The Role Of Trpm2 Channels On Diabetes

Diabetes is a growing concern and health challenge for the American people (b). Diabetes is a condition in which the body cannot react to insulin appropriately or either cannot produce insulin efficiently (w). “Without a properly functioning insulin signaling system, blood glucose levels become elevated and other metabolic abnormalities occur, leading to the development of serious, disabling complications” (w). There are numerous forms of diabetes amongst the nation, however, there are three main forms of diabetes. Most people have heard of type one diabetes, type two diabetes, and gestational diabetes because they are common. Type two diabetes deals with a resistance to insulin, while

     Diabetes mellitus is a group of metabolic disorders characterized by inadequate insulin secretion by the pancreas or cellular destruction leading to an insulin deficiency. Depending on the cause of the insulin shortage, diabetes can be subcategorized into type I and type II. Type I diabetes (T1DM) is usually mediated by the destruction of b-cells in the pancreas resulting in decreased insulin production and secretion. Type II diabetes (T2DM) is the failure of these b-cells to secrete adequate amounts of insulin to compensate for insulin resistance and increased gluconeogenesis combined with an overall resistance to the insulin action (8., 1997). T2DM accounts

Type 2 diabetes is a polygenic, complex disease that has become a worldwide health crisis. According to the World Health Organization over 422 million people in the world had this disease in 2014 (1), the Center for Disease Control and Prevention stated that in the United States alone 29 million people had diabetes in 2014 (2). While the genetic predisposition contributing to the diabetes phenotype is not fully understood to date it still remains an area of active research. There are also various environmental factors that contribute stress to the glucose homeostasis system that provide a different approach in understanding this disease. Comprehending the pathogenesis of the disease has been an area of constant research for decades. There is hope that pharmaceutical developments can follow along and find medical treatments that can target the key pathogenic elements of this disease.

Insulin resistance is the first physiological change occurring in type two diabetes. In these type two diabetic patients, insulin is unable to move glucose into liver, kidney and muscle cells although insulin is able to attach properly to the cell surface receptors. In order to rectify this, most patients with type two diabetes start secreting normal to very high levels of insulin, which can initially overcome this resistance. After a while, the pancreas cannot keep up with this high insulin production and the cells become resistant to glucose intake. Persistent hyperglycemia or high blood glucose levels are not desirable since this causes damage to the beta cells of the pancreas that produces the insulin hormone. This damage to beta cells further hampers insulin synthesis and patients at this stage are categorized as full-blown diabetic. Such patients consistently show a hyperglycemia state even after hours of fasting ( Hinkle & Cheever,

Diabetes Mellitus (DM) or Type 2 Diabetes is seen as a metabolic disease that is categorized by abnormally high blood glucose or hyperglycemia. Diabetes Mellitus is also formerly known as noninsulin-dependent diabetes mellitus and is the most common form of diabetes that is seen. Insulin is a hormone that is supplied to the body that allows us to efficiently use glucose as fuel. When carbohydrates are broken down into sugars in the stomach glucose enters the blood circulation simulating the pancreas to release insulin in an appropriate amount to become used for energy. With diabetes mellitus the body does not properly make use of the insulin supplied for the body. This causes the pancreas to produced an extra amount if insulin which the body cannot keep up with, causing an imbalance to the blood glucose levels (American Diabetes Association, 2015). In the united states diabetes affects almost 29.1 million people, while the another 86 million people have pre-diabetes but do not know. It is also known as the 7th leading cause of death in the country in the recent years (MedicineNet.com, 2016). For a patient suffering from a chronic form of diabetes mellitus understanding how these mechanisms lead to the condition can be used as preventative measures. Potential consequences as well as the causes and clinical manifestations will ensure a better knowledge on the issue to monitor the condition.

Characteristic of this family, each KCNJ11 subunit has 2 transmembrane domains. This KATP channel exists as an octamer, consisting of both KCNJ11 (Kir6.2) and SUR1 together, which are present in a 4:4 ratio in every channel [3]. It is KCNJ11 that has the pore forming region, and that sets the resting potential of the cell at -70 mV, as this is the equilibrium potential for K+ [3][6]. ATP binding to the KCNJ11 subunit is what causes the characteristically important closing step of the KATP channel, and the depolarizing of the cell, along with the rest of the cascade leading to insulin release [3]. This is intuitive, as increased glucose uptake will cause increased ATP production, and thus high ATP levels cause the insulin releasing cascade. However, an alternate mechanism exists to control the open vs. closed state of the channel. SUR1 is a regulatory subunit, whose role can be seen during interactions with MgADP (ADP bound to Mg for stabilization) [3]. When MgADP interacts with SUR1, it counteracts the effect from ATP binding to the KCNJ11 subunit, and causes stimulation of the channel, such that it will allow for the current of K+ to resume [3]. This is intuitive as well, as increasing levels of MgADP would indicate a shift in the [ATP]/[ADP] ratio towards ADP, meaning the cell is not taking up enough glucose to create sufficient ATP. The cellular stores of ATP are

Diabetes is a very common chronic medial disorder and expected to be a big medical challenge of the twenty first century (Clark, 2004). It is a condition, in which the glucose level in the blood becomes so high that the body is unable to utilize it properly. This long-term condition results when the pancreas of the victim is either not able to produce enough insulin (sometimes even cannot produce any insulin) or the insulin produced cannot work properly. Diabetes is divided into two main types: Type 1 and Type 2. Type 1, also known as insulin dependent diabetes milletus (Masharani, 2008) cannot be prevent while Type 2 can be prevented but if the patient is at pre-diabetes stage.

Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes in the U.S., and it is a severe disease with numerous life-threatening consequences. T2DM occurs when insulin, which is a hormone released by the pancreas for sugar metabolism, becomes low or cannot be utilized by cells. In the normal condition, insulin circulates in the bloodstream and enables to convert starch, sugar, and all polysaccharides complex into glucose, which cells use for energy; however, in T2DM, there is continuously too much glucose in the bloodstream. When cells don’t interact appropriately with insulin, blood sugar increases, and this phenomenon is called insulin resistance that leads to many health problems,

“If someone has Type 2 Diabetes their pancreas may not produce enough insulin or their cells resist the effects of insulin, and in extreme cases it may be a combination of both”. (AuthorSTREAM) Currently there are about 29.1 million people in the United States that have diabetes; 8.1 million of whom may be undiagnosed and/or unaware of their condition. For adults twenty years old or older, statistics say one in every ten people suffers from diabetes; in age sixty-five and older, statistics say that figure rises to more than one in four.

Type 1 diabetes, also referred to as Insulin Dependent Diabetes Mellitus (IDDM) or Juvenile Diabetes, can be caused by a genetic disorder. It can occur at any age, but it is most often diagnosed in children, adolescents, or young adults around 20 years old or before a person is 30 years of age. Insulin is a hormone produced by special cells, called the beta cells, in the pancreas, an organ located in the area behind the stomach. Insulin is needed to move blood sugar (glucose) into cells, where it is stored and later used for energy. In type 1 diabetes, these cells produce little or no insulin. Without enough insulin, glucose builds up in the bloodstream instead of going into the cells. The body is unable to

Incretins reduces gastric emptying and also inhibit glucagon release from the alpha-cells and improves the glycemic control alongside decreases the body weight and systolic blood pressure in type 2 diabetic patients [26]. Risk of hypoglycemia is low due glucose-dependent mechanism of action. Thus, incretin mimetics have become an important part for treating T2DM. Incretin based drugs include DPP-4 inhibitors and GLP-1 receptor agonists (Exenatide and Liraglutide).

Starting from the top with Group I ACs, this includes ACs 1, 3, and 8, this group is stimulated by the Ca2+/calmodulin signaling pathway via direct binding of calmodulin (CAM) to the ACs.9 A majority of the evidence of stimulation comes from overexpression system studies, but current evidence on the mechanism by which the binding of CAM to AC1, 3, or 8 stimulates activity has yet to be deciphered in a cohesive manner.9 However, on the other end of the spectrum exists Group III ACs, which includes ACs 5 and 6. The Ca2+/CAM signaling pathway inhibits their activity. Structural analyses done on ACs 5 and 6 provide evidence indicating that the Ca2+ ion displaces Mg2+ ions in the active site.10 Figure 3 shows the active site with emphasis on the Asp396 and Asp440, but also shown is their interactions between a Mn2+ ion and a Mg2+ ion. The

This increases the permeability of both membranes to molecules and ions with a molecular mass less than 1.5 kDa. Increased permeability leads to loss of water potential and consequently mitochondrial swelling, membrane rupture and decreased ATP production. Three components have been identified in the make-up of the MPTP. The voltage-dependent anion channel (VDAC) in the outer membrane, the adenine nucleotide translocase (ANT) in the inner membrane and cyclophilin-D (Cyp-D) in the mitochondrial matrix. VDAC is associated with IP3R in the ER and development of Ca2+microdomains, ANT exchanges cytosolic ADP for mitochondrial ATP and Cyp-D is a peptidyl-prolyl isomerase and has a role in many functions including transcription and apoptosis. Conformational changes are induced in all three by prolonged Ca2+ overload which produce transmembrane complexes leading to MPTP formation. It was found by Mukherjee et al (2015) that MPTP opening, mediated by toxin-induced Ip3R and RyR calcium release, resulted in diminished ATP production which led to impaired Ca2+ clearance, zymogen activation, cytokine production and finally necrosis. Intracellular ATP supplementation prevented this. Mukherjee then demonstrated that when MPTP opening was inhibited either genetically or via pharmacology, all responses of acute pancreatitis were diminished

Some of these adapter proteins also interact with a docking protein (SNARE) on the plasma membrane and assist FL-myoVa to act as a tether for releasing cargo4-6. For example, Gran A/B directly binds to syntaxin 1a, a SNARE protein responsible for docking the granule at the plasma

Diabetes Mellitus is “a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. It is a disease which is caused by the insufficient insulin secretion or decrease in the peripheral effects of insulin. It is a serious problem in terms of morbidity and mortality. The hyperglycemia is associated with long term damage, dysfunction and failure of various organs especially the eyes, kidneys, nerves, heart and blood vessels. It’s associated with many complications which includes blindness of the eyes and amputations of the extremities. It is also associated with neuropathy, retinopathy, and cardiovascular diseases which lead to mortalities.