Diabetes Gene Therapy

Name :E.Preetham Reddy

Id Number : 2012510127

Gene TherapyDefinition : the transplantation of normal

genes into cells in place of missing or defective ones in order to correct genetic disorders. Gene therapy is the use of DNA as a pharmaceutical agent to treat disease.

About the disease

• Diabetes mellitus : Diabetes mellitus (DM), also known as simply diabetes, is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period. Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced

Types of Diabetes mellitus:

The types of Diabetes are as follows:1.Type I DM2.Type II DM3.Gestational Diabetes

Diabetes mellitus type 1 (also known as type 1 diabetes, or T1DM; formerly insulin-dependent diabetes or juvenile diabetes) is a form of diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas.

Type II

• Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop.This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes". The primary cause is excessive body weight and not enough exercise

Gestational Diabetes

• Gestational diabetes (or gestational diabetes mellitus, GDM) is a condition in which women without previously diagnoseddiabetes exhibit high blood glucose levels during pregnancy (especially during their third trimester). Gestational diabetes is caused when insulin receptors do not function properly. This is likely due to pregnancy-related factors such as the presence of human placental lactogen that interferes with susceptible insulin receptors.

Diabetes Genome

• Genome : The haploid set of chromosomes in a gamete or microorganism, or in each cell of a multicellular organism.

Diabetes Genome : The approach used by researchers is therefore to examine lots of families with multiple offspring affected by diabetes, using a strategy called a genome-wide scan for linkage. By looking at short sequences of DNA that show inherited variations in length ('microsatellite' genetic markers), spaced evenly throughout the genome.

• The first genome-wide scan for type 1 diabetes

susceptibility regions was published in 1994; indeed, this was the first genome scan for a common human disease. Several more scans have been carried out since, each obtaining extremely strong evidence for linkage to the IDDM1 HLA region.

This 'meta-analysis' produced statistically significant evidence of linkage for only three regions (the previously identified IDDM1 and IDDM2, and a novel locus on chromosome 16q22-24) and 'suggestive' evidence for six regions (IDDM7, IDDM10, IDDM12, IDDM13 and IDDM15, and a novel locus on chromosome 1q42)

Targeted sequencing of genes associated with type 2

diabetes• For type 2 diabetes, more than 70 common

genetic variants have been identified by extensive genome-wide association studies. The coding and 5’ and 3’ untranslated regions of 130 genes (1.2 megabases in total) were sequenced in 1880 and 1840 controls. To increase efficiency, sequencing was done in pools (20 individuals per pool) and library preparation for each pool was done using the Agilent Sure Select target enrichment method.

Micro-RNA in the regulation of glucose

Micro RNAs (miRNA) are single-stranded transcribed RNAs of 19–25 nucleotides in length that are generated from endogenous hairpin structured transcripts throughout the genome

• Pancreatic islet-specific miR-375 inhibits insulin

secretion in mouse pancreatic β-cells by inhibiting the expression of the protein myotrophin. An overexpression of miR-375 can completely suppress glucose-induced insulin secretion, while inhibition of native miR-375 will increase insulin secretion. In another study, increasing the level of miR-9, a different miRNA, resulted in a severe defect in glucose-stimulated insulin release. This happens because miR-9 down-regulated the transcription factor Onecut2 (OC2) that controls the expression of Rab27a effector granuphilin, a key factor in controlling insulin release

Gene therapy of diabetes: glucose-stimulated insulin secretion in a human hepatoma cell line

While glucose responsiveness commenced at a lower concentration than normal islets, a secretion curve approaching normal physiological conditions was generated. Immunoelectron microscopy revealed the presence of insulin-containing granules, similar in size and appearance to those of the normal beta cell.

These results demonstrate that while it is most likely that the HEP G2ins/g cell line predominantly secretes insulin via the constitutive pathway, significant acute regulated release was seen in response to glucose, and thus represents significant

progress in the creation of a genetically engineered 'artificial beta cell' from a human hepatocyte cell line.

Other forms of diabetes mellitus include

congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes. Mechanism of insulin release in normal pancreatic beta cells — insulin production is more or less constant within the beta cells. Its release is triggered by food, chiefly food containing absorbable glucose.

symptoms

Diagnosis

• Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:

• Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)• Plasma glucose ≥ 11.1 mmol/l (200 mg/dl) two hours after a

75 g oral glucose load as in a glucose tolerance test• Symptoms of hyperglycemia and casual plasma glucose

≥ 11.1 mmol/l (200 mg/dl)• Glycated hemoglobin (Hb A1C) ≥ 6.5%

Prevention:•

There is no known preventive measure for type 1 diabetes.

Type 2 diabetes can often be prevented by a person being a normal body weight, physical exercise, and following a healthy diet. Dietary changes known to be effective in helping to prevent diabetes include a diet rich in whole grains and fiber, and choosing good fats, such as polyunsaturated fats found in nuts, vegetable oils, and fish.

Limiting sugary beverages and eating less red meat and other sources of saturated fat can also help in the prevention of diabetes. Active smoking is also associated with an increased risk of diabetes, so smoking cessation can be an important preventive measure as well.

Medications

• Metformin is generally recommended as a first line treatment for type 2 diabetes, as there is good evidence that it decreases mortality.

Routine use of aspirin, however, has not been found to improve outcomes in uncomplicated diabetes.

Angiotensin converting enzyme inhibitors (ACEIs) improve outcomes in those with DM while the similar medicationsangiotensin receptor blockers (ARBs) do not.

In gene therapy, the nucleic acid molecule is packaged within a "vector", which is used to get the molecule inside cells within the body.

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