin/IGF-1 and GPCRs are implicated in other malignancies, a similar crosstalk mechanism may be operative in other cancer cell types. Recent epidemiological studies linked administration of metformin with a reduced risk of pancreatic, breast, and prostate cancer in diabetic patients. We posit that crosstalk between insulin/IGF-1 receptor and GPCR signaling is a mechanism for promoting the development of certain types of cancer and a target for the prevention and therapy of these diseases via metformin administration. Clin Cancer Res; 16(9); OF1-7. (c)2010 AACR.

PMID: 20388847 [PubMed - as supplied by publisher]