CHAPTER 2 LITERATURE REVIEW

2.1 Gestational diabetes mellitus 2.1.1 Definition Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy.17 GDM is detected through the screening of pregnant women for clinical risk factors and, among at-risk women, testing for abnormal glucose tolerance that is usually, but not invariably, mild and asymptomatic. GDM appears to result from the same broad spectrum of physiological and genetic abnormalities that characterize diabetes outside of pregnancy. Indeed, women with GDM are at high risk for having or developing diabetes when they are not pregnant. Thus, GDM provides a unique opportunity to study the early pathogenesis of diabetes and to develop interventions to prevent the disease.20 2.1.2 Epidemiology GDM affects ~ 7% of all pregnancies, resulting in > 200,000 cases per year. Depending on the population sample and diagnostic criteria, the prevalence may range from 1 to 14%. Of all pregnancies complicated by diabetes, GDM accounts for ~ 90%.17 The prevalence of gestational diabetes is strongly related to the patient's race and culture. Prevalence rates are higher in black, Hispanic, Native American, and Asian women than in white women. For example, typically,

only 1.5-2% of white women develop gestational diabetes mellitus, whereas Native Americans from the southwestern United States may have rates as high as 15%. In Hispanic, black, and Asian populations, the incidence is 5-8%.6 In these high-risk populations, the recurrence risk with future pregnancies has been reported to be as high as 68%. In addition, approximately one-third will develop overt diabetes mellitus within 5 years of delivery, with higher-risk ethnicities having risks nearing 50%.6 Race also influences many complications of diabetes mellitus in pregnancy. For instance, black women have been shown to have lower rates of macrosomia, despite similar levels of glycemic control. Conversely, Hispanic women have higher rates of macrosomia and birth injury than women of other ethnicities, even with aggressive management.[8, 9] 2.1.3 Etiology and phatogenesis Pregnancy is normally attended by progressive insulin resistance that begins near mid-pregnancy and progresses through the third trimester to levels that approximate the insulin resistance seen in individuals with type 2 diabetes. The insulin resistance appears to result from a combination of increased maternal adiposity and the insulin-desensitizing effects of hormonal products of the placenta. The fact that insulin resistance rapidly abates following delivery suggests that the major contributors to this state of resistance are placental hormones. The second point is that pancreatic cells normally increase their insulin secretion to compensate for the insulin resistance of pregnancy (see

Figure 1, for example). As a result, changes in circulating glucose levels over the course of pregnancy are quite small compared with the large changes in insulin sensitivity. Robust plasticity of cell function in the face of progressive insulin resistance is the hallmark of normal glucose regulation during pregnancy.

Insulin sensitivity-secretion relationships in women with GDM and normal women during the third trimester and remote from pregnancy. Values were measured at the end of 3-hour hyperglycemic clamps (plasma glucose, about 180 mg/dl) (22). Prehepatic insulin secretion rates were calculated from steady-state plasma insulin and C-peptide levels. Insulin sensitivity index was calculated as steady-state glucose infusion rate divided by steady-state plasma insulin concentration. FFM, fat-free mass. Figure reproduced with permission from J. Clin. Endocrinol. Metab. (27). Copyright 2001, The Endocrine Society.

GDM is a form of hyperglycemia. In general, hyperglycemia results from an insulin supply that is inadequate to meet tissue demands for normal blood glucose regulation. Studies conducted during late pregnancy, when, as discussed below, insulin requirements are high and differ only slightly between normal and gestational diabetic women, consistently reveal reduced insulin responses to nutrients in women with GDM (1723). Studies conducted before or after pregnancy, when women with prior GDM are usually more insulin resistant than normal women (also discussed below), often reveal insulin responses that are similar in the 2 groups or reduced only slightly in women with prior GDM (18, 2226). However, when insulin levels and responses are expressed relative to each individuals degree of insulin resistance, a large defect in pancreatic cell function is a consistent finding in women with prior GDM (23, 25, 27). Potential causes of inadequate cell function are myriad and not fully described. Outside of pregnancy, there are 3 general settings that are recognized through classification as distinct forms of diabetes mellitus (12) as separate categories of cell dysfunction: (a) autoimmune; (b) monogenic; and (c) occurring on a background of insulin resistance. There is evidence that cell dysfunction in GDM can occur in all 3 major settings, a fact that is not surprising given that GDM is detected by what is, in essence, population screening for elevated glucose levels among pregnant women.

In women with GDM, an increased incidence of malformations occurs when the mother also has fasting hyperglycemia. Long-term complications to the offspring include an increased risk of glucose intolerance, diabetes, and obesity. Maternal complications associated with GDM include hypertension,

preeclampsia, and an increased risk of cesarean delivery. The hypertension may be related to insulin resistance. Therefore, interventions that improve insulin sensitivity may help prevent this complication. In addition, women with a history of GDM have an increased risk of developing diabetes after pregnancy compared to the general population, with a conversion rate of up to 3% per year. Autoimmune diabetes and GDM Type 1 diabetes results from autoimmune destruction of pancreatic cells. It accounts for approximately 510% of diabetes in the general population (12). Prevalence rates vary by ethnicity, with the highest rates in Scandinavians and the lowest rates (i.e., 0%) in full-blooded Native Americans. Type 1 diabetes is characterized by circulating immune markers directed against pancreatic islets (antiislet cell antibodies) or cell antigens (such as glutamic acid decarboxylase [GAD]). A small minority (less than 10% in most studies) of women with GDM have the same markers present in their circulation (17, 2831). Although detailed physiological studies of these women are lacking, they most likely have inadequate insulin secretion resulting from autoimmune damage to and destruction of pancreatic cells. They appear to have evolving type 1 diabetes,

which comes to clinical attention through routine glucose screening during pregnancy. The frequency of antiislet cell and anti-GAD antibodies detected in GDM tends to parallel ethnic trends in the prevalence of type 1 diabetes outside of pregnancy. Patients with antiislet cell or anti-GAD antibodies often, but not invariably, are lean, and they can rapidly develop overt diabetes after pregnancy (30). Monogenic diabetes and GDM Monogenic diabetes mellitus has been identified outside of pregnancy in 2 general forms. Some patients have mutations in autosomes (autosomal dominant inheritance pattern, commonly referred to as maturity-onset diabetes of the young [MODY], with genetic subtypes denoted as MODY 1, MODY 2, etc.). Others have mutations in mitochondrial DNA, often with distinct clinical syndromes such as deafness. In both instances, onset tends to occur at an early age relative to other forms of nonimmune diabetes (e.g., type 2 diabetes, described below), and patients tend not to be obese or insulin resistant. Both features point to abnormalities in the regulation of cell mass and/or function. Indeed, detailed metabolic studies have revealed abnormalities in glucose-mediated insulin secretion in some forms of MODY (32). Mutations that cause several subtypes of MODY have been found in women with GDM. These include mutations in genes coding for: (a) glucokinase (MODY 2) (29, 3335); (b) hepatocyte nuclear factor 1 (MODY 3) (29); (c) and insulin promoter factor 1 (MODY 4) (29). Together, these monogenic forms of GDM account for less than 10% of GDM cases

(29, 3336). They likely represent cases of preexisting diabetes that are first detected by routine glucose screening during pregnancy. Insulin resistance, cell dysfunction, and GDM The majority of women with GDM appear to have cell dysfunction that occurs on a background of chronic insulin resistance. As noted above, pregnancy normally induces quite marked insulin resistance. This physiological insulin resistance also occurs in women with GDM. However, it occurs on a background of chronic insulin resistance to which the insulin resistance of pregnancy is partially additive. As a result, pregnant women with GDM tend to have even greater insulin resistance than normal pregnant women. Differences in wholebody insulin sensitivity tend to be small in the third trimester, owing to the marked effects of pregnancy itself on insulin resistance. Nonetheless, precise and direct measures of insulin sensitivity applied during the third trimester have identified, in women with GDM, exaggerated resistance to insulins ability to stimulate glucose utilization (17, 18) and to suppress both glucose production (17, 18) and fatty acid levels (17). After delivery, when the acquired insulin resistance of pregnancy abates, women who had GDM end up, on average, with considerably greater insulin resistance than normal women. This finding, which has been consistent across studies in which whole-body insulin sensitivity has been measured directly (22, 23, 25, 26, 3740), indicates that most women who develop GDM have chronic insulin resistance. Sequential measurements of insulin sensitivity performed in the same women before pregnancy, early in the second

trimester, and in the third trimester have documented insulin resistance in both lean and obese women who go on to develop GDM (18,24). Only a small number of potential biochemical mediators of the chronic insulin resistance that frequently accompanies GDM and that likely contributes to the high risk of type 2 diabetes have been examined. It is likely that there is not a single underlying biochemical etiology. Women with GDM tend to be obese, so mechanisms promoting obesity and/or linking obesity to insulin resistance are likely to play a role. Small studies have revealed increased circulating levels of leptin (41) and the inflammatory markers TNF- (42) and C-reactive protein (43) and decreased levels of adiponectin (44, 45) in women with GDM. Increased content of fat in liver (46) and muscle (47) has also been reported in women with previous gestational diabetes. All of these findings are consistent with the current understanding of some potential causes of obesity-related insulin resistance. Defects in the binding of insulin to its receptor in skeletal muscle do not appear to be involved in the exaggerated insulin resistance of GDM (48). Alterations in the insulin signaling pathway (4952), abnormal subcellular localization of GLUT4 transporters (53), reduced expression of PPAR (49), increased expression of the membrane glycoprotein PC-1 (51), and reduced insulin-mediated glucose transport (52, 53) have been found in skeletal muscle or fat cells of women with GDM or a history thereof compared with normal women. Whether any of these defects is primary or the result of more fundamental defects in insulin action is currently unknown. Given that GDM represents a cross-section of young women

with glucose intolerance, mechanisms that lead to chronic insulin resistance in GDM are likely to be as varied as they are in the general population. It has long been thought (and taught) that GDM develops in women who cannot increase their insulin secretion when faced with the increased insulin needs imposed by late pregnancy. Serial studies of women who develop GDM do not support that concept. As illustrated in Figure Figure1,1, insulin secretion in obese women who develop GDM can increase considerably over weeks or months in association with the acquired insulin resistance of pregnancy. However, the increase occurs along an insulin sensitivity-secretion curve that is approximately 50% lower (i.e., 50% less insulin for any degree of insulin resistance) than that of normal women. These short-term responses appear to occur on a background of long-term deterioration of cell function that, over years, leads to progressive hyperglycemia and diabetes (see Link to diabetes after pregnancy, below). Longitudinal studies of lean and obese women before pregnancy, at the beginning of the second trimester, and in the third trimester also reveal an increase in insulin secretion in association with the acquired insulin resistance of pregnancy (18, 24). However, the increase is less than that which occurs in normal pregnant women despite somewhat greater insulin resistance in individuals with GDM. These small but elegant physiological studies reveal that the limitation in insulin secretion in women with GDM is not necessarily fixed. Rather, in at least some of them, insulin secretion is low relative to their insulin sensitivity but responsive to changing sensitivity. One approach to the prevention of diabetes after GDM has

taken advantage of this responsiveness (discussed below in Link to diabetes after pregnancy). Very little is known about the genetics of GDM in women with chronic insulin resistance. The few studies that have been done have compared allele frequencies of candidate genes in women with and without GDM, with no selection for specific phenotypic subtypes of GDM. Variants that differed in frequency between control and GDM subjects were found in genes coding for: (a) the islet-specific promoter of glucokinase (54), known to be important for glucose sensing by cells; (b) calpain-10 (55), a gene associated with type 2 diabetes in Hispanic Americans and some other ethnic groups; (c) the sulfonylurea receptor 1 (56), which is involved in glucose-stimulated insulin secretion; and (d) the 3 adrenoreceptor, which may regulate body composition. Whether these findings will be confirmed in larger studies with broader representation among women with GDM remains to be determined. 2.1.4 Sign and Simptoms For most women, gestational diabetes doesn't cause noticeable signs or symptoms. Rarely, gestational diabetes may cause excessive thirst or increased urination. 2.1.5 Diagnostic Criteria The oral glucose tolerance test (OGTT) most commonly used to diagnose GDM in the United States is the 3-hour, 100-g OGTT. According to diagnostic criteria recommended by the American Diabetes Association (ADA), GDM is

diagnosed if two or more plasma glucose levels meet or exceed the following thresholds fasting glucose concentration of 95 mg/dl, 1-hour glucose concentration of 180 mg/dl, 2-hour glucose concentration of 155 mg/dl, or 3-hour glucose concentration of 140 mg/dl.1,2,4 These values are lower than the thresholds recommended by the National Diabetes Data Group and are based on the Carpenter and Coustan modification.5 The ADA recommendations also include the use of a 2-hour 75-g OGTT with the same glucose thresholds listed for fasting, 1-hour, and 2-hour values. The World Health Organization (WHO) diagnostic criteria, which are used in many countries outside of North America, are based on a 2-hour 75-g OGTT. GDM is diagnosed by WHO criteria if either the fasting glucose is > 126 mg/dl or the 2-hour glucose is > 140 mg/dl.

Screening tests The best method for screening for gestational diabetes continues to be controversial. The 2-step system is currently recommended in the United States. A 50-g, 1-hour glucose challenge test (GCT) is followed by a 100-g, 3-hour oral

glucose tolerance test (OGTT) for those with an abnormal screening result. Alternatively, for high-risk women, or in areas in which the prevalence of insulin resistance is 5% or higher (eg, the southwestern and southeastern United States), a 1-step approach can be used by proceeding directly to the 100-g, 3-hour OGTT. The sensitivity of gestational diabetes mellitus testing depends on the threshold value used for the 50-g glucose challenge. Current recommendations from the American Diabetes Association "Standards of Medical Care in Diabetes-2010"[40] and the American College of Obstetricians and Gynecologists (ACOG)[43] note that a threshold value of 140 mg/dL results in approximately 80% detection of gestational diabetes, whereas a threshold of 130 mg/dL results in 90% detection. A potential disadvantage of using the lower value of 130 mg/dL is an approximate doubling in the number of OGTTs performed. Meltzer et al found that 2-step screening with a 1-hour, 50-g glucose screen, followed by (if necessary) an OGTT, was superior to 1-step screening with a 75-g OGTT. In a prospective, randomized, controlled trial, the total cost per woman screened was lower with the 2-step approach, because many patients with gestational diabetes were diagnosed on the basis of a glucose screen result of 10.3 mmol/L (185.4 mg/dL) or greater, thus obviating the additional blood draws and time required for the OGTT.[44] Other tests (eg, maternal HbA1C, random postprandial or fasting blood sugar level, or fructosamine level) are not recommended because of low sensitivity.

Patients undergoing oral glucose tolerance testing for gestational diabetes should undertake carbohydrate loading for 3 days preceding the test (>150 g carbohydrates) and an overnight fast of 814 hours the night before. The patient should remain seated during the test, and should not smoke. Two or more glucose values, as listed in the table below, must be met or exceeded for the diagnosis of gestational diabetes. The current recommendations from the American Diabetes Association "Standards of Medical Care in Diabetes-2010"[42] are to conduct a risk assessment for all pregnant women at the first prenatal visit. Women who are at very high risk should undergo testing as soon as possible, in order to identify those with occult type 2 diabetes, using the standard diagnostic approach to diabetes (see Preexisting Diabetes Diagnosis, below). Criteria for very high risk are as follows:

Severe obesity Gestational diabetes mellitus during a previous pregnancy or delivery of an LGA infant

Presence of glycosuria Diagnosis of polycystic ovarian syndrome Strong family history of type 2 diabetes

All pregnant women should be screened for gestational diabetes at 24-28 weeks' gestationincluding those with negative test results in the first trimesterunless they are at low risk. To be considered at low risk, a woman must meet all of the following criteria:

Age < 25 years Weight normal before pregnancy Member of an ethnic group with a low prevalence of diabetes No known diabetes in first-degree relatives No history of abnormal glucose tolerance No history of poor obstetric outcome

2.1.6 Complication There are both fetal and maternal complications associated with GDM. Fetal complications include macrosomia, neonatal hypoglycemia, perinatal mortality, congenital malformation, hyperbilirubinemia, polycythemia,

hypocalcemia, and respiratory distress syndrome. Macrosomia, defined as birth weight > 4,000 occurs in ~ 2030% of infants whose mother have GDM. Maternal factors associated with an increased incidence of macrosomia include hyperglycemia, high BMI, older age, and multiparity. This excess in fetal growth can lead to increased fetal morbidity at delivery, such as shoulder dystocia, and an

increased rate of cesarean deliveries. Neonatal hypoglycemia can occur within a few hours of delivery. This results from maternal hyperglycemia causing fetal hyperinsulinemia. The association between GDM and perinatal mortality has been more controversial. Several studies have concluded that the rate of perinatal mortality (including stillbirths and neonatal deaths) was increased in women with GDM in the past. However, recent studies have shown that, with the combination of increased antepartum monitoring, medical nutrition therapy (MNT), and insulin therapy if needed, this difference in perinatal mortality rates is potentially avoidable. Another controversial association is that between GDM and congenital malformations. The incidence of a major malformation in an infant whose mother does not have any history of diabetes is 13%. In women with a history of diabetes before pregnancy, this risk is increased three to eight times. In women with GDM, an increased incidence of malformations occurs when the mother also has fasting hyperglycemia. Long-term complications to the offspring include an increased risk of glucose intolerance, diabetes, and obesity. Maternal complications associated with GDM include hypertension,

preeclampsia, and an increased risk of cesarean delivery. The hypertension may be related to insulin resistance. Therefore, interventions that improve insulin sensitivity may help prevent this complication. In addition, women with a history of GDM have an increased risk of developing diabetes after pregnancy compared to the general population, with a conversion rate of up to 3% per year.

2.2 Coffee 2.2.1 Contains of Coffee Coffee contains a complex mixture of chemical compounds. Some components, particularly those related to the aroma, are produced during roasting of the green beans. The substances which during "brewing" dissolve in water to form the beverage are classified as nonvolatile taste components (including caffeine, trigonelline, chlorogenic acid, phenolic acids, amino acids,

carbohydrates, and minerals) and volatile aroma components including organic acids, aldehydes, ketones, esters, amines, and mercaptans. The major physiologically active substance in coffee is the alkaloid caffeine (C_8H_10 O_2N_4. H_2O), also called guaranine or methyltheobromine, which acts as a mild stimulant. Caffeine is a naturally occurring substance found in the leaves, seeds or fruits of more than 60 plants, including coffee and cocoa beans, cola nuts and tea leaves. These are used to make beverages such as coffee, tea and cola drinks, and foods such as chocolate. Caffeine is also contained in many over-the-counter (OTC) and prescription medications. In the United States, most of the population uses caffeine in some form. Coffee also contains minerals such as magnesium and chromium, which help the body use the hormone insulin, which controls blood sugar (glucose). In type 2 diabetes, the body loses its ability to use insulin and regulate blood sugar

effectively. Previous studies have found that people who drink four or more cups of coffee a day have a 50% lower risk of getting type 2 diabetes. A cup of coffee, depending on the strength, may contain some 20-100mg of caffeine. Some types of coffee may also contain significant amounts of the Bvitamin niacin, although this nutrient is of course readily available from other foods as well. Caffeine-containing tablets or medications should not be taken as well as cups of coffee or tea, since this would increase the true dosage. The effects of caffeine vary from person to person; some individuals can drink several cups of coffee in an hour and notice no effects, while others may feel a strong effect after just one serving. Caffeine is prohibited for competition athletes.

People who wish to avoid or minimise caffeine intake (see below) often use decaffeinated coffee, or coffee substitutes. One method of decaffeination is by treating the green beans (before roasting) with chlorinated hydrocarbon solvents; other methods are also used. Important coffee substitutes are chicory, and roasted cereals such as barley; although these are commonly used not as total substitutes but as "extenders". Under U.S. law, the addition of chicory or any other substance must be clearly stated on the label. 2.2.2 Caffeine Short-term effects Caffeine is a drug that has been widely used for centuries. Its main effect is that it is a mild stimulant of the central nervous system (CNS), helping to reduce feelings of drowsiness and fatigue. However, regular use may lead to

"habituation"; that is, no net benefit from use but, rather, a negative effect if the drug is not taken. Besides the above-mentioned CNS stimulant effect, caffeine also temporarily increases heartbeat, increases the blood pressure, and stimulates the action of the lungs; increases basal metabolic rate (BMR), and promotes urine production; and it relaxes smooth muscles, notably the bronchial muscle. Caffeine is used in treating migraine, either alone or in combination. It enhances the action of the ergot alkaloids used for the treatment of this problem, and also increases the potency of analgesics such as aspirin. It can somewhat relieve asthma attacks by dilating the bronchial airways. Too much caffeine can produce restlessness, nausea, headache, tense muscles, sleep disturbances, and cardiac arrhythmias (irregular heartbeats). Because caffeine increases the production of stomach acid it may worsen ulcer symptoms or cause acid reflux ("heartburn"). Evening use of caffeine may disrupt sleep and cause insomnia. Caffeine should be used with caution by people with heart disease and high blood pressure (hypertension), and by those suffering from the eye disease glaucoma. Caffeine medications should generally not be used in children. Many children are already consuming significant amounts of caffeine in drinks and food. In this connection, a nutritional concern is that children may choose fizzy drinks in preference to milk, thus getting "empty" calories at the expense of valuable nutrients.

2.2.3 Caffeine Long-term effects As already mentioned, some potentially harmful effects of coffee are recognized, particularly for people who should take few or no stimulants. Beyond this however, scientific studies of the effects of caffeine have in general failed to prove negative effects, although some have produced contradictory conclusions. An individual study may produce interesting results which may suggest fruitful directions for further research, but usually it is only when several independent studies confirm one another, and any contradictory results can be accounted for, that one can have reasonable confidence in the safety of a drug -- particularly an " optional" one like coffee. Although caffeine does not fall into the class of "addictive" drugs, it may be habit-forming. Some people may experience headache, fatigue, irritability and nervousness when their daily intake of caffeine is quickly and substantially altered. Such "withdrawal effects" may be responsible for confusing results in some studies. There are many complicating factors in long-term studies. One is the familiar "convergence of risk-factors" (e.g. that coffee-drinkers may be more likely to be smokers). Another is that many of the study subjects may deliberately change (or have previously changed) their consumption habits or behaviour, e.g. in response to discovering that they suffer from hypertension. There may also be significant differences in methods of coffee preparation between study populations, or over long periods of time.

Moderate caffeine consumption during pregnancy is generally considered safe. A study has not found any effect on low birth-weight or incidence of premature births. However, although it has been suggested that caffeine may stimulate milk production, cautious mothers may prefer to avoid such beverages during pregnancy or while breastfeeding. Furthermore, a large study has not shown any connection of coffee or tea consumption with breast-cancer incidence. Osteoporosis is another condition which particularly affects women. Previous studies have suggested caffeine consumption as a risk-factor, but a recent analysis concludes that such an effect is probably not significant except in conditions of calcium-deficiency, which can be easily corrected. There is even some actual positive news. The effect of caffeine on the risk of developing Parkinson's disease, which usually affects older people, has been found to be favourable for men. For women, previous results have been confusing; but a recent study suggests that a crucial factor may be the effect of hormone levels. Often caffeine may have a favourable effect against developing this disease; but when combined with hormone replacement therapy (HRT), it may have a negative one.

2.3 Coffee in Pregnancy In August 2010, the American College of Obstetricians and Gynecologists (ACOG) stated that moderate caffeine drinking -- less than 200 mg per day, or

about the amount in 12 ounces of coffee -- doesn't appear to have any major effects on causing miscarriage, premature delivery, or fetal growth. But the effects of larger caffeine doses are unknown, and other research shows that pregnant women who drink many cups of coffee daily may be at greater risk for miscarriage than non-drinkers or moderate drinkers. Again, it's not clear whether the coffee was responsible for that. 2.4 C-peptide A byproduct of insulin production, usually by the pancreas. The level of C-peptide is a gauge of how much insulin is being produced in the body. C-peptide is made up of chemical compounds called amino acids. When the pancreas produces insulin, it releases C-peptide into the bloodstream in the same way that the production of heat from burning coal or wood releases smoke into the atmosphere. The amount of C-peptide in the blood can indicate the presence or absence of disease. For example, abnormally low amounts of C-peptide in the blood suggest the insulin production is too low (or absent) because of type I diabetes, also known as juvenile or insulin-dependent diabetes. Abnormally high amounts of C-peptide warn of the possible presence of a tumor called an insulinoma that secretes insulin. Normal levels of C-peptide may signal that all is well. However, in a person with diabetes, a normal level of C-peptide indicates the body is making plenty of insulin but the body is just not responding properly to it. This is

the hallmark of type 2 diabetes (adult insulin-resistant diabetes). C-peptide, therefore, plays a crucial diagnostic role as regards insulin. Insulin is a hormone that regulates the body's use of glucose (blood sugar). Muscle cells and other types of cells need glucose to generate energy. The body manufactures glucose from food, mainly carbohydrates. It is the job of insulin to deliver glucose to an energy-consuming body site. There it knocks on the front door and places the glucose into the hands of the occupant. The occupant then uses the glucose to help its master -- the body -- walk, run, throw, lift, and carry out other activities. Football players, mountain climbers and lumberjacks all thrive on the energy glucose provides. Insulin also prevents glucose overload in the bloodstream by lowering the level of blood glucose as necessary. Insulin is released by cells in the pancreas called the islets of Langerhans. If the pancreas malfunctions, it may produce an inadequate supply of insulin, or no insulin at all. Blood sugar then increases because there is little or no insulin to regulate it. Type 1 diabetes then develops. Meanwhile, the reduced production of insulin also reduces the amount of C-peptide released into the bloodstream. If a patient reports symptoms of diabetes to a physician--symptoms that may include great thirst, frequent urination and fatigue--the physician can order a test that checks for the amount of C-peptide in the blood. If a patient reports symptoms consist with pancreatic cancer -- abdominal pain, cramps, weight loss, and jaundice-- the physician can again order the C-peptide test -- to determine the likelihood of a tumor.