Human insulin concentration

Fig. 7. Systemic (a) human insulin concentration and (b) glucose response following infusion of human insulin from external pump, 5 months postimplantation (Dziubla et ai, 2002).

First-line therapy includes nutritional and exercise interventions for all women, and caloric restrictions for obese women. If nutritional intervention fails to achieve fasting plasma glucose levels less than or equal to 105 mg/dL, 1-hour post-prandial plasma glucose concentrations less than or equal to 155 mg/dL, or 2-hour postprandial levels less than or equal to 130 mg/dL, then therapy with recombinant human insulin should be instituted glyburide may be considered after 11 weeks of gestation. 

Bioavailability of human insulin assessed from pharmacological data. After extravascu-lar administration only the time course governs the observed pharmacological effects. The pharmacological data was translated into theoretical plasma-concentration data using the PK/PD model. The results of the PK/PD analysis indicate that the doses administered can be accurately predicted from pharmacological data... 

AUC, area under curve of plasma concentration Av, avidin NLA, neutral avidin SA, streptavidin cHSA, cationized human serum albumin HIR MAb, human insulin receptor mAb PS product, permeability surface area product. 

Injection 500 units/mL (regular human insulin [rDNA]) Rx) Hu mull n R Regular U-500 (Concentrated) (Lilly)... 

Hypogiycemic reactions Hypoglycemia when using this concentrated insulin can be prolonged and severe. As with other human insulin preparations, hypoglycemia reactions may be associated with the administration of concentrated insulin. However, deep secondary hypoglycemic reactions may develop 18 to 24 hours after the original injection of concentrated insulin. 

Insulin Lispro was the first recombinant fast-acting insulin analogue to gain marketing approval (Table 8.3). It displays an amino acid sequence identical to native human insulin, with one alteration — an inversion of the natural proline lysine sequence found at positions 28 and 29 of the insulin jS-chain. This simple alteration significantly decreased the propensity of individual insulin molecules to self-associate when stored at therapeutic dose concentrations. The dimerization constant for Insulin Lispro is 300 times lower than that exhibited by unmodified human insulin. Structurally, this appears to occur as the change in sequence disrupts the formation of inter-chain hydrophobic interactions critical to self-association. 

There is a tendency to reserve semisynthetic and totally synthetic methods for the introduction of bonds and residues that cannot be specified by the genetic code. The present chapter will concentrate on these aspects. However, semisynthesis can have a role to play even when building structures that are completely accessible to the genetic code. The first industrial challenge for the emerging technologies of total chemical synthesis, recombinant protein expression, and semisynthesis was the economic production of human insulin in pharmaceutically usable quantity and quality. The semisynthetic human insulin that was made from porcine insulin proved exceptionally convenient to produce, and was the first introduction to human insulin for very many patients. 

All insulins in the USA and Canada are available in a concentration of 100 U/mL (U100). A limited supply of U500 regular human insulin is available for use in rare cases of severe insulin resistance in which larger doses of insulin are required. 

Regular Concentrated Lilly human insulin 500 u/mL 20 ml vials... 

Preparation of Human Insulin. Porcine insulin can be converted to the human insulin sequence by an enzyme-catalyzed transpeptidation reaction (10,11). Under appropriate conditions trypsin acts preferentially at LysB29 rather than ArgB22 to yield a covalent des[B30]insulin/trypsin complex (acyl—enzyme intermediate). In the presence of high concentrations of organic co-solvents and the /-butyl ester of threonine, transpeptidation predominates over hydrolysis to yield the /-butyl ester of human insulin. Following appropriate purification steps and acidolytic removal of the ester, human insulin suitable for treating patients is obtained. 

Insulin aspart is a rapid-acting synthetic insulin in which proline is replaced by aspartate at position 28 in the B chain. Insulin aspart has been reviewed (1). Its adverse effects do not differ from those of soluble human insulin and it has a similar effect on the blood glucose concentration (2). 

In an open comparison of insulin aspart and regular human insulin for 6 months in 882 patients with type 1 diabetes and extended to 714 patients for another 6 months, postprandial glucose concentrations were lower with insulin aspart (7). HbAic was slightly but significantly lower (7.78 versus 7.93%). There were no differences in hypoglycemic periods or adverse events. 

Fig. 2.1 Examples of ultradian oscillations in human insulin secretion and blood glucose concentration (a) during continuous enteral nutrition and (b) during constant glucose infusion. Closer inspection shows that the glucose oscillations lead the insulin oscillations by a few minutes. Redrawn from [39, 40].

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