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A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications.

Molavi B, Rassouli N, Bagwe S, Rasouli N - Vasc Health Risk Manag (2007)

Bottom Line: Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes.In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population.The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.

ABSTRACT
The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin.

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Diabetes is characterized by decompensated insulin secretion for insulin resistance at target organs including adipose tissue, liver and muscle. Insulin resistance is associated with increased proinflammatory cytokines. Inflammatory pathways in insulin resistance can be initiated by extracellular mediators such as cytokines and free fatty acid (FFA) or by intracellular stresses such as ER stress, excess ROS production by mitochondria or lipotoxicity. Activation of NF-κB pathway leads to induction of chemokines that recruit inflammatory cells, such as macrophages. (FFA Free fatty acid, ER Endoplasmic reticulum, DAG diacylglycerol, LCFA long chain fatty acid, IR insulin receptor).
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fig1: Diabetes is characterized by decompensated insulin secretion for insulin resistance at target organs including adipose tissue, liver and muscle. Insulin resistance is associated with increased proinflammatory cytokines. Inflammatory pathways in insulin resistance can be initiated by extracellular mediators such as cytokines and free fatty acid (FFA) or by intracellular stresses such as ER stress, excess ROS production by mitochondria or lipotoxicity. Activation of NF-κB pathway leads to induction of chemokines that recruit inflammatory cells, such as macrophages. (FFA Free fatty acid, ER Endoplasmic reticulum, DAG diacylglycerol, LCFA long chain fatty acid, IR insulin receptor).

Mentions: Obesity is associated with increased accumulation of macrophages in adipose tissues and increased levels of pro-inflammatory cytokines (Di Gregorio et al 2005). In addition, obesity results in excess lipid accumulation not only in adipose tissue but also in tissues such as the liver, skeletal muscle, heart and pancreas (Unger 2003). There is a strong correlation between intramyocellular fat content (IMCL) and insulin resistance (Perseghin et al 1999; Friedman 2002). Ectopic lipid accumulation with resultant functional impairment has been called lipotoxicity, a pathophysiologic event preceding diabetes (Friedman 2002). Increased level of reactive oxygen species (ROS) has been also known as a culprit in the pathogenesis of insulin resistance and diabetic complications (Petersen et al 2004; Schrauwen and Hesselink 2004; Houstis et al 2006; Mehta et al 2006). Insulin resistance and diabetes are associated with disruption and uncoupling of several key oxidative reactions that result in excessive production of ROS at mitochondrial and cellular levels (Nishikawa et al 2000). Increased production of reactive oxygen species in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are associated with atherosclerosis or cardiomyopathy in human investigations and animal models of oxidative stress (Mehta et al 2006; Madamanchi and Runge 2007). More recently, obesity-induced endoplasmic reticulum stress (increased unfolded protein response due to the disruption of the smooth operation of endoplasmic reticulum) has been demonstrated to result in peripheral insulin resistance (Hotamisligil 2005). Lipotoxicity, oxidative stress and endoplasmic reticulum stress are associated with activation of nuclear factor-κB (NF-κB), chronic inflammation and insulin resistance (Figure 1). Interventions aimed at modulating any of the above mentioned pathways are potential therapies for diabetes and its complications.


A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications.

Molavi B, Rassouli N, Bagwe S, Rasouli N - Vasc Health Risk Manag (2007)

Diabetes is characterized by decompensated insulin secretion for insulin resistance at target organs including adipose tissue, liver and muscle. Insulin resistance is associated with increased proinflammatory cytokines. Inflammatory pathways in insulin resistance can be initiated by extracellular mediators such as cytokines and free fatty acid (FFA) or by intracellular stresses such as ER stress, excess ROS production by mitochondria or lipotoxicity. Activation of NF-κB pathway leads to induction of chemokines that recruit inflammatory cells, such as macrophages. (FFA Free fatty acid, ER Endoplasmic reticulum, DAG diacylglycerol, LCFA long chain fatty acid, IR insulin receptor).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2350137&req=5

fig1: Diabetes is characterized by decompensated insulin secretion for insulin resistance at target organs including adipose tissue, liver and muscle. Insulin resistance is associated with increased proinflammatory cytokines. Inflammatory pathways in insulin resistance can be initiated by extracellular mediators such as cytokines and free fatty acid (FFA) or by intracellular stresses such as ER stress, excess ROS production by mitochondria or lipotoxicity. Activation of NF-κB pathway leads to induction of chemokines that recruit inflammatory cells, such as macrophages. (FFA Free fatty acid, ER Endoplasmic reticulum, DAG diacylglycerol, LCFA long chain fatty acid, IR insulin receptor).
Mentions: Obesity is associated with increased accumulation of macrophages in adipose tissues and increased levels of pro-inflammatory cytokines (Di Gregorio et al 2005). In addition, obesity results in excess lipid accumulation not only in adipose tissue but also in tissues such as the liver, skeletal muscle, heart and pancreas (Unger 2003). There is a strong correlation between intramyocellular fat content (IMCL) and insulin resistance (Perseghin et al 1999; Friedman 2002). Ectopic lipid accumulation with resultant functional impairment has been called lipotoxicity, a pathophysiologic event preceding diabetes (Friedman 2002). Increased level of reactive oxygen species (ROS) has been also known as a culprit in the pathogenesis of insulin resistance and diabetic complications (Petersen et al 2004; Schrauwen and Hesselink 2004; Houstis et al 2006; Mehta et al 2006). Insulin resistance and diabetes are associated with disruption and uncoupling of several key oxidative reactions that result in excessive production of ROS at mitochondrial and cellular levels (Nishikawa et al 2000). Increased production of reactive oxygen species in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are associated with atherosclerosis or cardiomyopathy in human investigations and animal models of oxidative stress (Mehta et al 2006; Madamanchi and Runge 2007). More recently, obesity-induced endoplasmic reticulum stress (increased unfolded protein response due to the disruption of the smooth operation of endoplasmic reticulum) has been demonstrated to result in peripheral insulin resistance (Hotamisligil 2005). Lipotoxicity, oxidative stress and endoplasmic reticulum stress are associated with activation of nuclear factor-κB (NF-κB), chronic inflammation and insulin resistance (Figure 1). Interventions aimed at modulating any of the above mentioned pathways are potential therapies for diabetes and its complications.

Bottom Line: Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes.In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population.The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.

ABSTRACT
The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin.

Show MeSH
Related in: MedlinePlus