contracture of the finger joints and large joints, associated with tight waxy skin. Changes begin in the metacarpophalangeal and proximal interphalangeal joints of the fifth finger and extend radially with involvement of the distal interphalangeal joints as well. Involvement of larger joints includes particularly the wrist and elbow, but also ankles and cervical and thoracolumbar spine (Komatsu et al., 2004). The limitation is only mildly disabling even when severe. With rare exception, LJM appears after the age of 10 years. The prevalence of LJM in T1D, evaluated in several studies ranges from 9 to 58% in paediatric and adult

The biochemical basis of LJM may be a consequence of changes in the connective tissue, probably due to alterations in the structural macromolecules of the extracellular matrix. The hyperglycaemia can alterate the glycation of protein with the formation of advanced glycation end products (AGEs), which resist to protein degradation and consequently increase thickness of basal membranes in the periarticular tissues (Shimbargger, 1987). Development of LJM is related to both age and diabetes duration (Cagliero et al., 2002), while others showed that it can be compromised also in a precocious age and with a short duration of diabetes (Komatsu et al., 2004). Of note, fluorescence of skin collagen, which reflects the accumulation of stable AGEs, increases linearly with age, but with abnormal rapidity in T1D and in correlation with the presence of retinopathy, nephropathy and

Some authors have showed that there is a clear link between upper limb musculoskeletal abnormalities and poor metabolic control (Ramchurn et al., 2009). It has been observed a reduction in frequency of LJM between the mid-70s and mid-90s in children, most likely due to the improved glucose control during this era (Infante et al., 2001; Lindsay et al., 2005).

Insulin oedema is a well-recognized and extremely rare complication of insulin therapy. It was found to occur equally in both sexes in adults, but a clear female predominance was noted in younger ages. The condition is self-limiting, but a progression to overt cardiac failure and development of pleural effusion has been reported. (Chelliah &

The pathophysiology remains vague. Intensive fluid resuscitation in an insulin-deficient catabolic state may lead to extravasation of fluid to the subcutaneous tissue, resulting in peripheral oedema. This may be exacerbated by the increased capillary permeability associated with chronic hyperglycemia. Renal tubular sodium reabsorption is enhanced by insulin therapy via stimulating the Na+/K+-ATPase as well as the expression of Na+/H+ exchanger 3 in the proximal tubule. Transient inappropriate hyperaldosteronism has also been suggested to contribute to the fluid retention (Bas et al., 2010). Loss of albumin from the circulation due to increased transcapillary leakage probably contributed to the formation of oedema and the decreased serum albumin, but was not severe enough to account for the magnitude of oedema (Wheatly & Edwards 1985). Cases with normal serum albumin have

Clinically, insulin oedema may present with a spectrum of severity until to frank anasarca. Pleural effusions have uncommonly been reported, although some of these patients were elderly and may have had pre-existing cardiac disease. Rarely, the oedema extended from peripheral tissues to serosal cavities with ascites and cardiac failure (Bas et al., 2010). Fluid and salt restriction should be implemented and this may be all that is necessary. Diuretic

patients (Lindsay et al., 2005).

neuropathy (Monnier et al., 1986).

**3.7 Type 1 diabetes and oedema**

Burge, 2004).

also been reported.

increasing bone resorption, whereas OPG, which neutralizes RANKL, has the opposite effect. Alterations or abnormalities of the RANKL/OPG system have been implicated in different metabolic bone diseases characterized by increased osteoclast differentiation and activation, and by enhanced bone resorption (Galluzzi et al., 2005). Therefore, bone could be an additional target of immune dysregulation.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a well-known susceptibility gene for autoimmune disorders, might also represent a possible link between immune system and bone. In animal studies CTLA4 expressed on T regulatory (Treg) cells impairs osteoclast formation (Zaiss et al., 2007). Therefore the failure of Treg cell function in clustering of multiple autoimmune diseases could represent a mechanism to explain both the occurrence of poly-reactive autoimmune processes and the increase of bone resorption in the same individuals.

In patients affected by both T1D and CD, the risk of developing osteopenia is probably influenced by the compliance to gluten-free diet. Osteopenia occurs more frequently in patients with diabetes and CD with poor compliance to GFD. Interestingly, recent observations indicate also an imbalance of cytokines relevant to bone metabolism in untreated celiac patients' sera and the direct effect of these sera on in vitro bone cell activity. In particular the RANKL/osteoprotegerin (OPG) ratio was increased in patients not on gluten-free diet. Actually, the only presence of a second disease, either AIT or CD, do not seems to increase the frequency of osteopenia, provided a good compliance to GFD in CD patients, while the association of three autoimmune diseases significantly increases the occurrence of osteopenia (37.5%). In addition, poor compliance to GFD of CD patients could increase the occurrence of osteopenia more in patients with three autoimmune diseases (80%) than in those with two autoimmune diseases (18.8%) (Valerio et al., 2008).

#### **3.5 Gastropathy**

Gastrointestinal motility disorders are found in a consistent proportion of children with T1D and are associated with significant morbidity: they are usually associated with dyspeptic symptoms, such as nausea, vomiting, fullness and epigastric discomfort, and could be an important cause of morbidity in diabetic patients. Gastroparesis has been shown to be significantly correlated with a poor metabolic control in a population of T1D children with gastric electrical abnormalities. (Cucchiara et al., 1998). Furthermore it is conceivable that delayed gastric emptying may cause a mismatch between the onset of insulin action and the delivery of nutrients into the small intestine (Rayner et al., 2001). Diabetic children with unexplained poor glycemic control should be investigated for abnormalities in gastric motility (Shen & Soffer 2000). On the other hand, hyperglycaemia itself can affect the neuromuscular mechanisms regulating gastrointestinal motility and delay the gastric emptying process (Jebbink et al., 1994). Therefore, it is of great importance to try to reverse abnormalities of gastric motility and improve gastric emptying in patients with T1D and gastroparesis by the use of domperidone in children with T1D. (Franzese et al., 2002b).

#### **3.6 Type 1 diabetes and limited joint mobility**

Type 1 diabetes can be associated with other less common disabling conditions of locomotor system: Dupuytren's contracture, stiff hand, carpal tunnel syndrome, and limited joint mobility (LJM). Limited joint mobility is one of the earliest clinically apparent long-term complications of T1D in childhood and adolescence, characterized by a bilateral painless

increasing bone resorption, whereas OPG, which neutralizes RANKL, has the opposite effect. Alterations or abnormalities of the RANKL/OPG system have been implicated in different metabolic bone diseases characterized by increased osteoclast differentiation and activation, and by enhanced bone resorption (Galluzzi et al., 2005). Therefore, bone could be

Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a well-known susceptibility gene for autoimmune disorders, might also represent a possible link between immune system and bone. In animal studies CTLA4 expressed on T regulatory (Treg) cells impairs osteoclast formation (Zaiss et al., 2007). Therefore the failure of Treg cell function in clustering of multiple autoimmune diseases could represent a mechanism to explain both the occurrence of poly-reactive autoimmune processes and the increase of bone resorption in the same

In patients affected by both T1D and CD, the risk of developing osteopenia is probably influenced by the compliance to gluten-free diet. Osteopenia occurs more frequently in patients with diabetes and CD with poor compliance to GFD. Interestingly, recent observations indicate also an imbalance of cytokines relevant to bone metabolism in untreated celiac patients' sera and the direct effect of these sera on in vitro bone cell activity. In particular the RANKL/osteoprotegerin (OPG) ratio was increased in patients not on gluten-free diet. Actually, the only presence of a second disease, either AIT or CD, do not seems to increase the frequency of osteopenia, provided a good compliance to GFD in CD patients, while the association of three autoimmune diseases significantly increases the occurrence of osteopenia (37.5%). In addition, poor compliance to GFD of CD patients could increase the occurrence of osteopenia more in patients with three autoimmune diseases

Gastrointestinal motility disorders are found in a consistent proportion of children with T1D and are associated with significant morbidity: they are usually associated with dyspeptic symptoms, such as nausea, vomiting, fullness and epigastric discomfort, and could be an important cause of morbidity in diabetic patients. Gastroparesis has been shown to be significantly correlated with a poor metabolic control in a population of T1D children with gastric electrical abnormalities. (Cucchiara et al., 1998). Furthermore it is conceivable that delayed gastric emptying may cause a mismatch between the onset of insulin action and the delivery of nutrients into the small intestine (Rayner et al., 2001). Diabetic children with unexplained poor glycemic control should be investigated for abnormalities in gastric motility (Shen & Soffer 2000). On the other hand, hyperglycaemia itself can affect the neuromuscular mechanisms regulating gastrointestinal motility and delay the gastric emptying process (Jebbink et al., 1994). Therefore, it is of great importance to try to reverse abnormalities of gastric motility and improve gastric emptying in patients with T1D and gastroparesis by the use of domperidone in children with T1D. (Franzese et al., 2002b).

Type 1 diabetes can be associated with other less common disabling conditions of locomotor system: Dupuytren's contracture, stiff hand, carpal tunnel syndrome, and limited joint mobility (LJM). Limited joint mobility is one of the earliest clinically apparent long-term complications of T1D in childhood and adolescence, characterized by a bilateral painless

(80%) than in those with two autoimmune diseases (18.8%) (Valerio et al., 2008).

an additional target of immune dysregulation.

**3.6 Type 1 diabetes and limited joint mobility**

individuals.

**3.5 Gastropathy**

contracture of the finger joints and large joints, associated with tight waxy skin. Changes begin in the metacarpophalangeal and proximal interphalangeal joints of the fifth finger and extend radially with involvement of the distal interphalangeal joints as well. Involvement of larger joints includes particularly the wrist and elbow, but also ankles and cervical and thoracolumbar spine (Komatsu et al., 2004). The limitation is only mildly disabling even when severe. With rare exception, LJM appears after the age of 10 years. The prevalence of LJM in T1D, evaluated in several studies ranges from 9 to 58% in paediatric and adult patients (Lindsay et al., 2005).

The biochemical basis of LJM may be a consequence of changes in the connective tissue, probably due to alterations in the structural macromolecules of the extracellular matrix. The hyperglycaemia can alterate the glycation of protein with the formation of advanced glycation end products (AGEs), which resist to protein degradation and consequently increase thickness of basal membranes in the periarticular tissues (Shimbargger, 1987). Development of LJM is related to both age and diabetes duration (Cagliero et al., 2002), while others showed that it can be compromised also in a precocious age and with a short duration of diabetes (Komatsu et al., 2004). Of note, fluorescence of skin collagen, which reflects the accumulation of stable AGEs, increases linearly with age, but with abnormal rapidity in T1D and in correlation with the presence of retinopathy, nephropathy and neuropathy (Monnier et al., 1986).

Some authors have showed that there is a clear link between upper limb musculoskeletal abnormalities and poor metabolic control (Ramchurn et al., 2009). It has been observed a reduction in frequency of LJM between the mid-70s and mid-90s in children, most likely due to the improved glucose control during this era (Infante et al., 2001; Lindsay et al., 2005).

#### **3.7 Type 1 diabetes and oedema**

Insulin oedema is a well-recognized and extremely rare complication of insulin therapy. It was found to occur equally in both sexes in adults, but a clear female predominance was noted in younger ages. The condition is self-limiting, but a progression to overt cardiac failure and development of pleural effusion has been reported. (Chelliah & Burge, 2004).

The pathophysiology remains vague. Intensive fluid resuscitation in an insulin-deficient catabolic state may lead to extravasation of fluid to the subcutaneous tissue, resulting in peripheral oedema. This may be exacerbated by the increased capillary permeability associated with chronic hyperglycemia. Renal tubular sodium reabsorption is enhanced by insulin therapy via stimulating the Na+/K+-ATPase as well as the expression of Na+/H+ exchanger 3 in the proximal tubule. Transient inappropriate hyperaldosteronism has also been suggested to contribute to the fluid retention (Bas et al., 2010). Loss of albumin from the circulation due to increased transcapillary leakage probably contributed to the formation of oedema and the decreased serum albumin, but was not severe enough to account for the magnitude of oedema (Wheatly & Edwards 1985). Cases with normal serum albumin have also been reported.

Clinically, insulin oedema may present with a spectrum of severity until to frank anasarca. Pleural effusions have uncommonly been reported, although some of these patients were elderly and may have had pre-existing cardiac disease. Rarely, the oedema extended from peripheral tissues to serosal cavities with ascites and cardiac failure (Bas et al., 2010). Fluid and salt restriction should be implemented and this may be all that is necessary. Diuretic

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Table 3. Non autoimmune associated conditions to Type 1 diabetes, causes and detection

#### **4. References**

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Eating disorders Dietary restriction Ameliorating of nutritional

Gastropathy Poor metabolic control Investigating of dyspeptic

Oedema Unknown Clinical examination Table 3. Non autoimmune associated conditions to Type 1 diabetes, causes and detection

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Monitoring of growth and physical development using

examination of the skin

Eventually controlled by Bone ultrasonography/

examination of the joint

growth charts

assistance

DEXA

symptoms

mobility

Routine clinical

In most instances no specific therapy is needed and spontaneous recovery is noted.

diabeticorum Parallel dermopathy Routine clinical

Probably even present, but worsened by poor metabolic

control/comorbidity

Impaired growth Poor metabolic control

mobility Parallel condition

Necrobiosis lipoidica

Osteopenia

Limited joint

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**5**

*Serbia*

**Hypoglycemia as a Pathological**

G. Bjelakovic1,I. Stojanovic1, T. Jevtovic-Stoimenov1, Lj. Saranac2,

*2Department of Pediatrics, Clinical Center Nis, Faculty of Medicine, University of Niš*

Maintenance of blood glucose homeostasis is fundamentally important for health. The maintain of stable levels of glucose in the blood is one of the most finely regulated of all homeostatic mechanisms and one in which the liver, the extrahepatic tissues, and several hormones play a part. Even mild disruptions of glucose homeostasis can have adverse

The physiological post absorptive serum glucose concentration in healthy humans range is 4, 4-5,8 mmol/L (80 to 105 mg/dL). The stability of the plasma glucose level is a reflection of the balance between the rates of whole body glucose production and glucose

Generally, hypoglycemia is defined as a serum glucose level below 3. 8 mmol/L (70 mg/dL).As a relatively rare disorder, hypoglycemia most often affects those humans at the

As a medical problem, hypoglycemia is diagnosed by the presence of three key features

1. Inborn error of metabolism (more common in the pediatric patient than in adults). Disturbance in carbohydrates metabolism: Malabsorption of glucose/galactose, alactasia, asucrasia, galactosemia, fructose intolerance. Glycogen storage disease, Type I ,or von Gierke Disease, glycogen storage disease, Type III, a deficiency of glycogen disbranching enzyme activity ( limit dextrinosis), Type VI glycogen storage disease, a

2. **Hormonal disturbance** .The hormone insulin plays a central role in the regulation of the blood glucose concentration. It is produced by the cells of islets of Langerhance in the pancreas. Insulin exerts hypoglycemic effect. Glucagon is the hormone produced by the

extremes of age, such as infants and the elderly, but may happen at any age.

3. relief of symptoms after the plasma glucose level is raised.

(known as Whipple's triad). Whipple's triad is: 1. symptoms consistent with hypoglycemia, 2. a low plasma glucose concentration, and

The etiology of hypoglycemia is numerous:

deficiency of liver phosphorylase )

**1. Introduction**

consequences.

utilization.

B. Bjelakovic2, D. Pavlovic1, G. Kocic1 and B.G. Bjelakovic3 *1Institute of Biochemistry, Faculty of Medicine, University of Niš*

*3Clinic of Internal Medicine, Department of Hepato-Gastroenterology,*

**Result in Medical Praxis**

*Faculty of Medicine, University of Niš*

### **Hypoglycemia as a Pathological Result in Medical Praxis**

G. Bjelakovic1,I. Stojanovic1, T. Jevtovic-Stoimenov1, Lj. Saranac2, B. Bjelakovic2, D. Pavlovic1, G. Kocic1 and B.G. Bjelakovic3 *1Institute of Biochemistry, Faculty of Medicine, University of Niš 2Department of Pediatrics, Clinical Center Nis, Faculty of Medicine, University of Niš 3Clinic of Internal Medicine, Department of Hepato-Gastroenterology, Faculty of Medicine, University of Niš Serbia*

#### **1. Introduction**

108 Type 1 Diabetes Complications

Ventura, A., Magazzù, G. & Greco, L. (1999). Duration of exposure to gluten and risk for

Ventura, A., Neri, E., Ughi, C., Leopaldi, A., Citta, A. & Not, T. (2000). Gluten-dependent

Westerholm-Ormio, M., Vaarala, O., Pihkala, P., Ilonen, J. & Savilahti, E. (2003).

Wheatly, T. & Edwards, O.M. (1985). Insulin oedema and its clinical significance: metabolic

Wu, Y., Humphrey, M.B. & Nakamura, M.C. (2008). Osteoclasts—the innate cells of the bone. *Autoimmunity*, Vol. 41, No. 3, (Apr 2008), pp. (183–194), 0891-6934 Yu, L., Brewer, K.W., Gates, S., Wu, A., Wang, T., Babu, S., Gottlieb, P., Freed, B.M., Noble,

Zaiss, M.M., Axmann, R., Zwerina, J., Polzer, K., Gückel, E., Skapenko, A., Schulze-Koops,

Zeglaoui, H., Landolsi, H., Mankai, A., Ghedira, I. & Bouajina, E. (2010). Type 1 diabetes

*Rheumatism*, Vol. 56, No. 12, (Dec 2007), pp. (4104–4112), 0004-3591

*Journal of Pediatrics*, Vol. 137, No. 2, (Aug 2000), pp. (263-265), 0022-3476 Viljamaa, M., Kaukinen, K., Huhtala, H., Kyronpalo, S., Rasmussen, M. & Collin, P. (2005).

*Gastroenterology*, Vol. 40, No. 4, (Apr 2005), pp. (437-443), 0036-5521

1999), pp. (297-303), 0016-5085

(May-Jun 1999), pp. (433-442), 0334-018X

0742-3071

pp. (328-335), 0021-972X

795), 0172-8172

autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. *Gastroenterology*, Vol. 117, No. 2, (Aug

diabetes-related and thyroid-related autoantibodies in patients with celiac disease.

Coeliac disease, autoimmune diseases and gluten exposure. *Scandinavian Journal of*

Immunologic Activity in the Small Intestinal Mucosa of Pediatric Patients With Type 1 Diabetes. *Diabetes*, Vol. 52, No. 9, (Sep 2003), pp. (2287-2295), 0012-1797 Westman, E., Ambler, G.R., Royle, M., Peat, J. & Chan, A. (1999). Children with celiac

disease and insulin dependent diabetes mellitus–growth, diabetes control and dietary intake. *Journal of Pediatric Endocrinology and Metabolism*, Vol. 12, No. 3,

studies in three cases. *Diabetic Medicine*, Vol. 2, No. 5, (Sep 1985), pp. (400-404),

J., Erlich, H., Rewers, M. & Eisenbarth, G. (1999). DRB1\*04 and DQ alleles: expression of 21 hydroxylase autoantibodies and risk of progression to Addison's disease. *Journal of Clinical Endocrinology and Metabolism*, Vol. 84, No. 1, (Jan 1999),

H., Horwood, N., Cope, A. & Schett, G. (2007). Treg cells suppress osteoclast formation. A new link between the immune system and bone. *Arthritis and*

mellitus, celiac disease, systemic lupus erythematosus and systemic scleroderma in a 15-year-old girl. *Rheumatology International*, Vol. 30, No. 6, (Apr 2010), pp. (793Maintenance of blood glucose homeostasis is fundamentally important for health. The maintain of stable levels of glucose in the blood is one of the most finely regulated of all homeostatic mechanisms and one in which the liver, the extrahepatic tissues, and several hormones play a part. Even mild disruptions of glucose homeostasis can have adverse consequences.

The physiological post absorptive serum glucose concentration in healthy humans range is 4, 4-5,8 mmol/L (80 to 105 mg/dL). The stability of the plasma glucose level is a reflection of the balance between the rates of whole body glucose production and glucose utilization.

Generally, hypoglycemia is defined as a serum glucose level below 3. 8 mmol/L (70 mg/dL).As a relatively rare disorder, hypoglycemia most often affects those humans at the extremes of age, such as infants and the elderly, but may happen at any age.

As a medical problem, hypoglycemia is diagnosed by the presence of three key features (known as Whipple's triad). Whipple's triad is:

The etiology of hypoglycemia is numerous:

Hypoglycemia as a Pathological Result in Medical Praxis 111

childhood. In adults, low blood glucose in the fasting state is almost always due to a serious underlying condition (Caraway & Watts,1986; King, 2011; Mayer, 1975; Service,1992)**.**

Carbohydrates are important components of the diet. The carbohydrates that we ingest range from simple monosaccharides (glucose, fructose and galactose) to disaccharides (lactose, sucrose) and complex polysaccharides, starch and glycogen. Most carbohydrates are digested by salivary and pancreatic amylases, and are further broken down into monosaccharides by enzymes in the brush border membrane (BBM) of enterocytes. Maltase, lactase and sucrase-isomaltase are disaccharidases involved in the hydrolysis of nutritionally important disaccharides, maltose, lactose, saccharose. Once monosaccharides are presented to the BBM, mature enterocytes, expressing nutrient transporters, transport

The resultant glucose and other simple carbohydrates, galactose (from lactose) and fructose (from succrose) are transported across the intestinal wall to the hepatic portal vein and then to liver parenchymal cells. Both fructose and galactose are readily converted to glucose by hepatocytes Absorption of glucose and galactose occurs by an active carrier-mediated transfer process. Fructose is absorbed by facilitated diffusion (Harper,1975; King, 2011;

Fructose and galactose are phosphorylated by specific enzymes, fructokinase and galactokinase, presented only in the liver, and converted to glucose. Glucose is transported from the liver via the bloodstream to be used by all the body cells as the most important source of energy. Glucose, as unique sugar in systemic blood circulation, leaves the blood, enters cells through specific transport proteins and has one principal fate: it is phosphorylated by ATP to form glucose-6-phosphate by hexokinase in all human body cells or by the action of glucokinase in hepatocytes. This step is notable because glucose-6 phosphate cannot diffuse through the membrane out of the cells (Haris, 1997; Harper,1979;

Maintenance of blood glucose homeostasis is fundamentally important for health. The plasma glucose level is tightly controlled throughout life in the normal individual, in spite of intermittent food ingestion and periods of fasting, as the net balance between the rates of glucose production and utilization. The stability of the plasma glucose level is a reflection of the balance between the rates of whole body glucose production and glucose utilization. The amount of plasma glucose level in healthy humans is usually maintained within a range of 4.4 to 5.8 mmol/L , 80 to 110 mg/dL), (Carraway & Watts,1986; King, 2011;

Glycogen is the storage form of glucose and serves as a tissue reserve for the body's glucose needs. Glycogen synthesis occurs in virtually all animal tissues, but it is especially prominent in the liver and skeletal muscles. In the liver, glycogen serves as a reservoir of

**2. Digestion and absorption of carbohydrates**

the sugars into the enterocytes, (Drozdowski & Thomson, 2006).

www.deo.ucsf.edu/type1/understanding-diabetes).

King,2011; Tietz,1986; Voet & Voet, 2004a).

**3. Glycemia - Physiological regulation**

Mayes,1975; Service, 1992; Voet & Voet, 2004a).

**4.1 Glycogen synthesis**

**4. Intermediary metabolism of carbohydrates**

cells of Langerhance islets in the pancreas. Its secretion is stimulated by hypoglycemia. The hormone glucagon, epinephrine, norepinephrine, growth hormone, and cortisol exert the opposite effects to insulin and they belong in the counter-regulatory hormones

The central nervous system requires glucose as its primary fuel. The brain uses more than 30% of blood glucose. The brain does not produce the glucose required for its functioning and it is completely dependent on the rest of the body for its supply. So, fluctuations in blood sugar levels can prove to be harmful for the brain; a continual supply of glucose is necessary as a source of energy for the nervous system and some other organs like erythrocytes, testes and kidney medulla .Gluconeogenesis, the biosynthesis of new glucose, (i.e. not glucose from glycogen) from other metabolites (lactic acid, amino acids and glycerol) is necessary for use as a fuel, since glucose is the sole energy source for these organs.

The symptoms caused by low blood sugar come from two sources and may resemble other medical conditions. The first symptoms are caused by the release of epinephrine from the nervous system. These include sweating, pale skin color, shakiness, trembling, rapid heart rate, a feeling of anxiety, nervousness, weakness, hunger, nausea and vomiting. Lowering of the brain's glucose causes: headache, difficulty in thinking, changes in vision, lethargy, restlessness, inability to concentrate or pay attention, mental confusion, sleepiness, stupor, and personality changes.

To treat low blood sugar immediately the patients should eat or drink something that has sugar in it, such as orange juice, milk, or a hard candy. It is need to find out the causes of hypoglycemia.

Laboratory diagnosis of hypoglycemia is very important in medical praxis especially in pediatric, internal medicine (hepatology, renal failure, and cardiology) neuropsychiatry disorders and so on.

Glucose is the name of the simple sugar found in plant and animal tissues. It is made within plants as a product of photosynthesis. Although glucose can be produced within the human body, most of it is supplied to people by dietary carbohydrate intake principally as starch. Once consumed and digested, glucose will either be used immediately or stored as glycogen for future use, (Caraway & Watts,1986; Mayer,1975).

Glucose is the major energy source for human body and is derived primarily from dietary carbohydrates (grains, starchy vegetables, and legumes), from body stores of carbohydrates (glycogen) and from the synthesis of glucose from protein and glycerol moiety of triglycerides (gluconeogenesis) (King, 2011).

The glucose level in blood is kept within narrow range through a variety of influences. While there is some variation in blood glucose as circumstance changes (feeding, prolonged fasting), levels above or below the normal range usually indicate disease.

High blood glucose due to diabetes mellitus is the most commonly encountered disorder of carbohydrate metabolism. Low blood glucose is an uncommon cause of serious diseases. There are numerous rare conditions that cause hypoglycemia in neonatal period and early

the opposite effects to insulin and they belong in the counter-regulatory hormones 3. The disorders of some organs (Liver and Kidney Disorders especially). Any abnormality in the functioning of the liver can disturb the process of blood-sugar regulation, resulting in hypoglycemia. On the other hand, kidney disorder can be one of

The central nervous system requires glucose as its primary fuel. The brain uses more than 30% of blood glucose. The brain does not produce the glucose required for its functioning and it is completely dependent on the rest of the body for its supply. So, fluctuations in blood sugar levels can prove to be harmful for the brain; a continual supply of glucose is necessary as a source of energy for the nervous system and some other organs like erythrocytes, testes and kidney medulla .Gluconeogenesis, the biosynthesis of new glucose, (i.e. not glucose from glycogen) from other metabolites (lactic acid, amino acids and glycerol) is necessary for use as

The symptoms caused by low blood sugar come from two sources and may resemble other medical conditions. The first symptoms are caused by the release of epinephrine from the nervous system. These include sweating, pale skin color, shakiness, trembling, rapid heart rate, a feeling of anxiety, nervousness, weakness, hunger, nausea and vomiting. Lowering of the brain's glucose causes: headache, difficulty in thinking, changes in vision, lethargy, restlessness, inability to concentrate or pay attention, mental confusion, sleepiness, stupor,

To treat low blood sugar immediately the patients should eat or drink something that has sugar in it, such as orange juice, milk, or a hard candy. It is need to find out the causes of

Laboratory diagnosis of hypoglycemia is very important in medical praxis especially in pediatric, internal medicine (hepatology, renal failure, and cardiology) neuropsychiatry

Glucose is the name of the simple sugar found in plant and animal tissues. It is made within plants as a product of photosynthesis. Although glucose can be produced within the human body, most of it is supplied to people by dietary carbohydrate intake principally as starch. Once consumed and digested, glucose will either be used immediately or stored as glycogen

Glucose is the major energy source for human body and is derived primarily from dietary carbohydrates (grains, starchy vegetables, and legumes), from body stores of carbohydrates (glycogen) and from the synthesis of glucose from protein and glycerol

The glucose level in blood is kept within narrow range through a variety of influences. While there is some variation in blood glucose as circumstance changes (feeding, prolonged

High blood glucose due to diabetes mellitus is the most commonly encountered disorder of carbohydrate metabolism. Low blood glucose is an uncommon cause of serious diseases. There are numerous rare conditions that cause hypoglycemia in neonatal period and early

fasting), levels above or below the normal range usually indicate disease.

6. Hypoglycemia as the complication of treatment of diabetes mellitus.

a fuel, since glucose is the sole energy source for these organs.

for future use, (Caraway & Watts,1986; Mayer,1975).

moiety of triglycerides (gluconeogenesis) (King, 2011).

the major causes of low blood sugar. 4. Infection-related hypoglycemia (in older adults)

5. The adverse medication reactions

and personality changes.

hypoglycemia.

disorders and so on.

cells of Langerhance islets in the pancreas. Its secretion is stimulated by hypoglycemia. The hormone glucagon, epinephrine, norepinephrine, growth hormone, and cortisol exert childhood. In adults, low blood glucose in the fasting state is almost always due to a serious underlying condition (Caraway & Watts,1986; King, 2011; Mayer, 1975; Service,1992)**.**

### **2. Digestion and absorption of carbohydrates**

Carbohydrates are important components of the diet. The carbohydrates that we ingest range from simple monosaccharides (glucose, fructose and galactose) to disaccharides (lactose, sucrose) and complex polysaccharides, starch and glycogen. Most carbohydrates are digested by salivary and pancreatic amylases, and are further broken down into monosaccharides by enzymes in the brush border membrane (BBM) of enterocytes. Maltase, lactase and sucrase-isomaltase are disaccharidases involved in the hydrolysis of nutritionally important disaccharides, maltose, lactose, saccharose. Once monosaccharides are presented to the BBM, mature enterocytes, expressing nutrient transporters, transport the sugars into the enterocytes, (Drozdowski & Thomson, 2006).

The resultant glucose and other simple carbohydrates, galactose (from lactose) and fructose (from succrose) are transported across the intestinal wall to the hepatic portal vein and then to liver parenchymal cells. Both fructose and galactose are readily converted to glucose by hepatocytes Absorption of glucose and galactose occurs by an active carrier-mediated transfer process. Fructose is absorbed by facilitated diffusion (Harper,1975; King, 2011; www.deo.ucsf.edu/type1/understanding-diabetes).

Fructose and galactose are phosphorylated by specific enzymes, fructokinase and galactokinase, presented only in the liver, and converted to glucose. Glucose is transported from the liver via the bloodstream to be used by all the body cells as the most important source of energy. Glucose, as unique sugar in systemic blood circulation, leaves the blood, enters cells through specific transport proteins and has one principal fate: it is phosphorylated by ATP to form glucose-6-phosphate by hexokinase in all human body cells or by the action of glucokinase in hepatocytes. This step is notable because glucose-6 phosphate cannot diffuse through the membrane out of the cells (Haris, 1997; Harper,1979; King,2011; Tietz,1986; Voet & Voet, 2004a).

#### **3. Glycemia - Physiological regulation**

Maintenance of blood glucose homeostasis is fundamentally important for health. The plasma glucose level is tightly controlled throughout life in the normal individual, in spite of intermittent food ingestion and periods of fasting, as the net balance between the rates of glucose production and utilization. The stability of the plasma glucose level is a reflection of the balance between the rates of whole body glucose production and glucose utilization. The amount of plasma glucose level in healthy humans is usually maintained within a range of 4.4 to 5.8 mmol/L , 80 to 110 mg/dL), (Carraway & Watts,1986; King, 2011; Mayes,1975; Service, 1992; Voet & Voet, 2004a).

#### **4. Intermediary metabolism of carbohydrates**

#### **4.1 Glycogen synthesis**

Glycogen is the storage form of glucose and serves as a tissue reserve for the body's glucose needs. Glycogen synthesis occurs in virtually all animal tissues, but it is especially prominent in the liver and skeletal muscles. In the liver, glycogen serves as a reservoir of

Hypoglycemia as a Pathological Result in Medical Praxis 113

In the proceses of glycogen catabolism or glycogenolysis, glycogen, stored in the liver and muscles, is converted first to glucose-1-phosphate and then into glucose-6-phosphate. (Mayes,1975; Voet &;Voet, 2004b). Three enzymes participate in glycogenolysis: glycogen phosphorylase, oligo-1,4-1,4–glucan transferase or trisaccharide transferase, and (1-6) glucosidase or - amylase. Glycogen phosphorylase catalyzes phosphorolytic cleavage of the -1,4 glycosidic linkages of glycogen (using inorganic phosphate), releasing glucose-1 phosphate as reaction product and limit dextrin. After extensive phosphorylase action on glycogen, the molecule contains four glucose residues in -1,4-glucosidic bond attached by

These structures can be further degraded by the action of a debranching enzyme, which carries out two distinct reactions. The first of these, known as oligo-a1,4-a-1,4) glucan transferase activity or trisaccharide transferase, removes a trisaccharide unit from limit branch and transfers this group to the end of another nearby glycogen chain, with resynthesis of the -1,4 bond. This leaves a single glucose residue in a-(1,6) linkage to the main chain*.* The -1,6-glucosidase or -amylase activity of the debranching enzyme then catalyzes hydrolysis of the (1,6) linkage, leaving a polysaccharide chain with one branch fewer and yielding free glucose. This is a minor fraction of free glucose released from glycogen (Fig 3), since that the major product of glycogen breakdown by phosphorylase activity is glucose-1-phosphate. Phosphoglucomutase catalyzes the reaction: glucose-1-

Glucose-6-phosphate is the first step of the glycolysis pathway if glycogen is the carbohydrate source of further energy needed. If energy is not immediately needed, the glucose-6-phosphate is converted to glucose, by the action of the enzyme glucose-6 phosphatase (mainly in liver), for distribution to various cells by blood, such as brain,

The reactions involved in tissue glycogen synthesis and degradation are carefully controlled and regulated by hormones. The primary hormone responsible for conversion of glucose to glycogen is insulin. Opposite effects to glycogen metabolism have its antagonists: glucagon, adrenaline, cortisol, growth hormone which facilitate glycogenolysis in liver and muscles.

Fig. 2. Glycogenesis

**4.2 Glycogen breakdown (glycogenolysis)**

a(1,6)-link to the glycogen molecule.

phosphate glucose-6-phosphate.

erythrocytes, adipocytes, etc.

glucose, readily converted into blood glucose for distribution to other tissues, whereas in muscles glycogen is broken down via glycolysis to provide energy for muscle contraction. In human body, glycogen is synthesized and stored when glucose levels are high and is broken down during starvation or periods of high glucose demand.

Glycogen is a highly branched polymeric structure containing glucose as the basic monomer (Mayes, 1975; Voet & Voet, 2004b)*.* It is composed of polymers of -1-4 linked glucose, interrupted by 1-6 linked branch point every 4-10 residues (Fig 1).

Fig. 1. Glycogen structure

Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis. Glycogen synthase will only add glucose units from UDP-glucose onto a preexisting glycogen chain that has at least four glucose residues. Linkage of the first few glucose units to form the minimal "primer" needed for glycogen synthase recognition is catalyzed by a protein called glycogenin, which attaches to the first glucose and catalyzes linkage of the first eight glucoses by alpha(1,4) bonds. The enzyme, glycogenin, initiates glycogenynthesis (oregonstate.edu/.../summer09/lecture/glycogennotes.html; Voet & Voet, 2004b).

The enzyme glycogen synthase then catalyzes elongation of glycogen chains initiated by glycogenin to a chane of 9 – 11 glucose molecule. Glycogen synthase catalyzes transfer of the glucose moiety of UDP-glucose to the hydroxyl at C4 of the terminal residue of a glycogen chain to form an (1-4)-glycosidic linkage (Fig 2) (Mayes,1975; King, 2011; Voet & Voet, 2004b; www.uic.edu/.../glycogen%20metab/Glycogen%20biochemistry.htm).

A branching enzyme forms the branching points in glycogen. The branches arise from -(1**-** 6) linkages which occur every 8 to 12 residues. Glycogen branches are formed by amylo-(1,4- 1,6)-transglycosylase**,** also known as branching enzyme*.* The branching enzyme transfers a segment from the end of a glycogen chain to the C6 hydroxyl of a glucose residue of glycogen to yield a branch with an -(1-6) linkage. In the presence of glycogenin, glycogen synthase, branching enzyme and UDP glucose (active glucose) form glycogen as a highly branched polymeric structure, containing glucose as the basic monomer (Figure 2).

Glycogen is synthesized and stored mainly in the liver and the muscles as well as in the cytoplasm of all human body cells as granules named "residual bodies", (Voet & Voet, 2004b).

Fig. 2. Glycogenesis

glucose, readily converted into blood glucose for distribution to other tissues, whereas in muscles glycogen is broken down via glycolysis to provide energy for muscle contraction. In human body, glycogen is synthesized and stored when glucose levels are high and is broken

Glycogen is a highly branched polymeric structure containing glucose as the basic monomer (Mayes, 1975; Voet & Voet, 2004b)*.* It is composed of polymers of -1-4 linked glucose,

Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis. Glycogen synthase will only add glucose units from UDP-glucose onto a preexisting glycogen chain that has at least four glucose residues. Linkage of the first few glucose units to form the minimal "primer" needed for glycogen synthase recognition is catalyzed by a protein called glycogenin, which attaches to the first glucose and catalyzes linkage of the first eight glucoses by alpha(1,4) bonds. The enzyme, glycogenin, initiates glycogenynthesis (oregonstate.edu/.../summer09/lecture/glycogennotes.html; Voet &

The enzyme glycogen synthase then catalyzes elongation of glycogen chains initiated by glycogenin to a chane of 9 – 11 glucose molecule. Glycogen synthase catalyzes transfer of the glucose moiety of UDP-glucose to the hydroxyl at C4 of the terminal residue of a glycogen chain to form an (1-4)-glycosidic linkage (Fig 2) (Mayes,1975; King, 2011; Voet &

A branching enzyme forms the branching points in glycogen. The branches arise from -(1**-** 6) linkages which occur every 8 to 12 residues. Glycogen branches are formed by amylo-(1,4- 1,6)-transglycosylase**,** also known as branching enzyme*.* The branching enzyme transfers a segment from the end of a glycogen chain to the C6 hydroxyl of a glucose residue of glycogen to yield a branch with an -(1-6) linkage. In the presence of glycogenin, glycogen synthase, branching enzyme and UDP glucose (active glucose) form glycogen as a highly

Glycogen is synthesized and stored mainly in the liver and the muscles as well as in the cytoplasm of all human body cells as granules named "residual bodies", (Voet & Voet, 2004b).

Voet, 2004b; www.uic.edu/.../glycogen%20metab/Glycogen%20biochemistry.htm).

branched polymeric structure, containing glucose as the basic monomer (Figure 2).

down during starvation or periods of high glucose demand.

Fig. 1. Glycogen structure

Voet, 2004b).

interrupted by 1-6 linked branch point every 4-10 residues (Fig 1).

#### **4.2 Glycogen breakdown (glycogenolysis)**

In the proceses of glycogen catabolism or glycogenolysis, glycogen, stored in the liver and muscles, is converted first to glucose-1-phosphate and then into glucose-6-phosphate. (Mayes,1975; Voet &;Voet, 2004b). Three enzymes participate in glycogenolysis: glycogen phosphorylase, oligo-1,4-1,4–glucan transferase or trisaccharide transferase, and (1-6) glucosidase or - amylase. Glycogen phosphorylase catalyzes phosphorolytic cleavage of the -1,4 glycosidic linkages of glycogen (using inorganic phosphate), releasing glucose-1 phosphate as reaction product and limit dextrin. After extensive phosphorylase action on glycogen, the molecule contains four glucose residues in -1,4-glucosidic bond attached by a(1,6)-link to the glycogen molecule.

These structures can be further degraded by the action of a debranching enzyme, which carries out two distinct reactions. The first of these, known as oligo-a1,4-a-1,4) glucan transferase activity or trisaccharide transferase, removes a trisaccharide unit from limit branch and transfers this group to the end of another nearby glycogen chain, with resynthesis of the -1,4 bond. This leaves a single glucose residue in a-(1,6) linkage to the main chain*.* The -1,6-glucosidase or -amylase activity of the debranching enzyme then catalyzes hydrolysis of the (1,6) linkage, leaving a polysaccharide chain with one branch fewer and yielding free glucose. This is a minor fraction of free glucose released from glycogen (Fig 3), since that the major product of glycogen breakdown by phosphorylase activity is glucose-1-phosphate. Phosphoglucomutase catalyzes the reaction: glucose-1 phosphate glucose-6-phosphate.

Glucose-6-phosphate is the first step of the glycolysis pathway if glycogen is the carbohydrate source of further energy needed. If energy is not immediately needed, the glucose-6-phosphate is converted to glucose, by the action of the enzyme glucose-6 phosphatase (mainly in liver), for distribution to various cells by blood, such as brain, erythrocytes, adipocytes, etc.

The reactions involved in tissue glycogen synthesis and degradation are carefully controlled and regulated by hormones. The primary hormone responsible for conversion of glucose to glycogen is insulin. Opposite effects to glycogen metabolism have its antagonists: glucagon, adrenaline, cortisol, growth hormone which facilitate glycogenolysis in liver and muscles.

Hypoglycemia as a Pathological Result in Medical Praxis 115

ATP depletion in cells, or low blood glucose level, lead to the activation of glycogenolysis and the enhancement of glucose degradation through glycolysis. Glycolysis is a central metabolic pathway of glucose metabolism, starting with glucose-6-phosphate, produced by glycogenolysis or gluconeogenesis. Glucose-6-phosphate could also be synthesized directly from blood-derived glucose by the action of hexokinase in all human body cells or by the

Glycolysis is the anaerobic catabolism of glucose. It occurs in cytosol of virtually all cells. The glycolytic pathway converts a molecule of glucose into 2 molecules of pyruvic acid and captures 2 molecules of ATP. If glycolysis proceeds in aerobic conditions 2 molecules of pyruvic acid enter mitochondria, transforms into acetyl-CoA which is oxidized by the citric acid cycle. One cycle provides 12 mol ATP per one molecule of pyruvate. Aerobic conditions provide a mechanism for converting NADH back to NAD+ which is essential for glycolysis

**4.3 Glycolysis**

to operate (Fig 4).

action of glucokinase in hepatocytes.

Fig. 4. Glycolysis and Gluconeogenesis

The principal enzymes of glycogen metabolism are glycogen synthase and glycogen phosphorylase, reciprocally regulated by allosteric effectors and covalent modification (through phosphorylation or dephosphorylation). Glycogen synthase is active when high blood glucose leads to intracellular glucose-6-P increase. Glycogen phosphorylase is active in the presence of high level of cyclic adenosine monophosphate (cAMP ) which suggests that the cells need chemical energy in the form of ATP.

Fig. 3. Glycogenolysis

Glucagon, synthesized by pancreatic -cells, and epinephrine (adrenaline), synthesized by adrenal medulla, regulate glycogen metabolism by covalent modification (phosphorylation and dephosphorylation) through cAMP cascades. Both hormones are produced in response to low blood glucose level. Glucagon activates cAMP formation in liver, while adrenaline activates its formation in muscle. Phosphorylation of the enzyme, via cAMP cascade, induced by adrenaline, results in further activation of glycogen phosphorylase. These regulatory processes ensure release of phosphorylated glucose from glycogen, for entry into glycolysis to provide ATP needed for muscle contraction.

Insulin, produced in response to high blood glucose, antagonizes effects of the cAMP cascade induced by glucagon and adrenaline. It is the only hormone inducing cAMP decrease (Mayes, 1975; Voet & Voet, 2004b).

#### **4.3 Glycolysis**

114 Type 1 Diabetes Complications

The principal enzymes of glycogen metabolism are glycogen synthase and glycogen phosphorylase, reciprocally regulated by allosteric effectors and covalent modification (through phosphorylation or dephosphorylation). Glycogen synthase is active when high blood glucose leads to intracellular glucose-6-P increase. Glycogen phosphorylase is active in the presence of high level of cyclic adenosine monophosphate (cAMP ) which suggests

Glucagon, synthesized by pancreatic -cells, and epinephrine (adrenaline), synthesized by adrenal medulla, regulate glycogen metabolism by covalent modification (phosphorylation and dephosphorylation) through cAMP cascades. Both hormones are produced in response to low blood glucose level. Glucagon activates cAMP formation in liver, while adrenaline activates its formation in muscle. Phosphorylation of the enzyme, via cAMP cascade, induced by adrenaline, results in further activation of glycogen phosphorylase. These regulatory processes ensure release of phosphorylated glucose from glycogen, for entry into

Insulin, produced in response to high blood glucose, antagonizes effects of the cAMP cascade induced by glucagon and adrenaline. It is the only hormone inducing cAMP

glycolysis to provide ATP needed for muscle contraction.

decrease (Mayes, 1975; Voet & Voet, 2004b).

that the cells need chemical energy in the form of ATP.

Fig. 3. Glycogenolysis

ATP depletion in cells, or low blood glucose level, lead to the activation of glycogenolysis and the enhancement of glucose degradation through glycolysis. Glycolysis is a central metabolic pathway of glucose metabolism, starting with glucose-6-phosphate, produced by glycogenolysis or gluconeogenesis. Glucose-6-phosphate could also be synthesized directly from blood-derived glucose by the action of hexokinase in all human body cells or by the action of glucokinase in hepatocytes.

Glycolysis is the anaerobic catabolism of glucose. It occurs in cytosol of virtually all cells. The glycolytic pathway converts a molecule of glucose into 2 molecules of pyruvic acid and captures 2 molecules of ATP. If glycolysis proceeds in aerobic conditions 2 molecules of pyruvic acid enter mitochondria, transforms into acetyl-CoA which is oxidized by the citric acid cycle. One cycle provides 12 mol ATP per one molecule of pyruvate. Aerobic conditions provide a mechanism for converting NADH back to NAD+ which is essential for glycolysis to operate (Fig 4).

Fig. 4. Glycolysis and Gluconeogenesis

Hypoglycemia as a Pathological Result in Medical Praxis 117

Lactate, formed by the oxidation of glucose in skeletal muscles and by erythrocytes through the proceses of anaerobic glycolysis, is transported to the liver and kidney, where it re-forms glucose, which again become available via the circulation for oxidation in the tissues. This

It has been noted that of the amino acids transported from muscles to the liver during starvation or under the action of cortisol, alanine predominate. Glucose-alanine cycle represents a cycling glucose from the liver to the muscles and alanine from muscles to liver, effecting a net transfer of amino nitrogen from muscle to liver and free energy from liver to muscle. At the level of muscles, pyruvate, formed by glycolysis, transforms to alanine by the action of alanine transaminase (ALT) or glutamate pyruvat transaminase (GPT). The reaction is freely reversible; at the level of hepatocytes alanine transfers to pyruvate by the

Glycerol, necessary for the synthesis of triacylglicerols and glycerophosholipids is derived, initially, from the blood glucose since free glycerol cannot be utilised readily for the synthesis of these lipids in tissues. Instead of free glycerol, adipose tissue uses -glycero phosphate or "active glycerol" produced during degradation of glucose by glycolysis.

process is known as the Cory cycle or lactic acid cycle (Fig 5).

Fig. 5. Cory cycle , glucose-alanine cycle and glycerol-glucose cycle

**4.4.1 Cory cycle**

**4.4.2 Glucose-alanine cycle**

action of the same anzyme (Fig 5).

Under anaerobic conditions 2 molecules of pyruvate, under the action of lactate dehydrogenaze, and by using NADH2, convert to 2 molecules of lactate. The reaction is freely reversible (Haris, 1997; Mayes, 1975; Voet & Voet, 2004b; users.rcn.com/.../I/ IntermediaryMetabolism.html).

#### **4.4 Gluconeogenesis**

If glucose is not obtained in the diet, during fasting , the body must produce new glucose from noncarbohydrate precursors by the proces of gluconeogenesis. The term gluconeogenesis means the generation (*genesis*) of new (*neo*) glucose.

The production of glucose from other metabolites is necessary to maintain the glucose level in the blood as a fuel source by the brain, erythrocytes, kidney medulla and testes, since glucose is the sole energy source for these organs. During starvation, however, the brain can derive energy from ketone bodies which are converted to acetyl-CoA. The adipose tissue needs glucose which is also necessary for the synthesis of triacylglycerls and glycerophospholipids. The main precursors for gluconeogenesis are lactate and alanine from muscle, glycerol from adipose tissue, and glucogenic amino acids from the proteolysis in peripheral tissues and proteins from the diet. The most of the amino acids, as well as their -keto acids, are TCA cycle intermediates. In addition, the gluconeogenetic processes are used to clear the intermediary products of metabolism of other tissues from the blood, e.g. lactate, produced by muscles and erythrocytes, and glycerol, which is continuously produced by adipose tissue.The principal organs responsible for gluconeogenesis are the liver and kidneys, which account for about 90% and 10% of the body's gluconeogenic activity, respectively. Interestingly, the mammalian organs that consume the most glucose, namely, brain and muscle, carry out very little glucose synthesis (Gerich et al, 2001; King, 2011; Mayes,1975; Voet & Voet, 2004b; Woerle & Stumvoll, 2001).

Gluconeogenesis is similar but not the exact reverse of glycolysis; some of the steps are the identical in reverse direction and three of them are new ones (Fig 4). In glycolysis energy barriers obstruct a simple reversal of glycolysis: reactions catalyzed by pyruvate kinase, phospho-fructokinase and hexokinase. These barriers are circumvented by new, special enzymes of gluconeogenesis: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructoso-1,6-diphosphatase and glucose-6-phosphatase. The conversion of lactate to glucose begins with the oxidation of lactate, by the action of lactate dehydrogenase, to pyruvate. In the presence of ATP, pyruvate carboxylase and CO2 convert pyruvat to oxaloacetate. The enzyme, phosphoenolpyruvate carboxykinase (PEPCK) transfers oxaloacetate to phosphoenolpyruvate in the presence of GTP and by elimination of CO2. Thus, with the help of these two enzymes, and lactate dehydrogenase, lactate can be converted to oxaloacetate. The pyruvate and oxaloacetate are the intermediary products of catabolic pathway of many glycolytic amino acids. The next steps of reversal glycolysis continue just to formation of fructose-1,6-diphosphate, the substrate for fructose-1, 6-diphosphatase. Fructose-6-phosphate, formed by elimination of inorganic phosphate, converts to glucose-6 phosphate (G6P). The energy required for the hepatic synthesis of glucose from lactate is derived from the oxidation of fatty acids. In the liver and kidney, G6P can be dephosphorylated to glucose by the enzyme glucose 6-phosphatase. This is the final step in the gluconeogenesis pathway.

#### **4.4.1 Cory cycle**

116 Type 1 Diabetes Complications

Under anaerobic conditions 2 molecules of pyruvate, under the action of lactate dehydrogenaze, and by using NADH2, convert to 2 molecules of lactate. The reaction is freely reversible (Haris, 1997; Mayes, 1975; Voet & Voet, 2004b; users.rcn.com/.../I/

If glucose is not obtained in the diet, during fasting , the body must produce new glucose from noncarbohydrate precursors by the proces of gluconeogenesis. The term

The production of glucose from other metabolites is necessary to maintain the glucose level in the blood as a fuel source by the brain, erythrocytes, kidney medulla and testes, since glucose is the sole energy source for these organs. During starvation, however, the brain can derive energy from ketone bodies which are converted to acetyl-CoA. The adipose tissue needs glucose which is also necessary for the synthesis of triacylglycerls and glycerophospholipids. The main precursors for gluconeogenesis are lactate and alanine from muscle, glycerol from adipose tissue, and glucogenic amino acids from the proteolysis in peripheral tissues and proteins from the diet. The most of the amino acids, as well as their -keto acids, are TCA cycle intermediates. In addition, the gluconeogenetic processes are used to clear the intermediary products of metabolism of other tissues from the blood, e.g. lactate, produced by muscles and erythrocytes, and glycerol, which is continuously produced by adipose tissue.The principal organs responsible for gluconeogenesis are the liver and kidneys, which account for about 90% and 10% of the body's gluconeogenic activity, respectively. Interestingly, the mammalian organs that consume the most glucose, namely, brain and muscle, carry out very little glucose synthesis (Gerich et al, 2001; King, 2011; Mayes,1975; Voet & Voet, 2004b; Woerle

Gluconeogenesis is similar but not the exact reverse of glycolysis; some of the steps are the identical in reverse direction and three of them are new ones (Fig 4). In glycolysis energy barriers obstruct a simple reversal of glycolysis: reactions catalyzed by pyruvate kinase, phospho-fructokinase and hexokinase. These barriers are circumvented by new, special enzymes of gluconeogenesis: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructoso-1,6-diphosphatase and glucose-6-phosphatase. The conversion of lactate to glucose begins with the oxidation of lactate, by the action of lactate dehydrogenase, to pyruvate. In the presence of ATP, pyruvate carboxylase and CO2 convert pyruvat to oxaloacetate. The enzyme, phosphoenolpyruvate carboxykinase (PEPCK) transfers oxaloacetate to phosphoenolpyruvate in the presence of GTP and by elimination of CO2. Thus, with the help of these two enzymes, and lactate dehydrogenase, lactate can be converted to oxaloacetate. The pyruvate and oxaloacetate are the intermediary products of catabolic pathway of many glycolytic amino acids. The next steps of reversal glycolysis continue just to formation of fructose-1,6-diphosphate, the substrate for fructose-1, 6-diphosphatase. Fructose-6-phosphate, formed by elimination of inorganic phosphate, converts to glucose-6 phosphate (G6P). The energy required for the hepatic synthesis of glucose from lactate is derived from the oxidation of fatty acids. In the liver and kidney, G6P can be dephosphorylated to glucose by the enzyme glucose 6-phosphatase. This is the final step in

gluconeogenesis means the generation (*genesis*) of new (*neo*) glucose.

IntermediaryMetabolism.html).

**4.4 Gluconeogenesis**

& Stumvoll, 2001).

the gluconeogenesis pathway.

Lactate, formed by the oxidation of glucose in skeletal muscles and by erythrocytes through the proceses of anaerobic glycolysis, is transported to the liver and kidney, where it re-forms glucose, which again become available via the circulation for oxidation in the tissues. This process is known as the Cory cycle or lactic acid cycle (Fig 5).

#### **4.4.2 Glucose-alanine cycle**

It has been noted that of the amino acids transported from muscles to the liver during starvation or under the action of cortisol, alanine predominate. Glucose-alanine cycle represents a cycling glucose from the liver to the muscles and alanine from muscles to liver, effecting a net transfer of amino nitrogen from muscle to liver and free energy from liver to muscle. At the level of muscles, pyruvate, formed by glycolysis, transforms to alanine by the action of alanine transaminase (ALT) or glutamate pyruvat transaminase (GPT). The reaction is freely reversible; at the level of hepatocytes alanine transfers to pyruvate by the action of the same anzyme (Fig 5).

Glycerol, necessary for the synthesis of triacylglicerols and glycerophosholipids is derived, initially, from the blood glucose since free glycerol cannot be utilised readily for the synthesis of these lipids in tissues. Instead of free glycerol, adipose tissue uses -glycero phosphate or "active glycerol" produced during degradation of glucose by glycolysis.

Fig. 5. Cory cycle , glucose-alanine cycle and glycerol-glucose cycle

Hypoglycemia as a Pathological Result in Medical Praxis 119

Insulin has a hypoglycemic effect. Secretion of insulin is a response to increased glucose level in the blood. In addition to the direct effects of hyperglycemia in enhancing the uptake of glucose into both the liver and peripheral tissues, the hormon insulin plays a central role in the regulation of the blood glucose concentration. Similarly, as blood glucose falls, the

Glucagon, as a direct antagonist of insulin, has a hyperglycemic effect. Secretion of glucagon is a response to decreased glucose level in the blood (Chattoraj & Watts,1986; Ginsberg,

Insulin is a small protein consisting of an alpha chain of 21 amino acids linked by two disulfide (S—S) bridges to a beta chain of 30 amino acids. The precursor of insulin is a proinsulin, which contains C peptide (conective peptide). The conversion of proinsulin to insulin requires biologic proteolysis (Ginsberg,1990; Bowen, 2010; Harper, 1975; Chattoraj &

The stimulus for insulin secretion is a high blood glucose. Insulin is produced by β cells of Langerhans islets in pancreas and is secreted into the blood as a direct response to hyperglycemuia. Beta cells have channels in their plasma membrane that serve as glucose detectors. When blood glucose levels rise (after a meal), insulin is secreted from the pancreas into the pancreatic vein, which empties into the portal vein system, so that insulin traverses the liver before it enters the systemic blood supply. Insulin acts to rapidly lower blood glucose concentration in several ways. It stimulates the active transport of glucose across plasma membranes through glucose transporter (GLUT 4) of muscle and adipose tissue. The liver, brain and red blood cells do not require insulin for glucose uptake. Insulin is an anabolic hormone. It promotes anabolic processes in these cells, such as increasing the rate of glycogenesis, lipidogenesis and proteins synthesis. The cellular uptake of glucose from the blood have the net effect of lowering the high blood glucose levels into the normal range. Insulin stimulates cells in most tissues of the body to preferentially use glucose as their metabolic fuel*.* It increases cellular glucose utilization by inducing the synthesis of several important glycolytic enzymes, namely, hexokinase, glucokinase, phosphofructokinase, and pyruvate kinase. In addition, insulin inhibit gluconeogenesis in liver. All of these physiological effects of insulin serve to lower blood glucose levels. In each case, insulin triggers these effects by binding to the insulin receptor - a transmembrane protein embedded in the plasma membrane of the responding cells. When the the glucose concentration in the blood falls, pancreas stops releasing insulin (Ginsberg, 1990 a, 1990b;

Pancreatic beta cells secrete amylin, a peptide of 37 amino acids. All of its actions (inhibition of glucagon secretion, slowing down the stomach emptying, sending a satiety signal to the brain) tend to supplement those of insulin, reducing the level of glucose in the blood (King, 2011; Silvestre et al, 2001; Young, 2005; users.rcn.com/.../I/IntermediaryMetabolism.html).

Glucagon is another 29 amino acid peptide hormone produced by pancreas. It is a hyperglycemic hormone (Bowen, 2007). Glucagon is produced by alpha (α) cells of

amount of insulin secreted by the pancreatic islets goes down.

1990 a, 1990b; Mayes,1975; King, 2011).

**5.2.1 Insulin**

Watts,1986).

Bowen, 2007; King, 2011).

**5.2.2 Amylin**

**5.2.3 Glucagon**

#### **4.4.3 Glycerol - Glucose cycle**

Glycerol, a product of the continual lipolysis, diffuses out of the tissue into the blood. It is converted back to glucose by gluconeogenic mechanisms in the liver and kidney. Thus, a continous cycle exists in which glucose is transported from the liver to adipose tissue and, hence, glycerol is returned to be synthesized into glucose by the liver. Glycerokinase, which requires ATP, catalyzes the conversion of glycerol to -glycero phosphate. Glycerokinase is present in liver and kidney. The enzyme -glycero phosphate dehydrogenase oxidizes glycero phosphate to the dihydroxacetone phosphate, the component of glycolysis, which enters the glycolytic pathway as a substrate for triose phosphate isomerase (Fig 4). Thus, liver is able to convert glycerol to blood glucose by making use of above enzymes - some of the enzyme of glycolysis and specific enzymes of gluconeogenic pathway, fructose-1,6 diphosphatase and glucose-6-phosphatase(Harris & Crabb, 1997; King, 2011; Mayes,1975).

Glucose produced by gluconeogenesis in the liver and kidney is released into the blood and is subsequently absorbed by all human body cells especially brain, heart, muscle, and red blood cells to meet their metabolic needs. In turn, pyruvate, lactate and glycerol produced in these tissues are returned to liver and kidney to be used as gluconeogenic substrates.

#### **5. The physiological regulation of carbohydrate metabolism**

#### **5.1 Glucose homeostasis**

The maintaining of stable levels of blood glucose is one of the most finely regulated of all homeostatic mechanisms and one in which the liver, extrahepatic tissues and several hormones play a part. Even mild disruptions of glucose homeostasis can have adverse consequences. The physiological post absorptive serum glucose concentration in healthy humans range is 4. 4-5.8 mmol/L (80 to 110 mg/dL).

Glycemia is controlled by several physiological processes. It tends to fluctuate to higher levels after meals, due to intestinal absorption of carbohydrates of low molecular weight present in the diet or broken down polysaccharides, such as starch or glycogen. On the other hand, glucose tends to decrease to lower levels induced by cell metabolism, particularly after stress, temperature regulation and physical exercise. Glucose can also be supplied via breakdown of cellular reserves of glycogen. Another input to glycemia levels is gluconeogenesis, whereby glycogen stored in the liver and skeletal muscles are depleted.

*The stability of the glycemia is a reflection of the balance between the rates of whole body glucose production and glucose utilization.* The glucose homeostasis is tightly regulated by the levels of hormones and substrates in blood and by the physiologic functions of body tissues and organs (Carraway & Watts, 1986; Haris, 1997; King,2011).

#### **5.2 Hormonal regulation of glycemia**

The hormones involved in glycemia regulation include insulin (which lowers the blood sugar level) and other hormons which raise blood sugar, namely antagonists of insulin such as glucagon, epinephrine, cortisol, growth hormone, thyreoid hormones (T3 and T4) and many others. The proper functions of these hormones is precise control of glucose concentration in the blood. Insulin and glucagon are two major hormones involved in regulation of blood glucose level. They are both secreted in response to blood sugar levels, but in opposite fashion. At the same time, enhanced insulin secretion induced increased glucagon secretion.

Insulin has a hypoglycemic effect. Secretion of insulin is a response to increased glucose level in the blood. In addition to the direct effects of hyperglycemia in enhancing the uptake of glucose into both the liver and peripheral tissues, the hormon insulin plays a central role in the regulation of the blood glucose concentration. Similarly, as blood glucose falls, the amount of insulin secreted by the pancreatic islets goes down.

Glucagon, as a direct antagonist of insulin, has a hyperglycemic effect. Secretion of glucagon is a response to decreased glucose level in the blood (Chattoraj & Watts,1986; Ginsberg, 1990 a, 1990b; Mayes,1975; King, 2011).

#### **5.2.1 Insulin**

118 Type 1 Diabetes Complications

Glycerol, a product of the continual lipolysis, diffuses out of the tissue into the blood. It is converted back to glucose by gluconeogenic mechanisms in the liver and kidney. Thus, a continous cycle exists in which glucose is transported from the liver to adipose tissue and, hence, glycerol is returned to be synthesized into glucose by the liver. Glycerokinase, which requires ATP, catalyzes the conversion of glycerol to -glycero phosphate. Glycerokinase is present in liver and kidney. The enzyme -glycero phosphate dehydrogenase oxidizes glycero phosphate to the dihydroxacetone phosphate, the component of glycolysis, which enters the glycolytic pathway as a substrate for triose phosphate isomerase (Fig 4). Thus, liver is able to convert glycerol to blood glucose by making use of above enzymes - some of the enzyme of glycolysis and specific enzymes of gluconeogenic pathway, fructose-1,6 diphosphatase and glucose-6-phosphatase(Harris & Crabb, 1997; King, 2011; Mayes,1975). Glucose produced by gluconeogenesis in the liver and kidney is released into the blood and is subsequently absorbed by all human body cells especially brain, heart, muscle, and red blood cells to meet their metabolic needs. In turn, pyruvate, lactate and glycerol produced in these tissues are returned to liver and kidney to be used as gluconeogenic substrates.

The maintaining of stable levels of blood glucose is one of the most finely regulated of all homeostatic mechanisms and one in which the liver, extrahepatic tissues and several hormones play a part. Even mild disruptions of glucose homeostasis can have adverse consequences. The physiological post absorptive serum glucose concentration in healthy

Glycemia is controlled by several physiological processes. It tends to fluctuate to higher levels after meals, due to intestinal absorption of carbohydrates of low molecular weight present in the diet or broken down polysaccharides, such as starch or glycogen. On the other hand, glucose tends to decrease to lower levels induced by cell metabolism, particularly after stress, temperature regulation and physical exercise. Glucose can also be supplied via breakdown of cellular reserves of glycogen. Another input to glycemia levels is gluconeogenesis, whereby glycogen stored in the liver and skeletal muscles are

*The stability of the glycemia is a reflection of the balance between the rates of whole body glucose production and glucose utilization.* The glucose homeostasis is tightly regulated by the levels of hormones and substrates in blood and by the physiologic functions of body tissues and

The hormones involved in glycemia regulation include insulin (which lowers the blood sugar level) and other hormons which raise blood sugar, namely antagonists of insulin such as glucagon, epinephrine, cortisol, growth hormone, thyreoid hormones (T3 and T4) and many others. The proper functions of these hormones is precise control of glucose concentration in the blood. Insulin and glucagon are two major hormones involved in regulation of blood glucose level. They are both secreted in response to blood sugar levels, but in opposite fashion. At the same time, enhanced insulin secretion induced increased

**5. The physiological regulation of carbohydrate metabolism**

humans range is 4. 4-5.8 mmol/L (80 to 110 mg/dL).

organs (Carraway & Watts, 1986; Haris, 1997; King,2011).

**5.2 Hormonal regulation of glycemia**

**4.4.3 Glycerol - Glucose cycle**

**5.1 Glucose homeostasis**

depleted.

glucagon secretion.

Insulin is a small protein consisting of an alpha chain of 21 amino acids linked by two disulfide (S—S) bridges to a beta chain of 30 amino acids. The precursor of insulin is a proinsulin, which contains C peptide (conective peptide). The conversion of proinsulin to insulin requires biologic proteolysis (Ginsberg,1990; Bowen, 2010; Harper, 1975; Chattoraj & Watts,1986).

The stimulus for insulin secretion is a high blood glucose. Insulin is produced by β cells of Langerhans islets in pancreas and is secreted into the blood as a direct response to hyperglycemuia. Beta cells have channels in their plasma membrane that serve as glucose detectors. When blood glucose levels rise (after a meal), insulin is secreted from the pancreas into the pancreatic vein, which empties into the portal vein system, so that insulin traverses the liver before it enters the systemic blood supply. Insulin acts to rapidly lower blood glucose concentration in several ways. It stimulates the active transport of glucose across plasma membranes through glucose transporter (GLUT 4) of muscle and adipose tissue. The liver, brain and red blood cells do not require insulin for glucose uptake. Insulin is an anabolic hormone. It promotes anabolic processes in these cells, such as increasing the rate of glycogenesis, lipidogenesis and proteins synthesis. The cellular uptake of glucose from the blood have the net effect of lowering the high blood glucose levels into the normal range. Insulin stimulates cells in most tissues of the body to preferentially use glucose as their metabolic fuel*.* It increases cellular glucose utilization by inducing the synthesis of several important glycolytic enzymes, namely, hexokinase, glucokinase, phosphofructokinase, and pyruvate kinase. In addition, insulin inhibit gluconeogenesis in liver. All of these physiological effects of insulin serve to lower blood glucose levels. In each case, insulin triggers these effects by binding to the insulin receptor - a transmembrane protein embedded in the plasma membrane of the responding cells. When the the glucose concentration in the blood falls, pancreas stops releasing insulin (Ginsberg, 1990 a, 1990b; Bowen, 2007; King, 2011).

#### **5.2.2 Amylin**

Pancreatic beta cells secrete amylin, a peptide of 37 amino acids. All of its actions (inhibition of glucagon secretion, slowing down the stomach emptying, sending a satiety signal to the brain) tend to supplement those of insulin, reducing the level of glucose in the blood (King, 2011; Silvestre et al, 2001; Young, 2005; users.rcn.com/.../I/IntermediaryMetabolism.html).

#### **5.2.3 Glucagon**

Glucagon is another 29 amino acid peptide hormone produced by pancreas. It is a hyperglycemic hormone (Bowen, 2007). Glucagon is produced by alpha (α) cells of

Hypoglycemia as a Pathological Result in Medical Praxis 121

induced gluconeogenesis results, primarily, in increased conversion of glycogenic amino acids (from protein breakdown in peripheral tissues) and glycerol (from fat) into glucose

Human growth hormone (GH; also called somatotropin), the protein of 191 amino acids, secreted by somatotrophs of the anterior part of pytuatary gland, regulates overall body and cell growth, carbohydrate, protein and lipid metabolism, and water-electrolyte balance. The GH-secreting cells are stimulated by growth hormone releasing hormone (GHRH) from hypothalamus and inhibited by somatostatin. The release of GH might be regulated not only by hypothalamic GHRH, but also by ghrelin derived from the stomach (Kojima et al., 2005). GH promotes body growth by binding to receptors on the surface of liver cells and stimulates them to release insulin-like growth factor-1 (IGF-1, also known as somatomedin). GH exerts the hyperglycemic effect, stimulating glycogenolysis and lypolysis in peripheral tissues. In liver, GH also stimulates glycogenolysis and glyconeogenesis (Barry, 1992c;

Thyroid hormones are derivatives of the amino acid tyrosine bound covalently to iodine. The two principal thyroid hormones are: triiodothyronin (T3) and thyroxin (T4). Thyroid hormones receptors are intracellular DNA-binding proteins that function as hormoneresponsive transcription factors. The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes. It is likely that all cells in the body are targets for thyroid hormones. Thyroid hormones affect oxidative metabolism, especially the metabolism of carbohydrates. Thyroid hormones enhance glucose absorption and the utilization of carbohydrates. They stimulate both the synthesis and disposal of glucose Hypothyroidism or thyroid hormone deficiency leads to decrease in basal metabolic rate and hypoglycemia (Bowen, 2010; Harper, 1975;

**6. Physiological functions of liver, kidneys and brain in carbohydrate**

them, the most important are liver, kidneys and brain.

**6.1 The role of liver in carbohydrate metabolism**

Beside hormones, some organs have the important roles in glycemia regulation. Among

The metabolic activities of the liver are essential for providing fuel to the brain, muscle, and other peripheral organs. The liver removes two-thirds of the glucose from the blood and all of the remaining monosaccharides (Lehninger,1977; Cherrington,1999). The absorbed glucose is converted into glucose 6-phosphate by hexokinase and the liver-specific glucokinase, whose Km (Michaelis constant) for glucose is sufficiently higher than the normal circulating concentration of glucose (5mM). The liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range. It possesses the key enzymes for glucose intake (hexokinase and glucokinase) and for

(Ginsberg, 1992c; Chattoraj & Watts, 1986; Gil, 1992; Litwak & Schmidt, 1997a;

users.rcn.com/.../I/IntermediaryMetabolism.html.)

**5.2.6 Growth hormone (GH)**

Frohman,1992; Litwak.& Schmidt, 1997b).

**5.2.7 Thyroid hormones**

Zmire et al, 1999).

**metabolism**

Langerhans islets as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides (GLP) (Ginsberg,1990b; Bowen, 2007). Glucagon is secreted in response to hypoglycemia. It is active in liver and adipose tissue*,* but not in other tissues. This peptide hormone travels through the blood to specific receptors on hepatocytes and adipocytes. When the concentration of glucose in blood decreases, α cells of the pancreas begin to release glucagon. Glucagon stimulates hepatocytes to glycogenolysis and gluconeogenesis, resulting in hyperglycemia. It increases the amount of cAMP and stimulates lipolysis, contributing to reduction of the cellular glucose utilization, the increasing of lipolysis in adipose tissue, providing glycerol and free fatty acids which enter oxidation cycle, producing the chemical energy (ATP) to most cells. Glycerol leaves the adipose tissue, and through the blood enters the hepatocytes where it may serve as the substrate in the process of gluconeogenesis (Fig 5).

#### **5.2.4 Epinephrine (adrenaline)**

Epinephrine is a hormone of adrenal medulla, which consists of masses of neurons that are the part of the sympathetic branch of the autonomic nervous system. Instead of releasing their neurotransmitters at a synapse, these neurons release them into the blood. Thus, although part of the nervous system, the adrenal medulla functions as an endocrine gland. It releases catecholamines: adrenaline (epinephrine) and noradrenalin (also called norepinephrine).

Synthesis of both catecholamines begins with the amino acid tyrosine, which is taken up by chromaffin cells. Called the "fight or flight" hormone, adrenaline prepares the organism for mobilization of large amounts of energy and dealing with stress. Together with cortisol and growth hormone they are named "stress hormones". Following release into blood, these hormones bind adrenergic receptors on target cells, where they induce essentially the same effects as direct sympathetic nervous stimulation. Adrenaline acts on liver and muscles. Mechanisms of the actions of adrenaline are the same as the mechanisms of glucagon. Through augmentation of cAMP in the cells, adrenaline initiates the enzyme cascade which leads to the activation of glycogen phosphorylase, leading to rapid breakdown of glycogen, inhibition of glycogen synthesis, stimulation of glycolysis and production of energy*.* In fat cell, it stimulates lipolysis, providing fatty acids as energy source in many tissues. Stimulation of lipolysis contributes to the reduction of the cellular glucose utilization and aids in conservation of dwindling reserves of blood glucose. The stimulation of hepatocytes to glycogenolysis and gluconeogenesis results in regulation of glycemia (Ginsberg,1990a; Chattoraj, & Watts, 1986; www.ncbi.nlm.nih.gov/books/NBK22429/).

#### **5.2.5 Glucocorticoids**

The glucocorticoids (cortisol as the principal one) get their name from their effect of raising the level of blood glucose. Glucocorticoids are a class of steroid hormones, synthesized and secreted from zone fasciculate of adrenal cortex, that exert distinct effects on liver, skeletal muscles, and adipose tissue (Bjelakovic et al,2008,2009). The effects of cortisol are best described as catabolic, because it promotes protein breakdown and decreases protein synthesis in skeletal muscles. However, in the liver, it stimulates gluconeogenesis, inducing increased gene expression of several enzymes of the gluconeogenic pathway. Cortisolinduced gluconeogenesis results, primarily, in increased conversion of glycogenic amino acids (from protein breakdown in peripheral tissues) and glycerol (from fat) into glucose (Ginsberg, 1992c; Chattoraj & Watts, 1986; Gil, 1992; Litwak & Schmidt, 1997a; users.rcn.com/.../I/IntermediaryMetabolism.html.)

#### **5.2.6 Growth hormone (GH)**

120 Type 1 Diabetes Complications

Langerhans islets as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides (GLP) (Ginsberg,1990b; Bowen, 2007). Glucagon is secreted in response to hypoglycemia. It is active in liver and adipose tissue*,* but not in other tissues. This peptide hormone travels through the blood to specific receptors on hepatocytes and adipocytes. When the concentration of glucose in blood decreases, α cells of the pancreas begin to release glucagon. Glucagon stimulates hepatocytes to glycogenolysis and gluconeogenesis, resulting in hyperglycemia. It increases the amount of cAMP and stimulates lipolysis, contributing to reduction of the cellular glucose utilization, the increasing of lipolysis in adipose tissue, providing glycerol and free fatty acids which enter oxidation cycle, producing the chemical energy (ATP) to most cells. Glycerol leaves the adipose tissue, and through the blood enters the hepatocytes where it may serve as the substrate in the process

Epinephrine is a hormone of adrenal medulla, which consists of masses of neurons that are the part of the sympathetic branch of the autonomic nervous system. Instead of releasing their neurotransmitters at a synapse, these neurons release them into the blood. Thus, although part of the nervous system, the adrenal medulla functions as an endocrine gland. It releases catecholamines: adrenaline (epinephrine) and noradrenalin (also called

Synthesis of both catecholamines begins with the amino acid tyrosine, which is taken up by chromaffin cells. Called the "fight or flight" hormone, adrenaline prepares the organism for mobilization of large amounts of energy and dealing with stress. Together with cortisol and growth hormone they are named "stress hormones". Following release into blood, these hormones bind adrenergic receptors on target cells, where they induce essentially the same effects as direct sympathetic nervous stimulation. Adrenaline acts on liver and muscles. Mechanisms of the actions of adrenaline are the same as the mechanisms of glucagon. Through augmentation of cAMP in the cells, adrenaline initiates the enzyme cascade which leads to the activation of glycogen phosphorylase, leading to rapid breakdown of glycogen, inhibition of glycogen synthesis, stimulation of glycolysis and production of energy*.* In fat cell, it stimulates lipolysis, providing fatty acids as energy source in many tissues. Stimulation of lipolysis contributes to the reduction of the cellular glucose utilization and aids in conservation of dwindling reserves of blood glucose. The stimulation of hepatocytes to glycogenolysis and gluconeogenesis results in regulation of glycemia (Ginsberg,1990a;

The glucocorticoids (cortisol as the principal one) get their name from their effect of raising the level of blood glucose. Glucocorticoids are a class of steroid hormones, synthesized and secreted from zone fasciculate of adrenal cortex, that exert distinct effects on liver, skeletal muscles, and adipose tissue (Bjelakovic et al,2008,2009). The effects of cortisol are best described as catabolic, because it promotes protein breakdown and decreases protein synthesis in skeletal muscles. However, in the liver, it stimulates gluconeogenesis, inducing increased gene expression of several enzymes of the gluconeogenic pathway. Cortisol-

Chattoraj, & Watts, 1986; www.ncbi.nlm.nih.gov/books/NBK22429/).

of gluconeogenesis (Fig 5).

norepinephrine).

**5.2.5 Glucocorticoids**

**5.2.4 Epinephrine (adrenaline)**

Human growth hormone (GH; also called somatotropin), the protein of 191 amino acids, secreted by somatotrophs of the anterior part of pytuatary gland, regulates overall body and cell growth, carbohydrate, protein and lipid metabolism, and water-electrolyte balance. The GH-secreting cells are stimulated by growth hormone releasing hormone (GHRH) from hypothalamus and inhibited by somatostatin. The release of GH might be regulated not only by hypothalamic GHRH, but also by ghrelin derived from the stomach (Kojima et al., 2005). GH promotes body growth by binding to receptors on the surface of liver cells and stimulates them to release insulin-like growth factor-1 (IGF-1, also known as somatomedin). GH exerts the hyperglycemic effect, stimulating glycogenolysis and lypolysis in peripheral tissues. In liver, GH also stimulates glycogenolysis and glyconeogenesis (Barry, 1992c; Frohman,1992; Litwak.& Schmidt, 1997b).

#### **5.2.7 Thyroid hormones**

Thyroid hormones are derivatives of the amino acid tyrosine bound covalently to iodine. The two principal thyroid hormones are: triiodothyronin (T3) and thyroxin (T4). Thyroid hormones receptors are intracellular DNA-binding proteins that function as hormoneresponsive transcription factors. The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes. It is likely that all cells in the body are targets for thyroid hormones. Thyroid hormones affect oxidative metabolism, especially the metabolism of carbohydrates. Thyroid hormones enhance glucose absorption and the utilization of carbohydrates. They stimulate both the synthesis and disposal of glucose Hypothyroidism or thyroid hormone deficiency leads to decrease in basal metabolic rate and hypoglycemia (Bowen, 2010; Harper, 1975; Zmire et al, 1999).

#### **6. Physiological functions of liver, kidneys and brain in carbohydrate metabolism**

Beside hormones, some organs have the important roles in glycemia regulation. Among them, the most important are liver, kidneys and brain.

#### **6.1 The role of liver in carbohydrate metabolism**

The metabolic activities of the liver are essential for providing fuel to the brain, muscle, and other peripheral organs. The liver removes two-thirds of the glucose from the blood and all of the remaining monosaccharides (Lehninger,1977; Cherrington,1999). The absorbed glucose is converted into glucose 6-phosphate by hexokinase and the liver-specific glucokinase, whose Km (Michaelis constant) for glucose is sufficiently higher than the normal circulating concentration of glucose (5mM). The liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range. It possesses the key enzymes for glucose intake (hexokinase and glucokinase) and for

Hypoglycemia as a Pathological Result in Medical Praxis 123

are concentrated in hypothalamic area. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and - cells and cells of pancreas, and it regulates induction/inhibition of glucose output from the liver. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose (the hypothalamus-pancreas) (Halmos & Suba, 2011). In addition, the hypothalamus can affect metabolic functions by neuroendocrine connections: the hypothalamus-pancreas axis (the control of insulin and glucagone release), the hypothalamus-adrenal axis (the control of the release of adrenaline and noradrenaline) and the hypothalamus-pituitary axis (release of glucocorticoids and thyroid hormones through adrenocorticotrophic hormone (ACTH) and thyroid-stimulating hormone (TSH) control, respectively, which modulate glucose

Recently, evidence is accumulating demonstrating that gastrointestinal hormones (peptides) are involved in regulating glucose metabolism through humoral gut–brain axis. Some of them are: ghrelin, neuropeptide Y (NPY), cholecystokinin - CCK, gastric inhibitory polypeptide - GIP, glucagon-like peptide (GLP) etc. (Kojima & Kangawa, 2005; King, 2011;

Generally, hypoglycemia is defined as a serum glucose level below (3.8 mmol/L or, 70 mg/dL). Hypoglycemia is a rare disorder, considered as pathophysiological state rather than a disease. Just as pain and fever require identification of the underlying condition, hypoglycemia warrants diagnosis of the primary disorder causing the low plasma glucose

The symptoms of hypoglycemia are not specific. For this reason it is necessary to demonstrate a low plasma glucose concentration concomitant with symptoms and subsequent relief of symptoms by correction of the hypoglycemia, i.e., Whipple's tirade. This triade can be considered to be the basis for a patient's symptoms, regardless of the cause of hypoglycemia (Service,1992). Whipple's triad considers: 1) symptoms consistent with hypoglycemia, 2) a low plasma glucose concentration, and 3) relief of symptoms after the plasma glucose level is raised. Hypoglycemia most often affects those at the extremes of age, such as infants and the elderly, but may happen at any age. Given the survival value of maintenance of the plasma glucose concentration, it is not surprising that very effective physiological mechanisms prevent or rapidly correct hypoglycemia

Hypoglycemic symptoms are related to the brain and the sympathetic nervous system. The central nervous system requires glucose as the preferred energy substrate. Though the brain accounts for only about 10% of body weight, it uses more than 30% of blood glucose. Hypoglycemic symptoms are mediated through both central and peripheral nervous systems. Once plasma glucose concentration fall belows 3.8 mmol/L or 70 mg/dL, a sequence of events begins to maintain glucose delivery to the brain and prevent

The first of all events is the stimulation of the autonomic nervous system and, after that, release of neuroendocrine hormones (counter-regulatory or anti-insulin hormones). Peripheral autonomic symptoms (adrenergic), including sweating, irritability, tremulousness, anxiety, tachycardia, and hunger, serve as an early warning system and

Korner & Leibel, 2003; Neary et al, 2004 ; Young, 2005).

**7. Neuro-endocrine defence to hypoglycemia**

metabolism.

concentration.

have evolved.

hypoglycemia.