These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE Effect of Insulin Therapy on Macrovascular Risk Factors in Type 2 Diabetes Michael S. Boyne, MD Many patients with type 2 diabetes require insulin therapy for improved
glycemic control after Diabetes Care 22 (Suppl. 3):C45–C53, 1999 Does insulin therapy of type 2 diabetes increase or decrease the risk of macrovascular disease? It is an apparently simple question, and one that clinicians face daily. Like many important clinical issues, this one is easy to ask but hard to answer. Even including the recently released U.K. Prospective Diabetes Study (UKPDS), no large randomized controlled clinical trial has been designed specifically to test the effect of insulin treatment on cardiovascular events. Such a study would be costly and would have to take into account many hard-to-control variables associated with type 2 diabetes. Also, the known adverse effects of poor diabetic control—from symptoms of hyperglycemia to worsening microvascular disease—weigh against initiating a study that intentionally withholds insulin therapy from those who need it to control glycemia. Without definitive proof of how insulin therapy affects cardiovascular disease (CVD), as many as 30–40% of people with type 2 diabetes now receive insulin (1). Based on average glycemic control (2), it could well be that even more people would benefit from its use. The persistent reluctance among many practitioners to start insulin can be attributed in part to the increased risk of hypoglycemia and insulin's unpopularity with patients. But the rationale often given is that insulin is atherogenic. Insulin, used therapeutically, is alleged to cause, rather than prevent, macrovascular disease. The reason for this concern is clear and is reviewed in this article. Some in vitro evidence suggests that insulin can promote lipid entry into atheromatous plaques and cause intimal hyperplasia. More impressively, a large body of evidence, though not entirely consistent, suggests that in the nondiabetic or prediabetic state, increased serum insulin (hyperinsulinism, or insulin resistance) is associated with increased incidence of CVD. There is also counterbalancing evidence that poor glycemic control causes increased risk of macrovascular disease. Hyperglycemia itself may be a risk factor, not only for small-vessel disease. The most important pathophysiological events, however, may be neither hyperinsulinemia nor hyperglycemia as such. The metabolic effects of poor diabetic control go well beyond hyperglycemia. It could well be that the effect of uncontrolled diabetes on macrovascular disease results from the associated lipid dysmetabolism, abnormalities of clotting factors, blood pressure, or other ill-defined derangements that accompany under-insulinization. Some of these factors are discussed, in support of the conclusion that when clinically indicated to control diabetes, insulin therapy reduces, rather than increases, the risk of macrovascular disease. SERUM INSULIN AS A CAUSE OF CVD Experimental evidence Hyperinsulinemia and the insulin resistance syndrome Insulin resistance and hyperinsulinemia are associated not only with diabetes, but also with a host of other metabolic abnormalities—e.g., dyslipidemia (hypertriglyceridemia, small dense LDL, and decreased HDL), hypertension, android/visceral obesity, and hyperuricemia. Other metabolic abnormalities associated with IRS include increases in the concentration of the procoagulant factors, plasminogen activator inhibitor 1, fibrinogen, factor VII, von Willebrand factor, and antithrombin III (6). It could very well be, therefore, that these other metabolic abnormalities, rather than the hyperinsulinism, result in a high incidence of macrovascular disease. The role of the insulin level itself in affecting risk has been closely evaluated. Epidemiological evidence Depres et al. (12), in a nested case-control study involving 2,103 nondiabetic French Canadian men, showed that after multivariate analysis controlling for age, hypertension, family history, smoking, dyslipidemia, obesity, and use of medications, fasting hyperinsulinemia yielded an odds ratio for CAD of 1.6. Of particular note, this study used a radioimmunoassay for insulin that did not cross-react with proinsulin. Proinsulin has been recognized to be a potential confounder in earlier studies (13). In fact, in some studies, proinsulin was more strongly correlated with insulin resistance and type 2 diabetes than were insulin levels (14). The Bruneck study complicated the issue by reporting that the relationship between CAD and fasting insulin is "U-shaped," whereas the association is "J-shaped" with postprandial insulin (15). A novel mechanism was proposed to explain these findings: atherogenicity might be related to a state of insufficient cell insulinization. That is, individuals with low plasma insulin concentrations or with hyperinsulinemia as seen in insulin-resistant states both have functionally reduced intracellular insulin effect, which may alter the function of cells involved in atherogenesis. If this theory were to prove correct, insulin in the right amount could be seen as anti-atherogenic, and either too little or too much would be deleterious. The epidemiological evidence, however, is not consistent. Several cross-sectional and prospective studies had negative associations between hyperinsulinemia and CAD risk. The Gothenburg Study of Men Born in 1913 showed no association in its 563 elderly subjects (16). Pima Indians, who have a high incidence of insulin resistance and type 2 diabetes, have a relatively low incidence of fatal CAD (17). A nested control study of 622 men in the Multiple Risk Factor Intervention Trial showed no significant relationship after 7–10 years of follow-up, with fasting insulin levels in patients and control subjects being the same (18). The Rancho Bernardo Study of 538 men and 705 women found that after 5 years' follow-up, fasting hyperinsulinemia was not a risk factor for CAD and postprandial hyperinsulinemia was inversely related to cardiovascular mortality (19). The lack of consistency in these studies may be attributed to differences in race, sex, geography, and methodology. In fact, even if insulin is a univariate risk factor in all circumstances, causality is not proven. Hyperinsulinism could well be a marker for other atherogenic factors. The data are most consistent in showing that the constellation of factors in IRS—hyperinsulinism, dyslipidemia, hypertension, and obesity—correlates with CAD. Data are much less clear on which elements do the harm. One theory, proposed by Stern et al. (13), is that compensatory hyperinsulinemia is associated with increased risk of CAD not causally, but because the two conditions spring from the common soil of insulin resistance. OBSERVATIONAL STUDIES OF THE EFFECTS OF INADEQUATE INSULIN (POOR DIABETIC CONTROL) ON CARDIOVASCULAR RISK— The above-cited and well-known evidence that insulin resistance increases the risk of CVD in people without diabetes cannot be directly applied to people with diabetes, much less to subsets, such as people treated with insulin or people with poor glycemic control. A host of metabolic abnormalities occur in diabetes, particularly when it is uncontrolled. Hyperglycemia is only the beginning. This constellation of dysmetabolism could well change the risk equation; the inadequate insulinization could be much more of a risk than any therapeutic hyperinsulinism as such. Clearly, diabetes is a syndrome of hyperglycemia and associated metabolic abnormalities; and clearly, the syndrome does increase CAD risk. The increased incidence of macrovascular disease in type 2 diabetes could be due to the glucose hypothesis, i.e., poor glycemic control is the cause of the accelerated atherosclerosis. Pathophysiologically, hyperglycemia might cause atherosclerosis by several mechanisms: advanced glycation end products (including collagen and proteins of blood vessel walls); production of oxidized LDL cholesterol; hemorrheological changes; and changes in vascular reactivity (20). If the glucose hypothesis is correct, one would expect improved glycemic control, by whatever means, to lead to decreased macrovascular events. The Diabetes Control and Complications Trial (DCCT) in type 1 diabetic patients provided minimal support for or against the hypothesis, having been designed and powered to test the glucose hypothesis on microvascular, not macrovascular, changes. The relative youth of participants assured that there would not be many major cardiovascular events. In following CVD, however, the DCCT researchers found a trend (P = 0.08) toward decreased macrovascular events in the group with the improved glycemic control after an average of 6.5 years (21,22). The data may be more informative on this particular point in the follow-up, called Epidemiology of Diabetes Interventions and Complications (EDIC), of DCCT participants. Several observational studies also provide suggestive evidence that hyperglycemia could be a cause of macrovascular disease. McGill et al. (23), in their necropsy study of 1,532 young people aged 15–34 years, showed more extensive fatty streaks in subjects with glycosylated hemoglobin values >8%, even after correction for dyslipidemia and cigarette smoking. In a 20-year follow-up of the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study, nondiabetic men who were in the upper 2.5% of the fasting and postprandial glucose distributions were at higher risk for cardiovascular mortality (24). CROSS-SECTIONAL STUDIES OF GLYCEMIC CONTROL AND VD— The World Health Organization Multinational Study of Vascular Disease in Diabetes (25) investigated 3,583 patients with diabetes and found an association between fasting glucose levels and prevalence of stroke and peripheral vascular disease (as evidenced by amputation and claudication). There was no association with CAD as determined by ischemic changes on an electrocardiogram. The ARIC study of 4,701 middle-aged men and women concluded that glucose intolerance and type 2 diabetes decreased the elasticity, thus increasing the stiffness, of arteries as determined by noninvasive ultrasound methods (26). A later case-control study of ARIC subjects also found a correlation between glycosylated hemoglobin levels and carotid intimal-medial thickening, with relative odds of 1.77 for each 1% increment in HbA1c (27).Intimal thickening is a valid surrogate marker for future cardiovascular events (28). The Framingham study also found a correlation of glycosylated hemoglobin with CVD in women but not men (29). PROSPECTIVE STUDIES OF GLYCEMIC CONTROL AND CVD— The Diabetes Intervention Study enrolled 1,139 people with newly diagnosed type 2 diabetes. Multivariate analysis after 11 years of follow-up found that glycemic control (specifically, postprandial glucose values), blood pressure, and triglycerides were each associated with a lower incidence of CAD and mortality (30). Andersson and Svardsudd (31), in a study of 411 Swedish subjects with newly detected diabetes, noted after a mean follow-up of 7.4 years that fasting blood glucose was a univariate predictor of cardiovascular events and mortality. Subjects with an average fasting blood glucose >7.8 mmol/l had a 50% higher cardiovascular mortality than did subjects with an average fasting blood glucose <7.8 mmol/l. Similar conclusions were reached in a prospective Finnish study with 229 diabetic subjects (32). This study also demonstrated increased risk in the subjects with the longest duration of diabetes, presumably reflecting a longer exposure to hyperglycemia. The more recent study by Lehto et al. (33) of 1,059 Finnish people with diabetes examined the risk factors among the 414 patients who had cardiovascular events (including 158 deaths) over 7 years. Hyperglycemia, as defined by fasting plasma glucose >13.4 mmol/l, and dyslipidemia (low HDL cholesterol, low HDL/total cholesterol ratio, or high triglycerides) independent of other cardiovascular risk factors, each increased mortality or morbidity twofold. The combination of hyperglycemia and dyslipidemia increased the risk of cardiovascular events by a factor of three. Interestingly, hemoglobin A1 and duration of diabetes were not independent risk factors. On the other hand, the Finnish study by Kuusisto et al. (32) did not find a statistically significant increase in CVD among subjects with impaired glucose tolerance. The Hisayama study, though, screened 2,427 subjects and demonstrated an increased risk of CVD, ascribing to subjects with impaired glucose tolerance a relative risk of 1.9 for the macrovascular events of myocardial infarction and stroke, whereas diabetic patients had a relative risk of 3.0 (34). The Whitehall study in Great Britain also showed higher risk in its impaired glucose tolerance arm (35). The predictive value of hyperglycemia as a risk for CVD is relatively weak in most studies, suggesting that common antecedents may underlie both type 2 diabetes and atherosclerotic heart disease (36). Klein, in the 1995 Kelly West lecture, reported the relationship between hyperglycemia and the incidence and progression of microvascular (i.e., retinopathy) and macrovascular (amputations and cardiovascular mortality) complications in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (37). However, HbA1c was more strongly predictive of retinopathy than of macrovascular disease. A 1% increment in HbA1c led to a 10% increased risk in the incidence of CAD and a 70% increased incidence of proliferative retinopathy. Most recently, the UKPDS study of 3,055 middle-aged British men with type 2 diabetes also demonstrated that hyperglycemia independently increased the risk of angina and fatal and nonfatal myocardial infarction (38,39). Hemoglobin A1c values >6.2% predicted increased risk: for each increment of 1%, the risk increased by 11%. Another approach to correlating glycemia to CVD is by way of microvascular disease. The DCCT and much other evidence unequivocally link long-term glycemia to retinopathy and nephropathy. Several studies suggest that microvascular disease predicts cardiovascular events and mortality. In these studies, proliferative retinopathy (40,41) and particularly clinical proteinuria (42,43) independently predicted CAD, intermittent claudication, congestive heart failure, and stroke. Also, the degree of glycemia as demonstrated by HbA1c was correlated with cardiovascular mortality independent of proteinuria. Therefore, if large-vessel disease correlates with microvascular disease, it, too, should be statistically related to hyperglycemia, whether causally related or not. Despite these positive cross-sectional and prospective data, a few cross-sectional studies fail to show an association between glycemia and macrovascular disease. Ito et al. (44) described 899 nonobese (average BMI of 23 kg/m2) Japanese patients with type 2 diabetes and macrovascular disease and found that in multivariate analysis, duration of diabetes was more closely correlated than fasting glucose. Similar findings were reported by Meigs et al. (45) in their 1,539 type 2 diabetic subjects in Massachusetts. However, this analysis used self-reported data provided by questionnaire rather than objective measures of the presence of CAD. Haffner et al. (46) also did not find a strong association between the degree of hyperglycemia and the prevalence of CAD in a study of diabetic Mexican Americans. In sum, although it is clear that glycemia is more strongly associated with microvascular than macrovascular disease, the bulk of evidence does confirm a relationship between the degree of diabetic control and the extent of large-vessel disease. It may well be that a variably long latent period of IRS, before the onset of frank hyperglycemia, induces atherogenicity, with the added effect of diabetes itself coming only after that foundation is laid. The extent of atherosclerosis would then depend heavily on the length and severity of the prediabetic insulin-resistant state and less heavily on the hyperglycemia. Microvascular complications, on the other hand, may be more specifically due to clinical hyperglycemia, thus correlating more tightly to duration of diabetes itself. In any case, the risk or benefit of insulin therapy when it is needed to control diabetes requires considerations that are very different from those operative in the prediabetic or mildly diabetic state. EFFECTS OF INSULIN THERAPY ON CARDIOVASCULAR EVENT RISK— Studying the effect of insulin therapy as such on cardiovascular events is fraught with difficulty in the absence of a randomized trial. In any study that does not purposely allow very poor diabetic control, it can almost certainly be assumed that those taking insulin have more severe diabetes, i.e., less endogenous insulin reserve and at least a history of less-well-controlled dysmetabolism. This said, several studies do suggest that excess mortality is associated with insulin therapy. In the National Health and Nutrition Examination Survey (NHANES I), after a 9-year follow-up, there was a trend toward excess cardiovascular mortality among people with insulin-requiring diabetes compared with those on oral hypoglycemic agents (47). The confidence intervals were wide, contributing to the statistical insignificance of the result. Also, there was no adjustment for the duration of diabetes and glycemic control. In a study of 689 diabetic Pima Indians >45 years of age who used a multivariate model controlling for duration of diabetes, the risk of cardiovascular mortality was significantly increased in insulin-treated patients (11 vs. 8 deaths, giving an incidence-rate ratio of 3.8) (17). Another study in Pima Indians, however, analyzed 824 people with diabetes and did not find an increased prevalence of CAD (as determined by electrocardiogram) among insulin-treated subjects; the researchers concluded that insulin therapy may not be atherogenic, but rather is a marker for more severe diabetes (48). A study of 197 German diabetic subjects did find a strong association between insulin dose and macrovascular events (49). Conversely, prospective studies comparing therapies have on the whole not been incriminating of insulin. The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study found a dramatically decreased mortality (relative reduction of 52%), after 1 year in 306 diabetic patients who had stringent glycemic control using insulin-glucose infusion during the acute phase of myocardial infarctions, compared with 314 patients who received conventional therapy (50). The University Group Diabetes Program was a long-term prospective randomized intervention trial accomplished between about 1961 and 1975 (51). It compared the efficacy of a fixed-dose insulin regimen, a variable-dose insulin regimen, and a diet plus oral placebo regimen in 619 patients with type 2 diabetes. Genuth (52) recently reviewed the subject of insulin therapy and cardiovascular risk, noting that the University Group Diabetes Program, despite its flaws, found no evidence that the insulin worsened outcome. Indeed, there was a slight trend toward fewer cardiovascular events. The Kumamoto Study evaluated 110 nonobese Japanese diabetic patients. After 6 years, the intensive insulin therapy group had significant reductions in microvascular complications compared with the standard insulin therapy group (53). There was no significant effect on macrovascular outcome, but, as with the DCCT, the small event rate would not be expected to yield a significant result. Despite these encouraging results, the 27-month pilot study of 153 men in the Veterans Administration Cooperative Study of Diabetes Mellitus (VACSDM) suggested that intensive therapy of type 2 diabetes with exogenous insulin resulted in more cardiovascular events (54). The much larger and longer UKPDS report described a trend toward reduced relative risk for fatal and nonfatal myocardial infarction, sudden death, heart failure, and amputation, but not for cerebrovascular disease, in the intensely controlled group after 10 years (55). However, despite the relatively large number of events, these endpoints did not achieve statistical significance (P = 0.052), which suggests either that glycemic control may play a smaller role than expected in macrovascular disease or that the follow-up period was too short. Subgroup analysis of the intensive therapy group showed that the insulin group (911 subjects) did not have any different outcomes than the chlorpropamide (619 subjects) or glyburide (615 subjects) groups, even though fasting plasma insulin concentrations were higher in the insulin group. Hence, it was concluded that intensive insulin therapy does not have a harmful effect on cardiovascular outcomes. Interestingly, the use of intensive treatment with metformin, specifically in obese subjects, resulted in even better macrovascular outcomes than treatment with insulin or sulfonylureas (56).This surprising but intriguing result would benefit by replication in other studies. EFFECTS OF INSULIN THERAPY ON CARDIOVASCULAR RISK FACTORS Insulin and dyslipidemia Even without frankly abnormal total plasma lipids, patients with type 2 diabetes have more small dense LDL particles, which have been shown to be atherogenic (59,60). The DCCT, which is the most carefully controlled randomized clinical trial on the effects of insulin therapy, found a 34% reduction in LDL cholesterol in the intensively treated group (21). In a follow-up report, the intensive insulin therapy group was also noted to have lower apolipoprotein B, lower cholesterol content of dense LDL and VLDL, and higher cholesterol content of buoyant LDL compared with the conventionally treated group (61). Caucasian subjects also had lower lipoprotein(a). Although the overall effect of intensive control on lipoprotein profile was anti-atherogenic, the study was, as mentioned, too short and in too young a cohort to expect an effect on macrovascular events. A disturbing DCCT subanalysis, however, found that the intensively treated people who gained the most weight had a distinct worsening of their cardiovascular risk factors (62). Smaller, more metabolically oriented studies have shown that insulin therapy improves hypertriglyceridemia, which as noted is a risk indicator for CAD events in individuals with diabetes. Some studies using bedtime insulin in addition to oral hypoglycemic agents showed that the lipid profile improved, at least in the short term (63). In a study of 19 diabetic subjects by Taskinen et al. (64), 4 weeks of insulin therapy to abruptly improve glycemic control decreased VLDL triglyceride 60%, increased HDL2 cholesterol 21% (due mostly to a redistribution of particles from HDL3 to HDL2), and resulted in a 2.3-fold increase in adipose tissue lipoprotein lipase (64). Other reports have confirmed that improved glycemic control with insulin induces reductions in VLDL triglyceride, LDL cholesterol and total cholesterol and increases HDL cholesterol (65–69). In a discordant result, the above-mentioned VACSDM found that despite improvement in the baseline HbA1c from a mean of 9.3 to 7.2%, there was no significant improvement in total triglycerides, LDL cholesterol, or HDL cholesterol and only a small improvement in total cholesterol (54). The improved glycemic control was accomplished by a variety of staged interventions, not only insulin treatment. Intensification of glycemic control using insulin in 60 poorly controlled type 2 diabetic men and women in Spain did not result in reduced lipoprotein(a) levels (70), so any improvement in the anti-atherogenic profile of lipoproteins may be independent of lipoprotein(a). It is also worth noting that the effect of insulin therapy on the lipoprotein profile may be dependent on the mode of delivery of insulin. Intraperitoneal insulin administration appears to normalize the lipoprotein profile compared with subcutaneous insulin, which causes peripheral hyperinsulinemia (71,72). The metabolism of remnant particles may also be improved by intraperitoneal delivery of insulin (73). The absorption of insulin preferentially into the hepatic portal vein could increase the activity of hepatic lipase, resulting in the observed changes, although this effect has not been proven. The weight of evidence, then, is consistent with the conclusion that improved glycemic control with insulin has a markedly beneficial effect on the cardiovascular risk profile of serum lipids. In recognizing the importance of CVD in type 2 diabetes, the management of dyslipidemia in diabetes is an important aspect of treatment, as summarized in a recent American Diabetes Association consensus statement (74) and in an excellent technical review by Haffner (75). A basic aspect of this management is glycemic control by whatever means are necessary, including insulin therapy. Insulin and blood pressure In the rat model, short-term insulin infusion increases blood pressure (77). However, in hyperglycemic Sprague-Dawley rats, poor glycemic control (by reducing their required insulin) also leads to hypertension (78). Prolonged insulin infusion in normotensive dogs has no effect on blood pressure (79). Hence, the data are conflicting in animal models. In humans, it has been known for some time that insulin, at least in the setting of refeeding, has a sodium-retaining effect (80), which is considered responsible for the clinical phenomenon of "insulin edema" sometimes seen with the treatment of diabetic ketoacidosis. Acutely, however, physiological increases in plasma insulin levels in insulin-resistant, obese individuals do not increase blood pressure, whether the individuals are hypertensive or normotensive (76). Human metabolic studies have been similarly inconsistent in proving a causal association of peripheral hyperinsulinemia due to chronic insulin administration and hypertension. In one retrospective study in 80 people with type 2 diabetes poorly controlled on oral hypoglycemic agents, insulin therapy was associated with increases in blood pressure compared with control subjects (81). The mean systolic blood pressure rose from 131 to 148 mmHg and the diastolic blood pressure from 81 to 89 mmHg. It should be noted, however, that there was also a mean increase in body weight of 5.9 kg. In another study of 12 obese diabetic women, decreasing the insulin dose led to decreases in blood pressure (82). However, this reduction in blood pressure was only seen in the women with essential hypertension and was seen with a decrease in body weight. The normotensive women had no changes in blood pressure. Several prospective studies examine the effect of exogenous insulin on blood pressure, but nearly all involve small numbers of subjects. In the Kumamoto study, there were no significant changes in blood pressure or lipids (53). The VACSDM also did not demonstrate any adverse effects of insulin on blood pressure in their 153 patients (54). Intensive insulin therapy in type 1 diabetic patients in the DCCT did not increase the incidence of hypertension (21). Also, it has been pointed out that patients with insulinomas (and who are therefore hyperinsulinemic but not insulin resistant or hyperglycemic) are generally normotensive (83). In addition, resection of the insulinomas does not lead to a fall in the mean blood pressure. Women with polycystic ovary syndrome also have insulin resistance and hyperinsulinemia, but they do not have an increased incidence of hypertension (84). Insulin has even been shown to be vasodilatory in some vascular beds, possibly mediated in part by nitric oxide (20). The role of nitric oxide has been looked on differently by others, however. Insulin's ability to induce vasodilation may be blunted in insulin-resistant states because of endothelial dysfunction, leading to decreased production of nitric oxide (85). Hence, it may be the syndrome of insulin resistance rather than insulin itself that is causally related to hypertension. This theory is also supported by evidence that troglitazone, a drug that decreases insulin resistance, lowers blood pressure in animal models and humans (86). The overall body of evidence at this time, therefore, is inconsistent. But in balance, the literature is not supportive of the hypothesis that insulin therapy has a hypertensive effect independent of body weight. Insulin and weight gain In the DCCT, patients in the intensive insulin therapy arm gained a mean of 4.6 kg after 5 years compared with patients in the conventional therapy group (22). In the UKPDS, the insulin therapy group had a 9.9 kg increase in body weight compared with 5.3 kg in the sulfonylurea therapy group and –1.3 kg in the metformin therapy group (39). Most of the weight occurred during the 1st year, with a slower accretion in the following years. The smaller VASCDM found no change in BMI in their 153 subjects treated for >30 months (54). An analysis of the Wisconsin Epidemiologic Study of Diabetic Retinopathy found a highly significant association between weight gain and improvement in glycosylated hemoglobin (91). The simplest explanation for weight gain during intensification of diabetes treatment would be that glucosuria is reduced, and the urinary calorie loss is therefore reduced. There is also evidence, though, that weight gain in the setting of insulin treatment is due to accumulation of adiposity. This could be by the same mechanism that affects the macrosomic child of a poorly controlled diabetic mother. Carlson and Campbell (92) examined body composition, energy expenditure, and substrate kinetics in six type 1 diabetic people receiving intensive insulin therapy, comparing them to six control subjects. They found that their subjects gained 2.6 ± 0.8 kg in the first 2 months due to increased body fat, without any change in lean body mass. The elimination of glycosuria accounted for 70% of this positive energy balance, and 30% was due to the reduction in daily energy expenditure. The reduction in the energy expenditure was said to be caused by a decrease in metabolic futile cycling involving the fuels of protein, free fatty acids, and glucose. It was estimated that caloric intake would have to be reduced ~20% to achieve thermodynamic balance. Presumably, similar metabolic changes occur in type 2 diabetes, but this has not been rigorously proven. Another possible mechanism by which insulin could induce weight gain is by the common clinical complaint that insulin increases appetite. Appetite is exceedingly difficult to study, however, and insulin's effect on desire for food has not been carefully studied. Certainly, if over-insulinization induces hypoglycemia, that would increase hunger and food intake. There is also a direct relationship between the levels of insulin in the cerebrospinal fluid and plasma insulin levels (93). To the extent that insulin crosses the blood-brain barrier, it might have a direct effect on appetite and satiety. However, insulin, along with leptin, inhibits the production of neuropeptide Y in the hypothalamic arcuate nucleus, thus mediating a decrease, not an increase, in food intake (94). Insulin also potentiates the action of leptin and directly enhances the satiety effect of cholecystokinin. Hence, most data support hyperinsulinemia causing decreased appetite and food intake. This has led to speculation that weight gain in type 2 diabetic subjects treated with insulin could worsen insulin resistance and in this way increase the risk of macrovascular disease (95), a theory supported by the above-mentioned comparison of risk factors in those DCCT subjects who gained the most and the least weight on their intensive control regimen (62). Irrespective of the mechanism, intensive insulin therapy does cause weight gain, which in and of itself could worsen insulin resistance, blood pressure, and dyslipidemia, thus aggravating atherosclerosis (62,95). Such a pathogenic sequence rests on a number of assumptions, none of which are proven, however; in fact, the data suggest no worsening of the atherogenic profile in studies—including the UKPDS—in which there was concurrent improvement in glycemic control and weight gain. Subjects on intensive treatment did not have more hypertension or dyslipidemia than did the control subjects on conventional treatment. However, the final proof will be missing until randomized studies assess macrovascular events as the clinical endpoint. The UKPDS group is extending their study by another 5 years to determine if strict glycemic control will significantly decrease the risk of cardiovascular events with longer follow-up, which will hopefully settle the issue. CONCLUSION— Clinicians with a patient in poor diabetic control, when dietary, lifestyle, and oral medication options have been exhausted, must decide between two potentially unattractive alternatives: allowing continued poor control of diabetes or starting insulin therapy. The most conclusive evidence for choosing good glycemic control with insulin is that doing so will retard or prevent diabetic retinopathy, neuropathy, and nephropathy. But the weight of evidence also supports the conclusion that insulin therapy will improve, rather than adversely affect, the risk of CVD. 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responses to starvation and weight loss. 95. Lasker RD: The Diabetes Control and Complications Trial: implications for policy and practice. N Engl J Med 329:1035–1056, 1993 From the Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to Christopher D. Saudek, MD, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Osler 576, Baltimore, MD 21287. E-mail: csaudek@welchlink.welch.jhu.edu. Address reprint requests to Michael S. Boyne, MD, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Blalock 904, Baltimore, MD 21287. Received for publication 6 July 1998 and accepted in revised form 22 December 1998. Abbreviations: ARIC, Atherosclerosis Risk in the Community; CAD, coronary artery disease; CVD, cardiovascular disease; DCCT, Diabetes Control and Complications Trial; IRS, insulin resistance syndrome; UKPDS, U.K. Prospective Diabetes Study; VACSDM, Veterans Administration Cooperative Study of Diabetes Mellitus. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
-cell failure.
However, many physicians are reluctant to institute insulin therapy in type 2 diabetes for
fear of accelerating atherosclerosis. The epidemiological evidence is reasonably sound
that hyperinsulinism correlates with increased cardiovascular disease in nondiabetic
people and those with early type 2 diabetes. It is much less clear, however, that insulin
concentration plays a negative role when less well controlled diabetes is considered. The
data are more consistent, in fact, with the glucose hypothesis, i.e., that hyperglycemia
is a risk factor, although the magnitude of the glucose effect is not well defined.
Certainly, the dysmetabolism associated with poor glycemic control could increase the risk
of macrovascular events through well-known mechanisms. There is direct evidence that
insulin therapy can reduce the risk of macrovascular events by improving glycemic control
and diabetes-associated dyslipidemias, although the beneficial effects may be
significantly compromised by excessive weight gain. Insulin therapy does not appear to
induce hypertension independent of changes in body weight. It is concluded that optimal
glycemic control confers a known benefit and can only be achieved with insulin therapy in
some people with type 2 diabetes. In these circumstances, the use of insulin has a net
benefit on cardiovascular risk, mediated primarily through improvement in dyslipidemia and
glycemia itself.