Diabetes mellitus is a chronic health problem affecting more than 15.7 million people in the United States.

1 The disease affects people in all age groups and from all walks of life. It is more prevalent among !".#$% and &ispanic frican mericans mericans !1'."$% compared with

whites !#.($%.1 Diabetes is a significant risk factor in coronar) heart disease and stroke* and it is the leading cause of blindness and end+stage renal disease* as well as a ma,or contributor to lower e-tremit) amputations. ENERGY METABOLISM Diabetes is a disorder of energ) metabolism resulting from an imbalance between insulin availabilit) and insulin need. lthough the respirator) and circulator) s)stems combine efforts to furnish the bod) with the o-)gen needed for metabolic purposes* it is the hormones from the endocrine pancreas !mainl) insulin and glucagon% in concert with the liver* that control the availabilit) and utili.ation of glucose* fat* and protein as a fuel for metabolic processes !/ig. 0(+1%. Glucose, Fat, and Protein Metabolism Glucose Metabolism 1lucose is a si-+carbon molecule2 it is an efficient fuel that* when metaboli.ed in the presence of o-)gen* breaks down to form carbon dio-ide and water. lthough man) tissues and organ s)stems are able to use other forms of fuel* such as fatt) acids and ketones* the brain and nervous s)stem rel) almost e-clusivel) on glucose as a fuel source. 3ecause the brain can neither s)nthesi.e nor store more than a few minutes4 suppl) of glucose* normal cerebral function re5uires a continuous suppl) from the circulation. Severe and prolonged h)pogl)cemia result in substantial brain d)sfunction. 3od) tissues obtain glucose from the blood. 3lood glucose levels usuall) reflect the difference between the amount of glucose released into the circulation b) the liver and the amount of glucose removed from the blood b) bod) cells. 1lucose is ingested in the diet and transported from the gastrointestinal tract* through the portal vein* to the liver before it gains access to the circulator) s)stem. The liver regulates blood glucose through three processes6 !1% gl)cogen s)nthesis !gl)cogenesis%* !(% gl)cogen breakdown !gl)cogenol)sis%* and !0% s)nthesis of glucose from noncarboh)drate sources !gluconeogenesis%. 7hen blood glucose levels rise* it is removed from the blood and converted to gl)cogen* the main short+term storage form of glucose. 7hen blood glucose levels fall* the liver gl)cogen stores

are broken down and released into the circulation.

lthough

skeletal muscle also participates in gl)cogen storage* it lacks the en.)me glucose+#+phosphatase that allows glucose to be broken down sufficientl) to pass through the cell membrane and enter the circulation* limiting its usefulness to the muscle cell. In addition to mobili.ing its gl)cogen stores* the liver s)nthesi.es glucose from noncarboh)drate sources such as amino acids* lactic acid* and the gl)cerol part of trigl)cerides. This glucose ma) be stored as gl)cogen or it ma) be released directl) into the circulation. Fat Metabolism /at is the most efficient form of fuel storage. It provides " kcal8g of stored energ)* compared with the 9 kcal8g provided b) carboh)drates and proteins. bout 9'$ of the calories in the normal merican diet are obtained from fats* which is about e5ual to the amount obtained from carboh)drates. Therefore* the use of fats b) the bod) for energ) is as important as the use of carboh)drates. In addition* man) of the carboh)drates consumed in the diet are converted to trigl)cerides for storage in adipose tissue. trigl)ceride contains three fatt) acids linked b) a gl)cerol molecule. The mobili.ation of fatt) acids for use as an energ) source is facilitated b) the action of en.)mes !lipases% that break trigl)cerides into a gl)cerol molecule and three fatt) acids. The gl)cerol molecule can enter the gl)col)tic pathwa) and be used along with glucose to produce energ)* or it can be used to produce glucose. The fatt) acids are transported to tissues where the) are utili.ed for energ). lmost all cells* with the e-ception of brain tissue and red blood cells* can use fatt) acids interchangeabl) with glucose for energ). lthough man) cells use fatt) acids as a fuel source* fatt) acids cannot be converted to glucose that can be used b) the brain for energ). large share of the initial degradation of fatt) acids occurs in the liver* especiall) when e-cessive amounts of fatt) acids are being used for energ). The liver uses onl) a small amount of the fatt) acids for its own energ) needs2 it converts the rest into ketones and releases them into the blood. In situations that favor fat breakdown* such as diabetes mellitus and fasting* large amounts of ketones are released into the bloodstream. 3ecause ketones are organic acids* the) cause ketoacidosis when the) are present in e-cessive amounts. Protein Metabolism ppro-imatel) three fourths of bod) solids are proteins. :roteins are essential for the formation of all bod) structures* including

genes* en.)mes* contractile structures in muscle* matriof bone* and hemoglobin of red blood cells. mino acids are the building blocks of proteins. Significant 5uantities of amino acids are present in bod) proteins. Unlike glucose and fatt) acids* there is onl) a limited facilit) for the storage of e-cess amino acids in the bod). ;ost of the stored amino acids are contained in bod) proteins. mino acids in e-cess of those needed for protein s)nthesis are converted to fatt) acids* ketones* or glucose and are stored or used as metabolic fuel. 3ecause fatt) acids cannot be converted to glucose* the bod) must break down proteins and use the amino acids as a ma,or substrate for gluconeogenesis during periods when metabolic needs e-ceed food intake. ormonal !ontrol o" Blood Glucose The hormonal control of blood glucose resides largel) with the endocrine pancreas. The pancreas is made up of two ma,or tissue t)pes6 the acini and the islets of <angerhans !/ig. 0(+(%. The acini secrete digestive ,uices into the duodenum* and the islets of <angerhans secrete glucose+regulating hormones into the blood. =ach islet is composed of beta cells that secrete insulin* alpha cells that secrete glucagon* and delta cells that secrete somatostatin. Insulin lowers the blood glucose concentration b) facilitating the movement of glucose into bod) tissues. 1lucagon maintains blood glucose b) increasing the release of glucose from the liver into the blood. Somatostatin inhibits the release of insulin and glucagon. Somatostatin also decreases gastrointestinal activit) after ingestion of food. 3) decreasing gastrointestinal activit)* somatostatin is thought to e-tend the time during which food is absorbed into the blood* and b) inhibiting insulin and glucagon* it is thought to e-tend the use of absorbed nutrients b) the tissues.( Insulin lthough several hormones are known to increase blood glucose levels* insulin is the onl) hormone known to have a direct effect in lowering blood glucose levels. The actions of insulin are threefold2 it !1% promotes glucose uptake b) target cells and provides for glucose storage as gl)cogen* !(% prevents fat and gl)cogen breakdown and inhibits gluconeogenesis* and !0% increases protein s)nthesis !Table 0(+1%. Insulin acts to promote fat storage b) increasing the transport of glucose into fat cells. It also facilitates trigl)ceride s)nthesis from glucose in fat cells and inhibits the intracellular breakdown of stored trigl)cerides. Insulin also inhibits protein breakdown and increases protein s)nthesis b) increasing the active transport of amino acids into

bod) cells. Insulin inhibits gluconeogenesis* or the building of glucose from new sources* mainl) amino acids. 7hen sufficient glucose and insulin are present* protein breakdown is minimal because the bod) is able to use glucose and fatt) acids as a fuel source. In children and adolescents* insulin is needed for normal growth and development. Insulin Synthesis and Release. Insulin is produced b) the pancreatic beta cells in the islets of <angerhans. The active form of the hormone is composed of two pol)peptide chains>an chain and a 3 chain !/ig. 0(+0%. ctive insulin is formed in the beta cells from a larger molecule called proinsulin. In converting proinsulin to insulin* en.)mes in the beta cell cleave proinsulin at specific sites to form two separate substances6 active insulin and a biologicall) inactive connecting peptide !?+peptide% chain that ,oined the were separated. and 3 chains before the) ctive insulin and the inactive ?+peptide

chain are packaged into secretor) granules and released simultaneousl) from the beta cell. The ?+peptide chains can be measured clinicall)* and this measurement can be used to stud) beta cell activit). /or e-ample* in,ected !e-ogenous% insulin in a person with t)pe ( diabetes would provide few or no ?+peptide chains* whereas insulin !endogenous% secreted b) the beta cells would be accompanied b) the secretion of ?+peptide chains. The release of insulin from the pancreatic beta cells is regulated b) blood glucose levels* increasing as blood glucose levels rise and decreasing when blood glucose levels decline. Secretion of insulin occurs in an oscillator) or pulsatile fashion. fter e-posure to glucose* a first+phase release of stored preformed insulin occurs* followed b) a second+phase release of newl) s)nthesi.ed insulin !/ig. 0(+9%. Serum insulin levels begin to rise within minutes after a meal* reach a peak in appro-imatel) 0 to 5 minutes* and then return to baseline levels within ( to 0 hours. Insulin secreted b) the beta cells enters the portal circulation and travels directl) to the liver* where appro-imatel) 5'$ is used or degraded. Insulin* which is rapidl) bound to peripheral tissues or destro)ed b) the liver or kidne)s* has a half+life of appro-imatel) 15 minutes once it is released into the general circulation. on target tissues* insulin binds to and activates a membrane receptor. It is the activated receptor that is responsible for the cellular effects of insulin.( The insulin receptor is a combination of four subunits>a large subunit that e-tends outside the cell membrane and is involved in insulin binding and a smaller

 subunit that is predominantl) inside the cell membrane and contains a kinase en.)me that becomes activated during insulin binding !/ig. 0(+5%. ctivation of the kinase en.)me results in phosphor)lation of the subunit* which in turn activates some en.)mes and inactivates others* thereb) directing the desired intracellular effect of insulin on glucose* fat* and protein metabolism. Glucose Transporters. 3ecause cell membranes are impermeable to glucose* the) re5uire a special carrier* called a glucose transporter* to move glucose from the blood into the cell. 7ithin seconds after insulin binds to its membrane receptor* the membranes of about @'$ of bod) tissues increase their uptake of glucose b) means of special glucose transporters. This is particularl) true of skeletal muscle and adipose tissues. ?onsiderable research has revealed a famil) of glucose transporters termed GLUT-1, GLUT-2, and so forth.0 1<UT+9 is the insulin+dependent glucose transporter for skeletal muscle and adipose tissue !/ig. 0(+#%. It is se5uestered inside the membrane of these cells and thus is unable to function as a glucose transporter until a signal from insulin causes it to move from its inactive site into the cell membrane* where it facilitates glucose entr). 1<UT+( is the ma,or transporter of glucose into beta cells and liver cells. It has a low affinit) for glucose and acts as a transporter onl) when plasma glucose levels are relativel) high* such as after a meal. 1<UT+1 is present in all tissues. It does not re5uire the actions of insulin and is important in transport of glucose into the nervous s)stem. Gluca#on 1lucagon* a pol)peptide molecule produced b) the alpha cells of the islets of <angerhans* maintains blood glucose between meals and during periods of fasting. <ike insulin* glucagon travels through the portal vein to the liver* where it e-erts its main action. Unlike insulin* glucagon produces an increase in blood glucose !see Table 0(+1%. The most dramatic effect of glucagon is its abilit) to initiate glycogenolysis or the breakdown of liver gl)cogen as a means of raising blood glucose* usuall) within a matter of minutes. 3ecause liver gl)cogen stores are limited* gluconeogenesis is important in maintaining blood glucose levels over time. 1lucagon also increases the transport of amino acids into the liver and stimulates their conversion into glucose. s with insulin* glucagon s)nthesis and secretion is regulated

b) blood glucose.

decrease in blood glucose concentration toa

h)pogl)cemic level produces an immediate increase in glucagon secretion* and an increase in blood glucose to h)pergl)cemic levels produces a decrease in glucagon secretion. &igh concentrations of amino acids* as occur after a protein meal* also can stimulate glucagon secretion. In this wa)* glucagon increases the conversion of amino acids to glucose as a means of maintaining the bod)4s glucose levels. 1lucagon levels also increase during strenuous e-ercise as a means of preventing a decrease in blood glucose. Ot$er ormones T$at A""ect Blood Glucose

Ather hormones that can affect blood glucose include the catecholamines* growth hormones* and the glucocorticoids. These hormones are sometimes called counter+regulator) hormones because the) counteract the storage functions of insulin in regulating blood glucose levels during periods of fasting* e-ercise* and other situations that either limit glucose intake or deplete glucose stores. Catecholamines. The catecholamines !epinephrine and norepinephrine% help to maintain blood glucose levels during periods of stress. =pinephrine inhibits insulin release and promotes gl)cogenol)sis b) stimulating the conversion of muscle and liver gl)cogen to glucose. ;uscle gl)cogen cannot be released into the blood2 nevertheless* the mobili.ation of these stores for muscle use conserves blood glucose for use b) other tissues such as the brain and the nervous s)stem. During periods of e-ercise and other t)pes of stress* epinephrine inhibits insulin release from the beta cells and thereb) decreases the movement of glucose into muscle cells. The catecholamines also increase lipase activit) and thereb) increase mobili.ation of fatt) acids* a process that conserves glucose. The blood glucose+elevating effect of epinephrine is an important home+ostatic mechanism during periods of h)pogl)cemia in insulintreated diabetics. Growth Hormone. 1rowth hormone has man) metabolic effects. It increases protein s)nthesis in all cells of the bod)* mobili.es fatt) acids from adipose tissue* and antagoni.es the effects of insulin. 1rowth hormone decreases cellular uptake and use of glucose* thereb) increasing the level of blood glucose. The increased blood glucose level stimulates further insulin secretion b) the beta cells. The secretion of growth hormone normall) is inhibited b) insulin and increased levels of blood glucose.

During periods of fasting* when both blood glucose levels and insulin secretion fall* growth hormone levels increase. =-ercise* such as running and c)cling* and various stresses* including anesthesia* fever* and trauma* increase growth hormone levels. ?hronic h)persecretion of growth hormone* as occurs in a condition called acromegal) !see ?hapter 01%* can lead to glucose intolerance and the development of diabetes mellitus. In children who alread) have diabetes* moderate elevations in growth hormone levels that occur during periods of growth can produce the entire spectrum of metabolic abnormalities associated with poor regulation* despite optimi.ed insulin treatment. Glucocorticoid Hormones. The glucocorticoid hormones* which are s)nthesi.ed in the adrenal corte- along with other corticosteroid hormones* are critical to survival during periods of fasting and starvation. The) stimulate gluconeogenesis b) the liver* sometimes producing a #+ to 1'+fold increase in hepatic glucose production. These hormones also moderatel) decrease tissue use of glucose. In predisposed persons* the prolonged elevation of glucocorticoid hormones can lead to h)pergl)cemia and the development of diabetes mellitus. In people with diabetes* even transient increases in cortisol can complicate control. There are several steroid hormones with glucocorticoid activit)2 the most important of these is cortisol* which accounts for appro-imatel) "5$ of all glucocorticoid activit) !see ?hapter 01%. ?ortisol levels increase during periods of stress* such as that produced b) infection* pain* trauma* surger)* prolonged and strenuous e-ercise* and acute an-iet). &)pogl)cemia is a potent stimulus for cortisol secretion.

%IABETES MELLIT&S The term diabetes is derived from a 1reek word meaning Bgoing throughC and mellitus from the <atin word for Bhone)C or Bsweet.C Deports of the disorder can be traced to the first centur) D* when retaeus the ?appadocian described the disorder as a chronic affection characteri.ed b) intense thirst and voluminous* hone)+sweet urine6 Bthe melting down of flesh into urine.C It was the discover) of insulin b) 3anting and 3est in 1"(( that transformed the once+fatal disease into a manageable chronic health problem.9 Diabetes is a disorder of carboh)drate* protein* and fat metabolism resulting from an imbalance between insulin availabilit) and insulin need. It can represent an absolute insulin deficienc)* impaired release of insulin b) the pancreatic beta cells* inade5uate or defective insulin receptors* or the production of inactive insulin or insulin that is destro)ed before it can carr) out its action. person with uncontrolled diabetes is unable to transport glucose into fat and muscle cells2 as a result* the bod) cells are starved* and the breakdown of fat and protein is increased. !lassi"ication and Etiolo#' lthough diabetes mellitus clearl) is a disorder of insulin availabilit)* it probabl) is not a single disease. revised s)stem for the classification of diabetes was developed in 1""7 b) the =-pert ?ommittee on the Diagnosis and ?lassification of Diabetes ;ellitus.5 The intent of the revised s)stem* which replaces the 1"7" classification s)stem* was to move awa) from a s)stem that focused on the t)pe of pharmacologic treatment used in management of diabetes to one based on disease etiolog). The revised s)stem continues to include t)pe 1 and t)pe ( diabetes* but uses rabic* rather than Doman* numerals and eliminates the use of Binsulin+dependentC and BnonEinsulindependentC diabetes mellitus !Table 0(+(%. T)pe 1 diabetes is due to pancreatic beta cell destruction predominantl) b) an autoimmune process. T)pe ( diabetes is the more prevalent t)pe and results from insulin resistance. Included in the classification s)stem are the categories of gestational diabetes mellitus !1D;2 i.e.* diabetes that develops during pregnanc)% and other specific t)pes of diabetes* man) of which occur secondar) to other conditions !e.g.* ?ushing4s s)ndrome* pancreatitis* acromegal)%. The revised classification s)stem also includes a s)stem for

diagnosing diabetes according to stages of glucose intolerance5 !Table 0(+0%. The revised criteria have retained the formercategor) of impaired glucose tolerance !I1T% and have added a new categor) of impaired fasting blood glucose !I/1%. The categories of I/1 and I1T refer to metabolic stages intermediate between normal glucose homeostasis and diabetes. fasting blood glucose of 11' mg8d< or less or a (+hour oral glucose tolerance test result of less than 19' mg8d< is considered normal. I/1 is defined as a fasting blood glucose of 11' mg8d< or greater but less than 1(# mg8d<. I1T reflects abnormal blood glucose measurements ! 19' mg8d< but <('' mg8d<% ( hours after an oral glucose load.5 =ach )ear* appro-imatel) 5$ of people with I/1 and I1T e-perience progression to diabetes. I/1 and I1T are associated with increased risk of atherosclerotic heart disease. ?alorie restriction and weight reduction are important in overweight people with I/1 and I1T.

T'(e ) %iabetes Mellitus T)pe 1 diabetes is caused b) beta cell destruction and insulin deficienc). It is immune+mediated !t)pe 1 % in more than "'$ of cases and idiopathic !t)pe 13% in less than 1'$ of cases. T)pe 1 diabetes* formerl) called juvenile diabetes* occurs more commonl) in )oung persons but can occur at an) age. The rate of beta cell destruction is 5uite variable* being rapid in some individuals and slow in others. The rapidl) progressive form commonl) is observed in children but also ma) occur in adults. The slowl) progressive form usuall) occurs in adults and is sometimes referred to as latent autoimmune diabetes in adults. In the United States and =urope* appro-imatel) 1'$ of people with diabetes mellitus have t)pe 1 diabetes. T)pe 1 diabetes is a catabolic disorder in which circulating insulin is virtuall) absent* glucagon levels are elevated* and pancreatic beta cells fail to respond to all insulin+producing stimuli. Ane of the actions of insulin is the inhibition of lipolysis !i.e.* fat breakdown% and release of free fatt) acids !// % from fat cells. In the absence of insulin* ketosis develops when these fatt) acids are released from fat cells and converted to ketoacids in the liver. 3ecause of the loss of beta function and complete lack of insulin* all people with t)pe 1 diabetes re5uire e-ogenous insulin replacement to reverse the catabolic state* control blood glucose levels* and prevent ketosis. T)pe 1 diabetes is thought to result from genetic predisposition !i.e.* diabetogenic genes%* a h)pothetical triggering event that involves an environmental agent that incites an immune

response and the production of autoantibodies that destro) beta cells. These autoantibodies ma) e-ist for )ears before the onset of h)pergl)cemia. ?ertain inherited human leukoc)te antigens !&< % are strongl) associated with the development of t)pe 1 diabetes. bout "5$ of persons with the disease have either &< +DD0 or &< +DD9 !see ?hapter @%. The fact that t)pe 1 diabetes is thought to result from an interaction between genetic and environmental factors has led to research into methods directed at prevention and earl) control of the disease. These methods include the identification of geneticall) susceptible persons and earl) intervention in persons with newl) diagnosed t)pe 1 diabetes. fter the diagnosis of t)pe 1 diabetes* there often is a short period of beta cell regeneration* during which s)mptoms of diabetes disappear and insulin in,ections are not needed. This is sometimes called the honeymoon period. Immune interventions designed to interrupt the destruction of beta cells before development of t)pe 1 diabetes are being investigated in the Diabetes :revention Trial* which is tr)ing to find a wa) to prevent complete and irreversible beta cell failure. The term idiopathic form of type 1 diabetes is used to describe those cases of beta cell destruction in which no evidence of autoimmunit) is present. Anl) a small number of people with t)pe 1 diabetes fall into this categor)2 most are of frican or sian descent. T)pe 13 diabetes is strongl) inherited. :eople with the disorder have episodic ketoacidosis caused b) var)ing degrees of insulin deficienc) with periods of absolute insulin deficienc) that ma) come and go. T'(e * %iabetes Mellitus T)pe ( diabetes mellitus describes a condition of fasting h)pergl)cemia that occurs despite the availabilit) of insulin. In contrast to t)pe 1 diabetes* t)pe ( diabetes is not associated with &< markers or autoantibodies. ;ost people with t)pe ( diabetes are older and overweight. The metabolic abnormalities that contribute to h)pergl)cemia in people with t)pe ( diabetes include !1% impaired insulin secretion* !(% peripheral insulin resistance* and !0% increased hepatic glucose production !/ig. 0(+7%. Insulin resistance initiall) stimulates insulin secretion from the beta cells in the pancreas to overcome the increased demand to maintain a normogl)cemic state. In time* the insulin response b) the beta cells declines because of e-haustion. This results in elevated postprandial blood glucose levels. During the evolutionar) phase* an individual with t)pe ( diabetes ma) not produce sufficient amounts of insulin levels because of beta cell failure. 3ecause people with t)pe ( diabetes do not have an absolute insulin deficienc)* the) are

less prone to ketoacidosis than are people with t)pe 1 diabetes. There also is evidence to suggest that insulin resistance not onl) contributes to the h)pergl)cemia in persons with t)pe ( diabetes* but also ma) pla) a role in other metabolic abnormalities. These include high levels of plasma trigl)cerides* low levels of high+densit) lipoproteins* h)pertension* abnormal fibrinol)sis* and coronar) heart disease. This constellation of abnormalities often is referred to as the insulin resistance syndrome, syndrome , or the metabolic syndrome.7 ppro-imatel) @'$ of persons with t)pe ( diabetes are overweight.@ The presence of obesit) and the t)pe of obesit) are important considerations in the development of t)pe ( diabetes. It has been found that people with upper bod) obesit) are at greater risk for developing t)pe ( diabetes than are persons with lower bod) obesit) !see ?hapter ("%. Abese people have increased resistance to the action of insulin and impaired suppression of glucose production b) the liver* resulting in both h)pergl)cemia and h)perinsulinemia. The increased insulin resistance has been attributed to increased visceral !intraabdominal% fat detected on computed tomograph) scan." In addition to increased insulin resistance* insulin release from beta cells in response to glucose is impaired. Aver time* insulin resistance ma) improve with weight loss* to the e-tent that man) people with t)pe ( diabetes can manage the condition with a weight+reduction program and e-ercise. Ot$er S(eci"ic T'(es The categor) of other specific t)pes of diabetes* formerl) known as secondary diabetes* describes diabetes that is associated with certain other conditions and s)ndromes. Such diabetes canoccur with pancreatic disease or the removal of pancreatic tissue and with endocrine diseases* such as acromegal) or ?ushing4s s)ndrome. =ndocrine disorders that produce h)pergl)cemia do so b) increasing the hepatic production of glucose or decreasing the cellular use of glucose. Several specific t)pes of diabetes are associated with monogenetic defects in beta cell function. These specific t)pes of diabetes* which resemble t)pe ( diabetes but occur at an earlier age !usuall) before (5 )ears of age%* were formerl) referred to as maturity-onset diabetes of the young !;ADF%.1' =nvironmental agents that have been associated with altered pancreatic beta cell function include viruses !e.g.* mumps* congenital rubella* co-sackievirus% and chemical to-ins. mong the suspected chemical to-ins are the nitrosamines* which sometimes are found in smoked and cured meats. The nitrosamines are related to strepto.ocin* which is used to induce diabetes in

e-perimental animals* and to the rat poison Gacor* which can produce diabetes when ingested b) humans. Several diuretics>thia.ides and loop diuretics>elevate blood glucose. These diuretics increase potassium loss* which is thought to impair insulin release. Ather drugs known to cause h)pergl)cemia are dia.o-ide* glucocorticoids* levodopa* oral contraceptives* s)mpathomimetics* phenothia.ines* phen)toin* and total parenteral nutrition !i.e.* h)peralimentation%. Drugrelated increases in blood glucose usuall) are reversed after use of the drug has been discontinued. Gestational %iabetes 1estational diabetes mellitus refers to glucose intolerance that is detected first during pregnanc). It occurs to various degrees in ($ to 5$ of pregnancies.11 It most fre5uentl) affects women with a famil) histor) of diabetes2 with gl)cosuria2 with a histor) of stillbirth or spontaneous abortion* fetal anomalies in a previous pregnanc)* or a previous large+ or heav)+for+date infant2 and those who are obese* of advanced maternal age* or have had five or more pregnancies. Diagnosis and careful medical management are essential because women with 1D; are at higher risk for complications of pregnanc)* mortalit)* and fetal abnormalities.1( /etal abnormalities include macrosomia !i.e.* large bod) si.e%* h)pogl)cemia* h)pocalcemia* pol)c)themia* and h)perbilirubinemia. The merican Diabetes ssociation ! D % ?linical :ractice Decommendations suggest that pregnant women who have not been identified as having glucose intolerance before the (9th week have a screening glucose tolerance test between the (9th and (@th week of pregnanc).11 &owever* women who are )ounger than (5 )ears* were of normal bod) weight before pregnanc)* have no famil) histor) of diabetes or poor obstetric outcome* and are not members of a high+risk ethnic8 racial group !e.g.* &ispanic* Hative merican* sian* frican merican% ma) not need to be screened. Treatment of 1D; includes close observation of mother and fetus because even mild h)pergl)cemia has been shown to be detrimental to the fetus. ;aternal fasting and postprandial blood glucose levels should be measured regularl). /etal surveillance depends on the degree of risk for the fetus. The fre5uenc) of growth measurements and determinations of fetal distress depends on available technolog) and gestational age. ll women with 1D; re5uire nutritional guidance because nutrition is the cornerstone of therap). The nutrition plan should provide the necessar) nutrients for maternal and fetal health* result in normogl)cemia and proper weight gain* and prevent

ketosis.1( If dietar) management alone does not achieve a fasting blood glucose level no greater than 1'5 mg8d< or a (+hour postprandial blood glucose no greater than 1(' mg8d<* the Third International 7orkshop on 1D; recommends therap) with human insulin. Aral antidiabetic agents ma) be teratogenic and are not recommended in pregnanc). Self+monitoring of blood glucose levels is essential. 7omen with 1D; are at increased risk for the development of diabetes 5 to 1' )ears after deliver). 7omen in whom 1D; is diagnosed should be followed up after deliver) to detect diabetes earl) in its course. These women should be evaluated during their first postpartum visit with a (+hour oral glucose tolerance test with a 75+g glucose load. Mani"estations o" %iabetes Diabetes mellitus ma) have a rapid or an insidious onset. In t)pe 1 diabetes* signs and s)mptoms often arise suddenl). T)pe ( diabetes usuall) develops more insidiousl). Its presence ma) be detected during a routine medical e-amination or when a patient seeks medical care for other reasons. The most commonl) identified signs and s)mptoms of diabetes are referred to as the three polys!pol)uria !i.e.* e-cessive urination%* pol)dipsia !i.e.* e-cessive thirst%* and pol)phagia !i.e.* e-cessive hunger%. These three s)mptoms are closel) related to the h)pergl)cemia and gl)cosuria of diabetes. 1lucose is a small* osmoticall) active molecule. 7hen blood glucose levels are sufficientl) elevated* the amount of glucose filtered b) the glomeruli of the kidne) e-ceeds the amount that can be reabsorbed b) the renal tubules. This results in gl)cosuria accompanied b) large losses of water in the urine. Thirst results from the intracellular deh)dration that occurs as blood glucose levels rise and water is pulled out of bod) cells* including those in the thirst center. ?ellular deh)dration also causes dr)ness of the mouth. This earl) s)mptom ma) be easil) overlooked in people with t)pe ( diabetes* particularl) in those who have had a gradual increase in blood glucose levels. :ol)phagia usuall) is not present in people with t)pe ( diabetes. In t)pe 1 diabetes* it probabl) results from cellular starvation and the depletion of cellular stores of carboh)drates* fats* and proteins. 7eight loss despite normal or increased appetite is a common occurrence in people with uncontrolled t)pe 1 diabetes. The cause of weight loss is twofold. /irst* loss of bod) fluids results from osmotic diuresis. Gomiting ma) e-aggerate the fluid loss in ketoacidosis. Second* bod) tissue is lost because the lack

of insulin forces the bod) to use its fat stores and cellular proteins as sources of energ). In terms of weight loss* there often is a marked difference between t)pe ( diabetes and t)pe 1 diabetes. 7eight loss is a common phenomenon in people with uncontrolled t)pe 1 diabetes* whereas man) people with uncomplicated t)pe ( diabetes have problems with obesit). Ather signs and s)mptoms of h)pergl)cemia include recurrent blurred vision* fatigue* paresthesias* and skin infections. In t)pe ( diabetes* these often are the s)mptoms that prompt a person to seek medical treatment. 3lurred vision develops as the lens and retina are e-posed to h)perosmotic effects of elevated blood glucose levels. <owered plasma volume produces weakness and fatigue. :aresthesias reflect a temporar) d)sfunction of the peripheral sensor) nerves. ?hronic skin infections are common in people with t)pe ( diabetes. &)pergl)cemia and gl)cosuria favor the growth of )east organisms. :ruritus and vulvovaginitis resulting from candidal infections are common initial complaints in women with diabetes. %ia#nostic Met$ods The diagnosis of diabetes mellitus in nonpregnant adults is based on fasting blood glucose levels* random blood glucose tests* or the results of a glucose challenge test !see Table 0(+0%. Testing for diabetes should be considered in all individuals 95 )ears of age and older. Testing should be considered at a )ounger age in people who are obese* have a first+degree relative with diabetes* are members of a high+risk group* women who have delivered an infant weighing more than " pounds or have received a diagnosis of 1D;* have h)pertension or h)perlipidemia* or have met the criteria for I1T or I/1 on previous testing.10 Blood Tests 3lood glucose measurements are used in both the diagnosis and management of diabetes. Diagnostic tests include the fasting blood glucose* random blood glucose* the glucose tolerance test* and gl)cos)lated hemoglobin. <aborator) and capillar)* or Bfinger stick*C glucose tests are used for glucose management in people with diagnosed diabetes. The fasting blood glucose has been suggested as the preferred diagnostic test because of ease of administration* convenience* patient acceptabilit)* and cost.5 1lucose levels are measured after food has been withheld for @ to 1( hours. If the fasting plasma glucose level is higher than 1(# mg8d< on two occasions* diabetes is diagnosed !see Table 0(+0%. random blood

glucose is one that is done without regard to meals or time of da). random blood glucose concentration that is une5uivocall) elevated !>('' mg8d<% in the presence of classic s)mptoms of diabetes such as pol)dipsia* pol)phagia* pol)uria* and blurred vision is diagnostic of diabetes mellitus at an) age. The oral glucose tolerance test is an important screening test for diabetes. The test measures the bod)4s abilit) to store glucose b) removing it from the blood. In people with normal glucose tolerance* blood glucose levels return to normal within ( to 0 hours after ingestion of a glucose load* in which case it can be assumed that sufficient insulin is present to allow glucose to leave the blood and enter bod) cells. 3ecause a person with diabetes lacks the abilit) to respond to an increase in blood glucose b) releasing ade5uate insulin to facilitate storage* blood glucose levels rise above those observed in normal people and remain elevated for longer periods !see Table 0(+0%. Glycosylated hemoglobin measures the amount of &b 1c !i.e.* hemoglobin into which glucose has been incorporated% in the blood. 7hen hemoglobin is released from the bone marrow* it normall) does not contain glucose. During its 1('+da) life span in the red blood cell* hemoglobin normall) becomes gl)cos)lated to form gl)cohemoglobins 1a and 1b !($ to 9$% and 1c !9$ to #$%. 3ecause glucose entr) into the red blood cell is not insulin dependent* the rate at which glucose becomes attached to the hemoglobin molecule depends on blood glucose. 1l)cos)lation is essentiall) irreversible* and the level of &b 1c present in the blood provides an inde- of blood glucose levels during the previous ( to 0 months. The D recommends initiating corrective measures for &b 1c levels greater than @$. &owever* after the United Iingdom :rospective Diabetes Stud) !UI:DS% stud)* the goal has been redefined as lowering the &b 1c to less than 7.'$* or even achieving normal gl)cemic levels of less than #.'$.19Technologic advances have provided the means for monitoring blood glucose levels b) using a drop of capillar) blood. This procedure has provided health professionals with a rapid and economical means for monitoring blood glucose and has given people with diabetes a wa) of maintaining near+normal blood glucose levels through self+monitoring of blood glucose. <aborator) tests that use plasma for the measurement of blood glucose give results that are 1'$ to 15$ higher than the finger stick method* which uses whole blood. ;an) blood glucose monitors approved for home use and some test strips now calibrate blood glucose readings to plasma values. It is important that people with diabetes know whether their monitors or glucose

strips provide whole blood or plasma test results. &rine Tests Urine glucose tests onl) reflect urine glucose levels and are influenced b) such factors as the renal threshold for glucose* fluid intake and urine concentration* urine testing methodologies* and some drugs. 3ecause of these factors* the D recommends that all people who use insulin should self+monitor their blood glucose* not urine glucose.10 Unlike glucose tests* urine ketone determinations remain an important part of monitoring diabetic control* particularl) in people with t)pe 1 diabetes who are at risk for developing ketoacidosis and in pregnant women with diabetes to check the ade5uac) of nutrition and glucose control.