Do Non-Insulin-dependent Diabetes Mellitus and Cardiovascular Disease Share Common Antecedents?

Traditionally, atherosclerotic cardiovascular disease has been regarded as a complication of both insulin-dependent (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM). In fact, diabetologists have even created their own name for this disorder. They call it macrovascular disease to distinguish it from microvascular disease, which is a complication of both types of diabetes. It is somewhat telling that only diabetologists refer to atherosclerotic disease in this parochial way. Recently, there has been a growing tendency to think of diabetes and cardiovascular disease as sharing the same, or similar, environmental and genetic antecedents, that is, as springing from a common soil. This idea was originated by Jarrett [1], who noted that cardiovascular complications were as common in newly diagnosed diabetic persons as in those whose diabetes was of long duration. Jarrett reasoned that if cardiovascular disease were a complication of diabetes, then its frequency would increase with increasing duration of diabetes. This correlation was not observed, however, at least not in the Whitehall Study [2]. Moreover, nondiabetic patients who were merely at increased risk by virtue of having impaired glucose tolerance seemed to have the same rate of cardiovascular disease as patients with long-established diabetes [2]. These findings led Jarrett to speculate that cardiovascular disease, rather than being a complication of diabetes, shared environmental and genetic antecedents with diabetes. Early-Life Influences Recently, Hales and colleagues [3] and Barker and associates [4] have called attention to early-life determinants of adult diseases. They have presented evidence indicating that low birth weight and low weight gain during the first year of life are associated with the occurrence of NIDDM and cardiovascular disease decades later [3, 4]. Hales and Barker [5] theorized that inadequate nutrition during fetal and early life might lead to inadequate development of pancreatic islet cells with a propensity toward islet cell failure and thus diabetes in adult life. Low birth weight and low weight at age 1 year were also shown by Barker and colleagues [6] to be associated with the insulin resistance syndrome in adults, a finding recently confirmed not only in non-Hispanic whites but also in Mexican Americans (Figure 1) [7]. This syndrome was initially described in lean persons by Reaven [8], who labeled it syndrome X. As described by Reaven, the syndrome consisted of insulin resistance, hyperinsulinemia, dyslipidemia with high triglyceride and low high-density lipoprotein cholesterol levels, and hypertension [8]. Clearly, most persons who manifest features of the syndrome have, in addition, obesity, and in particular abdominal obesity. The type of obesity they have is probably visceral obesity, but because most studies characterize the obesity using anthropometric measurements such as waist circumference rather than abdominal computed tomography scans, it is not possible to distinguish definitively between visceral and subcutaneous abdominal adiposity. Therefore, although I use the term abdominal obesity, the visceral adipose depot is in all likelihood the one directly linked to the insulin resistance syndrome and may be one of its determinants. Figure 1. Prevalence of the insulin resistance syndrome by ethnicity and tertile of birth weight in 562 patients from the San Antonio Heart Study. As with the insulin resistance syndrome, low birth weight has also been shown to predict future development of abdominal obesity. This finding has been documented in whites in a United Kingdom study [9] and in both non-Hispanic whites and Mexican Americans in the San Antonio, Texas, population [7]. Perhaps inadequate nutrition in early life limits adipocyte development, and perhaps visceral adipocytes, because of the greater ease with which they undergo hypertrophy [10], become the storage depot of choice when excess calories in adults encounter limited adipose storage sites. Can the theory be proved that inadequate nutrition in early life is the common soil that gives rise to both NIDDM and cardiovascular disease in adults? I have already alluded to a mechanism whereby this deficiency might lead to inadequate islet cell development, predisposing persons to later islet cell failure, and to a corresponding mechanism whereby the deficiency might also lead to abdominal obesity, which could in turn contribute to development of the insulin resistance syndrome in adults. If the insulin resistance syndrome could be shown to be an important risk factor for both NIDDM and cardiovascular disease, then the framework would exist for a comprehensive schema leading from nutritional deficiencies in early life to NIDDM and cardiovascular disease in adults. This hypothetical schema is shown in Figure 2. I will show that abundant evidence exists that each element of the insulin resistance syndrome is a risk factor for the future development of NIDDM. The evidence that the insulin resistance syndrome elements are also risk factors for future cardiovascular disease, however, is less conclusive. Figure 2. Schema for the common soil hypothesis for NIDDM and cardiovascular disease. The Insulin Resistance Syndrome: The Missing Link? One plausible theory is that insulin resistance places an extra demand on the pancreatic islet cells, compelling them to hypersecrete insulin, presumably for many years or even decades, and that this stress eventually leads to islet cell failure. In addition to theoretical considerations, however, empirical evidence also points to the insulin resistance syndrome as a precursor of diabetes. In fact, each element of the insulin resistance syndrome has been documented as a risk factor for NIDDM in at least two and up to ten prospective epidemiologic studies. Insulin resistance measured by the euglycemic insulin clamp technique in Pima Indians [11] and by the intravenous glucose tolerance test in whites [12] has been documented as a diabetes risk factor in prospective studies. Hyperinsulinemia, presumably reflecting compensatory hypersecretion of insulin, has also been documented to be a risk factor for NIDDM in at least six prospective epidemiologic studies [13-18]. Obesity and abnormal glucose tolerance are the classic risk factors for diabetes [13-24]. There is also evidence that abdominal obesity is an independent risk factor for diabetes [15-18, 22] and is perhaps more important than obesity itself. In the San Antonio Heart Study [25], overall obesity as reflected by body mass index (k/m2) is an independent risk factor for diabetes, but ceases to be so when the ratio of waist-to-hip circumference, a measure of abdominal obesity, is added to the predicting model (unpublished data). Evidence also suggests that the same is true for cardiovascular disease, namely, that abdominal obesity rather than generalized obesity is the stronger risk factor. Hypertension and dyslipidemia with high triglyceride and low high-density lipoprotein levels are well-known concomitants of NIDDM. Perhaps less well known is that these two features of the insulin resistance syndrome are also precursors of diabetes [13, 15, 18-2023, 24]. Thus, all of the elements of the insulin resistance syndrome are risk factors for NIDDM. Because low birth weight is associated with development of the insulin resistance syndrome in adults [6, 7], the argument can be made that the insulin resistance syndrome is the metabolic derangement that links early nutritional deficiency and later NIDDM. This formulation implies that insulin resistance and compensatory insulin hypersecretion are the principal precursors of NIDDM. However, Hales and Barker [5] have argued that early nutritional deficiency leads to stunted islet cell development and a predisposition to islet cell failure. Is it possible to reconcile these two views? The extensive epidemiologic data implicating hyperinsulinemia as a risk factor for diabetes is based on insulin assays that are now known to be nonspecific and to cross-react with proinsulin and other insulin precursors [26]. The relevance of this finding to the insulin resistance-insulin deficiency debate stems from the belief that the appearance of insulin precursors in the circulation signals a failing pancreas. We now generally accept that much, perhaps most, of the immunoassayable insulin in patients with established NIDDM is, in fact, not insulin but rather proinsulin [27-29]. The question at issue, however, is whether these findings extend to prediabetic persons. In other words, is diabetes preceded by a prolonged period of hyperinsulinemia reflecting a compensatory response to insulin resistance, or is it preceded by a prolonged period of hyperproinsulinemia reflecting islet cells on the verge of failure. Of note is the fact that high-risk populations such as Mexican Americans or patients with impaired glucose tolerancepopulations that may be presumed to include many prediabetic personshave elevated levels of both insulin and proinsulin [28-30]. However, the elevation of the latter is not disproportionate to the elevation of insulin itself. Thus, the ratio of proinsulin to insulin concentration is normal or at most minimally elevated [28-30]. These findings suggest that proinsulin plays at most a minor role during the prediabetic period. On the other hand, prospective data suggest that the fasting proinsulin concentration is a better predictor of future diabetes than is the specific insulin concentration (that is, a concentration measured with a radioimmunoassay that does not cross-react with proinsulin). Additional data implying a role for insulin deficiency in the pathogenesis of NIDDM are based on the insulin response to an oral glucose load. Several studies have found that diminished 30-minute or 2-hour insulin concentrations, or both, after oral glucose are predictive of future diabetes [13, 17, 31-33]. Haffner and colleagues [34] have recently p