Gestational Diabetes Mellitus

Gestational diabetes mellitusThomas A. Buchanan1 and Anny H. Xiang2

1Departments of Medicine, Obstetrics and Gynecology, and Physiology and Biophysics, and 2Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.

Address correspondence to: Thomas A. Buchanan, Room 6602 GNH, 1200 North State Street, Los Angeles, California 90089-9317, USA. Phone: (323) 226-4632; Fax: (323) 226-2796; E-mail: [email protected].

Published March 1, 2005

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy. 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.

Historical perspectiveFor more than a century, it has been known that diabetes antedating pregnancy can have severe adverse effects on fetal and neonatal outcomes (1). As early as in the 1940s, it was recognized that women who developed diabetes years after pregnancy had experienced abnormally high fetal and neonatal mortality (2). By the 1950s the term “gestational diabetes” was applied to what was thought to be a transient condition that affected fetal outcomes adversely, then abated after delivery (3). In the 1960s, O’Sullivan found that the degree of glucose intolerance during pregnancy was related to the risk of developing diabetes after pregnancy. He proposed criteria for the interpretation of oral glucose tolerance tests (OGTTs) during pregnancy that were fundamentally statistical, establishing cut-off values — approximately 2 standard deviations — for diagnosing glucose intolerance during pregnancy (4). In the 1980s those cut-off points were adapted to modern methods for measuring glucose and applied to the modern definition of gestational diabetes — glucose intolerance with onset or first recognition during pregnancy (5). While based on O’Sullivan’s values for predicting diabetes after pregnancy, the diagnosis of gestational diabetes mellitus (GDM) also identifies pregnancies at increased risk for perinatal morbidity (6–8) and long-term obesity and glucose intolerance in offspring (9–11).

Population perspective

Clinical detection of GDM is carried out to identify pregnancies at increased risk for perinatal morbidity and mortality. Available data do not identify a threshold of maternal glycemia at which such risk begins or increases rapidly. A multinational study, the Hyperglycemia and Adverse Pregnancy Outcome study, is underway to explore this issue in a large multiethnic cohort. In the absence of a defined glucose threshold for perinatal risk, many different sets of glycemic criteria have been proposed and are employed worldwide for the diagnosis of GDM. The criteria currently recommended by the American Diabetes Association (12) are based on O’Sullivan’s criteria (see above). The detection of GDM, a condition that is generally asymptomatic, involves screening in 2 sequential steps (Tables 1 and 2), followed by administration of a 2- or 3-hour OGTT (Table 3) to women determined to be at risk by screening. Women with very high clinical risk characteristics may be diagnosed with probable pregestational (preexisting) diabetes based on the criteria provided in Table 4. When the diagnostic criteria for a 3-hour OGTT presented in Table 3 was applied to a group of Caucasian women in Toronto, approximately 7% had GDM (6). The frequency of GDM may vary among ethnic groups (higher in groups with increased prevalence of hyperglycemia) (13–16) and with the use of different diagnostic criteria (higher when lower glucose thresholds are applied and vice versa) (4). Nonetheless, all approaches to GDM detection pinpoint — and thereby allow diagnosis of — women with glucose tolerance in the upper end of the population distribution during pregnancy. A small minority of those women have glucose levels that would be diagnostic of diabetes outside of pregnancy (Table 4). The great majority have lower glucose levels. Both groups impart to their offspring an increased risk of perinatal morbidity and long-term obesity and diabetes that appear to be related at least in part to fetal overnutrition in utero. They also incur for themselves a risk of diabetes after pregnancy that is the main focus of this paper.

Table 1

Screening for GDM, step 1: clinical risk assessmentA,B

Table 2

Screening for GDM, step 2: blood glucose screeningA

Table 3

Diagnosis of GDM during pregnancyA

Table 4

Probable pregestational diabetesA

Etiology and pathogenesisNormal pregnancy A detailed discussion of glucose regulation in pregnancy is beyond the scope of this paper. However, 2 points are important for the discussion that follows. First, pregnancy is

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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 β 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 β cell function in the face of progressive insulin resistance is the hallmark of normal glucose regulation during pregnancy.

Figure 1

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.

Gestational diabetes 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 (17–23). 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, 22–26). However, when insulin levels and responses are expressed relative to each individual’s degree of insulin resistance, a large defect in pancreatic β cell function is a consistent finding in women with prior GDM (23, 25, 27).

Potential causes of inadequate β 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 β cell dysfunction: (a) autoimmune; (b) monogenic; and (c) occurring on a background of insulin resistance. There is evidence that β 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.

Autoimmune diabetes and GDM Type 1 diabetes results from autoimmune destruction of pancreatic β cells. It accounts for approximately 5–10% 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 (anti–islet cell antibodies) or β cell antigens

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(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, 28–31). 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 β cells. They appear to have evolving type 1 diabetes, which comes to clinical attention through routine glucose screening during pregnancy. The frequency of anti–islet 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 anti–islet 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 β 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, 33–35); (b) hepatocyte nuclear factor 1α (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, 33–36). They likely represent cases of preexisting diabetes that are first detected by routine glucose screening during pregnancy.

Insulin resistance, β cell dysfunction, and GDM The majority of women with GDM appear to have β 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 whole-body 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 insulin’s 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, 37–40), 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-α (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 (49–52), abnormal subcellular localization of GLUT4 transporters (53), reduced expression of PPARγ (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 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 β 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 β

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 β3 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.

Link to diabetes after pregnancyThe hyperglycemia of GDM is detected at one point in a women’s life. If glucose levels are not already in the diabetic range, GDM could represent glucose intolerance that is limited to pregnancy, is chronic but stable, or is at a stage in the progression to diabetes. Long-term follow-up studies, recently reviewed by Kim et al. (57), reveal that most, but not all, women with GDM do progress to diabetes after pregnancy. Only approximately 10% of patients have diabetes soon after delivery (58). Incident cases appear to occur at a relatively constant rate during the first 10 years thereafter (57), and the few studies that have been conducted over a period of more than 10 years reveal a stable long-term risk of approximately 70% (57).

Most studies of risk factors for the development of diabetes after GDM fail to distinguish among the possible subtypes of GDM and diabetes discussed above. They generally reveal risk factors, such as obesity, weight gain, and increased age, that are known to be associated with type 2 diabetes. Relatively high glucose levels during and soon after pregnancy also correlate with increased risk of diabetes, perhaps because they identify women who are relatively close to developing diabetes when the diagnosis of GDM is made.

Longitudinal studies of the pathophysiology of diabetes that develops after GDM are limited to Hispanic women with clinical characteristics suggesting a risk for type 2 diabetes. Those studies have revealed much about the β cell defect that leads to type 2 diabetes after GDM in 1 ethnic group. First, weight gain and additional pregnancies, factors associated with chronic and acute insulin resistance, respectively, independently increase the risk of developing diabetes (59). Second, decreasing β cell function is associated with increasing hyperglycemia (Figure 2) (60). The impact of reduced β cell function on glucose levels is relatively small until the disposition index, which reflects acute insulin responses to glucose in relation to insulin resistance, is very low (approximately 10–15% of normal). Thereafter, relatively small differences in β cell function are associated with relatively large increases in glucose levels (60). Third, treatment of insulin resistance at the stage of impaired glucose tolerance results in a reciprocal downregulation of insulin secretion (61), which in turn is associated with a reduction in the risk of diabetes and with preservation of β cell function (62). Taken together, these 3 findings reveal a progressive loss of insulin secretion that appears to be caused by high insulin secretory demands imposed by chronic insulin resistance. Glycemia in the diabetic range is a relatively late consequence of the loss of insulin secretion. That loss can be slowed or stopped through the treatment of insulin resistance in order to reduce of high insulin secretory demands (62). Whether the same or similar mechanisms of progressive β cell dysfunction and opportunities for β cell preservation occur in other ethnic groups remains to be determined.

Figure 2

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Relationship between pancreatic β cell function and post-challenge glucose levels in women with prior GDM. Data are from 71 nonpregnant Hispanic women who had at least 2 (86% had at least 3) sets of oral and frequently sampled i.v. glucose tolerance tests that were scheduled at 15-month intervals between 15 and 75 months after the index pregnancy (totaling 280 sets of tests). Participants had fasting plasma glucose of less than 140 mg/dl at entry into the study and were followed until that value was exceeded. Disposition index (x axis) is the product of minimal model insulin sensitivity (SI) and the acute insulin response to i.v. glucose (AIRg), a measure of pancreatic β cell compensation for insulin resistance. The y axis shows glucose values at hour 2 of 75-g OGTTs. Symbols represent mean values for disposition index and corresponding 2-hour glucose values (± 1 SD) in each octile of disposition index. The mean disposition index was 2018 in Hispanic women without a history of GDM (arrow). Figure based on data from ref. 60.

Implications for clinical careTo date, insights into the mechanisms underlying impaired glucose regulation in GDM have not had an important impact on clinical management during pregnancy. The focus for antepartum care is on the use of standard antidiabetic treatments, mostly appropriate nutrition and exogenous insulin delivery but more recently administration of selected oral antidiabetic agents (63–65), to normalize maternal pre- and postprandial glucose levels and minimize fetal overnutrition. Fetal ultrasound measurements have also been used to refine the identification of pregnancies in which the fetus demonstrates signs of excessive adiposity — pregnancies in which the need to aggressively lower maternal glucose is the greatest (66, 67).

After pregnancy, the main focus of clinical care should be on reducing the risk of diabetes and detecting and treating diabetes that does develop. Measurement of fasting glucose in the immediate postpartum period will identify women with persistent fasting hyperglycemia in the diabetic range. Other women should have an OGTT sometime during the first 2–6 months postpartum and, if not diabetic, annual testing for diabetes. Family planning is important to reduce the occurrence of unplanned pregnancies in the presence of poorly controlled diabetes (68), a scenario that leads to serious birth defects in offspring (69).

Classification of patients into 1 of the 3 major subtypes of GDM discussed in this review can aid in clinical management. Lean patients are less likely to be insulin resistant than overweight or obese patients, so autoimmune and monogenic forms of diabetes should be considered in such patients. Screening for evolving autoimmune diabetes by measuring antibodies to GAD may be warranted, particularly in women with no strong family history of diabetes who are from ethnic groups in which type 1 diabetes is relatively common. Although there are no established treatments to modify the progression to type 1 diabetes, careful monitoring of glucose levels is advised because patients can rapidly develop diabetes after pregnancy (30). Genotyping for monogenic diabetes is still primarily a research tool, but clinical tests are being developed. Early-onset diabetes with a relevant family history (autosomal dominant inheritance for MODY; maternal inheritance for mitochondrial mutations) may provide a clue to the diagnosis. In addition, Ellard et al. (34) have provided 4 clinical criteria that have relatively high specificity for identifying women with the glucokinase mutations that cause 1 form of MODY, MODY2: (a) persisting fasting hyperglycemia (105–145 mg/dl) after pregnancy; (b) a small (less than 82

mg/dl) increment in glucose above the fasting level during a 75-g, 2-hour OGTT; (c) insulin treatment during at least 1 pregnancy but subsequently controlled on diet; and (d) a first-degree relative with type 2 diabetes, GDM, or fasting serum or plasma glucose greater than 100 mg/dl. The constellation was infrequent in patients in the United Kingdom, but 80% of women who met all 4 criteria had glucokinase mutations. Identification of monogenic forms of diabetes is important for genetic counseling.

There is currently no clinical role for genetic testing for variants that have been associated with polygenic forms of type 2 diabetes (see “Insulin resistance, β cell dysfunction, and GDM,” above). The variants cannot be used reliably to discriminate between normal individuals and individuals affected with diabetes and, just as importantly, testing is not available to clinicians. On the other hand, recent advances in the understanding of mechanistic links between GDM and type 2 diabetes have been translated into clinical care aimed at reducing the risk of diabetes. At least 2 studies of diabetes prevention in high-risk individuals have included women with a history of GDM. In the US Diabetes Prevention Program (DPP) (70), intensive lifestyle modification to promote weight loss and increase physical activity resulted in a 58% reduction in the risk of type 2 diabetes in adults with impaired glucose tolerance. GDM was one of the risk factors that led to inclusion in the study. Protection against diabetes was observed in all ethnic groups. Treatment with metformin in the same study also reduced the risk of diabetes, but to a lesser degree and primarily in the youngest and most overweight participants. To date, specific results from women with a history of GDM have not been published.

The Troglitazone in Prevention of Diabetes (TRIPOD) study was conducted exclusively on Hispanic women with recent GDM. Assignment to treatment with the insulin-sensitizing drug troglitazone was associated with a 55% reduction in the incidence of diabetes. Protection from diabetes was closely linked to initial reductions in endogenous insulin requirements and ultimately associated with stabilization of pancreatic β cell function (62). Stabilization of β cell function was also observed when troglitazone treatment was started at the time of initial detection of diabetes by annual glucose tolerance testing (71). The DPP and TRIPOD studies support clinical management that focuses on aggressive treatment of insulin resistance to reduce the risk of type 2 diabetes and, at least in Hispanic women, to preserve pancreatic β cell function.

Taken together, these 2 studies suggest that postpartum management of women with clinical characteristics suggesting a risk for type 2 diabetes should focus on treatment of insulin resistance and monitoring of glycemia both to assess success (as reflected by stabilization of glucose levels) and to detect diabetes if it develops.

Future directionsConsiderable work is needed to dissect the various mechanisms underlying maternal GDM and its evolution to diabetes after pregnancy. Large studies of screening for evolving autoimmune diabetes are necessary to more accurately define the clinical characteristics of women who need such screening as part of routine GDM management. Genetic studies may help identify women whose β cells will tolerate insulin resistance poorly, as well as women who develop poor insulin secretion for reasons unrelated to insulin resistance. Studies of gene-environment interactions

and additional studies of insulin action in muscle and fat may identify causes of insulin resistance, especially as they relate to obesity. Better understanding of mechanisms that can lead to GDM should allow more rational development and administration of therapy during pregnancy, as well as more rational approaches to prevention of both GDM and diabetes after pregnancy. GDM is an especially attractive target for such studies because the disease is detected in the course of routine clinical care and it provides an opportunity to study relatively early stages of glucose dysregulation that may be fundamental to the long-term pathobiology of diabetes.

AcknowledgmentsWe thank our long-term collaborators Siri Kjos, Ruth Peters, and Richard Bergman for their contributions to studies on the pathogenesis of type 2 diabetes after GDM in Hispanic women. Our work cited in this paper was supported by research grants from the NIH (R01-DK46374, R01-DK61628, and M01-RR00043), the American Diabetes Association (Clinical Research Award and Distinguished Clinical Scientist Award), and Parke-Davis Pharmaceutical Research (the TRIPOD study).

FootnotesNonstandard abbreviations used: DPP, Diabetes Prevention Program; GAD, glutamic acid decarboxylase; GDM, gestational diabetes mellitus; MODY, maturity-onset diabetes of the young; OGTT, oral glucose tolerance test; TRIPOD; Troglitazone in Prevention of Diabetes.

Conflict of interest: T.A. Buchanan and A.H. Xiang receive grant support from Takeda Pharmaceuticals North America Inc. T.A. Buchanan is also a consultant to Takeda Pharmaceuticals North America Inc. and is on the company’s Actos Speakers’ Bureau.

References1. Duncan, M. On puerperal diabetes. Trans. Obstet. Soc. Lond. 1882. 24:256-285.

2. Miller, HC. The effect of diabetic and prediabetic pregnancies on the fetus and newborn infant. J. Pediatr. 1946. 26:455-461.

3. Carrington, ER, Shuman, CR, Reardon, HS. Evaluation of the prediabetic state during pregnancy. Obstet. Gynecol. 1957. 9:664-669.

View this article via: PubMed

4. O’Sullivan, JB, Mahan, CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes. 1964. 13:278-285.


5. American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus Diabetes Care. 2003. 26(Suppl. 1):S5-S20.

View this article via: PubMed CrossRef

6. Naylor, CD, Sermer, M, Chen, E, Sykora, K. Cesarean delivery in relation to birth weight and gestational glucose tolerance: pathophysiology or practice style? JAMA. 1996. 275:1165-1170.


7. Magee, MS, Walden, CE, Benedetti, TJ, Knopp, RH. Influence of diagnostic criteria on the incidence of gestational diabetes and perinatal morbidity. JAMA. 1993. 269:609-615.


8. Schmidt, MI, et al. Gestational diabetes mellitus diagnosed with a 2-h 75-g oral glucose tolerance test and adverse pregnancy outcomes. Diabetes Care. 2001. 24:1151-1155.


9. Pettitt, DJ, Knowler, WC. Long-term effects of the intrauterine environment, birth weight, and breast-feeding on Pima Indians. Diabetes Care. 1998. 21(Suppl. 2):B138-B141.


10. Silverman, BL, Rizzo, TA, Cho, NH, Metzger, BE. Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care. 1998. 21(Suppl. 2):B142-B149.


11. Vohr, BR, McGarvey, ST, Tucker, R. Effects of maternal gestational diabetes on offspring adiposity at 4-7 years of age. Diabetes Care. 1999. 22:1284-1291.


12. American Diabetes Association. Diagnosis and classification of diabetes mellitus Diabetes Care. 2004. 27(Suppl. 1):S5-S10.


13. King, H. Epidemiology of glucose intolerance and gestational diabetes in women of childbearing age. Diabetes Care. 1998. 21(Suppl. 2):B9-B13.


14. Ben-Haroush, A, Yogev, Y, Hod, M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet. Med. 2004. 21:103-113.


15. Weijers, RN, Bekedam, DJ, Smulders, YM. Determinants of mild gestational hyperglycemia and gestational diabetes mellitus in a large Dutch multiethnic cohort. Diabetes Care. 2002. 25:72-77.


16. Gunton, JE, Hitchman, R, McElduff, A. Effects of ethnicity on glucose tolerance, insulin resistance and beta cell function in 223 women with an abnormal glucose challenge test during pregnancy. Aust. N. Z. J. Obstet. Gynecol. 2001. 41:182-186.

View this article via: CrossRef

17. Xiang, AH, et al. Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes mellitus. Diabetes. 1999. 48:848-854.


18. Catalano, PM, Huston, L, Amini, SB, Kalhan, SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes. Am. J. Obstet. Gynecol. 1999. 180:903-916.


19. Catalano, PM, Tyzbir, ED, Roman, NM, Amini, SB, Sims, EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am. J. Obstet. Gynecol. 1991. 165:1667-1672.


20. Yen, SCC, Tsai, CC, Vela, P. Gestational diabetogenesis: quantitative analysis of glucose-insulin interrelationship between normal pregnancy and pregnancy with gestational diabetes. Am. J. Obstet. Gynecol. 1971. 111:792-800.


21. Buchanan, TA, Metzger, BE, Freinkel, N, Bergman, RN. Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am. J. Obstet. Gynecol. 1990. 162:1008-1014.


22. Homko, C, Sivan, E, Chen, X, Reece, EA, Boden, G. Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J. Clin. Endocrinol. Metab. 2001. 86:568-573.


23. Kautzky-Willer, A, et al. Pronounced insulin resistance and inadequate betacell secretion characterize lean gestational diabetes during and after pregnancy. Diabetes Care. 1997. 20:1717-1723.


24. Catalano, PM, et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am. J. Physiol. 1993. 264:E60-E67.


25. Ryan, EA, et al. Defects in insulin secretion and action in women with a history of gestational diabetes. Diabetes. 1995. 44:506-512.


26. Osei, K, Gaillard, TR, Schuster, DP. History of gestational diabetes leads to distinct metabolic alterations in nondiabetic African-American women with a parental history of type 2 diabetes. Diabetes Care. 1998. 21:1250-1257.


27. Buchanan, TA. Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J. Clin. Endocrinol. Metab. 2001. 86:989-993.


28. Petersen, JS, et al. GAD65 autoantibodies in women with gestational or insulin dependent diabetes mellitus diagnosed during pregnancy. Diabetologia. 1996. 39:1329-1333.


29. Weng, J, et al. Screening for MODY mutations, GAD antibodies, and type 1 diabetes–associated HLA genotypes in women with gestational diabetes mellitus. Diabetes Care. 2002. 25:68-71.


30. Mauricio, D, et al. Islet cell antibodies identify a subset of gestational diabetic women with higher risk of developing diabetes shortly after pregnancy. Diabetes Nutr. Metab. 1992. 5:237-241.

31. Catalano, PM, Tyzbir, ED, Sims, EAH. Incidence and significance of islet cell antibodies in women with previous gestational diabetes. Diabetes Care. 1990. 13:478-482.


32. Fajans, SS, Bell, GI, Polonsky, KS. Molecular mechanisms and clinical patho-physiology of maturity-onset diabetes of the young. N. Engl. J. Med. 2001. 345:971-980.


33. Kousta, E, et al. Glucokinase mutations in a phenotypically selected multiethnic group of women with a history of gestational diabetes. Diabet. Med. 2001. 18:683-684.


34. Ellard, S, et al. A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia. 2000. 43:250-253.


35. Saker, PJ, et al. High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population. Diabetologia. 1996. 39:1325-1328.


36. Chen, Y, Liao, WX, Roy, AC, Loganath, A, Ng, SC. Mitochondrial gene mutations in gestational diabetes mellitus. Diabetes Res. Clin. Pract. 2000. 48:29-35.


37. Ward, WK, et al. Insulin resistance and impaired insulin secretion in subjects with a history of gestational diabetes mellitus. Diabetes. 1985. 34:861-869.


38. Ward, WK, Johnston, CLW, Beard, JC, Benedetti, TJ, Porte (Jr), D. Abnormalities of islet B cell function, insulin action and fat distribution in women with a history of gestational diabetes: relation to obesity. J. Clin. Endocrinol. Metab. 1985. 61:1039-1045.


39. Catalano, PM, et al. Subclinical abnormalities of glucose metabolism in subjects with previous gestational diabetes. Am. J. Obstet. Gynecol. 1986. 155:1255-1263.


40. Damm, P, Vestergaard, H, Kuhl, C, Pedersen, O. Impaired insulin-stimulated nonoxidative glucose metabolism in glucose-tolerant women with previous gestational diabetes. Am. J. Obstet. Gynecol. 1996. 174:722-729.


41. Kautzky-Willer, A, et al. Increased plasma leptin in gestational diabetes. Diabetologia. 2001. 44:164-172.


42. Winkler, G, et al. Tumor necrosis factor system and insulin resistance in gestational diabetes. Diabetes Res. Clin. Pract. 2002. 56:93-99.


43. Retnakaran, R, et al. C-reactive protein and gestational diabetes: the central role of maternal obesity. J. Clin. Endocrinol. Metab. 2003. 88:3507-3512.


44. Retnakaran, R, et al. Reduced adiponectin concentration in women with gestational diabetes: a potential factor in progression to type 2 diabetes. Diabetes Care. 2004. 27:799-800.


45. Williams, MA, et al. Plasma adiponectin concentrations in early pregnancy and subsequent risk of gestational diabetes mellitus. J. Clin. Endocrinol. Metab. 2004. 89:2306-2311.


46. Tiikkainen, M, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes. Res. 2002. 10:859-867.


47. Kautzky-Willer, A, et al. Increased intramyocellular lipid concentration identifies impaired glucose metabolism in women with previous gestational diabetes. Diabetes. 2003. 52:244-251.


48. Damm, P, et al. Insulin receptor binding and tyrosine kinase activity in skeletal muscle from normal pregnant women and women with gestational diabetes. Obstet. Gynecol. 1993. 82:251-259.


49. Catalano, PM, et al. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am. J. Physiol. 2002. 282:E522-E533.

50. Shao, J, Yamashita, H, Qiao, L, Draznin, B, Friedman, JE. Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. Diabetes. 2002. 51:19-29.


51. Shao, J, et al. Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 over expression in skeletal muscle from obese women with gestational diabetes (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. Diabetes. 2000. 49:603-610.


52. Friedman, JE, et al. Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes. 1999. 48:1807-1814.


53. Garvey, WT, et al. Multiple defects in the adipocyte glucose transport system cause cellular insulin resistance in gestational diabetes. Diabetes. 1993. 42:1773-1785.


54. Zaidi, FK, et al. Homozygosity for a common polymorphism in the islet-specific promoter of the glucokinase gene is associated with a reduced early insulin response to oral glucose in pregnant women. Diabet. Med. 1997. 14:228-234.


55. Leipold, H, et al. Calpain-10 haplotype combination and association with gestational diabetes mellitus. Obstet. Gynecol. 2004. 103:1235-1240.


56. Rissanen, J, et al. Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin. Diabetes Care. 2000. 23:70-73.


57. Kim, C, Newton, KM, Knopp, RH. Gestational diabetes and the incidence of type 2 diabetes. Diabetes Care. 2002. 25:1862-1868.


58. Kjos, SL, et al. Gestational diabetes mellitus: the prevalence of glucose intolerance and diabetes mellitus in the first two months postpartum. Am. J. Obstet. Gynecol. 1990. 163:93-98.


59. Peters, RK, Kjos, SL, Xiang, A, Buchanan, TA. Long-term diabetogenic effect of a single pregnancy in women with prior gestational diabetes mellitus. Lancet. 1996. 347:227-230.


60. Buchanan, TA, et al. Changes in insulin secretion and sensitivity during the development of type 2 diabetes after gestational diabetes in Hispanic women. Diabetes. 2003. 52(Suppl. 1):A34.

61. Buchanan, TA, et al. Response of pancreatic B-cells to improved insulin sensitivity in women at high risk for type 2 diabetes. Diabetes. 2000. 49:782-788.


62. Buchanan, TA, et al. Preservation of pancreatic B-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002. 51:2769-2803.

63. Langer, O, Conway, DL, Berkus, MD, Xenakis, EM, Gonzales, O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N. Engl. J. Med. 2000. 343:1134-1138.


64. Hellmuth, E, Damm, P, Molsted-Pedersen, L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Acta. Obstet. Gynecol. Scand. 2000. 79:958-962.


65. Glueck, CJ, Goldenberg, N, Streicher, P, Wang, P. Metformin and gestational diabetes. Curr. Diab. Rep. 2003. 3:303-312.


66. Kjos, SL, et al. A randomized controlled trial utilizing glycemic plus fetal ultrasound parameters vs glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia. Diabetes Care. 2001. 24:1904-1910.


67. Buchanan, TA, et al. Use of fetal ultrasound to select metabolic therapy for pregnancies complicated by mild gestational diabetes. Diabetes Care. 1994. 17:275-283.


68. Kjos, SL, Peters, RK, Xiang, A, Schaefer, U, Buchanan, TA. Hormonal choices after gestational diabetes: subsequent pregnancy, contraception and hormone replacement. Diabetes Care. 1998. 21(Suppl. 2):B50-B57.


69. Towner, D, et al. Congenital malformations in pregnancies complicated by non-insulin-dependent diabetes mellitus: increased risk from poor maternal metabolic control but not from exposure to sulfonylurea drugs. Diabetes Care. 1995. 18:1446-1451.


70. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N. Engl. J. Med. 2002. 346:393-403.


71. Xiang, AH, et al. Pharmacological treatment of insulin resistance at two different stages in the evolution of type 2 diabetes: impact on glucose tolerance and β-cell function. J. Clin. Endocrinol. Metab. 2004. 89:2846-2851.


72. Kjos, SL, Buchanan, TA. Gestational diabetes mellitus. N. Engl. J. Med. 1999. 341:1749-1756.


estational diabetes mellitus

Thomas A. Buchanan 1 dan Anny H. Xiang 2

1Departments Kedokteran, Obstetri dan Ginekologi, dan Fisiologi dan Biofisika, dan2Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, Amerika Serikat.

Alamat korespondensi untuk: Thomas A. Buchanan, Ruang 6602 GNH, 1200 Utara State Street, Los Angeles, California 90089-9317, USA. Telepon: (323) 226-4632, Fax: (323) 226-2796, E-mail: [email protected].

Diterbitkan Maret 1, 2005

Diabetes mellitus gestasional (GDM) didefinisikan sebagai intoleransi glukosa dari berbagai derajat yang pertama kali terdeteksi selama kehamilan. GDM terdeteksi melalui skrining ibu hamil untuk faktor risiko klinis dan, di antara perempuan berisiko, pengujian untuk toleransi glukosa abnormal yang biasanya, tetapi tidak selalu, ringan dan tanpa gejala. GDM muncul hasil dari spektrum yang luas yang sama kelainan fisiologis dan genetik yang menjadi ciri diabetes di luar kehamilan. Memang, wanita dengan GDM memiliki risiko tinggi untuk memiliki atau terkena diabetes ketika mereka tidak hamil. Jadi, GDM memberikan kesempatan unik untuk mempelajari patogenesis awal diabetes dan untuk mengembangkan intervensi untuk mencegah penyakit.Perspektif sejarah

Selama lebih dari satu abad, telah diketahui bahwa diabetes kehamilan antedating dapat memiliki efek samping yang parah pada hasil janin dan neonatal (1). Pada awal tahun 1940-an, hal itu diakui bahwa perempuan yang mengalami diabetes setelah kehamilan tahun telah mengalami kematian janin normal dan neonatal yang tinggi (2). Pada tahun 1950-an "gestational diabetes" Istilah diterapkan untuk apa yang dianggap suatu kondisi yang mempengaruhi hasil sementara janin buruk, kemudian mereda setelah melahirkan (3). Pada tahun 1960, O'Sullivan menemukan bahwa tingkat intoleransi glukosa selama kehamilan terkait dengan risiko pengembangan diabetes setelah kehamilan. Ia mengusulkan kriteria untuk interpretasi tes toleransi glukosa oral (OGTTs) selama kehamilan yang fundamental statistik, membangun cut-off nilai - sekitar 2 deviasi standar - untuk mendiagnosis intoleransi glukosa selama kehamilan (4). Pada 1980-an mereka cut-off poin disesuaikan dengan metode modern untuk mengukur glukosa dan diterapkan dengan definisi modern gestational diabetes - intoleransi glukosa dengan onset atau pengakuan pertama selama kehamilan (5). Sementara berdasarkan nilai O'Sullivan untuk memprediksi diabetes setelah kehamilan, diagnosis diabetes mellitus gestasional (GDM) juga mengidentifikasi kehamilan pada peningkatan risiko untuk morbiditas perinatal (6-8) dan jangka panjang obesitas dan intoleransi glukosa pada keturunannya (9-11 ).Populasi perspektif

Deteksi klinis GDM dilakukan untuk mengidentifikasi kehamilan meningkatkan risiko untuk morbiditas

dan mortalitas perinatal. Data yang tersedia tidak mengidentifikasi ambang batas glikemia ibu di mana risiko tersebut dimulai atau meningkat pesat. Sebuah studi multinasional, Hiperglikemia dan studi Kehamilan Hasil samping, sedang berlangsung untuk mengeksplorasi masalah ini dalam sebuah kohort multietnis besar. Dengan tidak adanya glukosa ambang batas yang ditetapkan untuk risiko perinatal, set berbagai kriteria glikemik telah diusulkan dan digunakan di seluruh dunia untuk diagnosis GDM. Kriteria saat ini direkomendasikan oleh American Diabetes Association (12) didasarkan pada kriteria O'Sullivan (lihat di atas). Deteksi GDM, suatu kondisi yang umumnya asimtomatik, melibatkan skrining dalam 2 langkah berurutan (Tabel 1 dan 2), diikuti dengan pemberian 2 - atau 3-jam OGTT (Tabel 3) untuk perempuan bertekad untuk berada di risiko dengan skrining . Wanita dengan karakteristik yang sangat tinggi risiko klinis dapat didiagnosis dengan diabetes kemungkinan pregestational (sudah ada sebelumnya) berdasarkan kriteria yang diberikan dalam Tabel 4. Ketika kriteria diagnostik untuk OGTT 3-jam disajikan dalam Tabel 3 diterapkan kepada sekelompok wanita Kaukasia di Toronto, sekitar 7% memiliki GDM (6). Frekuensi GDM dapat bervariasi antara kelompok etnis (lebih tinggi dalam kelompok dengan peningkatan prevalensi hiperglikemia) (13-16) dan dengan menggunakan kriteria diagnostik yang berbeda (lebih tinggi ketika ambang glukosa lebih rendah diterapkan dan sebaliknya) (4). Meskipun demikian, semua pendekatan untuk deteksi GDM menentukan - dan dengan demikian memungkinkan diagnosis - wanita dengan toleransi glukosa pada ujung atas dari distribusi penduduk selama kehamilan. Sebuah minoritas kecil dari para wanita memiliki kadar glukosa yang akan diagnostik diabetes luar kehamilan (Tabel 4). Sebagian besar memiliki kadar glukosa lebih rendah. Kedua kelompok memberikan kepada keturunannya peningkatan risiko morbiditas perinatal dan jangka panjang obesitas dan diabetes yang tampaknya terkait setidaknya sebagian kelebihan gizi janin di dalam rahim. Mereka juga dikenakan untuk diri mereka sendiri dengan risiko diabetes setelah kehamilan yang merupakan fokus utama dari makalah ini.

Anaesthetic management of patients with diabetes mellitus

1. G. R. McAnulty 1 , 2. H. J. Robertshaw 2 and 3. G. M. Hall 1 ,*

+ Author Affiliations

1. 1Department of Anaesthesia and Intensive Care Medicine, St George’s Hospital Medical School, London SW17 0RE, UK. 2Department of Anaesthesia, Imperial College of

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Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK

Key words

Keywords : complications, diabetes; blood, glucose; hormones, insulin; metabolism, hypoglycaemia

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Br J Anaesth 2000; 85: 80–90

The prevalence of diabetes mellitus in both adults and children has been steadily rising throughout the world for the past 20–30 yr.29 55 97 Recent changes in diagnostic criteria, if widely adopted, will probably also lead to more patients being classified as having diabetes.16 Inevitably, diabetic patients presenting for incidental surgery, or surgery related to their disease, will place an increasing burden on anaesthetic services. Conflict will occur between an economic need to minimize hospital stay and traditional approaches to managing perioperative diabetic patients that rely on a period of inpatient preoperative ‘stabilization’.

Better glycaemic control in diabetic patients undergoing major surgery has been shown to improve perioperative mortality and morbidity.44 90 Simple avoidance of hypoglycaemia and gross hyperglycaemia are no longer adequate in the light of this knowledge. While there can be little argument about the management of diabetic patients undergoing major procedures, their management for minor surgery is an increasing dilemma. Under what circumstances are day‐case anaesthesia and surgery appropriate? Does admission on the day of surgery add to the risk for the diabetic patient? What investigations, if any, are needed to assess the cardiovascular system of an asymptomatic diabetic who presents for major surgery? Unfortunately, there are few data to provide answers to these questions. An understanding of the pathophysiology of diabetes and of the importance of recent research should improve the perioperative care of diabetic surgical patients. This review will discuss some recent developments in the field. It will not provide ‘recipes’ or algorithms for management. These can be found in any of the standard texts.

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Revised diagnostic criteria for diabetes mellitus

Recently, both the American Diabetes Association (ADA) and the World Health Organization (WHO) published recommendations for new diagnostic criteria for diabetes mellitus.1 106 Both bodies advise a reduction in the threshold limit for fasting plasma glucose concentrations and reaffirm a more aetiologically based nomenclature. The terms type 1 (pancreatic B‐cell destruction) and type 2 (defective insulin secretion and, usually, insulin resistance) diabetes are recommended to replace completely the frequently misleading terms ‘insulin‐dependent’ and ‘non‐insulin‐dependent’ diabetes. The ADA has specified that the diagnosis of diabetes mellitus should be made if a ‘casual’ (random) plasma glucose value in an asymptomatic individual is

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>11.1 mmol litre–1. If a fasting plasma glucose is >7.0 mmol litre–1 (6.1 mmol litre–1 blood glucose) in an asymptomatic individual, the test should be repeated on a different day and a diagnosis made if the value remains above this limit. The ADA defines fasting plasma glucose concentrations between 6.1 and 7.0 mmol litre–1 (5.6–6.1 mmol litre–1 blood glucose) as representing ‘impaired fasting glycaemia’. The WHO also recommends that a diagnosis of diabetes mellitus be made if a random plasma glucose concentration is >11.1 mmol litre–1 (venous whole blood >10.0 mmol litre–1). It can also be diagnosed with a fasting plasma glucose concentration of >7.0 mmol litre–1 and a second similar test or an oral glucose tolerance test producing a result in the diabetic range.

The change in the fasting plasma glucose concentrations used to define diabetes and the role of a standard oral glucose tolerance test may make it difficult to compare epidemiological studies using these new criteria with those using previous ones. Inevitably, some individuals will be diagnosed as having diabetes using criteria based solely on (lower) fasting plasma glucose concentrations who would not have been so diagnosed under the earlier definitions. There will be others who would have fulfilled the definition using an oral glucose tolerance test but who will have acceptable fasting values. Thus it is likely that the new definitions will define as diabetic a group of glucose intolerant individuals.52

In addition to the two common types of diabetes, a number of causes of glucose intolerance can be defined according to a specific causal or pathological process. Gestational diabetes is glucose intolerance which has its onset in, or is first diagnosed during, pregnancy. The severity varies and the definition applies whether or not insulin is administered in treatment. Women with diabetes diagnosed before pregnancy are defined as having ‘diabetes mellitus and pregnancy’, not gestational diabetes.1 The neonatal outcome of type 1 diabetic women who become pregnant is poor. Their infants are approximately five times more likely to be stillborn and 10 times more likely to have congenital malformations than those born to non‐diabetic mothers.10 Management in a specialist centre may improve the incidence of perinatal mortality.34 Abnormally increased membrane transport of glucose, even in mothers whose diabetes is well controlled, may explain the continuing high rates of congenital malformations (particularly macrosomia) despite improved treatment.48 Increasing the frequency of insulin administration from two to four times daily during pregnancy can lead to better maternal glycaemic control with a lower incidence of neonatal hypoglycaemia and hyperbilirubinaemia without increasing the risk of maternal hypoglycaemia.73

There is a number of rare genetic causes of glucose intolerance. Among these are defects of B‐cell function (formerly called maturity‐onset diabetes of the young, or MODY) and defects in insulin action (formerly called type A insulin resistance). Diffuse diseases of the exocrine pancreas (such as pancreatitis), specific viral infections which destroy pancreatic B cells (rubella, Coxsackie B, cytomegalovirus, mumps and others) and immune‐mediated processes (insulin autoantibodies or insulin receptor antibodies) can also lead to a ‘diabetic state’.1 Endocrinopathies associated with excess secretion of counter‐regulatory hormones (such as growth hormone, cortisol, glucagon and epinephrine) can lead to hyperglycaemia.

A number of drugs can induce glucose intolerance either by inhibiting the secretion of insulin or by interfering with the peripheral action of insulin.1 In anaesthesia, glucocorticoids and









adrenergic agonists are most frequently implicated. The new oral corticosteroid, deflazacort, may be less ‘diabetogenic’ than prednisolone or betamethasone.2

‘Metabolic syndrome’ (also called syndrome X or insulin resistance syndrome) is a non‐causally linked cluster of symptoms which carry a high risk of macrovascular disease. The cluster includes impaired glucose tolerance or diabetes, insulin resistance, raised arterial pressure, raised plasma triglycerides, central obesity and microalbuminuria.1


Pathophysiology

Type 1 diabetics completely lack insulin secretion, making them prone to lipolysis, proteolysis and ketogenesis. These processes are inhibited by minimal levels of insulin secretion and are rare in type 2 diabetics unless there is an additional stress such as sepsis or dehydration.122 Obviously, both groups are subject to the effects of hyperglycaemia.

Diabetics are at increased risk of myocardial ischaemia, cerebrovascular infarction and renal ischaemia because of their increased incidence of coronary artery disease,94 arterial atheroma51 and renal parenchymal disease.14 Increased mortality is found in all diabetics undergoing surgery44 90 and type 1 diabetics are particularly at risk of post‐operative complications.111 Increased wound complications are associated with diabetes24 64 72 126 and anastomotic healing is severely impaired when glycaemic control is poor.118

The ‘stress response’ to surgery is associated with hyperglycaemia in non‐diabetic patients as a result of increased secretion of catabolic hormones in the presence of a relative insulin deficiency. This deficiency arises from a combination of reduced insulin secretion41 and insulin resistance.109 Insulin resistance may result, in part, from the increase in secretion of catecholamines, cortisol and growth hormone42 and involves an alteration of post‐receptor binding of insulin and subsequent reduction of trans‐membrane glucose transport.79 Some, at least, of the metabolic effects of the suppression of insulin secretion are reversed by intraoperative insulin infusion37 and both oral and i.v. perioperative administration of glucose enhance postoperative glucose utilization rates.56 62 80

Adverse effects of hyperglycaemia

The consequences of a reduction in, or complete lack of, insulin‐mediated metabolic processes can be classified according to chronicity and to histopathological effects.

Acute consequences of untreated, or inadequately treated, diabetes mellitus include dehydration (resulting from the osmotic diuretic effect of glycosuria), acidaemia (because of accumulation of lactic and/or ketoacids), fatigue, weight loss and muscle wasting (because of lipolysis and proteolysis in absolute insulin deficiency). Ketoacidosis is rare in type 2 diabetics but is frequently a presenting symptom of type 1 disease. It is a medical emergency that still carries a considerable mortality rate of up to 15%.4 49 The mortality of hyperosmolar non‐ketotic



























hyperglycaemic coma in type 2 diabetics may be even greater,63 probably reflecting a more elderly population with a higher incidence of co‐existing disease.

Ketoacidosis is treated by rehydration and insulin infusion with frequent measurements of serum electrolytes and acid–base status. Sequential estimations of blood β‐hydroxybutyrate concentrations and concomitant continuation of intensive insulin therapy may expedite treatment.124 Non‐ketotic hyperglycaemic coma is frequently precipitated by infection and is commonly associated with multi‐organ system dysfunction. Blood glucose concentrations may be extremely high.33

Chronic effects of diabetes can be divided into microvascular (including proliferative retinopathy and diabetic nephropathy), neuropathic (autonomic and peripheral neuropathies) and macrovascular complications (atherosclerotic disease). The incidence of microvascular and neuropathic complications in types 1 and 2 diabetics is similar when adjusted for duration of disease and quality of glycaemic control. The cumulative lifetime incidence of proliferative retinopathy, proteinuria and distal neuropathy is roughly 50% for both type 1 and type 2 diabetics. This implies that the primary cause of these complications is hyperglycaemia itself, as the underlying metabolic pathology is different for type 1 and type 2 disease.31 Macrovascular complications (as measured by rates of coronary artery, cerebrovascular and peripheral vascular disease) are also similar for type 1 and 2 diabetics (cardiovascular mortality is 30–54% for type 1 and 38–41% for type 2 diabetes).31 In type 2 patients, at least, abnormally high concentrations of plasminogen activator inhibitor‐1 (PAI‐1) and, therefore, impaired fibrinolysis, have been implicated in the accelerated rates of development of atherosclerotic disease.83

Improved glycaemic control has a beneficial effect on microvascular and neuropathic complications in type 2 diabetes.114 Although there is probably no adverse effect,83 improvement in glycaemic control alone appears not to improve the incidence of macrovascular disease in these patients.114 However, tight control of blood pressure (with an angiotensin‐converting enzyme inhibitor or a β‐blocker) in patients with type 2 diabetes and hypertension reduces the risk of diabetes‐related death, including that secondary to macrovascular complications, as well as the risk of other diabetes‐related complications and eye disease.115 116


Diabetic therapy

The problems of insulin replacement

Insulin is secreted into the bloodstream from pancreatic B cells via the portal system so that there is normally a portal–peripheral insulin concentration gradient which cannot be mimicked by subcutaneous or i.v. insulin administration. Additionally, even the most sophisticated artificial insulin delivery systems cannot hope to replicate the complex local interaction between the B cells and A, D and PP cells of the islets of Langerhans (which secrete glucagon, somatostatin and pancreatic polypeptide, respectively) and the effects of the extrapancreatic neurohormonal system. Insulin secretion in response to varying states of feeding or starvation changes by 20‐ to 50‐fold and maintains a basal insulin secretion during the fasting state. Insulin administered














subcutaneously, even if timed optimally, will inevitably have inadequate peak concentrations for expected postprandial periods, and its duration of action may be frequently too short to avoid periods of hypoinsulinaemia and subsequent risk of lipolysis and proteolysis in patients with no endogenous insulin secretion.

Insulin is synthesized in the pancreas as part of a longer‐chain protein called proinsulin. This is cleaved by membrane‐bound proteases producing the polypeptides insulin and C‐peptide. These two polypeptides are secreted into the circulation in equimolar amounts. C‐peptide is useful experimentally in determining native insulin production in type 2 diabetic subjects receiving insulin. It was once thought that C‐peptide had no physiological role other than facilitating the folding of the proinsulin molecule. However, more recent studies point to a possible role for C‐peptide in glucose transport in skeletal muscle, renal tubular function and in the prevention of autonomic neuropathy.119

Hypoglycaemic therapy

Type 1 diabetics require insulin. Type 2 diabetics may require insulin but, in many cases, maintain reasonable glycaemic control with an appropriate diet and often the use of oral hypoglycaemic drugs.

Therapeutic insulin may be extracted from beef (now rarely used) or pork pancreas, or synthesized using recombinant DNA technology from Escherichia coli.6 The amino acid sequences of insulin differ somewhat between species; however, modifying porcine insulin can produce human‐sequence insulin. It was hoped that the replacement of animal‐ by human‐sequence insulins would reduce the induction of antibodies and therefore insulin resistance, but clinical trials have been disappointing.66

The three types of insulin preparation are classified according to their length of action. Soluble insulins have a rapid onset and short duration of action (depending upon the route of administration). When injected subcutaneously the duration of action is from 30 min up to 8 h with a peak at 2–4 h. Human‐sequence soluble insulin has a slightly shorter onset time and duration of action. Insulin lispro, a recently introduced recombinant human insulin analogue, has an even shorter duration of action. Soluble insulin injected i.v. has a half‐life of approximately 5 min.6

Longer‐acting insulin preparations are made with suspensions of insulin with either protamine (‘isophane insulin’) or zinc (‘crystalline insulin’) salts or both together. They are often administered in combination with soluble insulin to obtain rapid onset together with a long duration of action.6 They are not suitable for i.v. use. Long‐acting insulins may act for up to 36 h for animal‐91 and 24 h for human‐sequence preparations.47

There are four groups of oral hypoglycaemic agents: the sulphonylureas, the biguanides, the (recently developed) thiazolidinediones and modifiers of glucose absorption from the gut. In the main, sulphonylureas enhance the secretion of insulin in response to glucose and increase sensitivity to its peripheral actions. Biguanides (metformin is the only compound in this group available in the UK) promote glucose utilization and reduce hepatic glucose production.








Thiazolidinediones, which are still under clinical evaluation (and currently under a cloud because of reported hepatotoxicity), enhance insulin action in the periphery and inhibit hepatic gluconeogenesis, perhaps via a specific receptor mechanism. The α‐glucosidase inhibitor, acarbose, suppresses the breakdown of complex carbohydrates in the gut and therefore delays the rise in postprandial blood glucose concentrations.100

Intensive, effective glycaemic control of type 2 diabetes results in a reduction of microvascular, but probably not macrovascular, complications of the disease.31 114 Where adequate control can be achieved (haemoglobin A1c concentration 7–8%31) there is no clear advantage for any therapeutic agent; oral hypoglycaemics and insulin have similar effects.76 Metformin may be a better choice in obese type 2 diabetics. It was associated with a lower incidence of mortality and diabetes‐related morbidity when used as a first‐line treatment compared with either sulphonylureas or insulin in the recently‐reported UK Prospective Diabetes Study (UKPDS).113 However, addition of metformin to patients receiving sulphonylureas in the UKPDS was associated with a worrying increase in mortality. Despite concerns about rare but potentially lethal lactic acidosis, which may be more likely in the elderly,100 in association with renal failure25 and hepatic failure and after surgery,71 metformin is well tolerated and less likely to cause hypoglycaemia than sulphonylureas or insulin.28 113

Interest in the potassium channel‐blocking effect of sulphonylureas and, hence, interference with myocardial ischaemic preconditioning, has increased recently.5 Glimepiride may not block potassium channels,58 but angioplasty patients receiving sulphonylureas have greater mortality and morbidity than those given insulin.30 The general implications of this observation are not clear but, until data from well‐conducted studies are available, it would seem prudent to convert patients taking sulphonylureas to insulin several days before cardiac or other major surgery or procedures where myocardial perfusion may be compromised.

Perioperative therapy

Type 2 diabetics not receiving insulin and undergoing minor surgery usually can be managed satisfactorily without insulin.108 However, diabetic patients scheduled for major surgery, who are receiving hypoglycaemic medication or who have poor glycaemic control, should be established on insulin therapy preoperatively. Continuous i.v. infusion of insulin is a better option than intermittent s.c. bolus regimens11 and, at least in perioperative cardiac surgical patients, may be associated with improved outcome.27 Although intermittent i.v. bolus regimens are still used,87 this approach is difficult to recommend.38 45

Adsorption of insulin on to the surface of syringes, i.v. fluid bags and i.v. giving sets is an unavoidable problem. In solutions with a concentration of insulin of >400 ng ml–1 (∼10 U litre–1) the effect is minimal.8 However, significant amounts of insulin may be adsorbed on to giving sets, particularly if they have a relatively high surface area, thereby reducing initial rates of insulin delivery if a high‐volume, low‐insulin concentration regimen is used.69 More consistent delivery can be achieved with more concentrated solutions of lower volume administered from a syringe.92
























When normal oral nutrition is not possible, parenteral administration of carbohydrate is required to safeguard against inadvertent hypoglycaemia and excessive catabolism. Safety is always a concern when insulin infusions are administered. Glucose–insulin–potassium (GIK) systems, such as the Alberti regimen, are inherently safe because they provide insulin and glucose in the same solution.107 With separate glucose and insulin infusions one may be stopped inadvertently with potentially disastrous consequences. However, separate infusions were preferred by nursing staff and resulted in marginally improved perioperative glycaemic control when compared with a GIK system in one randomized controlled trial of 58 surgical patients.101 Fifty per cent glucose solutions containing 0.25 or 0.5 U insulin ml–1 can provide amounts of glucose and insulin equivalent to the more conventional systems using 10% glucose and avoid the administration of large volumes of free water.68 However, the hypertonic 50% solution needs to be infused into a central vein.


The metabolic challenge of surgery for the diabetic patient

The immediate perioperative problems facing the diabetic patient are: (i) surgical induction of the stress response with catabolic hormone secretion; (ii) interruption of food intake, which may be prolonged following gastrointestinal procedures; (iii) altered consciousness, which masks the symptoms of hypoglycaemia and necessitates frequent blood glucose estimations; and (iv) circulatory disturbances associated with anaesthesia and surgery, which may alter the absorption of subcutaneous insulin.

Surgery evokes the ‘stress response’, that is, the secretion of catecholamines, cortisol, growth hormone and, in some cases, glucagon. These hormones oppose glucose homeostasis, as they have ‘anti‐insulin’ and hyperglycaemic effects. Gluconeogenesis is stimulated and peripheral glucose uptake decreased. Although diabetics need increased insulin during the perioperative period, requirements for glucose and insulin in this period are unpredictable and close monitoring is essential, especially in the unconscious or sedated patient.

Diabetic patients established on longer‐acting insulin are at risk of hypoglycaemia if regular food intake is interrupted, and of lipolysis and proteolysis if insulin therapy is delayed. Postoperative wound healing and infection may be influenced by the adequacy of perioperative glycaemic control.72 118


Options for the perioperative management of diabetes

The main concern for the anaesthetist in the perioperative management of diabetic patients has been the avoidance of harmful hypoglycaemia; mild hyperglycaemia has tended to be seen as acceptable. This has been attributed to the difficulties of measuring blood glucose when the reduced level of consciousness perioperatively masks signs and symptoms of hypoglycaemia. However, in the past decade the availability of more accurate and easy‐to‐use glucose monitors,










with evidence that good glycaemic control improves short‐term outcome, makes the practice of ‘permissive hyperglycaemia’ unacceptable.

One survey of anaesthetic practice in the Oxford region of the UK suggests that anaesthetists are likely to manage hyperglycaemia in perioperative diabetic patients more aggressively now than they did in 1985.22 However, of the 172 respondents in this survey, 22% still preferred to maintain blood glucose at >10 mmol litre–1 in diabetic patients and 2% preferred a value of >13 mmol litre–1. The vast majority of respondents maintained glycaemic control for type 1 diabetic patients undergoing major surgery with glucose and insulin infusions, either separately or combined. Nearly 90% of respondents did not consider it necessary, in type 2 diabetics undergoing minor surgery, for there to be any greater intervention than omitting the usual hypoglycaemic therapy and avoidance of glucose‐containing i.v. solutions. Surprisingly, 17% of senior anaesthetists had the same approach to type 2 diabetics undergoing major surgery. Cost and inconvenience may influence decisions about the intensity of blood glucose management and, until recently, there has been little evidence to support strategies aimed at tightening glycaemic control.35 Between the two extremes of a diet‐controlled stable type 2 diabetic presenting for minor surgery and the ‘brittle’ type 1 patient undergoing major abdominal surgery, about whom there is little argument, there remains considerable disagreement about the ideal regimen for managing blood glucose.


Monitoring techniques

The advent of semi‐automated devices has improved the accuracy of measurement of blood and capillary glucose concentrations in both the community and hospital.7 For these machines to be effective they must be calibrated regularly and people using them must be trained.

Recent work has suggested that measurement of circulating β‐hydroxybutyrate concentrations may be helpful in treating acutely unstable diabetes70 124 and the development of a bedside device will enable the usefulness of sequential estimations of ketonaemia to be assessed.70

Glycosylated haemoglobin (HbAc1) measurement has no value in the perioperative period but is a valuable guide to long‐term glycaemic control.31 If HbAc1 values have been consistently >8% it is probable that microvascular complications of diabetes are present.


Anaesthetic technique and the diabetic patient

Anaesthetic techniques, particularly the use of spinal, epidural, splanchnic or other regional blockade, may modulate the secretion of the catabolic hormones and any residual insulin secretion. The perioperative increase in circulating glucose, epinephrine and cortisol concentrations found in non‐diabetic patients exposed to surgical stress under general anaesthesia is blocked by epidural anaesthesia.39 125 The perioperative infusion of phentolamine, a competitive α‐adrenergic receptor blocking drug, decreases the glycaemic response to surgery by














partially reversing the suppression of insulin secretion.75 Interestingly, a small study of non‐diabetic patients showed preservation of the insulin response to a bolus of glucose after the use of low, but not high, spinal anaesthesia.40 This implies that basal islet cell secretion is maintained by β‐adrenergic stimulation. Whether extensive spinal blockade is detrimental in type 2 diabetics is not known. Cataract surgery in type 2 patients using local analgesia, when compared with general anaesthesia, was associated with much less disruption of glucose metabolism: blood glucose, lactate, β‐hydroxybutyrate, serum cortisol, insulin and plasma non‐esterified fatty acid concentrations were measured perioperatively.3

Diabetic patients undergoing surgery with neural blockade will usually resume oral intake earlier than after general anaesthesia. It is now common practice in cataract surgery to allow normal oral intake and hypoglycaemic therapy throughout the perioperative period. In a series of 12 000 cataract extractions under local anaesthesia, in which patients were not starved, eight patients showed evidence of brain stem anaesthesia, and one developed cerebral spread of local anaesthetic solution. In only one patient was surgery postponed because of persistent nausea.43 However, the possibility of having to convert a regional technique to general anaesthesia may militate against this practice in other forms of surgery. At present, there is no evidence that regional anaesthesia alone, or in combination with general anaesthesia, confers any benefit in the diabetic surgical patient, in terms of mortality and major complications.

Regional anaesthesia may carry greater risks in the diabetic patient with autonomic neuropathy. Profound hypotension may occur with deleterious consequences in a patient with co‐existing coronary artery, cerebrovascular or renovascular disease. The risks of infection and vascular damage may be increased with the use of regional techniques in diabetic patients; epidural abscesses occur more commonly following spinal and epidural anaesthesia.54 77 Conversely, a diabetic peripheral neuropathy presenting after epidural anaesthesia may be confused with an anaesthetic complication of regional blockade.50


Anaesthetic agents and diabetes

Induction agents may affect glucose homeostasis perioperatively. Etomidate blocks adrenal steroidogenesis and hence cortisol synthesis, by its action on 11β‐hydroxylase and cholesterol cleavage enzymes, and consequently decreases the hyperglycaemic response to surgery by approximately 1 mmol litre–1 in non‐diabetic subjects.26 The effects on diabetic patients have not been established.

Benzodiazepines decrease the secretion of ACTH, and so the production of cortisol, when used in high doses during surgery.18 They reduce sympathetic stimulation but, paradoxically, stimulate growth hormone secretion and result in a decrease in the glycaemic response to surgery. These effects are minimal when midazolam is given in usual sedative doses, but may be relevant if the drug is given by continuous i.v. infusion to patients in intensive care.

High‐dose opiate anaesthetic techniques produce not only haemodynamic, but also hormonal and metabolic stability. These techniques effectively block the entire sympathetic nervous system












and the hypothalamic–pituitary axis, probably by a direct effect on the hypothalamus and higher centres.36 Abolition of the catabolic hormonal response to surgery will, therefore, abolish the hyperglycaemia seen in normal patients and may be of benefit in the diabetic patient.59

Halothane, enflurane and isoflurane, in vitro, inhibit the insulin response to glucose in a reversible and dose‐dependent manner.19 32 The effect of propofol on insulin secretion is not known. Diabetic patients show a reduced ability to clear lipids from the circulation.123 Although this is unlikely to be relevant during short anaesthetics when propofol is used for maintenance or as an induction agent only, it may have implications for patients receiving propofol for prolonged sedation in the intensive care unit.


Complications of diabetes

Microvascular, neuropathic and macrovascular complications of diabetes mellitus are of special concern for the anaesthetist. Of particular importance are coronary heart disease, diabetic nephropathy and autonomic neuropathy because these may have a direct effect on the development of perioperative complications. In addition, young patients with long‐standing type 1 diabetes and poor glycaemic control were found to have significantly decreased lung volume, lung diffusing capacity and cardiac stroke index during exercise when compared with patients treated with intensive insulin therapy.78

Because of glycosylation of collagen in the cervical joints, part of a generalized phenomenon called ‘stiff joint syndrome’,98 diabetic patients are more likely to present with difficult laryngoscopy and intubation. Stiffness of the fourth and fifth interphalangeal joints is a common feature and the resulting alteration in palm print may be a good predictor of difficult intubation.74

However, in one retrospective review of the anaesthetic records of 725 patients who underwent renal and/or pancreatic transplantation (of whom 209 were diabetic), none were reported as having ‘moderate to extreme difficulty’ of laryngoscopy. A total of 4.8% of the diabetics presented ‘minimal to moderate’ difficulty for intubation compared with 1.0% of the non‐diabetics. All were intubated successfully although one was intubated electively with the aid of a fibre‐optic flexible laryngoscope.120

Coronary heart disease

Diabetic men are more than four times as likely, and women five times as likely, to have coronary heart disease (CHD) than non‐diabetics.15 The annual cardiac event rate for untreated patients is 2.5% and even treated patients have more aggressive coronary disease and experience worse outcomes at any stage of the disease.96 Some patients may have significant CHD causing myocardial ischaemia and even suffer myocardial infarction without typical symptoms. This may result from autonomic neuropathy,67 but such ‘silent ischaemia’ is unlikely to occur without the co‐existence of multiple risk factors. However, even selective screening targeted at patients with specific multiple risk factors has been discouraged because there is no evidence to support intervention (in the form of angioplasty or surgery) for asymptomatic diabetic patients.99 What is the anaesthetist to do when presented with an asymptomatic diabetic patient who has some or all
















of the other risk factors such as advanced age, smoking, hyperlipidaemia and hypertension? Perioperative management of such a patient may be altered if it is known that there is a likelihood of myocardial ischaemia even if intervention by coronary artery bypass grafting or angioplasty (although perhaps not coronary stenting) carries an unacceptable risk:benefit ratio.81 Asymptomatic type 1 diabetics with severe nephropathy scheduled for renal transplantation have been shown to benefit from preoperative screening and appropriate coronary revascularization.65 A similar strategy may well be appropriate for high‐risk diabetics, particularly those with ‘metabolic syndrome’, about to undergo major, elective non‐cardiac surgery.

Diabetic patients have a worse outcome after coronary artery bypass surgery96 and tend to stay in hospital longer.60 They are more likely to develop postoperative renal failure13 and suffer delayed stroke.46 Deep sternal wound infection rates are also higher than in the non‐diabetic population,126

but the incidence may be reduced by improving diabetic control with continuous insulin infusions.27 Mortality following coronary artery bypass surgery in diabetics is generally reported as significantly greater than that in non‐diabetics.110

Diabetic nephropathy

In most countries, the leading causes of end‐stage renal failure are hypertension and diabetes mellitus. In the USA, 30–40% of patients with type 1 diabetes will develop diabetic nephropathy and end‐stage renal failure.93 There is now substantial evidence that angiotensin‐converting enzyme (ACE) inhibitors have a renal protective effect in patients with type 1 diabetes.61 This may also be the case in type 2 diabetes, but the evidence is less convincing. No agent has been shown to be renoprotective in the perioperative period and some of the traditional drugs used for this purpose may be harmful.17 105 Ensuring adequate renal perfusion by expanding the extracellular space (salt loading) or, more specifically, the intravascular space with appropriate haemodynamic monitoring may reduce the risk of postoperative renal dysfunction. Hydration with 0.45% sodium chloride solution alone provides better protection against radiocontrast medium‐induced renal failure in at‐risk subjects than saline with the addition of furosemide or mannitol.102

Autonomic neuropathy

Diabetic patients frequently develop neuropathy, most commonly a distal symmetrical sensory or sensorimotor polyneuropathy with a variable degree of autonomic involvement.12 Autonomic dysfunction, which is of particular importance to the anaesthetist, is detectable in up to 40% of type 121 and 17% of type 2 diabetic patients.23 Only a small proportion of these patients are symptomatic, with signs and symptoms such as gastroparesis, postural hypotension, gustatory sweating, diabetic diarrhoea and bladder paresis.121 Many pathogenic mechanisms have been suggested for diabetic autonomic neuropathy, including local ischaemia,112 tissue accumulation of sorbitol,20 altered function of neuronal Na+/K+‐ATPase pump activity103 and immunologically mediated damage.21

The cardiovascular effects of insulin are paradoxical in autonomic neuropathy patients. In normal subjects, i.v. or s.c. insulin administration activates the sympathetic nervous system, causing an increase in circulating norepinephrine, supine arterial pressure and peripheral vascular























resistance.85 At the supraphysiological concentrations often used in the treatment of diabetes, vasodilation occurs with decreased peripheral vascular resistance and increased flow.85 These observations suggest that insulin has dual effects, namely a vasoconstrictor effect mediated by the sympathetic nervous system at low insulin concentrations, and a vasodilator effect, perhaps mediated by nitric oxide release at higher concentrations. In patients with autonomic neuropathy, insulin causes a decrease in supine arterial pressure and exacerbates postural hypotension.

Detection of autonomic neuropathy in patients without symptoms has relied on methods such as assessment of heart rate variability (HRV).104 In diabetic autonomic neuropathy, there is loss of HRV. The severe impairment of HRV in patients with end‐stage diabetic nephropathy probably results from autonomic neuropathy and partly from co‐existing heart disease.57 The loss of HRV may be a contributory risk factor for ventricular arrhythmias and sudden death in these patients.57

The presence of autonomic dysfunction in diabetics undergoing coronary artery surgery is not, however, automatically associated with haemodynamic instability during induction and the cardiovascular responses in non‐diabetic and diabetic patients were very similar.53

Diabetic gastroparesis is characterized by a delay in gastric emptying without any gastric outlet obstruction.117 The increased amount of gastric contents enhances the risk of acid aspiration during the induction of anaesthesia.82 These patients are often asymptomatic and unpredictable difficulties in tracheal intubation increase even further the risk of aspiration.88 Studies have shown little effect of pro‐kinetic agents, such as cisapride, in reducing the volume of gastric contents in diabetics.89

Postoperative respiratory arrest seems to be more common in diabetic patients. Acute, unexpected respiratory problems in the recovery room are more common in men, in those aged >60 years, and in obese or diabetic patients.95


Wound healing and infection

It has long been recognized that wound healing is impaired in diabetic patients.9 44 This observation has been repeated in animal models where it has been shown that pre‐ and postoperative glycaemic control with insulin, not postoperative alone, can restore normal anastomotic healing.118 Recent work suggests that better glycaemic control with insulin infusions may reduce the incidence of deep sternal wound infections in diabetic patients who have undergone cardiac surgery.27 This observation is supported by a study demonstrating better preservation of neutrophil function with ‘aggressive’ glycaemic control using an insulin infusion, compared with intermittent therapy, in diabetic cardiac surgical patients.86 Interestingly, high‐dose insulin and glucose infusions, aimed at maintaining supranormal plasma insulin concentrations and euglycaemia in non‐diabetic burns patients, significantly decreased donor‐site healing time after skin grafting.84


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Conclusion

It is well known that diabetic patients are at greater risk of perioperative mortality and morbidity after major surgery and have a higher incidence of co‐existing disease. Over recent years evidence has accumulated that improving glycaemic control in both the short and long term improves outcome. Attention to detail in the day‐to‐day management of the disease itself and associated conditions, such as hypertension, reduces the devastating consequences of microvascular and macrovascular complications. In addition, a more aggressive approach to glycaemic control in the perioperative period results in better wound healing, lower morbidity and shorter hospital stays. Gone are the days when anaesthetists could tolerate ‘permissive hyperglycaemia’ with the idea that this approach was in the patient’s best interest. Tight metabolic control in the perioperative period is imperative and is a goal which is attainable in most patients.

Br Anaesth J 2000; 85: 80-90Prevalensi diabetes mellitus pada orang dewasa dan anak-anak telah terus meningkat di seluruh dunia untuk masa 20-30 yr.29 55 97 Perubahan terbaru dalam kriteria diagnostik, jika diadopsi secara luas, mungkin akan juga mengarah pada lebih banyak pasien yang diklasifikasikan sebagai memiliki diabetes .16 Tak pelak lagi, pasien diabetes menyajikan untuk operasi insidental, atau operasi yang berhubungan dengan penyakit mereka, akan menempatkan beban meningkat pada layanan anestesi. Konflik akan terjadi antara kebutuhan ekonomi untuk meminimalkan tinggal di rumah sakit dan pendekatan tradisional untuk mengelola pasien diabetes perioperatif yang mengandalkan pada periode 'stabilisasi' rawat inap pra operasi.Kontrol yang lebih baik glikemik pada pasien diabetes yang menjalani operasi besar telah ditunjukkan untuk meningkatkan angka kematian perioperatif dan morbidity.44 90 Sederhana menghindari hipoglikemia dan hiperglikemia bruto tidak lagi memadai dalam terang pengetahuan ini. Meskipun ada argumen bisa sedikit tentang pengelolaan pasien diabetes menjalani prosedur utama, manajemen mereka untuk operasi kecil adalah suatu dilema yang meningkat. Dalam keadaan apa yang sehari-kasus anestesi dan pembedahan sesuai? Apakah masuk pada hari operasi menambah risiko untuk pasien diabetes? Investigasi apa, jika ada, diperlukan untuk menilai sistem kardiovaskular dari diabetes tanpa gejala yang menyajikan untuk operasi besar? Sayangnya, ada sedikit data untuk memberikan jawaban atas pertanyaan-pertanyaan ini. Pemahaman tentang patofisiologi diabetes dan pentingnya penelitian terbaru harus meningkatkan perawatan pasien perioperatif bedah diabetes. Review ini akan membahas beberapa perkembangan terakhir di lapangan. Ini tidak akan memberikan 'resep' atau algoritma untuk manajemen. Ini dapat ditemukan dalam teks-teks standar.Sebelumnya Bagian BagianRevisi diagnostik kriteria untuk diabetes melitusBaru-baru ini, baik American Diabetes Association (ADA) dan Organisasi Kesehatan Dunia (WHO) menerbitkan rekomendasi untuk kriteria diagnostik baru untuk diabetes mellitus.1 106 Kedua badan menyarankan pengurangan batas ambang untuk konsentrasi glukosa plasma puasa dan menegaskan kembali lebih aetiologically berbasis nomenklatur. Jenis istilah 1 (pankreas penghancuran sel B) dan tipe

2 (sekresi insulin rusak dan, biasanya, resistensi insulin) diabetes dianjurkan untuk mengganti sepenuhnya diabetes istilah yang sering menyesatkan 'insulin-dependent' dan 'non-insulin-dependent ". ADA telah menetapkan bahwa diagnosis diabetes mellitus harus dibuat jika 'santai' (acak) glukosa plasma nilai dalam individu asimtomatik adalah> 11,1 mmol liter-1. Jika glukosa plasma puasa> 7.0 mmol liter-1 (6.1 mmol liter-1 glukosa darah) pada individu asimtomatik, tes harus diulang pada hari yang berbeda dan diagnosis dilakukan jika nilai masih di atas batas ini. ADA mendefinisikan konsentrasi glukosa plasma puasa antara 6,1 dan 7,0 mmol liter-1 (5,6-6,1 mmol liter-1 glukosa darah) sebagai mewakili 'glycaemia puasa terganggu'. WHO juga merekomendasikan bahwa diagnosis diabetes mellitus dilakukan jika konsentrasi plasma glukosa acak> 11,1 mmol liter-1 (darah vena secara keseluruhan> 10,0 mmol liter-1). Hal ini juga dapat didiagnosis dengan konsentrasi glukosa plasma puasa> 7.0 mmol liter-1 dan tes serupa kedua atau tes toleransi glukosa oral memproduksi hasil dalam kisaran diabetes.Perubahan dalam konsentrasi glukosa plasma puasa digunakan untuk mendefinisikan diabetes dan peran tes toleransi glukosa oral mungkin standar membuat sulit untuk membandingkan penelitian epidemiologi menggunakan kriteria baru dengan mereka yang menggunakan yang sebelumnya. Tak pelak, beberapa orang akan didiagnosis diabetes dengan menggunakan kriteria yang hanya didasarkan pada (lebih rendah) konsentrasi glukosa plasma puasa yang tidak akan begitu didiagnosis bawah definisi sebelumnya. Akan ada orang lain yang akan telah memenuhi definisi menggunakan tes toleransi glukosa oral tetapi siapa yang akan memiliki nilai puasa diterima. Jadi kemungkinan bahwa definisi baru akan mendefinisikan sebagai diabetes kelompok glukosa toleran individuals.52Selain dua jenis diabetes umum, sejumlah penyebab intoleransi glukosa dapat didefinisikan sesuai dengan proses kausal atau patologis tertentu. Gestational diabetes adalah glukosa intoleransi yang memiliki onset dalam, atau pertama kali didiagnosis selama, kehamilan. Keparahan bervariasi dan definisi berlaku atau tidak insulin diberikan dalam pengobatan. Wanita dengan diabetes didiagnosis sebelum kehamilan didefinisikan sebagai memiliki 'diabetes mellitus dan kehamilan', bukan kehamilan diabetes.1 Hasil neonatal tipe 1 diabetes wanita yang hamil yang miskin. Bayi mereka sekitar lima kali lebih mungkin lahir mati dan 10 kali lebih mungkin untuk memiliki cacat bawaan lahir dibandingkan non-diabetes mothers.10 Manajemen di sebuah pusat spesialis dapat meningkatkan kejadian perinatal mortality.34 transportasi membran peningkatan glukosa abnormal , bahkan di ibu yang diabetes terkontrol dengan baik, dapat menjelaskan tingginya tingkat cacat bawaan terus (terutama makrosomia) meskipun treatment.48 meningkatkan Peningkatan frekuensi pemberian insulin dari dua sampai empat kali sehari selama kehamilan dapat menyebabkan kontrol glikemik yang lebih baik ibu dengan kejadian yang lebih rendah dari hipoglikemia neonatal dan hiperbilirubinemia tanpa meningkatkan risiko ibu hypoglycaemia.73Ada sejumlah penyebab genetik langka intoleransi glukosa. Di antaranya adalah cacat dari B-fungsi sel (sebelumnya disebut diabetes onset dewasa kaum muda, atau MODY) dan cacat pada aksi insulin (sebelumnya disebut tipe A resistensi insulin). Penyakit menyebar dari pankreas eksokrin (seperti pankreatitis), infeksi virus tertentu yang menghancurkan sel B pankreas (rubella, Coxsackie B, cytomegalovirus, gondok dan lain-lain) dan kekebalan-mediated proses (insulin autoantibodi atau antibodi reseptor insulin) juga dapat menyebabkan .1 'diabetes negara Endocrinopathies terkait dengan sekresi kelebihan hormon kontra-regulasi (seperti pertumbuhan, kortisol hormon glukagon, dan epinefrin) dapat menyebabkan hiperglikemia.Sejumlah obat dapat menginduksi intoleransi glukosa baik dengan menghambat sekresi insulin atau

dengan mengganggu dengan tindakan perifer insulin.1 Dalam anestesi, glukokortikoid dan agonis adrenergik yang paling sering terlibat. Para kortikosteroid oral baru, deflazacort, mungkin kurang 'diabetogenik' daripada prednisolone atau betamethasone.2'Sindrom metabolik' (juga disebut sindrom X atau sindrom resistensi insulin) adalah sekelompok non-kausal terkait gejala yang membawa risiko tinggi penyakit makrovaskuler. Cluster ini termasuk gangguan toleransi glukosa atau diabetes, resistensi insulin, peningkatan tekanan arteri, mengangkat trigliserida plasma, obesitas sentral dan microalbuminuria.1Sebelumnya Bagian Bagian

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Gestational Diabetes Mellitus

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