**5.1 Use of insulin in a common diabetes therapy – its advantages and disadvantages**

Type 1 diabetes mellitus is underlied by the shortage of insulin, which plays a crucial role of carbohydrate and fat metabolism. Its absence causes rather a complex array of serious impairments in patients' health, e.g. hiperglycaemia, ketoacidosis, coma and even death. Hence, the injection of exogenous insulin to diabetic individual is essential to: (a) maintain a normal glucose concentration and (b) avoid the advanced microvascular complications, such as retinopathy, nephropathy or neuropathy.

Insulin was discovered by Banting and Best and this event was a milestone in the treatment of patients with diabetes (Bliss, 1982). Initially, bovine, porcin and even some fish analogues were applied to avoid diabetic ketoacidosis. However, gradually the scientists were challenged by the uprising problems in patients injected with animal insulins (mainly because of their rather high impurity and immunogenicity) and were forced to develop a new class of insulins. Improved techniques used for insulin purification combined with other compounds like protamine and zinc, enabled to manufacture protamine insulin with the prolonged time of activity and later, the more stable protamine zinc insulin (Hagedorn et al., 1936). Moreover, further scientific discoveries shed light on better understanding of insulin structure and activity and initiated a new avenue to design human insulin analogues characterized by the properties of prolonged hormone activity in a bloodstream.

At present, there are few types of short-acting insulin analogues used in anti-diabetes therapy, and among them:


Long-acting insulin analogues are crucial to mimic the endogenous insulin secretion. Thereby a specific modification of insulin structure was essential to obtain longer acting analogues. There are two approaches leading to diminish absorption: the first one is to change the isoelectric point of insulin and the second one is to acetylate a hydrophobic residue with fatty acid.


After long years of experience and observations, nowadays, multiple daily injection program is believed to be the most reasonable approach in modern diabetic treatment in order to mimic the physiological insulin release. However, it implies that patients have to undertake more inconvenient therapy resulting from the scheduled injections of both shortand long-acting insulins. To deal with this problem, clinicians and patients may choose an alternative method, which requires biphasic insulin analogues administration.

Patients with pre-diagnosed type 2 diabetes should take seriously into account the radical change of their lifestyle in order to cause a delay of possible medical intervention. Under conditions when diet or changing a lifestyle may not be sufficient enough, additional pharmacological treatment is required to avoid a severe consequence of this disease.

Nowadays, medicine is focused on delivery a large number of drugs. From pharmacological point of view, these compounds should be effective in improving insulin efficiency or

challenged by the uprising problems in patients injected with animal insulins (mainly because of their rather high impurity and immunogenicity) and were forced to develop a new class of insulins. Improved techniques used for insulin purification combined with other compounds like protamine and zinc, enabled to manufacture protamine insulin with the prolonged time of activity and later, the more stable protamine zinc insulin (Hagedorn et al., 1936). Moreover, further scientific discoveries shed light on better understanding of insulin structure and activity and initiated a new avenue to design human insulin analogues

At present, there are few types of short-acting insulin analogues used in anti-diabetes






After long years of experience and observations, nowadays, multiple daily injection program is believed to be the most reasonable approach in modern diabetic treatment in order to mimic the physiological insulin release. However, it implies that patients have to undertake more inconvenient therapy resulting from the scheduled injections of both shortand long-acting insulins. To deal with this problem, clinicians and patients may choose an

Patients with pre-diagnosed type 2 diabetes should take seriously into account the radical change of their lifestyle in order to cause a delay of possible medical intervention. Under conditions when diet or changing a lifestyle may not be sufficient enough, additional

Nowadays, medicine is focused on delivery a large number of drugs. From pharmacological point of view, these compounds should be effective in improving insulin efficiency or

changes is the product, which acts about 20 hours (Heise et al., 2002).

alternative method, which requires biphasic insulin analogues administration.

pharmacological treatment is required to avoid a severe consequence of this disease.

by removal of threonine at B30 (Havelund et al., 2004).

characterized by the properties of prolonged hormone activity in a bloodstream.

therapy, and among them:

2005).

residue with fatty acid.

lasts for next 3-4 hours (Howey et al., 1994)

effective in enhancing its secretion from pancreas. Among those substances are: sulfonylureas, biguanides, thiazolidinediones, meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics and dipeptidyl peptidase 4 inhibitors.


Development of the obesity associated with diabetes requires using a novel combination treatment, which aims at retarding the microvascular and macrovascular complications occurring in diabetes and obesity. Therefore, some anti-diabetic agents have been indicated to maintain an adequate glucose level in an organism suffering from diabetes. The number of anti-diabetic drugs delivered by subcutaneous injection increases constantly and to date there are numerous agents already launched into market, as well as others, tested in the clinical trials (Fig. 8).


Diabetes mellitus has been associated with the increased mortality risk due to non-diabetic factors, like several types of solid tumours, including the cancers of colon, breast and pancreas. Similar associations have been noted for central obesity and other conditions associated with increased levels of circulating insulin. These observations have given rise to the hypothesis that growth of these tumours, which are characterised by abnormal expression and function of the insulin–IGF-1 series of receptors, may be promoted by the trophic action of insulin interacting with these receptors. The cancer risk associated with diabetes may also be influenced by therapy in a given diabetic individual: for example, the risk of colon cancer is higher in individuals on insulin, patients on metformin are less likely to be diagnosed with cancer, and the risk of mortality from solid tumours is lower for metformin than for exogenous insulin or sulfonylureas. As a recognition dawns that cancer should be numbered among the complications of diabetes, the possibility that therapies for diabetes may influence tumour progression is likely to attract the increasing interest and concern. Furthermore, the observation that both endogenous insulin and exogenous insulin therapy are associated with tumour progression raises the questions as to the safety of the insulin analogues, which have subtly modified receptor binding properties and may accelerate the growth and proliferation of both healthy and tumour cell lines in culture.

Fig. 8. Sites of action of major oral therapeutical agents used in the treatment of type 2 diabetes. Pharmacological therapies aimed at: inhibiting carbohydrate breakdown in the gut (α-glucosidase inhibitors), stimulating insulin secretion (sulfonylureas, repaglinide, nateglinide), suppressing hepatic gluconeogenesis (thiazolidinediones, biguanide), or accelerating skeletal muscle glucose metabolism (thiazolidinediones, biguanide) exhibit beneficial effects on fasting and/or postprandial plasma glucose, and consequently concord overall metabolic control in type 2 diabetic patients. Thus, a need for concerted combination therapy to successfully control a burden of hyperglycaemia in a majority of DM2 patients becomes a growing expectation by physicians and other health caregivers.

### **5.2 New agents – new hopes and new perspectives**

The growing number of people with diabetes still requires novel combined treatments aimed at retardation of microvascular and macrovascular complications in the future. Therefore, anti-diabetic complications agents are sought to maintain an adequate glucose level in an organism. The number of anti-hyperglycaemic drugs delivered by subcutaneous injection increases constantly and to date there are numerous agents launched into market and examined in clinical trials. However, no such compounds/drugs that could be successfully applied in the treatment of diabetes have emerged hitherto, as the validated outcomes of clinical trials. Intensive studies are continued in order to develop a modern formula for effective amelioration of a burden associated with diabetes and late diabetic complications in diabetic patients in the future.

risk of colon cancer is higher in individuals on insulin, patients on metformin are less likely to be diagnosed with cancer, and the risk of mortality from solid tumours is lower for metformin than for exogenous insulin or sulfonylureas. As a recognition dawns that cancer should be numbered among the complications of diabetes, the possibility that therapies for diabetes may influence tumour progression is likely to attract the increasing interest and concern. Furthermore, the observation that both endogenous insulin and exogenous insulin therapy are associated with tumour progression raises the questions as to the safety of the insulin analogues, which have subtly modified receptor binding properties and may accelerate the growth and proliferation of both healthy and tumour cell lines in culture.

Fig. 8. Sites of action of major oral therapeutical agents used in the treatment of type 2 diabetes. Pharmacological therapies aimed at: inhibiting carbohydrate breakdown in the gut

(α-glucosidase inhibitors), stimulating insulin secretion (sulfonylureas, repaglinide, nateglinide), suppressing hepatic gluconeogenesis (thiazolidinediones, biguanide), or accelerating skeletal muscle glucose metabolism (thiazolidinediones, biguanide) exhibit beneficial effects on fasting and/or postprandial plasma glucose, and consequently concord overall metabolic control in type 2 diabetic patients. Thus, a need for concerted combination therapy to successfully control a burden of hyperglycaemia in a majority of DM2 patients

The growing number of people with diabetes still requires novel combined treatments aimed at retardation of microvascular and macrovascular complications in the future. Therefore, anti-diabetic complications agents are sought to maintain an adequate glucose level in an organism. The number of anti-hyperglycaemic drugs delivered by subcutaneous injection increases constantly and to date there are numerous agents launched into market and examined in clinical trials. However, no such compounds/drugs that could be successfully applied in the treatment of diabetes have emerged hitherto, as the validated outcomes of clinical trials. Intensive studies are continued in order to develop a modern formula for effective amelioration of a burden associated with diabetes and late diabetic

becomes a growing expectation by physicians and other health caregivers.

**5.2 New agents – new hopes and new perspectives** 

complications in diabetic patients in the future.

Studies on the formation of AGEs have been conducted with the goal to find promising pharmacological agents used in prevention or curing diabetic complications. The main target for these agents is to retard the formation of AGEs or to brake the AGE cross-links formed during Maillard reaction.

In order to prevent the AGEs formation the following therapeutic inhibitors have been developed and studied:


Among the newest agents tested in both *in vitro* and *in vivo* studies are poly(amido)amine PAMAM dendrimers and β-resorcylidene aminoguanidine (RAG), a derivative of aminoguanodine.



Fig. 9. The proposed mechanism of anti-glycation action of poly(amido)amine dndrimers (PAMAM).

Under conditions of excessive glucose the model protein (bovine serum albumin, BSA) undergoes extensive glycation (A), which becomes retarded and reduced to a large extent in the presence of poly(amido)amine dndrimers, generation 4.0 (PAMAM G4.0).
