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Physiologically, insulin, C-peptide and glucagon are released in a pulsatile fashion in metabolically healthy people (Hansen et al., 1982) with a periodicity of pulses ranging from 8 to 30min. The insulin release in the basal state ranges from 14 to 17 mU min~\ the concentration in peripheral venous blood from 10 to 20mUr', while portal insulin concentration is three times higher. Following an oral glucose load, a total of 0.9 U insulin per 150 min and 10 g ingested glucose are secreted (1.35 U per 12 g carbohydrate).

Pulsatile insulin is more effective in suppressing hepatic glucose production while it exhibits an equipotent effect on glucose utilization (Bratusch-Marrain et al., 1986). The application of pulsatile insulin may thus reduce free insulin levels (Waldhausl et al., 1985) and insulin resistance and may contribute more effectively to a reduction in hormone load in insulin-treated diabetic patients.

To shorten periods of hyperinsulinaemia in insulin-treated diabetic patients, attempts have been made to find insulin analogues with equipotent biological activities but faster absorption from subcutaneous injection sites and shorter half-lives. In addition, long-acting insulin analogues have been developed to provide a more continuous 24 h basal insulin supply than neutral protamine human insulin. The fast-acting monomeric insulin analogues Asp-B9-Glu-B27 and Asp-BlO have been tested in normal subjects by several workers (Vora et al., 1988; Brange et al., 1990) and exhibited a faster onset of action with a more rapid rise in plasma concentration and an earlier and more pronounced hypoglycaemic effect than human insulin. However, there was also a quicker return to preinjection levels (Jorgensen and Drejer, 1990).

Clinical trials on the effects of long-acting insulin analogues showed only a small intraindividual variation of absorption from the injection site with an appreciable advantage over Ultratard HM-insulin. The biopotency was no different from that of human insulin. Analogue Arg-B27, Gly-A21, Thr-B30 NH2 was the first one chosen for clinical trials (Jorgensen and Dryer, 1990). Further studies with a diarginine-insulin (Arg-B31 and Arg-B32) exhibited almost identical insulin receptor binding and full biological activity compared with native insulin. These in vitro results (Zeuzem et al., 1990), have not, however, been put to clinical tests.

A prolonged insulin action can also be achieved by encapsulation of insulin in liposomes before subcutaneous injection. The extended hypoglycaemic response is believed to be a result of a lower metabolic clearance rate. Currently, the encapsulation efficiency, however, is only 5% (Spangler, 1990). Further investigations are needed.

7.2 TYPE-I DIABETES MELLITUS 7.2.1 Complications

Conventional insulin treatment with its fixed insulin dosage and food intake has dominated therapy of insulin-dependent diabetes mellitus for nearly 70 years. It has sharply reduced the mortality of diabetic coma. Nevertheless diabetic coma is still the largest single cause of death in diabetic patients under the age of 20 years with an episode rate of 7%, and diabetic coma accounts for 15% of deaths in diabetics under the age of 50 years.

The occurrence of late complications is still very high. Waldhausl (1986) reported a prevalence of 41% diabetic retinopathy, 25% neuropathy and 15% diabetic nephropathy. Normal HBA, levels were only seen in 20.7% of metropolitan and in only 4.1% of rural Type-I diabetic patients. Although definitive proof is lacking, it is now generally accepted that the microangiopathy of diabetes is related to the level of glycaemia, and near-normoglycaemia should be the outstanding aim of treatment (Tchoubroutsky, 1978). The failure of conventional insulin treatment to maintain consistently normal blood glucose was felt to be a consequence of not considering the physiological pattern of insulin release. The kinetics of plasma free insulin during a conventional regimen with one or two daily subcutaneous injections of intermediate-acting insulin is unphysiological, and appropriate meal-related plasma insulin peaks cannot be achieved. The new intensified methods of insulin delivery, multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII), however, are more physiological. Consequently, a near-normal glycaemic control can be achieved only with these regimens (Pelkonen et al.. 1985).

In 1979, Phillips et al., proposed the u+n regimen, which involved a single dose of very-long-acting ultralente insulin to act as background (u) and then several injections of variable amounts of soluble insulin (n) given when

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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