Differential Associations of Oral Glucose Tolerance Test–Derived Measures of Insulin Sensitivity and Pancreatic β-Cell Function With Coronary Artery Calcification and Microalbuminuria in Type 2 Diabetes

OBJECTIVE

We evaluated relationships of oral glucose tolerance testing (OGTT)–derived measures of insulin sensitivity and pancreatic β-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease.

RESEARCH DESIGN AND METHODS

A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and β-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria.

RESULTS

The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio −0.78 [95% CI −1.51 to −0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30–0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes.

CONCLUSIONS

Lower β-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.     

Heterogeneity of Patients With Latent Autoimmune Diabetes in Adults: Linkage to Autoimmunity Is Apparent Only in Those With Perceived Need for Insulin Treatment: Results from the Nord-Tr?ndelag Health (HUNT) study

OBJECTIVE—Subjects with the diagnosis of latent autoimmune diabetes in adults (LADA) are more prone to need insulin treatment than those with type 2 diabetes. However, not all patients with LADA develop the need for insulin treatment, indicating the heterogeneity of LADA. We investigated this heterogeneity by comparing phenotypes of LADA with and without perceived need for insulin treatment (data obtained at times when diagnosis of LADA was not investigated) and also compared LADA and type 2 diabetes phenotypes.RESEARCH DESIGN AND METHODS—We used data from the all population–based Nord-Trøndelag Health study (n = 64,931), performed in 1995–1997. Data were assembled for individuals with LADA (n = 106) and type 2 diabetes (n = 943).RESULTS—In the comparison of individuals with LADA both with and without the need for insulin, insulin-treated subjects had higher titers of GAD antibodies (P < 0.001) and lower fasting C-peptide levels (P < 0.001). GAD antibodies and C-peptide correlated negatively (r = −0.40; P = 0.009). In the comparison of individuals with LADA and type 2 diabetes, all without the need for insulin, markers of metabolic syndrome were equally prevalent and pronounced. Age, C-peptide, and glucose levels were also similar. In the comparison of insulin-treated individuals with LADA and type 2 diabetes, more patients with LADA received insulin (40 vs. 22%, P < 0.001) and C-peptide levels were lower (P < 0.001). Patients with LADA were leaner but were still overweight (mean BMI 28.7 vs. 30.9 kg/m² in type 2 diabetes, P < 0.001). In the comparison of type 2 diabetic patients with and without insulin, insulin-treated subjects were more obese and had higher A1C and lower C-peptide levels (P < 0.001).CONCLUSIONS—Our conclusions are that 1) the need for insulin treatment in LADA is linked to the degree of autoimmunity and β-cell failure, 2) subjects with LADA and type 2 diabetes without the need for insulin treatment are phenotypically similar, and 3) insulin treatment in type 2 diabetic patients is associated with both insulin resistance and β-cell insufficiency.Autoimmunity is the major cause of type 1 diabetes. Autoimmunity is also assumed to be the major cause of latent autoimmune diabetes in adults (LADA) because this category of diabetes shares biochemical markers of β-cell–directed autoimmunity with “classic” type 1 diabetes. In clinical practice, autoimmunity in classic type 1 diabetes as well as in LADA is usually documented by antibodies against GAD.LADA is considered a “mild” form of type 1 diabetes. Mild indicates the fact that patients with LADA do not by clinical judgment need insulin from the time of diagnosis. However, within the first few years after the diagnosis of diabetes a need for insulin treatment develops in many patients with LADA. This distinguishes patients with LADA from those with nonautoimmune type 2 diabetes in whom a need for insulin treatment develops later than in those with LADA (1). An early need for insulin treatment in patients with LADA points to ongoing autoimmune-mediated destruction of β-cells in these patients.Risk factors for type 2 diabetes, such as age, obesity, and lack of physical activity, are associated with the development of LADA (2). In fact, odds ratios in terms of risk for diabetes for these factors of insulin resistance were the same for LADA and type 2 diabetes. This raises the question of the relative importance of autoimmunity vis-à-vis insulin resistance for the etiology of LADA and whether etiology differs among patients with LADA. Support for etiological heterogeneity comes from the large UK Prospective Diabetes Study (UKPDS), in which only a minority of patients with the diagnosis of LADA, when defined solely as GAD antibody positivity, developed the need for insulin treatment during 6 years of follow-up (1). The heterogeneity of LADA is also evident when one compares phenotypes of patients with LADA in different studies (3–6).Heterogeneity of patients with LADA could be further elucidated by comparing phenotypes of insulin-treated patients with LADA with those not treated with insulin. However, several conditions have to be met for such comparisons to be valid. First, groups of diabetic subjects to be compared must be drawn from the same geographically defined population. A population-based study is necessary to avoid the possible biases incurred by studying referral patients or patients selected for inclusion in clinical intervention studies. Second, the perceived need for insulin treatment has to be unbiased by LADA classification, because it has been shown that insulin treatment is initiated earlier when prior knowledge of autoimmunity, measured as GAD antibodies, is available (7). Third, valid comparison groups of insulin-treated and non–insulin-treated type 2 diabetic patients from the same population must be at hand.We had the opportunity to study patients with LADA and type 2 diabetes fulfilling the above-mentioned conditions, who were identified and characterized in the Nord-Trøndelag (HUNT) study. The HUNT study was performed between 1995 and 1997. The study was open to all adult subjects (∼90,000) living in a geographically defined area and had a high attendance rate (70%). To our knowledge, the patients with LADA and type 2 diabetes defined in the HUNT study did not participate in any study at the time of diagnosis and initiation of treatment, thereby minimizing any deviation from standard clinical practice and obviating increased attentiveness for signs of insufficient metabolic control and insulin requirement. Further, autoantibodies, such as GAD antibodies, were not measured by doctors (general practitioners) responsible for treatment in the region as part of the diabetes workup before and at the time of assembling data in 1995–1997. Thus, patients with autoimmune diabetes not requiring insulin at time of diagnosis were regarded and treated as type 2 diabetic patients. This assumption provided a unique opportunity to use the need for insulin as clinically perceived as a parameter for subclassifying patients with LADA and to compare phenotypes of insulin-treated and non–insulin-treated patients with LADA with respective groups of type 2 diabetic patients. Specifically, we wished to assess the influence of autoimmunity and β-cell insufficiency vis-à-vis insulin resistance factors for the perceived need for insulin treatment in patients with LADA.     

Evolution of Percutaneous Coronary Intervention in Patients with Diabetes: A report from the National Heart, Lung, and Blood Institute�Csponsored PTCA (1985�C1986) and Dynamic (1997�C2006) Registries

OBJECTIVE

To evaluate the association of successive percutaneous coronary intervention (PCI) modalities with balloon angioplasty (BA), bare-metal stent (BMS), drug-eluting stents (DES), and pharmacotherapy over the last 3 decades with outcomes among patients with diabetes in routine clinical practice.

RESEARCH DESIGN AND METHODS

We examined outcomes in 1,846 patients with diabetes undergoing de novo PCI in the multicenter, National Heart, Lung, and Blood Institute–sponsored 1985–1986 Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry and 1997–2006 Dynamic Registry. Multivariable Cox regression models were used to estimate the adjusted risk of events (death/myocardial infarction [MI], repeat revascularization) over 1 year.

RESULTS

Cumulative event rates for postdischarge (31–365 days) death/MI were 8% by BA, 7% by BMS, and 7% by DES use (P = 0.76) and for repeat revascularization were 19, 13, and 9% (P < 0.001), respectively. Multivariable analysis showed a significantly lower risk of repeat revascularization with DES use when compared with the use of BA (hazard ratio [HR] 0.41 [95% CI 0.29–0.58]) and BMS (HR 0.55 [95% CI 0.39–0.76]). After further adjustment for discharge medications, the lower risk for death/MI was not statistically significant for DES when compared with BA.

CONCLUSIONS

In patients with diabetes undergoing PCI, the use of DES is associated with a reduced need for repeat revascularization when compared with BA or BMS use. The associated death/MI benefit observed with the DES versus the BA group may well be due to greater use of pharmacotherapy.The practice of percutaneous coronary intervention (PCI) has evolved rapidly in the past 3 decades, with technological advancements from balloon angioplasty (BA) to bare-metal stents (BMS) and the more recent drug-eluting stents (DES) (1). Comparisons of device-specific outcomes have yielded similar results, with a recent meta-analysis reporting a significant reduction in the rate of target lesion revascularization, but not mortality, with DES use compared with BMS use (2).Coronary angioplasty in patients with diabetes has been shown to have a higher rate of infarction and a greater need for additional revascularization procedures (3). In a large consecutive series of patients treated by elective stent implantation, patients with diabetes were at higher risk for in-hospital mortality and subsequent revascularization, which ultimately resulted in a significantly lower cardiac event-free survival rate (4). Yet, the benefit of DES over BMS remains unclear. A pooled analysis (5) reported a significant difference in survival in favor of BMS over the DES, whereas no significant difference in mortality was observed in another analysis of 14 randomized controlled trials (6). Given these inconsistent findings and the growing percentage of diabetic patients undergoing PCI, the impact of advances in PCI technology and adjunct improvement in pharmacotherapy on outcomes in patients with diabetes needs to be assessed.We, therefore, investigated the effectiveness of PCI in patients with diabetes by comparing 1-year rates of death/myocardial infarction (MI) and repeat revascularization across the three device modalities: BA, BMS, and DES. Data from the multicenter, National Heart, Lung, and Blood Institute (NHLBI)-sponsored 1985–1986 Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry and the 1997–2006 Dynamic Registry were used for this purpose.