A novel therapeutic agent for type 2 diabetes mellitus sglt2 inhibitor,medication of type 1 diabetes,type 2 diabetes insulin sensitive cells - PDF Books


Background: Diabetes is one of the most common chronic diseases, affecting almost 3 million in Canada alone and is characterized by increased blood glucose levels.
A novel strategy for the treatment of diabetes mellitus - sodium glucose co-transport inhibitors. Dapagliflozin, a novel selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus.
A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Single-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy volunteers and patients with type 2 diabetes mellitus.
Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose co-transporter (SGLT2) inhibitors, exhibits anti-diabetic efficacy in rodent models.
Sodium glucose co-transport inhibitors may offer promising treatment for patients suffering from diabetes.
The inhibitors act by increasing the loss of glucose in urine by decreasing the reabsorption of glucose from the proximal tubules of nephrons. Those who are over 40 years of age, are overweight, have high cholesterol or triglyceride levels, have a close relative with diabetes, are smokers, have high blood pressure, have had gestational diabetes or pre-diabetes are at an increased risk of developing diabetes. Aims: The aim of this review was to assess the efficacy of sodium glucose co-transport inhibitors in the treatment of diabetes as well as any adverse effects.
Materials and Methods : Databases such as MEDLINE, COCHRANE and EMBASE were systematically searched for literature on the efficacy of sodium glucose co-transport inhibitors in improving the glycemic control of patients with diabetes. Some patients suffer from pre-diabetes, in which the blood glucose level of the patient is raised above normal, but is not sufficient for the blood glucose range for diabetes. Results: Research showed that sodium glucose co-transport inhibitors significantly decreased blood glucose levels by increasing glucosuria. Diabetes type 1 involves decreased secretion of insulin by the pancreas, while diabetes type 2 refers to increased resistance of cells to insulin.
Due to the diuretic effects of these inhibitors, diabetic patients who were suffering from hypertension showed a decrease in blood pressure. Current treatment for diabetesTreatment modalities employed for diabetic patients include education, lifestyle modifications regarding physical activity, weight management and diet. Anti-hyperglycemic agents, which include Alpha-glucosidase inhibitors, DPP-4 inhibitors, Sulfonylureas and meglitinides, Thiazolidinediones and biguanides, lower the blood glucose level. The most common adverse effect seen in patients on these medications was mycotic infection of the urinary or genital tract. Insulin may also be used if the blood glucose level cannot be controlled by oral medications [Table 2]. Conclusion: Sodium glucose co-transport inhibitors may be an effective line of treatment for diabetes. Table 2: Treatments of diabetes mellitusClick here to viewOral anti-diabetic drugs act in various ways to lower blood glucose levels. Alpha-glucosidase inhibitors prevent the breakdown of starches, which slow the entry of glucose into the blood stream. The blood glucose level can then be matched with an impaired insulin response or sensitivity. Biguanides reduce the amount of glucose released into the blood stream by the liver and muscles and increase uptake of glucose by them, in effect reducing the blood glucose level. Dipeptidyl peptidase-4 (DPP-4) increases blood concentration of the incretin GLP-1 (glucagon-like-peptide-1), which inhibits glucagon release, the effect of which decreases blood glucose, but, more significantly, increases insulin secretion. Sulfonylureas and meglitinides stimulate the beta cells in the pancreas to increase the endogenous release of insulin; insulin, in turn, decreases the blood glucose level.
Thiazolidinediones help to influence insulin-sensitive genes, which enhance the production of messenger RNAs (mRNAs) of insulin-dependent enzymes. Adverse effects of oral anti-diabeticsAll of the oral anti-hyperglycemic drugs are accompanied by some undesirable side effects. Since DPP-4 acts as a suppressor of neoplasms, patients on DPP-4 inhibitors may be at increased risk of developing different types of tumors and cancers.
Sulfonylureas and meglitinides produce excessive secretion of insulin and may cause hypoglycemia. Another side effect may be weight gain due to increased insulin secretion, resulting in greater utilization of glucose by the cells. The kidneys can add glucose to the blood stream in periods of fasting by gluconeogenesis or they may remove excess glucose from the blood when present. All of the blood contents, except blood cells and proteins, are filtered into Bowman's capsule of the glomeruli of the kidneys through the process of ultrafiltration.
The blood plasma filtered into Bowman's capsule also contains all of the blood's glucose, which is completely reabsorbed into the blood vessels from the proximal convoluted tubules in normal individuals. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Unless the blood contains an excess of glucose, all of the filtered glucose is reabsorbed with only negligible amounts of glucose being excreted in the urine. The reabsorption of glucose from the proximal tubules of the nephrons to the capillaries surrounding them consists of two steps.
First, the glucose must be transported from the tubules into the tubular epithelial cells, and then are transported from the tubular cells to the blood vessels. The transport of glucose from the tubules into the tubular epithelial cells is accomplished by sodium glucose co-transporters (SGLTs). SGLTs encompass a family of membrane proteins that act as carrier proteins for the secondary active co-transport of glucose, amino acids and some other substances across the inner tubular membrane of proximal renal tubules as well as the intestinal epithelium. The kidneys contain two sodium glucose co-transporters, SGLT-2 and SGLT-1, arranged in a series along the length of the proximal tubules. The low-affinity transporter, SGLT-2, is responsible for the reabsorption of most of the glucose in the kidneys.
Mechanism of Action of SGLT-2 InhibitorsSGLT2 inhibitors block the reabsorption of filtered glucose, leading to the excretion of glucose in urine, bringing the blood glucose levels back to normal.
The mechanism is as follows: as the blood plasma is filtered into Bowman's capsule, all the glucose in the blood is also filtered into Bowman's capsule.
The glucose passes along to the proximal tubule, as the SGLT-2 inhibitors have blocked the reabsorption of glucose into the blood.
Most of the glucose that is filtered into Bowman's capsule is excreted in the urine, thus lowering the blood glucose level of the patient.
This action holds potential promise for patients suffering from diabetes mellitus in terms of improvements in glycemic control. In addition, the loss of glucose in the urine, which is associated with SGLT-2 inhibition, provides an additional benefit of weight loss and the diuretic properties of SGLT-2 inhibition may help counter hypertension in diabetics.
Although the action of these inhibitors would suggest that they may be effective for both type 1 and type 2 diabetes, research to date has focused exclusively on type 2 diabetes. In addition to original studies, systematic reviews were also identified and their references examined for other studies.
The search was limited human researches, which were published during or after 2005 and included searches for sodium glucose co-transport inhibitor, SGLT inhibitor, SGLT-2 inhibitor diabetes, renal transporter inhibitor diabetes and sodium glucose co-transporter diabetes. The studies which had an unreliable study design,, were limited to a specific ethnic group or reported incomplete results were excluded from this review.
The literature was also assessed for quality of methods independently by the two authors and the results were compared. Fifty-eight original studies and reviews were selected with seven additional studies identified through other sources. The remaining 27 articles were assessed for quality, relevance to this review, clarity and completeness of reported results and study methods. After a detailed analysis, six studies were identified for inclusion in this review [Figure 1]. All of the research reported that the SGLT-2 inhibitors were significantly effective in decreasing blood glucose levels and in weight reduction. However, urinary and genital tract infections were found to be a side effect in patients taking these medications. In three randomized controlled trials with SGLT-2 inhibitors [2],[3],[4] , significant improvement in glycemic control was reported. Patients were divided into three groups randomly; the first group was given insulin, the second group 10 mg dapagliflozin and the third group 20 mg dapagliflozin. Although the patients receiving 20 mg dapagliflozin showed the most decrease in blood glucose levels, this group also showed more genital infections than the other groups.
A randomized controlled trial [6] carried out in type 2 diabetic patients showed significant glucosuria and thus reduction in blood glucose levels.
The patients also demonstrated decrease in serum uric acid and increase in serum magnesium, serum phosphate, hematocrit and urine volume, although these changes were small. Facilitative transport, which is driven by the concentration gradient across cellular membranes, occurs in essentially all cell types and is controlled by the GLUT transporter family.
Secondary active transport is the first step in transcellular glucose transport in the intestine and kidney and is mediated by the SGLT transporter family. SGLT-2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney and accounts for approximately 90% of glucose reabsorption.
In addition, the glucosuria seen with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. Although long-term safety data are lacking, studies to date have generally found SGLT-2 inhibitors to be safe and well-tolerated. Although the current research has mainly focused on its efficacy in improving the glycemic control in patients with diabetes type 2, theoretically it may also benefit patients with diabetes type 1. The efficacy of SGLT-2 inhibitors has been tested in rats, mice and dogs through many trials, although trials in humans are severely lacking. Trials assessing the long-term usefulness of these drugs in diabetic patients have not been conducted as yet. The research on SGLT-2 inhibitors has mainly focused on Dapagliflozin; other SGLT-2 inhibitors should also be assessed in humans. SGLT-2 inhibitors may also benefit patients suffering from renal glucosuria due to diabetes mellitus as well as other causes (e.g.



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