`
`Glucose Homeostasis - Mechanism and Defects
`
`Leszek Szablewski
`Medical University ofWarsaw
`Poland
`
`1. Introduction
`
`Glucose is an essential metabolic substrate of all mammalian cells. D-glucose is the major
`carbohydrate presented to the cell for energy production and many other anabolic
`requirements. Glucose and other monosaccharides are transported across the intestinal wall
`to the hepatic portal vein and then to liver cells and other tissues. There they are converted
`to fatty acids, amino acids, and glycogen.. or are oxidized by the various catabolic pathways
`of cells.
`Most tissues and organs, such as the brain, need glucose constantly, as an important source
`of energy. The low blood concentrations of glucose can causes seizures, loss of
`consciousness, and death. On the other hand, long lasting elevation of blood glucose
`concentrations, can result in blindness, renal failure, vascular disease, and neuropathy.
`Therefore, blood glucose concentrations need to be maintained within narrow limits. The
`process of maintaffiing blood glucose at a steady-state level is called glucose homeostasis.
`This is accomplished by the finely hormone regulation of peripheral glucose uptake, heaptic
`glucose production and glucose uptake during carbohydrate ingestion. This maintenance is
`achieved through a balance of several factors, including the rate of consumption and
`intestinal absorption of dietary carbohydrate, the rate of utilization of glucose by peripheral
`tissues and the loss of glucose through the kidney tubule, and the rate of removal or release
`of glucose by the liver and kidney. To avoid postprandial hyperglycemia (uncontrolled
`increases in blood glucose levels following meals) and fasting hypoglycemia (decreased in
`blood glucose levels during periods of fasting), the body can adjust levels by a variety of
`cellular mechanisms. Important mechanisms are conveyed by hormones, cytokines, and fuel
`substrates and are sensed through of cellular mechanisms.
`Diabetes mellitus is one of the clinical manifestations of long-term metabolic abnormalities
`involving multiple organs and hormonal pathways that impair the body's ability to
`maintain glucose homeostasis. As a result of impaired glucose homeostasis is a
`hyperglycemia. Prolonged elevation of blood glucose concentrations causes a number of
`complications like blindness, renal failure, cardiac and peripheral vascular disease,
`neuropathy, foot ulcers, and limb amputation. Vascular complications represent the leading
`cause of mortality and morbidity in diabetic patients.
`Hypoglycemia is abnormally low levels of sugar (glucose) in the blood. Low levels of sugar
`in the blood interfere with the function of much organ system. A person with hypoglycemia
`may feel weak, drowsy, confused, hungry, and dizzy. The other signs of low blood sugar
`are: paleness, headache, irritability, trembling, sweating, rapid heart beat, and a cold. The
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`most common cause of hypoglycemia is a complication of diabetes. Low level of glucose in
`the blood occurs most often in people who use insulin to lower their blood sugar.
`Hypoglycemia can occur as a side effect of some oral diabetes medication that increases
`insulin production. People with diabetes who reduce food intake to lose weight are more
`likely to have hypoglycemia.
`
`2. Role of glucose in mammalian cells metabolism
`2.1 Glucose as a source of cellular energy
`Glucose is rapidly metabolized to produce ATP (adenosine triphosphate), a high energy end
`product. Glucose is oxidized through a large series of reactions that extract the greatest
`amount of possible energy from it. If glucose metabolism occurs in the presence of oxygen
`(aerobically), the net production are 36 molecules of ATP from one molecule of glucose, and
`2 molecules of ATP, if glucose metabolism occurs in the absence of oxygen (anaerobically).
`For details see [Szablewski, 2011].
`
`2.1.1 Glycolysis
`Glycolysis is the first pathway which begins the complete oxidation of glucose to pyruvate.
`It takes place in the cytoplasm of the cell. Glycolysis occurs virtually in all tissues. This
`pathway is unique in the sense that it can proceed in both aerobic and anaerobic conditions.
`Glycolysis is the pathway which cleaves the six carbon glucose molecule into two molecules
`of the three carbon compound pyruvate. The end result of glycolysis is two molecules of
`ATP and two molecules of NADH+H+ (Nicotinamide adenine dinucleotide- reduced form).
`NAD is used as an electron acceptor. This cofactor is present only in limited amounts and
`once reduced to NADH+H+, as in this reaction,. it must be re-oxidized to NAD to permit
`continuation of the pathway. This process occurs by the one of the two methods: aerobic
`metabolism of glucose or anaerobic glycolysis.
`
`2.1.2 Oxidative decarboxylation
`During aerobic metabolism of glucose in the mitochondria, pyruvate is oxidized. During
`this reaction NAD is uses as an electron and proton acceptor, and pyruvate is converted to
`acetyl coenzyme-A (abbreviated as "acetyl-CoA''). The carboxyl group of pyruvate leaves
`the molecule as C02 and the remaining two carbons become acetyl-CoA. This reaction
`occurs twice since each glucose (six carbons) produce 2 pyruvates (three carbons each).
`Consequently, these processes produce 2 NADH+H+, 2 Acetyl...COA, and 2 C02.
`
`2.1.3 Krebs cycle
`Further series of reactions, all which occur inside mitochondria (mitochondrial matrix) of
`eukaryotic cells, is collectively called "Krebs Cycle", also known as the "Citric Acid Cycle"
`or the "Tricarboxylic Acid Cycle". In this cycle, acetyl-CoA is oxidized ultimately to C02. It
`is to note, that the molecules that are produced in these reactions can be used as building
`blocks for a large number of important processes, including the synthesis of fatty acids,
`steroids, cholesterol, amino acids, and the purines and pyrimidines. Fuel for Krebs cycle
`comes from lipids, carbohydrates, and proteins, which produce the molecule acetyl-CoA.
`While the Krebs cycle does produce C(h this cycle does not produce significant chemical
`energy in the form of ATP directly. This cycle produces NADH+H+ and FADH~ which feed
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`into the respiratory cycle, also located inside mitochondria (inner mitochondrial membrane).
`It is electron transport chain that is responsible for production of large quantities of ATP.
`The electron transport chain converts NADH+H+ and FADHz into reactants that the Krebs
`cycle requires to function. If oxygen is not present, the electron transport chain cannot
`function, which halts the Krebs cycle.
`
`2.1.4 Electron transport chain
`Oxidative phosphorylation is a series of reactions that utilize the energy from NADH+H+
`and FADH2 electron carriers to produce more ATP. Embedded in the inner membrane of the
`mitochondria are the series of proteins that use the stored energy from NADH+H+ and
`FADI-Iz to pump protons into the membrane space. This results in an electrical and chemical
`gradient of protons. The enzyme ATP synthase (ATPase) uses the proton gradient to drive
`the reaction of producing A TP from ADP and inorganic phosphate. The electron transport
`chain consists of a series of proteins (called cytochromes) that are embedded in the inner
`mitochondria membrane and an. enzyme ATP synthase. There are four complexes, namely,
`I, II, III, and IV. fu complex IV, the electrons are combined with protons and oxygen to form
`water, the final end-product. The oxygen acts as the final electron acceptor and without
`oxygen, soothe reaction does not proceed and therefore only anaerobic respiration is
`possible. The end result of electron transport chain is three molecules of ATP, if a donor of
`protons and electrons is NADH+H+ and one molecule of H20. If a donor of protons and
`electrons is FADH2, the end result of electron transport chain is two molecules of ATP and
`one molecule of HzO.
`
`2.1.5 The metabolism of lactate
`The anaerobic glycolysis occurs in the absence of oxygen (anaerobically). During anaerobic
`glycolysis, earlier obtained pyruvate is reduced to a compound called lactate. This reduction
`of pyruvate to lactate is coupled to the oxidation of NADH+H+ to NAD. Glycolysis and
`reduction of pyruvate to lactate are coupled to the net production of two molecules of A TP
`from one molecule of glucose. Accumulation of lactate also causes a reduction in
`intracellular pH. Therefore lactate is removed to other tissues and dealt with by one of the
`two mechanisms: 1) Lactate is converted back to pyruvate. This process is enzymatically
`catalyzed by lactate dehydrogenase. fu this reaction, lactate becomes oxidized (loses two
`electrons) and is converted to pyruvate. The pyruvate then proceeds to be further oxidized
`by a second mechanism, the aerobic metabolism of glucose. 2) Conversion of lactate to
`glucose in the process of gluconeogenesis.
`
`2.2 Gluconeogenesis
`Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non(cid:173)
`carbohydrate carbon substrate such as lactate, glycerol, and glucogenic amino acids. One
`common substrate is lactic acid formed in the skeletal muscle in the absence of oxygen. It
`may also come from erythrocytes, which obtain energy solely from glycolysis. The lactic
`acid is released to the blood stream and transported into liver. Here it is converted to
`glucose. The glucose is then returned to the blood for use by muscle as an energy source and
`to replenish glycogen stores. This cycle is termed the "Cori cycle". The gluconeogenesis of
`the cycle is net consumer energy, costing the. body four moles of ATP more than are
`produced during glycolysis. Therefore, the cycle cannot be sustained indefinitely. The
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`process of gluconeogenesis uses some of the reactions of glycolysis (in reverse direction) and
`some reactions unique to this pathway to re-synthesize glucose. This pathway requires an
`energy input, but has a role of maintaining a circulating glucose concentration in the blood
`stream even in the absence of dietary supply. Fatty acids cannot be converted into glucose in
`animals with the exception of odd-chain acids, which yield propionyl..Co~ a precursor of
`succinyl..CoA. Glycerol, which is a part of all triacylglycerols, can also be used in
`gluconeogenesis. On the other hand, in humans and other mammals, in which glycerol is
`derived from glucose, glycerol is sometimes not considered a true gluconeogenic substrate,
`as it cannot be used to generate new glucose. For details see [Szablewski, 2011].
`
`2.3 Glycogenesis
`Glycogenesis is the process of glycogen synthesis in which glucose molecules are added to
`chains of glycogen to storage in liver and muscle. This process acts during rest periods
`following the Cori cycle, in the liver, and also activated by insulin in response to high
`glucose levels. For details see [Szablewski, 2011].
`
`2.4 Glycogenolysis
`When the blood sugar levels fall, glycogen stored in the tissue, especially glycogen of
`muscle and liver may be broken down. This process of breakdown of glycogen is called
`"Glycogenolysis" (also known as "Glycogenlysis"). Glycogenolysis occurs in the liver and
`muscle. Hepatocytes can consume glucose-6-phosphate in glycolysis, or remove the
`phosphate group and release the free glucose into the blood stream for uptake by other cells.
`Since muscle cells lack enzyme glucose-6-phosphatase, they cannot convert glucose-6-
`phosphate into glucose and therefore use the glucose-6-phosphate for their own energy
`demands. For details see [Szablewski, 2011].
`
`2.5 Pentose phosphate pathway
`The pentose phosphate pathway (also called "Phosphogluconate pathway'' or "Hexose
`monophosphate shunt'') is primarily a cytoplasmic anabolic pathway that converts the six
`carbons of glucose to five carbons (pentose) sugars and reducing equivalents. The primary
`functions of this pathways are: 1) To generate reducing equivalents (NADH+H+) for
`reductive biosynthesis reactions within cells; 2) To provide the cell with ribose-5-phosphate
`for the synthesis of the nucleotides and nucleic acids; 3) To metabolize dietary pentose
`sugars derived from the digestion of nucleic acids as well as rearrange the carbon skeleton
`of dietary carbohydrates into glycolytic/ gluconeogenic intermediates. This pathway is an
`alternative to glycolysis. While it does involve oxidation of glucose, its primary role is
`anabolic rather than catabolic. It is to note, that 30% of the oxidation of glucose in the liver
`occurs via the pentose phosphate pathway. For details see [Szablewski, 2011].
`
`2.6 Lipogenesis
`Lipogenesis is the process by which simple sugars such as glucose are converted to fatty
`acids. Lipogenesis starts with acetyl..CoA and builds up by the addition of two carbon units.
`Fatty acids are subsequently esterified with glycerol to form triglycerides that are packed in
`very low-density lipoprotein (VLDL) and secreted from the liver. For details see
`[Szablewski, 2011].
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`3. Glucose homeostasis
`3.1 Definition of glucose homeostasis
`Most tissues and organs need glucose constantly, as an important source of energy. The low
`blood concentrations of glucose can cause seizures, loss of consciousness, and death. On the
`other hand, long lasting elevation of glucose concentrations, can result in blindness, renal
`failure, vascular disease etc. therefore, blood glucose concentrations need to be maintained
`within narrow limits. The process of maintaining blood glucose at a steady-state level is
`called "glucose homeostasis" [DeFronzo, 1988]. This is accomplished by the finely hormone
`regulation of peripheral glucose uptake, hepatic glucose production. and glucose uptake
`during carbohydrates ingestion. For details see [Szablewski, 2011].
`
`3.2 Mechanisms of glucose homeostasis
`To avoid postprandial hypoglycemia and fasting hypoglycemia, the body can adjust glucose
`levels by secreting two hormones, insulin and glucagon that work in opposition to each
`other. During periods of hyperglycemia, the ~-cells of the pancreatic islets of Langerhans
`secrete more insulin. Insulin is synthesized in ~-cells of pancreas in response to an elevation
`in blood glucose and amino acid after a meal. The major function of insulin is to counter the
`concerned action of a number of hyperglycemia-generating hormones to maintain low blood
`glucose levels. It also plays an important role in the regulation of glucose metabolism. This
`hormone regulates glucose metabolism at many sites reducing hepatic glucose output, via
`decreased gluconeogenesis and glycogenolysis, facilitates the transport of glucose into
`striated muscle and adipose tissue, and inhibits glucagon secretion. Insulin is not secreted if
`the blood concentration is ~ 3 mmoljL, but is secreted in increasing amounts as glucose
`concentrations increase beyond this threshold [Gerich, 1993]. When blood glucose levels
`increase over about 5 mmolfL the ~ells increase their output of insulin. The glucagon
`producing a-cells of the pancreatic islets of Langerhans remain quiet, and hold on their
`hormone. It is to note, that postprandially, the secretion of insulin occurs in two phases. An
`initial rapid release of preformed insulin, followed by increased insulin synthesis and
`release in response to blood glucose. Long-term release of insulin occurs if glucose
`concentrations remain high [Aronoff et al., 2004; Cryer, 1992]. On the other hand, during
`periods of hypoglycemia, the a-cells of the pancreatic islets of Langerhans secrete more
`glucagon. It is the principal hormone responsible for maintaining plasma glucose at
`appropriate levels during periods of increased functional demand [Cryer, 2002]. This
`hormone counteracts hypoglycemia and opposes insulin actions by stimulating hepatic
`glucose production. It induces a catabolic effect, mainly by activating liver glycogenolysis
`and gluconeogenesis, which results in the release of glucose to the bloodstream, thereby
`increasing blood glucose levels. The digestion and absorption of nutrients are associated
`also with increased secretion of multiple gut hormones that act on distal targets. There are
`more than 50 gut hormones and peptides synthesized and released from the gastrointestinal
`tract. These hormones are synthesized by specialized enteroendocrine cells located in the
`epithelium of the stomach, small bowel, and large bowel. It was demonstrated that ingest
`food caused a more potent release of insulin than glucose infused intravenously [Perley &
`Kipnis, 1967]. This effect, termed the ''incretin effect" suggests that signals from the gut are
`important in the hormonal regulation of glucose disappearance. Incretin hormones are
`peptide hormones secreted from the gut and specific criteria have to be fulfilled for an agent
`to be called an incretin. They have a number of important biological effects, as for example,
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`release of insulin, inhibition of glucagon, maintenance of p-cells mass, and inhibition of
`feeding. Several incretin hormones have been characterized, but currently, GLP-1
`(Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Polypeptide) are the
`only known incretins. Both GLP-1 and GIP are secreted in a nutrient-dependent manner and
`stimulate glucose-dependent insulin secretion. Gut hormones are secreted at low basal
`levels in the fasting state. The secretion of gut hormones is regulated, at least in part, by
`nutrients. Plasma levels of most gut hormones rise quickly within minutes of nutrient
`uptake and fall rapidly thereafter mainly because they are cleared by the kidney and are
`enzymatically inactivated [Drucker, 2007].
`
`4. Defects in glucose homeostasis
`
`4.1 Hyperglycemia
`Hyperglycemia is the technical term for high blood glucose (sugar). It develops when there
`is too much sugar in the blood. High blood glucose happens when the body has too little
`insulin or when the body cannot use insulin properly. Hyperglycemia is a serious health
`problem for those with diabetes. In people with diabetes, there are two specific types of
`hyperglycemia that occur. Fasting hyperglycemia is defined as a blood sugar greater than
`90 - 130 mg/ dL (5 - 7.2 mmol/L) after fasting for at least 8 hours. Postprandial (after-meal
`hyperglycemia) is defined as a blood sugar usually greater than 180 mg/ dL (10 mmol/L).
`Hyperglycemia in diabetes may be caused by: skipping or forgetting insulin or oral glucose(cid:173)
`lowering medicine, eating too many grams of carbohydrates for the amount of insulin
`administered, eating too much food and having too many calories, infection, illness,
`increased stress, decreased activity or exercising less than unusual, strenuous physical
`activity. Early signs and symptoms of hyperglycemia include the following: increased thirst,
`headaches, difficulty concentrating, blurred vision, frequent urination, fatigue (weak, tired
`feeling), weight loss, blood sugar more than.180 mg/ dL (10 mmol/L), high levels of sugar in
`the urine. Prolonged hyperglycemia in diabetes may result in: vaginal and skin infections,
`slow-healing cuts and sores, decreased vision, nerve damage causing painful cold or
`insensitive feet, stomach and intestinal problems. In people without diabetes postprandial
`or post-meal sugars rarely go over 140 mg/ dL (7.8 mmol/L), but occasionally, after a large
`meal, a 1 - 2 hour post-meal glucose levels can reach 180 mg/ dL (10 mmol/L). Blood
`glucose levels can vary from day to day. An occasional high level (above 10 mmol/L) is not
`problem, as long as it returns to normal (below 7 mmol/L; 126 mg/ dL) within 12 - 24 hours.
`Persistently high blood glucose levels (above 15 mmol/L; 270 mg/ dL) for more than 12 - 24
`hours can result in the symptoms of hyperglycemia. For details see [Szablewski, 2011].
`
`4.1.11mpalred glucose tolerance and Impaired fasting glucose
`There are two forms of pre-diabetes: impaired glucose tolerance (IGI) and impaired fasting
`glucose (IFG). Impaired glucose tolerance is a transition phase between normal glucose
`tolerance and diabetes, also referred to as prediabetes. In impaired glucose tolerance, the
`levels of blood glucose are between normal and diabetic. People with IGT do not have
`diabetes. Each year, only 1 - 5% of people whose test results show IGT actually develop
`diabetes. Weight loss and exercise may help people with IGT return their glucose levels to
`normal. Impaired glucose tolerance is a combination of impaired secretion of insulin and
`reduced insulin sensitivity (insulin resistance). Fasting blood glucose levels are normal or
`moderately raised. IGT is diagnosed when: 1) plasma glucose, two hours after consuming 75 g
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`glucose, appears to be superior to 7.8 mmol/L (normal level) but remains inferior to 11.1
`mmolfL (diabetes level). The level of plasma glucose is measured by means of an Oral
`Glucose Tolerance Test (OCTT). The procedure typically involves testing glucose levels after
`an eight hour fasting period, and measuring it again two hours after drinking a sugar
`solution. Generally, if the test shows 'blood glucose levels in the 140 and 199 mg/ dL range,
`two hours after the drink, this could signify impaired glucose tolerance. 2) Fasting plasma
`glucose is less than 7.0 mmolfL (6.1- 6.9 mmol/L), a level above normal, but below the
`threshold for diagnosis of diabetes. Impaired glucose tolerance is often affiliated with
`several other similar related risk factors such as high blood pressure (hypertension),
`increased LDL-cholesterol, reduced HDL-cholesterol. A person has impaired fasting glucose
`when fasting plasma glucose is 100 to 125 mg/ dL. This level is higher than normal but less
`than the level indicating a diagnosis of diabetes. Diabetes mellitus is characterized by
`recurrent or persistent hyperglycemia and is diagnosed by demonstrating any one of the
`following: fasting plasma glucose level ~ 7.0 mmol/L (126 mg/ dL), plasma glucose ~ 11.1
`mmolfL (200 mg/ dL) two hours after a 75 g oral glucose load as in a glucose tolerance test,
`symptoms of hyperglycemia and casual plasma glucose ~ 11.1 mmoljdL, glycated
`hemoglobin (HbA1c) ~ 6.5%.
`
`4.1.2 Type 1 diabetes mellitus
`Type 1 diabetes mellitus (previously known as juvenile or insulin~dependent diabetes)
`results due to autoimmune progressive destruction of insulin~producing f3<ells by CD4+
`and CDS+ T cells and macrophages infiltrating the islets [Foulis et al., 1991]. Although, the
`etiology of type 1 diabetes is believed to have a major genetic component, studies on the risk
`of developing type 1 suggest that environmental factor may be important etiological
`determinants. Evidence of an autoimmune etiology is found in about 95% of these cases and
`is classified as type 1A, and the remaining 5% lacks defined markers of autoimmunity and
`therefore are classified as type 18, also termed idiopathic [Todd, 1999]. Type 1 diabetes is
`observed in approximately 10% of patients with diabetes mellitus [Gilespie, 2006]. Type 1
`diabetes is a complex polygenic disorder. It cannot be classified strictly by dominant,
`recessive, or intermediate inheritance, making identification of diseases susceptibility or
`resistant gene difficult [Atkinson & Eisenbarth, 2001; Rabinovit:ch. 2000]. The lifetime of type
`1 diabetes risk for a number of the general population is often quoted as 0.4%. Eight-five
`percent of cases of type 1 diabetes occur in individuals with no family of the disease.
`Differences in risk also depend on which parent has diabetes. The risk increases to 1 - 2% if
`the mother has diabetes and intriguingly to 3 - 7% if the father has diabetes [Haller &
`Atkinson, 2005; Warram et al., 1988]. The sibling risk is 6% [Risch, 1987]. Monozygotic twins
`have a concordance rate of 30 to 50%, whereas dizygotic twins have a concordance rate of 6
`to 10% [Haller & Atkinson. 2005]. Disease susceptibility is highly associated with inheritance
`of the HLA (Human Leukocyte Antigen) alleles DR3 and DR4 as well as the associated
`alleles DQ2 and DQ8. More than 9% of patients with type 1 diabetes express either DR3DQ2
`or DR4DQ8. Heterozygous genotypes DR3/DR4 are most common in children diagnosed
`with type 1 diabetes prior to the age of 5 (50%) [Atkinson & Eisenbarth, 2001]. Individuals
`with the HLA haplotype DRB1 *Q302-DQA1 *0301, especially when combined with
`DRB*10201-DQA1 *0501 are highly susceptible (10 - 2~fold increase) to type 1 diabetes. On
`the other hand, HLA class IT haplotypes such as DR2DQ6 confer dominant protection [Todd
`& Wicker, 2001]. Individuals with the haplotype DRB1*0602~DQA1*0102 rarely develop type
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`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:24)(cid:25)(cid:22)(cid:3)
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:26)
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`Diabetes- Damages and Treatments
`
`1 diabetes [Peakman, 2001]. Candidate genes studies also identified the insulin gene as the
`second most important genetic susceptibility factor [Bell et al., 1984]. Whole genome screen
`has indicated that there are at least 15 other loci associated with type 1 diabetes [Concannon
`et al., 1998; Cox et al., 2001]. To date, no single gene is either necessary or sufficient to
`predict the development of type 1 diabetes. Although type 1 diabetes is likely a polygenic
`disorder, epidemiological pattern of type 1 diabetes suggests that environmental factors are
`involved [Dorman & "Bunker, 2000].
`
`4.1.3 Type 2 diabetes mellitus
`Type 2 diabetes m.ellitus, previously called non-insulin-dependent diabetes mellitus, is a
`complex heterogeneous group of metabolic disorders including hyperglycemia and
`impaired insulin action and/ or insulin secretion. Current theories of type 2 diabetes include
`a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic P(cid:173)
`cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver
`[Lin & Sun, 2010]. The etiology of human type 2 diabetes is multifactorial with genetic
`background and environmental factors of the modem world which favor the development
`of obesity. Several findings indicate that genetics is an important contributing factor. It has
`been estimated that 30 - 70% of type 2 diabetes risk can be attributed to genetics [Poulsen et
`al., 1999]. The lifetime risk of type 2 diabetes is about 7% in a general population, about 40%
`in offspring of one parent with type 2 diabetes, and about 70% if both parents have type 2
`diabetes [Majithia & Florez, 2009]. Patterns of inheritance suggest that type 2 diabetes is
`both polygenic and heterogeneous -
`i.e. multiple genes are involved and different
`combinations of genes play a role in different subsets of individuals [Doria et al., 2008].
`Genetic research effort have led to the identification of at least 27 type 2 diabetes
`susceptibility genes [Staiger et al., 2009] and most recent genome-wide association studies
`have identified 20 common genetic variants associated with type 2 diabetes [Ridderstral &
`Groop, 2009]. Since skeletal muscle accounts for - 75% of whole body insulin-stimulated
`glucose uptake, defects in this tissue play a major role in glucose homeostasis in patients
`with type 2 diabetes [Bjomholm & Zierath, 2005]. Insulin resistance in skeletal muscle is
`among the earliest detectable defects in humans with type 2 diabetes [Mauvais-Jarvis &
`Kahn. 2000]. Type 2 diabetic patients are characterized by a decreased fat oxidative capacity
`and high levels of circulating free fatty acid [Blaak et al., 2000]. The latter is known to cause
`insulin resistance by reducing stimulated glucose uptake most likely via accumulation of
`lipid inside the muscle cell [Boden, 1999]. A reduced fat oxidative capacity and metabolic
`inflexibility are important components of skeletal muscle insulin resistance [Phielix &
`Mensink, 2008].
`
`4.1.4 Gestational diabetes mellitus
`Gestational diabetes mellitus is defined as ''carbohydrate intolerance With onset or first
`recognition during pregnancy" [Metzger, 1991]. This definition includes pregnancies in
`which the following occur: insulin therapy is required, diabetes persists after delivery, and
`diabetes may have been present, but not recognized, prior to the pregnancy [Avery & Rossi,
`1994]. Women at risk of type 2 diabetes are at risk of gestational diabetes m.ellitus [Cheung.
`2009]. Gestational diabetes m.ellitus is a heterogeneous disorder in which age, obesity, and
`genetic background contribute to the severity of the disease. Multiparous women have a
`very high prevalence of gestational diab