and acute insulin response (AIR) (25-g intravenous glucose challenge). Sixty-three subjects developed diabetes over an average follow-up of 6.9 ؎ 4.9 years. In 224 subjects, who remained nondiabetic, follow-up measurements of M and AIR were available. At baseline, ALT, AST, and GGT were related to percent body fat (r ‫؍‬ 0.16, 0.17, and 0.11, respectively), M (r ‫؍‬ ؊0.32, ؊0.28, and ؊0.24), and HGO (r ‫؍‬ 0.27, 0.12, and 0.14; all P < 0.01). In a proportional hazard analysis with adjustment for age, sex, body fat, M, and AIR, higher ALT [relative hazard 90th vs. 10th centiles (95% CI): 1.9 (1.1-3.3), P ‫؍‬ 0.02], but not AST or GGT, predicted diabetes. Elevated ALT at baseline was associated prospectively with an increase in HGO (r ‫؍‬ 0.21, P ‫؍‬ 0.001) but not with changes in M or AIR (both P ‫؍‬ 0.1). Higher ALT concentrations were cross-sectionally associated with obesity and whole-body and hepatic insulin resistance and prospectively associated with a decline in hepatic insulin sensitivity and the development of type 2 diabetes. Our findings indicate that high ALT is a marker of risk for type 2 diabetes and suggest a potential role of the liver in the pathogenesis of type 2 diabetes.

OBJECTIVE—Periodontal disease may contribute to the increased mortality associated with diabetes. RESEARCH DESIGN AND METHODS—In a prospective longitudinal study of 628 subjects aged ≥35 years, we examined the effect of periodontal disease on overall and cardiovascular disease mortality in Pima Indians with type 2 diabetes. Periodontal abnormality was classified as no or mild, moderate, and severe, based on panoramic radiographs and clinical dental examinations. RESULTS—During a median follow-up of 11 years (range 0.3–16), 204 subjects died. The age- and sex-adjusted death rates for all natural causes expressed as the number of deaths per 1,000 person-years of follow-up were 3.7 (95% CI 0.7–6.6) for no or mild periodontal disease, 19.6 (10.7–28.5) for moderate periodontal disease, and 28.4 (22.3–34.6) for severe periodontal disease. Periodontal disease predicted deaths from ischemic heart disease (IHD) (P trend = 0.04) and diabetic nephropathy (P trend &lt; 0.01). Death rates from other causes were not associated with periodontal disease. After adjustment for age, sex, duration of diabetes, HbA1c, macroalbuminuria, BMI, serum cholesterol concentration, hypertension, electrocardiographic abnormalities, and current smoking in a proportional hazards model, subjects with severe periodontal disease had 3.2 times the risk (95% CI 1.1–9.3) of cardiorenal mortality (IHD and diabetic nephropathy combined) compared with the reference group (no or mild periodontal disease and moderate periodontal disease combined). CONCLUSIONS— Periodontal disease is a strong predictor of mortality from IHD and diabetic nephropathy in Pima Indians with type 2 diabetes. The effect of periodontal disease is in addition to the effects of traditional risk factors for these diseases.

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Lower levels of MetSO and higher levels of select AGE are associated with increased incident CVD and may help account for the limited benefit of intensive glucose lowering in type 2 diabetes.

Objective To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes. Methods and Results CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment. Conclusions Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

OBJECTIVETo determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM).RESEARCH DESIGN AND METHODSProgression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM.RESULTSAfter adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.2 ± 0.5 mm3 vs. 4.2 ± 1.1 mm3; P < 0.01). AAC progression was in general not significantly increased with more frequent statin use; in a subgroup of participants initially not receiving statins, however, progression of both CAC and AAC was significantly increased in frequent statin users.CONCLUSIONSMore frequent statin use is associated with accelerated CAC in T2DM patients with advanced atherosclerosis.

A lthough the number of children and youth with type 2 diabetes is increasing, a clear case definition that describes children with type 2 diabetes at presentation remains elusive. Most initial diagnoses are decided on the clinical picture at presentation (1). Characteristics and risk factors have been outlined in several review and clinical articles (2-4). The purpose of this study was to describe the characteristics of youth presenting for an initial visit to the outpatient clinic of a large tertiary children's care center and diagnosed with type 2 diabetes.For this retrospective study, data were abstracted from a consecutive sample of 98 patients' medical records at Texas Children's Hospital starting 1 January 1998 and ending 31 October 2001. The sample's mean age at diagnosis was 13.6 years (SD 2.33; range 8.7-18.4 years). Fifty-one percent of the children were female and 49% were male (female: male ratio 1:1). For 43% race/ethnicity was not specified; the remaining participants were 28.6% African American, 22.4% Hispanic, 3.1% non-Hispanic white, and 3.1% Asian. Of those for whom data were available, a maternal history of type 2 diabetes was reported by 32.7% (18/55) and an unspecified type of diabetes by 12.7% (7/55). Twenty-seven percent (13/47) reported a father with type 2 diabetes and 21% (10/47) an unspecified type of diabetes.Mean BMI was 34.67 kg/m 2 (SD 6.91). Ninety-three percent had a BMI Ն95th percentile. All but three of the individuals had BMIs Ն85th percentile. Of those for whom data were recorded, acanthosis nigricans was identified in 94% (48/51). A Tanner stage of 3, 4, or 5 was identified in 73.2% (49/67).Blood pressure readings indicated that 49.4% (41/83) had a systolic (SBP) and 10.8% (9/83) a diastolic (DBP) Ն95th percentile for age, sex, and height (n ϭ 83). Fifty-five percent (46/83) had SBP and 19.3% (16/83) DBP readings Ն90th percentile for blood pressure. Of 72 pulse rates recorded, 2.6% were Ն95th percentile for age. Average HbA 1c was 10.38 (SD 3.52) (n ϭ 95).Of those who had symptoms documented in the medical record, 83.6% (56/ 67) reported polyuria, 83.9% (52/62) polydipsia , and 61% (36/59) polyphagia. Seventy-five percent reported both polyuria and polydipsia (46/61). Of the cases available, 46.2% (24/52) reported all three of the polys at initial presentation, 46.8% (29/62) had weight loss, and 62.5% (30/48) had ketones. Of those for whom islet cell antibody data were recorded (50/98), 49 had JDF units Ͻ5. Fifty-three percent were started on insulin, 46.3% on oral agents, and 13.7% on both insulin and oral agent (n ϭ 96). Initial mean insulin dose was 0.6 units/kg.Our sample is similar to those described in previous reports except for a more even ratio of female to male subjects, a greater percent with elevated SBP and/or DBP, and more individuals reporting weight loss. We are the first to report blood pressure by the 95th and 90th percentiles and the first to report pulse rate. These data contribute to the growing body of clinical evidence defining the characteristics of ...

OBJECTIVETo determine whether plasma levels of advanced glycation end products and oxidation products play a role in the development of atherosclerosis in patients with type 2 diabetes (T2D) over nearly 10 years of the VA Diabetes Trial and Follow-up Study.RESEARCH DESIGN AND METHODSBaseline plasma levels of methylglyoxal hydroimidazolone, Nε-carboxymethyl lysine, Nε-carboxyethyl lysine (CEL), 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone (G-H1), 2-aminoadipic acid (2-AAA), and methionine sulfoxide were measured in a total of 411 participants, who underwent ultrasound assessment of carotid intima-media thickness (CIMT), and computed tomography scanning of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) after an average of 10 years of follow-up.RESULTSIn risk factor–adjusted multivariable regression models, G-H1 was associated with the extent of CIMT and CAC. In addition, 2-AAA was strongly associated with the extent of CAC, and CEL was strongly associated with the extent of AAC. The combination of specific advanced glycation end products and oxidation products (G-H1 and 2-AAA) was strongly associated with all measures of subclinical atherosclerosis.CONCLUSIONSSpecific advanced glycation end products and metabolic oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing T2D.