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NIDDM — the devastating disease
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Diabetes Research and Clinical Practice 28 Supp!. (1995) 53-511
NIDDM -
the devastating disease Edward S, Horton*
Joslin Diabetes Center Harvard Medical School Boston, 1 Joslin Place, Boston, MA 02215, USA
Abstract Of the various types of diabetes mellitus, non-insulin-dependent diabetes (NIDDM) is by far the most common and is increasing rapidly in many populations around the world. It is a heterogeneous disorder, characterized by a genetic predisposition and interaction between insulin resistance and decreased pancreatic f3-cell function. There is a strong association between the presence of obesity and low levels of physical exercise and the development of NIDDM. However, NIDDM may also develop in lean individuals and the incidence increases significantly with increasing age. A diagnosis of impaired glucose tolerance or gestational diabetes is a strong predictor for future development of NIDDM and should signal appropriate interventions to prevent or delay the progression to NIDDM. NIDDM is frequently associated with other conditions such as hypertension, hypertriglyceridemia and decreased high-density lipoprotein which are additional risk factors for atherosclerosis and cardiovascular disease. The 'insulin resistance syndrome', which includes obesity, NIDDM, hypertension, hyperinsulinemia and dyslipidemia is a major and increasing cause of morbidity and mortaility in many populations. In addition, people with NIDDM and poor glycemic control may develop severe microvascular complications of diabetes, including retinopathy, nephropathy and neuropathy. Appropriate diet, weight control and increased physical activity will increase insulin sensitivity in insulin resistant patients and are effective treatments for patients with NIDDM or may prevent the development of NIDDM in susceptible individuals. If these measures are unsuccessful, then oral hypoglycemic agents or insulin therapy may be required. Maintaining near normal blood glucose levels will decrease the development or progression of long-term complications of diabetes and should be a major goal of therapy, balancing intensive treatment with the increased risk of severe hypoglycemia. Because of the increasing prevalence of NIDDM in many populations, increased awareness of the disease, surveillance of high-risk populations and early diagnosis and treatment are all important in reducing the morbidity associated with this disease.
Keywords:
Non-insulin-dependent diabetes; Heterogeous disorder; Atherosclerosis; Hypoglycemia
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1. Introduction
Diabetes mellitus is not a single disease, but a group of disorders of varying etiology and
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pathogenesis that are characterized by increased fasting and postprandial blood glucose concentrations, insulin deficiency and/or decreased insulin action, abnormalities of glucose, lipid and protein metabolism and the development of both acute and long-term complications. Acute complications of diabetes include severe hyperglycemia,
0168-8227/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0168-8227(95) 01087-T
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leading to polyuria, increased thirst, dehydration, weight loss, blurred vision, fatigue and occasionally hyperosmotic non-ketotic coma. In severe insulin deficiency or stress, ketoacidosis may occur. People with diabetes that are not adequately treated may be more prone to infection and may demonstrate poor wound healing. Long-term complications include the development of microvascular abnormalities, leading to retinopathy and nephropathy, the development of peripheral neuropathy and other neuropathic disorders, premature cataract formation and accelerated macrovascular disease, leading to premature coronary artery disease, cerebrovascular disease and peripheral vascular disease. Because of its acute and long-term complications, diabetes is a major cause of morbidity and mortality and it is increasing in prevalence in many populations around the world. In the United States today, there are estimated to be more than 13 million people with diabetes mellitus, approximately 6% of the total population. However, about half of those with diabetes have not yet been diagnosed. This is because the symptoms are often absent and not very specific in NIDDM, the most common form of the disease. Early diagnosis and treatment are important since there is now strong evidence that the development of the long-term complications of diabetes can be significantly decreased by proper treatment. In addition, the onset of diabetes in those who are genetically susceptible may be prevented or delayed by appropriate changes in diet, exercise and other lifestyle habits. NIDDM is by far the most common form of diabetes, accounting for over 90% of cases world wide. It is a heterogenous disorder characterized by a genetic predisposition and interaction between insulin resistance and decreased {3-cell function. Patients with NIDDM may have few or none of the classic symptoms of diabetes mellitus when first discovered. They are not absolutely dependent on exogenous insulin for survival and are not prone to the development of ketoacidosis except during conditions of severe stress such as those caused by infections, trauma or surgery. In Western countries, there is a strong association
between the presence of obesity and low levels of physical exercise and the development of NIDDM. However, NIDDM may also develop in lean individuals. It is usually diagnosed after the age of 30 and the incidence increases significantly with increasing age. 2. Prevalence of NIDDM and associated risk factors Compared to Caucasians, there is an increased prevalence of NIDDM in Blacks, Hispanics, and native Americans in the United States. Based on the Second National Health and Nutrition Examination Survey, (NHANES 11), which covered Blacks and non-Hispanic Caucasians [1], and the Hispanic Health and Nutrition Examination Survey (HHANES), which covered Mexican Americans, Puerto Ricans and Cubans [2], the overall prevalence of NIDDM in the US populations is 6.6% in the age range 20-74 years and is as high as 17.7% in those aged 65-74. Combining the data of both surveys, the highest rates of NIDDM are observed in Mexican Americans and Puerto Ricans; Cubans and Blacks have intermediate rates and non-Hispanic, Caucasians have the lowest rates [3,4]. Compared to Caucasians, the Hispanic population has rates that are more than 2-fold greater [5] and Blacks have rates that are increased by 50-60%. The prevalence of NIDDM is also increased in Asian Americans [6,7]. The highest rates of NIDDM in the US population have been observed in Native Americans with the highest occurring in the Pima Indians of Southwest Arizona where NIDDM occurs in 35% of adults [8]. While there are strong genetic factors in the development of NIDDM, as evidence by the importance of a positive family history as a risk factor for developing NIDDM, numerous modifiable risk factors have also been identified. These include the development of obesity, decreased physical activity and low level of physical fitness [9-16]. Although the pathogenesis of NIDDM is not fully understood, it is clear that at least three factors are important: a genetic predisposition to the disease; a decrease in the action of insulin in
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insulin sensitive tissues, including adipose tissue, skeletal muscle and liver; and a defect in pancreatic f:l-cell function [17]. Conditions associated with the development of insulin resistance increase the risk of NIDDM greatly. Chief among these are obesity and advancing age. Insulin resistance and hyperinsulinemia are also associated with hypertension, hypertriglyceridemia, decreased HDL-cholesterol and increased risk of a therosclerosis and cardiovascular disease [18-25]. It is well documented that moderate degrees of weight reduction in obese individuals and increased levels of physical activity and physical training are associated with decreases in fasting and postprandial insulin concentrations, improved insulin sensitivity and improved plasma glucose concentrations in individuals with NIDDM [26-35]. Weight reduction and increased physical activity are also associated with improvement in several other cardiovascular risk factors, including decreased blood pressure and improvement in lipid profiles [30,31,36,37]. Physical inactivity, on the other hand, is associated with the development of insulin resistance and decreased glucose tolerance [38]. Recently, prospective studies of the development of NIDDM in both male and female populations have demonstrated that regular physical activity has a protective effect on the development of NIDDM [39-41]. These data suggest that lifestyle interventions to decrease the development of obesity and increase physical activity may be beneficial in individuals who are at increased risk of developing NIDDM [42,43]. 3. Gestational diabetes mellitus as a risk factor for NIDDM
The term gestational diabetes mellitus (GDM) is used to describe glucose intolerance that has its onset or is first detected during pregnancy. Women with diagnosed diabetes before conception are not classified as having GDM. GDM occurs in about 2% of pregnant women, usually during the second or third trimester when levels of insulin-antagonist hormones increase and insulin resistance normally occurs. After parturi-
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tion, patients with GDM should be reclassified on the basis of plasma glucose testing. In most cases, glucose tolerance returns to normal following parturition, although over time a significant percentage of women with a history of GDM will develop overt NIDDM with cumulative prevalence ranging from 6% to as high as 62%, depending on the duration of follow-up [44]. The increase in risk for NIDDM associated with a history of GDM has been demonstrated in varied geographic locations in the United States [45-48]. In addition, a similar increase in risk for NIDDM is seen in countries throughout the world, including Denmark [49], Sweden [50,51], Russia [52], Ireland [53], United Kingdom [54], and Australia [55], strongly suggesting that this is a widespread phenomenon. The ability to describe a precise assessment of long-term risk for the development of NIDDM is obscured by the high likelihood that the testing for GDM during pregnancy is detecting women who already had NIDDM or IGT that was undiagnosed until pregnancy. For example, Harris et al. [56] found that 3.8% of 817 non-pregnant American women of childbearing age had OGTTs that would have met the criteria for GDM had they been pregnant. In addition, Kjos et al. performed 2-h OGTTs 5-8 weeks post-partum on over 200 women with a recent history of GDM and found an incidence of IGT and DM of 19% and 9%, respectively [57]. These studies support the idea that many women with GDM are already glucose intolerant in the non-pregnant state, and further support the diagnosis of GDM as yielding a population with a high prevalence of already impaired glucose tolerance with a high risk for future development of NIDDM. Despite the positive predictive value of GDM for the development of NIDDM, little has been done in terms of formal studies to decrease the future development of NIDDM. Women with a history of GDM who go on to develop NIDDM have been shown in some studies to have greater body mass index (BMI) [58], although another recent study showed no relationship [49]. Weight reduction is a common clinical recommendation for women with a history of GDM, and these
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studies raise the importance of clarifying whether weight reduction is actually beneficial in decreasing the long-term risk of diabetes. The finding of greater insulin resistance post-partum in women with a history of GDM [59,60] also raises the possibility of pharmacologic intervention to increase insulin sensitivity. Stowers [61] reported the use of chlorpropamide and diet in an attempt to improve glucose tolerance in women with a history of GDM. Intravenous glucose tolerance tests performed yearly (following 3 weeks of chlorpropamide withdrawal) demonstrated a sustained improvement in glucose tolerance at a mean follow-up of 3 years. 4. Impaired glucose tolerance as a risk factor for NIDDM Impaired glucose tolerance (IGT) as defined either by the National Diabetes Data Group (NDDG) [62] or the World Health Organization (WHO) also has a high prevalence in the US population [1]. In NHANES II, the identified rates were 4.6% using NDDG criteria and 11.2% using WHO criteria [3]. If the latter definition is accepted, i.e. fasting plasma glucose < 140 mgy'dl and 2-h post 75-g glucose challenge between 140 and 199 mgy'dl, the prevalence of IGT is approximately twice that of NIDDM in the US population. In addition to the above mentioned risk factors for NIDDM, the presence of IGT and a history of GDM significantly increase the risk of subsequent development of NIDDM [63-65,56]. As with NIDDM, the prevalence of IGT increases with increasing age and with obesity [66]. It is also increased in minority populations and when there is a family history of diabetes [6]. The progression of IGT to NIDDM has been studied in several Caucasian populations in the US, Great Britain and Europe with 1-5% of patients developing NIDDM per year [67-71]. In high risk populations such as the Pima Indians, the rate of progression to NIDDM is as high as 5-10% per year [72]. Data from NHANES II indicate that the characteristics of people with IGT (age, plasma glucose, past obesity, family history of diabetes, physical inactivity) are intermediate
between patients with NIDDM and those people with normal glucose tolerance, suggesting that IGT may be an intermediate step in the development of overt NIDDM [3]. Furthermore, it has been observed that IGT may be transient or intermittent in some individuals and does not inevitably proceed to NIDDM [69,71]. Factors such as weight gain, the development of hyperinsulinemia and/or insulin resistance and physical inactivity may be important and modifiable factors in the progression of IGT to NIDDM [73,74]. Since there are no established treatments for IGT, regular screening for IGT is not common and little is known about interventions that may prevent or delay the progression to NIDDM in high-risk populations. At present, no large scale, randomized, prospective, controlled clinical trials have been conducted to determine whether or not progression of IGT to NIDDM can be prevented or delayed. Epidemiological data suggest that the prevention of obesity and increased levels of physical activity have a protective effect. 5. Interventions to prevent or treat NIDDM Since insulin resistance is the earliest abnormality detected in individuals who subsequently develop NIDDM [75,76], and insulin resistance can be reduced through weight reduction and exercise [28,31,77-80], it seems logical to base an intervention strategy on lifestyle modifications that will reduce obesity and increase physical activity. Although it is not known whether reversing insulin resistance will prevent or delay the onset of NIDDM, epidemiological data suggest that regular physical exercise has a protective effect [39-41]. Furthermore, the combination of moderate weight reduction and increased physical conditioning, when sustained over a period of 5 years, significantly improves glucose tolerance, blood pressure, lipids and hyperinsulinemia [81]. A drawback of this approach, however, is the need for intensive efforts to promote sustained lifestyle modification and the relatively low longterm success rates achieved [82-87]. While easier to administer, pharmacological interventions using both sulfonylurea and
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biguanides have been inconclusive with regard to preventing or delaying the progression of IGT to NIOOM [71,88,89]. Agents which lower postprandial glucose concentrations may decrease insulin resistance secondarily. In addition, some agents may have direct effects on peripheral or hepatic insulin sensitivity, thus improving IGT or preventing the development and / or progression of NIOOM. While there are many pharmacological agents that could be used, including agents that alter the digestion and absorption of nutrients from the gastrointestinal tract, agents that enhance glucose stimulated insulin secretion, agents that effect hepatic or peripheral glucose metabolism, and newly developed 'insulin sensitizing' drugs, the two most widely studied classes of compounds are the sulfonylurea and the biguanides, both of which have been used extensively in the treatment of patients with NIOOM. In general, it is best to take a stepped approach to the treatment of NIOOM. There are two major goals of therapy: to achieve normal metabolic and biochemical control and to prevent the long-term complications of diabetes. To achieve the first goal, therapy should be directed towards achieving normal or near normal plasma glucose concentrations, both fasting and in the postprandial state, normal glycated hemoglobin and normal serum cholesterol and triglycerides. Vascular complications may be prevented by maintaining normal levels of these biochemical indices and also by lowering elevated blood pressure and encouraging patients to stop cigarette smoking and to reduce excess body weight. There is universal agreement that the first steps in therapy should be the correction of obesity and inactivity. Even moderate degrees of weight loss will decrease the underlying insulin resistance that results in fasting hyperglycemia. As a result of the diminished insulin resistance there is a decrease in hepatic glucose production and an increase in peripheral glucose uptake, both of which improve blood glucose levels. Current recommendations are to decrease caloric intake by 500-1000 kcaIjday below daily expenditure to achieve a weight loss of 25-35 pounds 00-15 kg), and to increase physical activity, particularly aer-
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obic activities such as walking, swimming, cycling or simply increased energy expenditure in activities of daily life. Once these measures have been implemented, oral hypoglycemic agents may be added to the treatment regimen and, if needed, insulin therapy may be used. In patients with severe insulin resistance, insulin requirements may be quite large in order to achieve normal blood glucose concentrations, often as much as 100 units/day or more, given as individual doses before meals and at bedtime. In lean patients who have predominantly insulin deficiency rather than insulin resistance, much lower doses of insulin are required to achieve good metabolic control. 6. Prevention of long-term complications of diabetes The recently completed Diabetes Control and Complications Trial [90], a large, multicenter study conducted by the National Institutes of Health and carried out in 29 diabetes centers in the United States and Canada examined whether intensive treatment of patients with 100M, with the goal of maintaining blood glucose concentrations as close to the normal range as possible, could decrease the long-term complications of diabetes. A total of 1441 patients with 100M were followed for up to 9 years and monitored closely for the development or worsening of diabetic retinopathy, nephropathy, neuropathy, hyperlipidemia and macrovascular disease. The primary prevention cohort consisted of 726 patients with no retinopathy at baseline and the secondary intervention cohort consisted of 715 patients with mild retinopathy. Patients in both groups were randomly assigned to intensive therapy either with an external pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring and diabetic team support or to conventional therapy with one or two daily insulin injections and less stringent monitoring. This study has demonstrated conclusively that intensified therapy and improved glycemic control in patients with 100M has a major impact on the development of long-term complications of dia-
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betes, decreasing significantly the development and progression of retinopathy, nephropathy and neuropathy, and improving lipid profile, associated with increased risk of macrovascular disease. Although this study was confined to patients with IDDM, it is well documented that hyperglycemia is also associated with the presence or progression of long-term complications in patients with NIDDM. Thus it seems logical to assume that improved glycemic control in patients with NIDDM will also be extremely beneficial in reducing the development or progression of retinopathy, nephropathy, neuropathy and perhaps macrovascular disease. However, in patients with NIDDM, therapeutic measures such as diet, weight reduction and increased physical activity may be effective and should be tried before resorting to oral hypoglycemic agents or insulin therapy. Questions regarding the potential harmful effects of aggressive insulin therapy in NIDDM remain to be resolved. However, because of the increasing prevalence of NIDDM in many populations, increased awareness of the disease, surveillance of high-risk populations and early diagnosis and treatment are all important in reducing the morbidity associated with this disease. References [1]
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[50] Efendic, S., Hanson, U., Persson, B., Wajngot, A and Luft, R. (1987) Glucose tolerance, insulin release and insulin sensiivity in normal-weight women with previous gestational diabetes mellitus. Diabetes 36, 413-419. [51] Hagbard, L. and Svanborg, A (1960) Prognosis of diabetes mellitus with onset during pregnancy. Diabetes 9, 296-302. [52] Konradi, L.l. and Matveeva, O.F. (1974) Prognostic value of disorders of glucose tolerance in pregnant women. Prabl. Endocrino!. 20, 10-13. [53J Hadden, D.R. (1979) Asymptomatic diabetes in pregnancy. In: H.W. Sutherland and J.M. Stowers (Eds.), Carbohydrate Metabolism in Pregnancy and the Newborn. Berlin, Springer-Verlag pp. 407-424. [54] Stowers, J.M., Sutherland, H.W. and Kerridge, D.F. (1985) Long-range implications for the mother: the Aberdeen experience. Diabetes 34, Suppl. 2, 106-110. [55J Grant, P.T., Oats, J.N. and Beischer, N.A (1986) The long-term follow-up of women with gestational diabetes. Aust. N.Z. J. Obstet. Gynaecol. 26, 17-22. [56] Harris, M.l. (1988) Gestational diabetes may represent discovery of pre-existing glucose intolerance. Diabetes Care 11, 401-411. [57J Kjos, S.L., Buchanan, T.A, Greenspoon, J.S., Montero. M., Bernstein, G.S. and Mestman, J.H. (1990) Gestational diabetes mellitus: The prevalence of glucose intolerance and diabetes mellitus in the first 2 months postpartum. Am. J. Obstet. Gyneco!. 163, 93-98. [58] O'Sullivan, J.B. (1982) Body weight and subsequent diabetes mellitus J. Am. Med. Assoc. 248, 949-952. [59] Catalano, P.M., Bernstein, I.M., Wolfe, R.R., Srikanta, S., Tyzbir, E. and Sims, E.AH. (1986) Subclinical abnormalities of glucose metabolism in subjects with previous gestational diabetes. Am. J. Obstet. Gynecol. 155, 1255-1262. [60] Ward, W.K., Johnston, e.L.W., Beard, J.e., Benedetti, T.J., Halter, J.B. and Porte, D. (1985) Insulin resistance and impaired insulin secretion in subjects with histories of gestational diabetes mellitus. Diabetes 34, 864-869. [61] Stowers, J.M. (1984) In: H.W. Sutherland and J.M. Stowers (Eds.), Metabolism in Pregnancy and the Newborn. Churchill Livingstone, New York, pp. 181-183. [62] National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28, 1039-1057. [63] Eriksson, KF. and Lindgarde, F. (1990) Impaired glucose tolerance in a middle-aged male urban population: a new approach for identifying high-risk cases. Diabetologia 33, 526-531. [64] Harris, M.I., Hadden, W.e., Knowler, W.e. and Bennett, P.H. (1985) International criteria for diagnosis of diabetes and impaired glucose tolerance. Diabetes Care 8,562-567. [65] Yudkin, J.S., Alberti, KG.M.M., Mclarty, D.G. and Swai, AB.M. (1990) Impaired glucose tolerance. Br. Med. J. 301, 397-402.
[66] Harris, M.l. (1990) Epidemiology of diabetes mellitus among the elderly in the United States. Clin. Geriatr. Med. 6, 703-719. [67] Birmingham Diabetes Survey Working Party (1976) Ten-year follow-up report of the Birmingham diabetes survey of 1961. Br. Med. J. 2, 35-37. [68] Jarrett, R.J., Keen, H. and McCartney, P. (1984) The Whitehall study: lO-year follow-up report on men with impaired glucose tolerance with reference to worsening to diabetes and predictors of death. Diabetic Med. 1, 279-283. [69] Keen, H., Harrett, R.J. and McCartney, P. (1982) The lO-year follow-up of the Bedford survey (1862-72): glucose tolerance and diabetes. Diabetologia 22, 73-78. [70] O'Sullivan, J.B. and Mahan, e.M. (1968) Prospective study of 352 young patients with chemical diabetes. N. Engl. J. Med. 278, 1038-1041. [71] Sartor, G., Schersten, B., Carlstrom, S., Melander, A, Norden, A and Pesson, G. (1980) Ten-year follow-up of subjects with impaired glucose tolerance: prevention of diabetes by tolbutamide and diet regulation. Diabetes 29,41-49. [72] Saad, M.F., Knowler, W.e., Pettitt, D.J., Nelson, R.G., Mott, D.M. and Bennett, P.H. (1988) The natural history of impaired glucose tolerance in the Pima Indians. N. Engl. J. Med. 319, 1500-1506. [73] Annuzzi, G., Vaccaro, 0., Caprio, S., DiBonito, P., Riccardi. G. and Rivellese, A (1985) Association between low habitual physical activity and impaired glucose tolerance. Clin. Physiol. 5, 63-70. [74] Horton, E.S. (1988) Exercise and decreased risk of NIDDM. N. Eng!. J. Med. 325, 197 (editorial). [75] Lilloja, S., Mott, D.M., Howard, B.Y., Bennett, P.H., Yki-Jarvinen, H., Freymond, D., Nyomba, B.L., Zurlo, F., Swinburn, B. and Bogardus, e. Impaired glucose tolerance as a disorder of insulin action. N. Engl. J. Med. 318,1217-1225. [76] Lilloja, S., Mott, D.M., Zawadzki, J.K, Young, AA, Abbott, W.G.H., Knowler, w.c, Bennett, P.H., Moll, P. and Bogardus, e. In vivo insulin action is a familial characteristic in non-diabetic Pima Indians. [77J ADA Technical Review (1990) Exercise and NIDDM. Diabetes Care 13, 785-789. [78] ADA Position Statement (1990) Diabetes mellitus and exercise. Diabetes Care 13, 804-805. [79] Bogardus, c, Ravussin, E., Robbins, n.c, Wolfe, R.R., Horton, E.S. and Sims, E.A (1984) Effects of physical training and diet therapy on carbohydrate metabolism in patients with glucose intolerance and non-insulin-dependent diabetes mellitus. Diabetes 33,311-318. [80] Jovanovic-Peterson, L., Durak, E. and Peterson, e.M. (1989) Randomized trial of diet versus diet plus cardiovascular conditioning on glucose levels in gestational diabetes. Am. J. Obstet. Gyneco!. 161,415-419. [81] Fitz, J.D., Sperling, E.M. and Fein, H.G. (1983) A hypocaloric-high-protein diet as primary therapy for
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adults with obesity-related diabetes: effective long-term use in a community hospital. Diabetes Care 6, 328-333. Blair, S.N. (1993) Evidence for success of exercise in weight loss and control. Ann. Intern. Med. 119,702-706. Brownell, K.D. and Karmer, F.M. (1989) Behavioral management of obesity. Med. Clin. North. Am. 73, 185-201. Brownell, K.D., Marlatt, GA., Lichtenstein, E. and Wilson, G.T. (1986) Understanding and preventing relapse. Am. Psychol. 41, 765-782. Foreyt, J.P. and Goodrick, G.K. (I 993) Evidence for success of behavior modification in weight loss and control. Ann. Intern. Med. 119,698-701. Jeffrey, R.W. (]993) Minnesota studies on communitybased approaches to weight loss and control. Ann. Intern. Med. 119,719-721.
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[87] Wadden, T.A. (]993) Treatment of obesity by moderate and severe caloric restriction: Results of clinical research trials. Ann. Intern. Med. 119, 688-693. [88] Jarrett, RJ., Keen, H., Fuller, H. and McCartney, M. (1979) Worsening to diabetes in men with impaired glucose tolerance ('borderline diabetes'). Diabetologia 16, 25-30. [89] Melander, A., Bitzen, P.-O., Sartor, G., Schersten, B. and Wahlin-Boll, E. (1990) Will sulfonylurea treatment of impaired glucose tolerance delay development and complications of NIDDM? Diabetes Care 13, 53-58. [90] The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977-986.
C1llfn CAL JlJl1ltTITCIE
ELSEVIER
Diabetes Research and Clinical Practice 28 Supp!. (1995) 53-511
NIDDM -
the devastating disease Edward S, Horton*
Joslin Diabetes Center Harvard Medical School Boston, 1 Joslin Place, Boston, MA 02215, USA
Abstract Of the various types of diabetes mellitus, non-insulin-dependent diabetes (NIDDM) is by far the most common and is increasing rapidly in many populations around the world. It is a heterogeneous disorder, characterized by a genetic predisposition and interaction between insulin resistance and decreased pancreatic f3-cell function. There is a strong association between the presence of obesity and low levels of physical exercise and the development of NIDDM. However, NIDDM may also develop in lean individuals and the incidence increases significantly with increasing age. A diagnosis of impaired glucose tolerance or gestational diabetes is a strong predictor for future development of NIDDM and should signal appropriate interventions to prevent or delay the progression to NIDDM. NIDDM is frequently associated with other conditions such as hypertension, hypertriglyceridemia and decreased high-density lipoprotein which are additional risk factors for atherosclerosis and cardiovascular disease. The 'insulin resistance syndrome', which includes obesity, NIDDM, hypertension, hyperinsulinemia and dyslipidemia is a major and increasing cause of morbidity and mortaility in many populations. In addition, people with NIDDM and poor glycemic control may develop severe microvascular complications of diabetes, including retinopathy, nephropathy and neuropathy. Appropriate diet, weight control and increased physical activity will increase insulin sensitivity in insulin resistant patients and are effective treatments for patients with NIDDM or may prevent the development of NIDDM in susceptible individuals. If these measures are unsuccessful, then oral hypoglycemic agents or insulin therapy may be required. Maintaining near normal blood glucose levels will decrease the development or progression of long-term complications of diabetes and should be a major goal of therapy, balancing intensive treatment with the increased risk of severe hypoglycemia. Because of the increasing prevalence of NIDDM in many populations, increased awareness of the disease, surveillance of high-risk populations and early diagnosis and treatment are all important in reducing the morbidity associated with this disease.
Keywords:
Non-insulin-dependent diabetes; Heterogeous disorder; Atherosclerosis; Hypoglycemia
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1. Introduction
Diabetes mellitus is not a single disease, but a group of disorders of varying etiology and
* Tel.: + 1 6177322501; Fax: + I 617 7322574,
pathogenesis that are characterized by increased fasting and postprandial blood glucose concentrations, insulin deficiency and/or decreased insulin action, abnormalities of glucose, lipid and protein metabolism and the development of both acute and long-term complications. Acute complications of diabetes include severe hyperglycemia,
0168-8227/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0168-8227(95) 01087-T
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leading to polyuria, increased thirst, dehydration, weight loss, blurred vision, fatigue and occasionally hyperosmotic non-ketotic coma. In severe insulin deficiency or stress, ketoacidosis may occur. People with diabetes that are not adequately treated may be more prone to infection and may demonstrate poor wound healing. Long-term complications include the development of microvascular abnormalities, leading to retinopathy and nephropathy, the development of peripheral neuropathy and other neuropathic disorders, premature cataract formation and accelerated macrovascular disease, leading to premature coronary artery disease, cerebrovascular disease and peripheral vascular disease. Because of its acute and long-term complications, diabetes is a major cause of morbidity and mortality and it is increasing in prevalence in many populations around the world. In the United States today, there are estimated to be more than 13 million people with diabetes mellitus, approximately 6% of the total population. However, about half of those with diabetes have not yet been diagnosed. This is because the symptoms are often absent and not very specific in NIDDM, the most common form of the disease. Early diagnosis and treatment are important since there is now strong evidence that the development of the long-term complications of diabetes can be significantly decreased by proper treatment. In addition, the onset of diabetes in those who are genetically susceptible may be prevented or delayed by appropriate changes in diet, exercise and other lifestyle habits. NIDDM is by far the most common form of diabetes, accounting for over 90% of cases world wide. It is a heterogenous disorder characterized by a genetic predisposition and interaction between insulin resistance and decreased {3-cell function. Patients with NIDDM may have few or none of the classic symptoms of diabetes mellitus when first discovered. They are not absolutely dependent on exogenous insulin for survival and are not prone to the development of ketoacidosis except during conditions of severe stress such as those caused by infections, trauma or surgery. In Western countries, there is a strong association
between the presence of obesity and low levels of physical exercise and the development of NIDDM. However, NIDDM may also develop in lean individuals. It is usually diagnosed after the age of 30 and the incidence increases significantly with increasing age. 2. Prevalence of NIDDM and associated risk factors Compared to Caucasians, there is an increased prevalence of NIDDM in Blacks, Hispanics, and native Americans in the United States. Based on the Second National Health and Nutrition Examination Survey, (NHANES 11), which covered Blacks and non-Hispanic Caucasians [1], and the Hispanic Health and Nutrition Examination Survey (HHANES), which covered Mexican Americans, Puerto Ricans and Cubans [2], the overall prevalence of NIDDM in the US populations is 6.6% in the age range 20-74 years and is as high as 17.7% in those aged 65-74. Combining the data of both surveys, the highest rates of NIDDM are observed in Mexican Americans and Puerto Ricans; Cubans and Blacks have intermediate rates and non-Hispanic, Caucasians have the lowest rates [3,4]. Compared to Caucasians, the Hispanic population has rates that are more than 2-fold greater [5] and Blacks have rates that are increased by 50-60%. The prevalence of NIDDM is also increased in Asian Americans [6,7]. The highest rates of NIDDM in the US population have been observed in Native Americans with the highest occurring in the Pima Indians of Southwest Arizona where NIDDM occurs in 35% of adults [8]. While there are strong genetic factors in the development of NIDDM, as evidence by the importance of a positive family history as a risk factor for developing NIDDM, numerous modifiable risk factors have also been identified. These include the development of obesity, decreased physical activity and low level of physical fitness [9-16]. Although the pathogenesis of NIDDM is not fully understood, it is clear that at least three factors are important: a genetic predisposition to the disease; a decrease in the action of insulin in
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insulin sensitive tissues, including adipose tissue, skeletal muscle and liver; and a defect in pancreatic f:l-cell function [17]. Conditions associated with the development of insulin resistance increase the risk of NIDDM greatly. Chief among these are obesity and advancing age. Insulin resistance and hyperinsulinemia are also associated with hypertension, hypertriglyceridemia, decreased HDL-cholesterol and increased risk of a therosclerosis and cardiovascular disease [18-25]. It is well documented that moderate degrees of weight reduction in obese individuals and increased levels of physical activity and physical training are associated with decreases in fasting and postprandial insulin concentrations, improved insulin sensitivity and improved plasma glucose concentrations in individuals with NIDDM [26-35]. Weight reduction and increased physical activity are also associated with improvement in several other cardiovascular risk factors, including decreased blood pressure and improvement in lipid profiles [30,31,36,37]. Physical inactivity, on the other hand, is associated with the development of insulin resistance and decreased glucose tolerance [38]. Recently, prospective studies of the development of NIDDM in both male and female populations have demonstrated that regular physical activity has a protective effect on the development of NIDDM [39-41]. These data suggest that lifestyle interventions to decrease the development of obesity and increase physical activity may be beneficial in individuals who are at increased risk of developing NIDDM [42,43]. 3. Gestational diabetes mellitus as a risk factor for NIDDM
The term gestational diabetes mellitus (GDM) is used to describe glucose intolerance that has its onset or is first detected during pregnancy. Women with diagnosed diabetes before conception are not classified as having GDM. GDM occurs in about 2% of pregnant women, usually during the second or third trimester when levels of insulin-antagonist hormones increase and insulin resistance normally occurs. After parturi-
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tion, patients with GDM should be reclassified on the basis of plasma glucose testing. In most cases, glucose tolerance returns to normal following parturition, although over time a significant percentage of women with a history of GDM will develop overt NIDDM with cumulative prevalence ranging from 6% to as high as 62%, depending on the duration of follow-up [44]. The increase in risk for NIDDM associated with a history of GDM has been demonstrated in varied geographic locations in the United States [45-48]. In addition, a similar increase in risk for NIDDM is seen in countries throughout the world, including Denmark [49], Sweden [50,51], Russia [52], Ireland [53], United Kingdom [54], and Australia [55], strongly suggesting that this is a widespread phenomenon. The ability to describe a precise assessment of long-term risk for the development of NIDDM is obscured by the high likelihood that the testing for GDM during pregnancy is detecting women who already had NIDDM or IGT that was undiagnosed until pregnancy. For example, Harris et al. [56] found that 3.8% of 817 non-pregnant American women of childbearing age had OGTTs that would have met the criteria for GDM had they been pregnant. In addition, Kjos et al. performed 2-h OGTTs 5-8 weeks post-partum on over 200 women with a recent history of GDM and found an incidence of IGT and DM of 19% and 9%, respectively [57]. These studies support the idea that many women with GDM are already glucose intolerant in the non-pregnant state, and further support the diagnosis of GDM as yielding a population with a high prevalence of already impaired glucose tolerance with a high risk for future development of NIDDM. Despite the positive predictive value of GDM for the development of NIDDM, little has been done in terms of formal studies to decrease the future development of NIDDM. Women with a history of GDM who go on to develop NIDDM have been shown in some studies to have greater body mass index (BMI) [58], although another recent study showed no relationship [49]. Weight reduction is a common clinical recommendation for women with a history of GDM, and these
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studies raise the importance of clarifying whether weight reduction is actually beneficial in decreasing the long-term risk of diabetes. The finding of greater insulin resistance post-partum in women with a history of GDM [59,60] also raises the possibility of pharmacologic intervention to increase insulin sensitivity. Stowers [61] reported the use of chlorpropamide and diet in an attempt to improve glucose tolerance in women with a history of GDM. Intravenous glucose tolerance tests performed yearly (following 3 weeks of chlorpropamide withdrawal) demonstrated a sustained improvement in glucose tolerance at a mean follow-up of 3 years. 4. Impaired glucose tolerance as a risk factor for NIDDM Impaired glucose tolerance (IGT) as defined either by the National Diabetes Data Group (NDDG) [62] or the World Health Organization (WHO) also has a high prevalence in the US population [1]. In NHANES II, the identified rates were 4.6% using NDDG criteria and 11.2% using WHO criteria [3]. If the latter definition is accepted, i.e. fasting plasma glucose < 140 mgy'dl and 2-h post 75-g glucose challenge between 140 and 199 mgy'dl, the prevalence of IGT is approximately twice that of NIDDM in the US population. In addition to the above mentioned risk factors for NIDDM, the presence of IGT and a history of GDM significantly increase the risk of subsequent development of NIDDM [63-65,56]. As with NIDDM, the prevalence of IGT increases with increasing age and with obesity [66]. It is also increased in minority populations and when there is a family history of diabetes [6]. The progression of IGT to NIDDM has been studied in several Caucasian populations in the US, Great Britain and Europe with 1-5% of patients developing NIDDM per year [67-71]. In high risk populations such as the Pima Indians, the rate of progression to NIDDM is as high as 5-10% per year [72]. Data from NHANES II indicate that the characteristics of people with IGT (age, plasma glucose, past obesity, family history of diabetes, physical inactivity) are intermediate
between patients with NIDDM and those people with normal glucose tolerance, suggesting that IGT may be an intermediate step in the development of overt NIDDM [3]. Furthermore, it has been observed that IGT may be transient or intermittent in some individuals and does not inevitably proceed to NIDDM [69,71]. Factors such as weight gain, the development of hyperinsulinemia and/or insulin resistance and physical inactivity may be important and modifiable factors in the progression of IGT to NIDDM [73,74]. Since there are no established treatments for IGT, regular screening for IGT is not common and little is known about interventions that may prevent or delay the progression to NIDDM in high-risk populations. At present, no large scale, randomized, prospective, controlled clinical trials have been conducted to determine whether or not progression of IGT to NIDDM can be prevented or delayed. Epidemiological data suggest that the prevention of obesity and increased levels of physical activity have a protective effect. 5. Interventions to prevent or treat NIDDM Since insulin resistance is the earliest abnormality detected in individuals who subsequently develop NIDDM [75,76], and insulin resistance can be reduced through weight reduction and exercise [28,31,77-80], it seems logical to base an intervention strategy on lifestyle modifications that will reduce obesity and increase physical activity. Although it is not known whether reversing insulin resistance will prevent or delay the onset of NIDDM, epidemiological data suggest that regular physical exercise has a protective effect [39-41]. Furthermore, the combination of moderate weight reduction and increased physical conditioning, when sustained over a period of 5 years, significantly improves glucose tolerance, blood pressure, lipids and hyperinsulinemia [81]. A drawback of this approach, however, is the need for intensive efforts to promote sustained lifestyle modification and the relatively low longterm success rates achieved [82-87]. While easier to administer, pharmacological interventions using both sulfonylurea and
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biguanides have been inconclusive with regard to preventing or delaying the progression of IGT to NIOOM [71,88,89]. Agents which lower postprandial glucose concentrations may decrease insulin resistance secondarily. In addition, some agents may have direct effects on peripheral or hepatic insulin sensitivity, thus improving IGT or preventing the development and / or progression of NIOOM. While there are many pharmacological agents that could be used, including agents that alter the digestion and absorption of nutrients from the gastrointestinal tract, agents that enhance glucose stimulated insulin secretion, agents that effect hepatic or peripheral glucose metabolism, and newly developed 'insulin sensitizing' drugs, the two most widely studied classes of compounds are the sulfonylurea and the biguanides, both of which have been used extensively in the treatment of patients with NIOOM. In general, it is best to take a stepped approach to the treatment of NIOOM. There are two major goals of therapy: to achieve normal metabolic and biochemical control and to prevent the long-term complications of diabetes. To achieve the first goal, therapy should be directed towards achieving normal or near normal plasma glucose concentrations, both fasting and in the postprandial state, normal glycated hemoglobin and normal serum cholesterol and triglycerides. Vascular complications may be prevented by maintaining normal levels of these biochemical indices and also by lowering elevated blood pressure and encouraging patients to stop cigarette smoking and to reduce excess body weight. There is universal agreement that the first steps in therapy should be the correction of obesity and inactivity. Even moderate degrees of weight loss will decrease the underlying insulin resistance that results in fasting hyperglycemia. As a result of the diminished insulin resistance there is a decrease in hepatic glucose production and an increase in peripheral glucose uptake, both of which improve blood glucose levels. Current recommendations are to decrease caloric intake by 500-1000 kcaIjday below daily expenditure to achieve a weight loss of 25-35 pounds 00-15 kg), and to increase physical activity, particularly aer-
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obic activities such as walking, swimming, cycling or simply increased energy expenditure in activities of daily life. Once these measures have been implemented, oral hypoglycemic agents may be added to the treatment regimen and, if needed, insulin therapy may be used. In patients with severe insulin resistance, insulin requirements may be quite large in order to achieve normal blood glucose concentrations, often as much as 100 units/day or more, given as individual doses before meals and at bedtime. In lean patients who have predominantly insulin deficiency rather than insulin resistance, much lower doses of insulin are required to achieve good metabolic control. 6. Prevention of long-term complications of diabetes The recently completed Diabetes Control and Complications Trial [90], a large, multicenter study conducted by the National Institutes of Health and carried out in 29 diabetes centers in the United States and Canada examined whether intensive treatment of patients with 100M, with the goal of maintaining blood glucose concentrations as close to the normal range as possible, could decrease the long-term complications of diabetes. A total of 1441 patients with 100M were followed for up to 9 years and monitored closely for the development or worsening of diabetic retinopathy, nephropathy, neuropathy, hyperlipidemia and macrovascular disease. The primary prevention cohort consisted of 726 patients with no retinopathy at baseline and the secondary intervention cohort consisted of 715 patients with mild retinopathy. Patients in both groups were randomly assigned to intensive therapy either with an external pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring and diabetic team support or to conventional therapy with one or two daily insulin injections and less stringent monitoring. This study has demonstrated conclusively that intensified therapy and improved glycemic control in patients with 100M has a major impact on the development of long-term complications of dia-
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betes, decreasing significantly the development and progression of retinopathy, nephropathy and neuropathy, and improving lipid profile, associated with increased risk of macrovascular disease. Although this study was confined to patients with IDDM, it is well documented that hyperglycemia is also associated with the presence or progression of long-term complications in patients with NIDDM. Thus it seems logical to assume that improved glycemic control in patients with NIDDM will also be extremely beneficial in reducing the development or progression of retinopathy, nephropathy, neuropathy and perhaps macrovascular disease. However, in patients with NIDDM, therapeutic measures such as diet, weight reduction and increased physical activity may be effective and should be tried before resorting to oral hypoglycemic agents or insulin therapy. Questions regarding the potential harmful effects of aggressive insulin therapy in NIDDM remain to be resolved. However, because of the increasing prevalence of NIDDM in many populations, increased awareness of the disease, surveillance of high-risk populations and early diagnosis and treatment are all important in reducing the morbidity associated with this disease. References [1]
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