Biotransformation and Other Liver Functions in Patients with Type 2 Diabetes Mellitus

The dissertation is devoted to a comprehensive evaluation of the functional state of the liver in patients with type 2 diabetes mellitus in comparison with type 1 diabetes mellitus, overweight, and obesity. The study covers clinical, biochemical, ultrasonographic, and gamma-scintigraphic characteristics of the hepatobiliary system, as well as the state of the biotransformation (monooxygenase) function of the liver assessed by antipyrine pharmacokinetics. The work separately examines the effect of different groups of modern hypoglycemic agents — glibenclamide, metformin, their combination, and insulins — on the liver functions under study. The aim is to clarify the character and severity of hepatic disturbances in type 2 diabetes and to determine the influence of hypoglycemic therapy on the functional state of the organ.

The problem of diabetes mellitus (DM) is a pressing medical and social issue that ranks among the priorities of the national healthcare systems of virtually all countries worldwide. Summarizing data on the prevalence of the disease, a panel of experts from the International Diabetes Institute concluded in 1997 that an epidemic of type 2 DM is developing among the adult population of the world, associated with the growing number of individuals with overweight and obesity [39,107,122]. The severity and relevance of the problem are determined by the wide prevalence of DM, high mortality, and early disability of patients. The course of DM is characterized by the development of complications (diabetic micro- and macroangiopathies), which largely determine the clinical course of the disease and its prognosis. These complications are the most frequent cause of disability and mortality [3,6,33,36]. The severity of metabolic disorders in patients with DM depends, according to a number of authors, on the functional state of the liver as well [13,14,15,35,41,90]. There is no doubt that chronic hyperglycemia may affect the liver itself [24]. Nevertheless, the pathogenesis of liver damage in DM is still not fully understood, and the set of the most informative tests for assessing its functional state has not been determined.

Staff members of our clinic described, in the 1990s, a new variant of genetically determined hepatosis [37,42,59,75,77]. Its basis lies in alterations in the system of microsomal monooxygenases and enzymes of glutathione metabolism — universal systems responsible for the metabolism of exogenous and endogenous substances. The consequence of this is disturbances of metabolic homeostasis that promote the onset and/or aggravation of the disease. From these positions, we hypothesized the possible involvement of similar defects in the course of DM. The biological significance of the biotransformation (monooxygenase) system in the body under conditions of hyperglycemia against the background of lifelong administration of hypoglycemic drugs determined our interest in studying the functional state of the liver in patients with type 2 DM in comparison with type 1 DM. We did not encounter any studies devoted to a comprehensive investigation of liver functions in patients with different types of DM and obesity. The present study is dedicated to addressing this task.

Interest in this problem has not waned, since the introduction of increasingly sensitive and highly informative methods of liver investigation makes it possible to determine more fully and thoroughly the frequency, severity, and character of its damage, to detect changes at early stages of the disease, and to carry out prevention and treatment in a timely and differentiated manner.

AIM OF THE STUDY

To evaluate comprehensively the functional state of the liver in type 2 DM and to assess the effect of different groups of hypoglycemic drugs on liver functions.

OBJECTIVES OF THE STUDY

1. Within the framework of clinical and biochemical hepatic syndromes, to assess comprehensively the state of liver functions in patients with type 2 DM depending on the severity of the disease.

2. To perform a comparative analysis of the functional state of the liver among patients with type 2 and type 1 DM, overweight, and obesity.

3. To investigate the biotransformation function of the liver in patients with varying degrees of severity of the process in the main group as well as in the comparison and control groups.

4. To examine the effect of drug hypoglycemic therapy on the functional state of the liver in patients with type 2 DM, including the biotransformation function.

SCIENTIFIC NOVELTY

For the first time, a comprehensive clinical, biochemical, sono- and gamma-scintigraphic study of the functional state of the liver, including the biotransformation function, was carried out in patients with type 2 DM. The study revealed that type 2 DM, alongside its main syndromes caused by chronic hyperglycemia, is characterized by the presence of a hepatobiliary syndrome.

It was established that the hepatobiliary syndrome in patients with type 2 DM manifests as a significant decrease in the activity of the liver monooxygenase system and a mild degree of cytolysis, cholestasis, hepatodepressive, and mesenchymal-inflammatory clinical and biochemical disturbances. The detected changes depend on the severity of the pathological process caused by chronic hyperglycemia and on the degree of suppression of the liver biotransformation function.

For the first time, a targeted analysis of a set of investigations of the functional state of the liver, including the biotransformation function of the liver system, was performed in patients with type 2 DM. Comparative data on the studied liver functions were obtained in patients with both types of DM and in patients with overweight and obesity, demonstrating qualitative and quantitative differences. In patients with type 2 DM, functional liver insufficiency was established, characterized by a complete and pronounced impairment of the biotransformation function: prolongation of the antipyrine half-life and shortening of its clearance, as well as signs of cytolysis, cholestasis, hepatodepressive, and mesenchymal-inflammatory disturbances. In patients with type 1 DM, a partial impairment of biotransformation was found — prolongation of the antipyrine half-life with normal clearance — along with hepatodepressive disturbances.

The investigation of the effect of modern hypoglycemic agents — glibenclamide, metformin, their combination, and insulins — on the functional state of the liver in patients with type 2 DM established that, with normalization of glycemia, a number of liver functions improve, with the exception of the biotransformation function.

PRACTICAL SIGNIFICANCE OF THE WORK

The revealed disturbances of liver function in type 2 DM are proposed for use in the assessment of the state of patients with this disease for the prevention of severe complications and treatment. Given the paucisymptomatic character of hepatopathy, the use of the most sensitive tests will promote the early detection of the hepatobiliary syndrome. The detected hepatopathy suggests the cautious prescription of drugs that adversely affect the liver, taking into account their slow metabolism and the development of metabolic disturbances during active measures aimed at normalizing glycemia.

STATEMENTS DEFENDED

1. The clinical course of type 2 DM is characterized by the presence of functional liver insufficiency, consisting of a significant decrease in the biotransformation function and a mild degree of cytolysis, cholestasis, hepatodepressive, and mesenchymal-inflammatory clinical and biochemical disturbances.

2. The severity of disturbances of the functional state of the liver in type 2 DM corresponds to the degree of suppression of the liver biotransformation function, the duration and severity of chronic hyperglycemia, and is aggravated in the presence of overweight or obesity, but does not correlate with anthropometric data (BMI, W/H ratio), the severity of the disease, or the type of therapy.

3. Changes in the functional state of the liver in type 2 DM have a similar character of damage, but with a lower frequency, to that in patients with overweight or obesity in the presence of close kinship. In patients with type 1 DM, in contrast to type 2 DM, a partial impairment of biotransformation was revealed: prolongation of the antipyrine half-life with normal clearance and mild hepatodepressive disturbances.

4. The use in type 2 DM of modern hypoglycemic agents — glibenclamide, metformin, their combination, or insulins — in optimal dosages does not aggravate the existing disturbances of liver function, but neither does it exert a substantial beneficial effect on them, except for individual biochemical parameters.

IMPLEMENTATION OF THE RESULTS

The developed method for assessing the activity of the liver monooxygenase system in patients with type 2 DM has been implemented in the practice of medical institutions in Ulan-Ude: City Polyclinic No. 1, the City Clinical Infectious Diseases Hospital, the Endocrine Department of the Republican Clinical Hospital; and in Irkutsk: City Clinical Hospital No. 10 and the Irkutsk Regional Clinical Hospital. The testing was carried out in 2001–2004 and demonstrated the expediency of its use in this category of patients.

REVIEW OF THE LITERATURE

CHAPTER 1. MODERN ASPECTS OF TYPE 2 DIABETES MELLITUS