Type 2 diabetes and obesity are common metabolic disorders characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. One approach to increase muscle glucose disposal is to reverse/improve these insulin-signaling defects. Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. In contrast, physical training and metformin improve whole-body glucose disposal but have minimal effects on proximal insulin-signaling steps. A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). A different strategy to increase muscle glucose disposal is by stimulating insulin-independent glucose transport. AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge and becomes activated in situations of energy consumption, such as muscle contraction. Several studies have shown that pharmacologic activation of AMPK increases glucose transport in muscle, independent of the actions of insulin. AMPK activation is also involved in the mechanism of action of metformin and adiponectin. Moreover, in the hypothalamus, AMPK regulates appetite and body weight. The effect of AMPK to stimulate muscle glucose disposal and to control appetite makes it an important pharmacologic target for the treatment of type 2 diabetes and obesity.
"Type 1 diabetes is characterized by absolute insulin deficiency due to viral or autoimmune destruction of pancreatic beta cells, while the major feature of the more common type 2 variant is obesity-linked impairment of intracellular insulin signaling [1-3]. Apart from its well-known effect on blood sugar levels, insulin is known to regulate the growth, differentiation and metabolism of its target cells at multiple levels . Insulin signaling pathways have been shown to converge on and modulate the transcription of a plethora of genes . "
[Show abstract][Hide abstract] ABSTRACT: There has been an increasing body of epidemiologic and biochemical evidence implying the role of cerebral insulin resistance in Alzheimer-type dementia. For a better understanding of the insulin effect on the central nervous system, we performed microarray-based global gene expression profiling in the hippocampus, striatum and prefrontal cortex of streptozotocin-induced and spontaneously diabetic Goto-Kakizaki rats as model animals for type 1 and type 2 diabetes, respectively.
Following pathway analysis and validation of gene lists by real-time polymerase chain reaction, 30 genes from the hippocampus, such as the inhibitory neuropeptide galanin, synuclein gamma and uncoupling protein 2, and 22 genes from the prefrontal cortex, e.g. galanin receptor 2, protein kinase C gamma and epsilon, ABCA1 (ATP-Binding Cassette A1), CD47 (Cluster of Differentiation 47) and the RET (Rearranged During Transfection) protooncogene, were found to exhibit altered expression levels in type 2 diabetic model animals in comparison to non-diabetic control animals. These gene lists proved to be partly overlapping and encompassed genes related to neurotransmission, lipid metabolism, neuronal development, insulin secretion, oxidative damage and DNA repair. On the other hand, no significant alterations were found in the transcriptomes of the corpus striatum in the same animals. Changes in the cerebral gene expression profiles seemed to be specific for the type 2 diabetic model, as no such alterations were found in streptozotocin-treated animals.
According to our knowledge this is the first characterization of the whole-genome expression changes of specific brain regions in a diabetic model. Our findings shed light on the complex role of insulin signaling in fine-tuning brain functions, and provide further experimental evidence in support of the recently elaborated theory of type 3 diabetes.
"For example, an HFD results in a small increase in anti-inflammatory macrophages (sometimes referred to as M2) but with a large increase in the amount of proinflammatory macrophages (sometimes referred to as M1), with secretion from macrophages and adipocytes of a variety of inhibitory insulin-signaling cytokines as well as additional macrophage-attracting chemokines. This inflammatory signaling cascade is thought to impair insulin signal transduction, predominantly through a blockade of insulin receptor substrate protein function that generates a state of insulin resistance (8). A critical physiologic role of this inflammatory response in insulin signaling was established because pharmacologic and genetic blockade of macrophage inflammation were both found to prevent HFD-induced insulin resistance but not the development of obesity (9). "
[Show abstract][Hide abstract] ABSTRACT: Previous studies have demonstrated that mice fed a high-fat diet (HFD) develop insulin resistance with proinflammatory macrophage infiltration into white adipose tissue. Concomitantly, adipocytes undergo programmed cell death with the loss of the adipocyte-specific lipid droplet protein perilipin, and the dead/dying adipocytes are surrounded by macrophages that are organized into crown-like structures. This study investigated whether adipocyte cell death provides the driving signal for macrophage inflammation or if inflammation induces adipocyte cell death.
Two knockout mouse models were used: granulocyte/monocyte-colony stimulating factor (GM-CSF)-null mice that are protected against HFD-induced adipose tissue inflammation and cyclophilin D (CyP-D)-null mice that are protected against adipocyte cell death. Mice were fed for 4-14 weeks with a 60% HFD, and different markers of cell death and inflammation were analyzed.
HFD induced a normal extent of adipocyte cell death in GM-CSF-null mice, despite a marked reduction in adipose tissue inflammation. Similarly, depletion of macrophages by clodronate treatment prevented HFD-induced adipose tissue inflammation without any affect on adipocyte cell death. However, CyP-D deficiency strongly protected adipocytes from HFD-induced cell death, without affecting adipose tissue inflammation.
These data demonstrate that HFD-induced adipocyte cell death is an intrinsic cellular response that is CyP-D dependent but is independent of macrophage infiltration/activation.
"If these drugs are available they represent a useful option since they improve glycaemic control thereby inducing glycosuria without any direct effect on insulin secretion, but will improve it just like phloridzin in animal models; these drugs might in fact be considered as phloridzin analogues. As mentioned above, metformin may act through the AMPK pathway  by increasing insulin sensitivity with no hypoglycaemic event. In addition, it has a protective effect on beta cells, attenuating the reactive oxygen species production . "
[Show abstract][Hide abstract] ABSTRACT: Although it is now well established that the deleterious effects of chronic hyperglycaemia (i.e., glucose toxicity) play an important role in the progressive impairment of insulin secretion and sensitivity, the two major actors of the pathogenesis of type 2 diabetes mellitus, the precise biochemical and molecular mechanisms responsible for the defects induced by glucose toxicity still remain to be defined.
here we will briefly report on convincing evidence that glucose toxicity acts through oxidative stress, modifications in the exosamine pathway, protein kinase C and others. After inducing or contributing to the genesis of type 2 diabetes, these same mechanisms are considered responsible for the appearance and worsening of diabetic specific microvascular complications, while its role in increasing the risk of cardiovascular diseases is less clear. Recent intervention studies (ADVANCE, ACCORD, VADT), conducted to evaluate the effects of strict glycaemic control, apparently failed to demonstrate an effect of glucose toxicity on cardiovascular diseases, at least in secondary prevention or when diabetes is present for a prolonged time. The re-examination, 20 years later, of the population studied in the UKPDS study, however, clearly demonstrated that the earliest is the strict glycaemic control reached, the lowest is the incidence of cardiovascular diseases observed, including myocardial infarction.
The acquaintance of the role of glucose toxicity should strongly influence the usual therapeutic choices and glycaemic targets where the reduced or absent risk of hypoglycaemia, durability of action, and data on prolonged safety should be the preferred characteristics of the drug of choice in the treatment of type 2 diabetes mellitus.
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