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Rich66 · 09-27-2009, 12:02 PM

http://www.pharmacorama.com/en/Sections/Insulin_4.php

Enhancers of insulin effects, metformin

The drugs which potentiate the effects of insulin are metformin and thiazolidinediones derivatives.
Metformin is a biguanide. It decreases hyperglycemia without risk of hypoglycemia because it does not lower glycemia in healthy subjects. It has an antihyperglycemic effect. Contrary to sulfonylureas, metformin does not stimulate insulin secretion. It can thus be regarded as a potentialisator of insulin.

Its mechanism of action is complex. It acts in the presence of insulin:

by increasing glucose uptake and utilization by tissues, in particular by skeletal muscles
by decreasing hepatic glucose production: it decreases hepatic gluconeogenesis, i.e. formation of glycogen from the amino acids and lipids.
By decreasing intestinal absorption of glucose

Clinical trials show that metformin in diabetics reduces the fasting glycemia, glycosylated hemoglobin, blood cholesterol and triglycerides.
Metformin is not metabolized by biotransformations. It is present in the plasma in a free form, unbound toproteins. Its plasma half-life is about two to four hours. It is eliminated by the kidney and, in the event of renal impairment, risks to accumulating. The renal impairment is thus a contraindication to its prescription.
It is indicated in the treatment of type 2 diabetes mellitus not balanced by an adapted life style, particularly in overweight subjects. It is sometimes used as additive to insulin therapy in the treatment of insulin-dependant diabetes. Metformin could delay the mortality of the diabetics, especially the obese.
The most severe adverse effect of metformin is lactic acidosis, which can be fatal. Its premonitory signs are cramps, digestive disorders, intense abdominal pains, asthenia. These signs must lead to discontinuation of treatment and hospitalization. This lactic acidosis is seen especially in patients with renal or hepatic impairment. The diagnosis is confirmed by determination of blood lactic acid.
It can have other adverse effects: various digestive disorders, nausea, vomiting, diarrhea, especially at the beginning of treatment.
Metformin must be stopped before a radiological examination using iodized contrast agents because they are hyperosmolar and create a cellular dehydration, likely to induce lactic acidosis.

Curr Cancer Drug Targets. 2009 Sep;9(6):748-60.
Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy.

TEXT purchase

van der Veeken J, Oliveira S, Schiffelers RM, Storm G, van Bergen En Henegouwen PM, Roovers RC.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor-1 receptor (IGF-1R) can contribute to tumor development and -progression through their effects on cell proliferation, inhibition of apoptosis, angiogenesis, anchorage-independent growth and tumor-associated inflammation. EGFR-targeting monoclonal antibodies and small molecule tyrosine kinase inhibitors are currently in clinical use for the treatment of several types of cancer. However, primary and acquired resistance to these agents often occurs and thereby limits the clinical efficacy of mono-specific targeted therapy. Results from both in vitro and in vivo studies indicate that cross-talk between EGFR and IGF-1R can lead to acquired resistance against EGFR-targeted drugs.multi-layered cross-talk and its involvement in the induction of resistance to targeted therapies provide a clear rationale for dual targeting of EGFR and IGF-1R. This review describes the interface between the EGFR and IGF-1R signaling networks and the implications of the extensive cross-talk between these two receptor systems for cancer therapy. EGFR and IGF-1R interact on multiple levels, either through a direct association between the two receptors, by mediating the availability of each others ligands, or indirectly, via common interaction partners such as G protein coupled receptors (GPCR) or downstream signaling molecules. This We discuss several (potential) strategies to simultaneously inhibit EGFR and IGF-1R signaling as promising novel therapeutic approaches.

PMID: 19754359 [PubMed - indexed for MEDLINE]

09-27-2009, 12:02 PM	#12
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea http://www.pharmacorama.com/en/Sections/Insulin_4.php Enhancers of insulin effects, metformin The drugs which potentiate the effects of insulin are metformin and thiazolidinediones derivatives. Metformin is a biguanide. It decreases hyperglycemia without risk of hypoglycemia because it does not lower glycemia in healthy subjects. It has an antihyperglycemic effect. Contrary to sulfonylureas, metformin does not stimulate insulin secretion. It can thus be regarded as a potentialisator of insulin. Its mechanism of action is complex. It acts in the presence of insulin: by increasing glucose uptake and utilization by tissues, in particular by skeletal muscles by decreasing hepatic glucose production: it decreases hepatic gluconeogenesis, i.e. formation of glycogen from the amino acids and lipids. By decreasing intestinal absorption of glucose Clinical trials show that metformin in diabetics reduces the fasting glycemia, glycosylated hemoglobin, blood cholesterol and triglycerides. Metformin is not metabolized by biotransformations. It is present in the plasma in a free form, unbound toproteins. Its plasma half-life is about two to four hours. It is eliminated by the kidney and, in the event of renal impairment, risks to accumulating. The renal impairment is thus a contraindication to its prescription. It is indicated in the treatment of type 2 diabetes mellitus not balanced by an adapted life style, particularly in overweight subjects. It is sometimes used as additive to insulin therapy in the treatment of insulin-dependant diabetes. Metformin could delay the mortality of the diabetics, especially the obese. The most severe adverse effect of metformin is lactic acidosis, which can be fatal. Its premonitory signs are cramps, digestive disorders, intense abdominal pains, asthenia. These signs must lead to discontinuation of treatment and hospitalization. This lactic acidosis is seen especially in patients with renal or hepatic impairment. The diagnosis is confirmed by determination of blood lactic acid. It can have other adverse effects: various digestive disorders, nausea, vomiting, diarrhea, especially at the beginning of treatment. Metformin must be stopped before a radiological examination using iodized contrast agents because they are hyperosmolar and create a cellular dehydration, likely to induce lactic acidosis. Curr Cancer Drug Targets. 2009 Sep;9(6):748-60. Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy. TEXT purchase van der Veeken J, Oliveira S, Schiffelers RM, Storm G, van Bergen En Henegouwen PM, Roovers RC. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands. Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor-1 receptor (IGF-1R) can contribute to tumor development and -progression through their effects on cell proliferation, inhibition of apoptosis, angiogenesis, anchorage-independent growth and tumor-associated inflammation. EGFR-targeting monoclonal antibodies and small molecule tyrosine kinase inhibitors are currently in clinical use for the treatment of several types of cancer. However, primary and acquired resistance to these agents often occurs and thereby limits the clinical efficacy of mono-specific targeted therapy. Results from both in vitro and in vivo studies indicate that cross-talk between EGFR and IGF-1R can lead to acquired resistance against EGFR-targeted drugs.multi-layered cross-talk and its involvement in the induction of resistance to targeted therapies provide a clear rationale for dual targeting of EGFR and IGF-1R. This review describes the interface between the EGFR and IGF-1R signaling networks and the implications of the extensive cross-talk between these two receptor systems for cancer therapy. EGFR and IGF-1R interact on multiple levels, either through a direct association between the two receptors, by mediating the availability of each others ligands, or indirectly, via common interaction partners such as G protein coupled receptors (GPCR) or downstream signaling molecules. This We discuss several (potential) strategies to simultaneously inhibit EGFR and IGF-1R signaling as promising novel therapeutic approaches. PMID: 19754359 [PubMed - indexed for MEDLINE]