Production of Insuhn

A S. cerevisiae strain optimized for the production of insuHn by some of the recombinant strategies outHned previously must comply with the cultivation conditions prevailing at industrial scale. 

Regulation of fasting serum glucose, improvement of glucose utilization, improvement in energy. Beta-cells activation and enhancement of insuhn production (Sugano et al., 1984). 

The market for biopharmaceuticals is over 90 bilhon. The most well-known products of the modem biotechnology industry are the mammahan polypeptides such as erythropoietin (EPO) with an 14 bilhon market human insuhn (Novolin and Humuhn), 5.6 bilhon interferon alpha (Intron... 

The term visceral adipose tissue (VAT) refers to fat cells located within the abdominal cavity and includes omental, mesenteric, retroperitoneal, and perinephric adipose tissue. VAT has been shown to correlate with insuhn resistance and explain much of the variation in insuhn resistance seen in a population of African-Americans. Visceral adipose tissue represents 20% of fat in men and 6% of fat in women. This fat tissue has been shown to have a higher rate of lipolysis than subcutaneous fat, resulting in an increase in free fatty acid production. These fatty acids are released into the portal circulation and drain into the liver, where they stimulate the production of very-low-density lipoproteins and decrease insuhn sensitivity in peripheral tissues. VAT also produces a number of cytokines which cause insulin resistance. These factors drain into the portal circulation and reduce insulin sensitivity in peripheral tissues. ... 

I Pharmacology. Insulin is an anabolic and anticatabolic hormone. It plays major roles in protein, carbohydrate, and fat metabolism. For a complete review of insuhn action, the reader is referred to a diabetes physiology text. Endogenously produced insuhn is cleaved from the larger proinsulin peptide in the cell to the active peptide of insuhn and C-peptide, which can be used as a marker for endogenous insuhn production. All commercially available insuhn preparations contain only the active insulin peptide. 

InsuHn Hspro (sold under the trade names Humalog and Liprolog) exemplifies engineered short-acting insuHn products. This product displays an amino acid sequence identical to native human insuHn, with the exception that the natural pro-Hne-lysine sequence characteristics of positions 28 and 29 of the insuHn B chain have been reversed. The sequence inversion leads to local conformational changes, eHminating hydrophobic interactions critical to dimer stabiHzation. As a result, de-oligomerization occurs rapidly upon injection and the product can be administered at meal times rather than 30 min before. The different forms and formulations of insuHn are shown on the supplementary CD-ROM. 

The polymerization of insuHn and proinsulin to dimers and hexamers is a very important process which takes place in the pancreas and impacts upon the pharmaceutical application of insuHn, because the dissociation of the polymers is the rate-limiting processes in the absorption and action in the tissues of the biological active monomeric insulin [45]. The polymerization diminishes osmotic pressure and hy-drophobicity and improves solubility. A positive correlation between expression yield and the degree of polymerization was found [46] that supports yeast in vivo polymerization of insulin precursors and accentuates its importance. However, polymerization can also account for a drawback by retention of product in the vacuole [47]. Intracellular retention of a substantial quantity of the synthesized insulin precursor indicated that the insulin precursor followed two different intracellular routes in the late secretory pathway [12, 47]. Constitutive secretion to the culture supernatant may reflect saturation of a sorting mechanism in the late Golgi due to overexpression. The kexin cleaves the leader-insulin precursor peptide in a late Golgi compartment to yield free insulin precursor, and... 

Insulin lowers the concentration of glucose in blood by inhibiting hepatic glucose production and by stimulating the uptake and metabohsm of glucose by muscle and adipose tissue (Table 60-1). These two important effects occur at different concentrations of insuhn. Glucose production is inhibited half maximally by an insuhn concentration of about 20 /mnits/mL, whereas glucose uthization is stimulated half maximally at about 50 /runits/mL. 

The key role of insuhn in protein metabolism usually is evident only in diabetic patients with persistently poor glycemic control. Insulin stimulates amino acid uptake and protein synthesis and inhibits protein degradation in muscle and other tissues. The increased conversion of amino acids to glucose also results in increased production and excretion of urea and ammonia. In addition, there are increased circulating concentrations of branched-chain amino acids as a result of increased proteolysis, decreased protein synthesis, and increased release of branched-chain amino acids from the liver. 

Type 2 Diabetes A complex disease based on gradual resistance to insuhn and diminished production of insulin. Treatment often progresses from oral medications to insulin injections as disease progresses. Also referred to as adult onset diabetes and non-insulin-dependent diabetes mel-litus (NIDDM). 

Platelet-derived growth factor (PDGF) Induces migration of several cells to the wound site. Stimulates macrophages to produce and secrete TGF-(3. Affects blood vessel maturation. Indnces the production of VEGF and insuhn-like growth factor (IGF). Enhances fibroblast proliferation and prodnction of ECM. Barrientos et al. (2008)... 

The use of oral antidiabetic drugs may be necessary. Insuhn production is initially only moderately impaired in type 2 diabetes, so oral medication can often be used to improve insulin production (e.g. sulphonylureas), to regulate inappropriate release of glucose by the liver and attenuate insulin resistance to some extent (e.g. metformin), and to substantially attenuate insulin resistance (e.g. thiazohdinediones). A Hnal resort is insuhn therapy to maintain normal or near-normal glucose levels. 

Diabetes mellitus (DM) is an increasingly common disease of sugar metabolism. Juvenile-onset diabetes, also known as Type I or insulin-dependent diabetes (IDDM), is an autoimmune disease that results in decreased release of insulin by the pancreas. Late-onset diabetes, also known as Type II or non-insulin-dependent diabetes (NIDDM), results from reduced sensitivity of cells to the insulin signal. A convenient animal model for studying diabetes and testing alternative therapies is the streptozotocin-freated diabetic rat. Streptozotocin (STZ) attacks the pancreas and decreases insulin production and release, thus, mimicking many aspects of the human disease. Since insulin is not orally absorbed, the oral administration of vanadium compounds that are insuhn-mimetic or insulin-enhancing would be a very attractive therapy ... 

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