Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: a concurrent validity study

OBJECTIVE

We aimed to determine the corneal confocal microscopy (CCM) parameter that best identifies diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes and to describe its performance characteristics.

RESEARCH DESIGN AND METHODS

Concurrent with clinical and electrophysiological examination for classification of DSP, CCM was performed on 89 type 1 diabetic and 64 healthy subjects to determine corneal nerve fiber length (CNFL), density, tortuosity, and branch density. Area under the curve (AUC) and optimal thresholds for DSP identification in those with diabetes were determined by receiver operating characteristic (ROC) curve analysis.

RESULTS

DSP was present in 33 (37%) subjects. With the exception of tortuosity, CCM parameters were significantly lower in DSP case subjects. In ROC curve analysis, AUC was greatest for CNFL (0.88) compared with fiber density (0.84, P = 0.0001), branch density (0.73, P < 0.0001), and tortuosity (0.55, P < 0.0001). The threshold value that optimized sensitivity and specificity for ruling in DSP was a CNFL of ≤14.0 mm/mm² (sensitivity 85%, specificity 84%), associated with positive and negative likelihood ratios of 5.3 and 0.18. An alternate approach that used separate threshold values maximized sensitivity (threshold value ≥15.8 mm/mm², sensitivity 91%, negative likelihood ratio 0.16) and specificity (≤11.5 mm/mm², specificity 93%, positive likelihood ratio 8.5).

CONCLUSIONS

Among CCM parameters, CNFL best discriminated DSP cases from control subjects. A single threshold offers clinically acceptable operating characteristics, although a strategy that uses separate thresholds to respectively rule in and rule out DSP has excellent performance while minimizing unclassified subjects. We hypothesize that values between these thresholds indicate incipient nerve injury that represents those individuals at future neuropathy risk.Diabetic sensorimotor polyneuropathy (DSP) represents a diffuse symmetrical and length-dependent injury to peripheral nerves that has major implications on quality of life, morbidity, and from a public health perspective, costs (1,2). At present, underdiagnosis impedes the benefits of early identification, the emphasis on early management, and the prevention of neuropathy-related sequelae. Furthermore, the lack of an early biomarker for nerve injury hinders the process of drug development in clinical research (3). Practice recommendations for screening—such as examination with the monofilament or vibration tuning fork—are not being systematically performed (4,5), which highlights the urgent need for a valid screening test in clinical practice that overcomes the limitations in their specificity as predictive markers for the future onset of neuropathy (5,6).The prevailing concept of the natural history of DSP is that the initiating injury to the peripheral nervous system occurs in the small, unmyelinated, and thinly myelinated Aδ- and C-type nerve fibers (7,8). The gold-standard method for evaluating such morphological change in small nerve fibers can be accomplished by the examination of intraepidermal nerve fibers in skin biopsy samples (9). However, this biopsy strategy has inherent limitations as a generalized screening test in all patients with type 1 diabetes, including the invasive nature of the procedure and its cost. As an alternative, the small nerve fibers in the subbasal nerve plexus of the Bowman layer of the cornea can be directly visualized reliably and noninvasively by a technique of in vivo corneal confocal microscopy (CCM) (10–15). The cornea is extremely sensitive—there appear to be more nerve endings in the cornea than any other anatomical site in the body—and it is thus a practical location to evaluate changes in small nerve morphology (16). Corneal nerve fibers are thought to closely represent those that are involved in the length-dependent process of DSP despite the fact that they do not arise from the longest nerves in the body. Rather, they arise from the ophthalmic division (V1) of the trigeminal nerve, which anatomically shares similarities with spinal nerves (those traditionally evaluated in DSP) because it has both motor and sensory roots, and morphologically, the small nerve endings in the cornea share features with those that arise from spinal nerves that terminate in the epidermis.CCM parameters, including corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and the tortuosity coefficient (TC) have been studied in case-control analyses of DSP (10–15,17,18). However, evaluation of the diagnostic performance of these parameters in type 1 diabetes has been limited to small cohorts or to analyses using reference definitions of DSP that do not reflect recommendations for classification based on electrophysiological testing in research studies (17,19). Acknowledging the ultimate need for a screening test that can predict future onset of DSP, we first sought to determine the performance of CCM parameters in identifying the presence or absence of DSP. We used a gold-standard definition based on nerve conduction studies in the cross-sectional baseline evaluation of an ongoing longitudinal cohort study of patients with type 1 diabetes.     

Diabetic Neuropathy: A cross-sectional study of the relationships among tests of neurophysiology

OBJECTIVE

To determine the relationships among large, small, and autonomic fiber neurophysiological measures in a cross-sectional study of patients with diabetes.

RESEARCH DESIGN AND METHODS

We assessed 130 individuals: 25 healthy subjects and 105 subjects with diabetes. Subjects were classified by the presence or absence of neuropathy by physical examination. All subjects underwent autonomic testing, nerve conduction studies, quantitative sensory testing, and nerve-axon reflex vasodilation in addition to quantifiable neurological examination and symptom scores. Correlation and cluster analysis were used to determine relationships between and among different neurophysiological testing parameters.

RESULTS

Results of neurophysiological tests were abnormal in patients with clinical evidence of diabetic neuropathy compared with results in healthy control subjects and in those without neuropathy (P < 0.01, all tests). The correlations among individual tests varied widely, both within (r range <0.5–>0.9, NS to <0.001) and between test groups (r range <0.2–>0.5, NS to <0.01). A two-step hierarchical cluster analysis revealed that neurophysiological tests do not aggregate by typical “small,” “large,” or “autonomic” nerve fiber subtypes.

CONCLUSIONS

The modest correlation coefficients seen between the different testing modalities suggest that these techniques measure different neurophysiological parameters and are therefore not interchangeable. However, the data suggest that only a small number of neurophysiological tests are actually required to clinically differentiate individuals with neuropathy from those without. The natural clustering of both patients and healthy control subjects suggests that variations in the population will need to be considered in future studies of diabetic neuropathy.Microvascular complications of diabetes, which include retinopathy, neuropathy, and nephropathy are major contributors to morbidity and mortality. Although neuropathy severity is related to duration and degree of glycemic control, individual subjects may have widely disparate clinical presentations despite similar risk factors. Neuropathy progression preferentially affecting nerve fiber subtypes may explain some clinical heterogeneity, but different neurophysiological tests are required to identify dysfunction of different nerve populations in diabetes.Nerve conduction studies, assessing large myelinated fibers, are widely used both in clinical practice and as end points in longitudinal investigations of diabetic neuropathy (1,2). Damage to small thinly and unmyelinated nerves or autonomic fibers can be measured by quantitative sensory testing, autonomic testing, and laser Doppler flowmetry (3–6). To date, few investigators have examined the relationships between different measures of neurophysiological function in diabetic and other peripheral neuropathies (4,7–10).A cross-sectional study of diabetic neuropathy was used to determine the relationships among large, small, and autonomic fiber neurophysiological measures. We hypothesized that measures assessing similar neurophysiological functions would correlate and cluster together along typical nerve fiber subtypes (small, large, or autonomic). In addition, we determined the sensitivity and specificity of these neurophysiological measures using the Neuropathy Disability Score (NDS) as a gold standard (11). Because this clinical measure is weighted toward large fiber assessment, we hypothesized that neurophysiological tests of large fiber function would have higher sensitivity and specificity than measures of small fiber or autonomic function.     

Corneal Nerve Loss Detected With Corneal Confocal Microscopy Is Symmetrical and Related to the Severity of Diabetic Polyneuropathy

OBJECTIVE

To establish if corneal nerve loss, detected using in vivo corneal confocal microscopy (IVCCM), is symmetrical between right and left eyes and relates to the severity of diabetic neuropathy.

RESEARCH DESIGN AND METHODS

Patients (n = 111) with type 1 and type 2 diabetes and 47 age-matched healthy control subjects underwent detailed assessment and stratification into no (n = 50), mild (n = 26), moderate (n = 17), and severe (n = 18) neuropathy. IVCCM was performed in both eyes and corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) and the tortuosity coefficient were quantified.

RESULTS

All corneal nerve parameters differed significantly between diabetic patients and control subjects and progressively worsened with increasing severity of neuropathy. The reduction in CNFD, CNBD, and CNFL was symmetrical in all groups except in patients with severe neuropathy.

CONCLUSIONS

IVCCM noninvasively detects corneal nerve loss, which relates to the severity of neuropathy, and is symmetrical, except in those with severe diabetic neuropathy.Diabetic sensorimotor polyneuropathy (DSPN) is a length-dependent, symmetrical neuropathy with initial involvement of sensory and autonomic nerve fibers (NFs), followed by motor nerve involvement (1). It is the most common long-term complication of diabetes and is the main initiating factor for foot ulceration and lower extremity amputation with substantial associated healthcare costs (2). Conventional techniques of electrophysiology and quantitative sensory testing along with an assessment of neurological disability offer a relatively robust means of defining neuropathic severity (3) but have limitations in detecting the earliest stages of nerve damage (4,5).In vivo corneal confocal microscopy (IVCCM) is a rapidly expanding technique to quantify the severity of neuropathy in DSPN (6). It has been used to demonstrate early nerve damage in diabetes and a range of other peripheral neuropathies (7,8) with good sensitivity and specificity (9). Recently, corneal nerve damage detected with IVCCM has been related to the level of previous glycemic exposure and blood pressure (10) and HbA_1c even in healthy subjects (11). In a study of subjects with idiopathic small fiber neuropathy, corneal nerve damage was associated with higher serum triglycerides (8). It has also shown significant nerve regeneration before improvement in a range of established measures of neuropathy, including quantitative sensory testing, neurophysiology, and intraepidermal NF density, after simultaneous pancreas and kidney transplantation (12) and after an improvement in glycemia and cardiovascular risk factors for DSPN (13).Corneal NF loss correlates with intraepidermal NF loss (4), and corneal NF length (CNFL), particularly, has shown superior discriminative capacity to diagnose DSPN (14). Recent studies show that quantification of corneal nerve morphology is highly reproducible and does not differ significantly between observers (15) and occasions (16) in subjects with diabetes and healthy individuals. As a functional correlate, corneal sensation has been found to decrease with increasing neuropathic severity (17).Perkins et al. (18) and Bromberg and Jaros (19) have previously reported high interside symmetry of nerve conduction studies (NCS) consistent with the symmetrical nature of diabetic neuropathy. Whilst Petropoulos et al. (16) have shown that central corneal innervation is highly symmetrical between right eyes (REs) and left eyes (LEs) of young healthy subjects, it is unknown whether corneal nerve loss in diabetic neuropathy maintains its symmetry in different stages of DSPN. This is relevant to further establish parallels in terms of pathophysiology between corneal and peripheral somatic nerve damage but also has practical relevance when examining patients to allow examination of only one eye. The purpose of the present, cross-sectional, observational study was to establish if corneal nerve loss, detected using IVCCM, is symmetrical between REs and LEs with increasing severity of diabetic neuropathy.     

Prediction of Incident Diabetic Neuropathy Using the Monofilament Examination: A 4-year prospective study

OBJECTIVE

To determine the specific monofilament examination score that predicts the subsequent 4-year incidence of diabetic neuropathy with the highest degree of diagnostic accuracy.

RESEARCH DESIGN AND METHODS

Longitudinal follow-up of 175 of 197 (89%) participants in the Toronto Diabetic Neuropathy Cohort without baseline neuropathy for incident neuropathy. We examined the baseline monofilament examination score (and other simple sensory screening tests) by receiver operating characteristic (ROC) curve analysis.

RESULTS

Incident diabetic neuropathy developed in 50 (29%) participants over a mean follow-up of 4.1 years (interquartile range 2.6–7.1 years). Although male sex, longer diabetes duration, taller height, and higher blood pressure at baseline were associated with incident neuropathy, the strongest association was with a lower baseline monofilament score (score out of 8 was 3.7 ± 2.5 for incident neuropathy vs. 5.7 ± 2.3 for those who did not develop neuropathy; P < 0.001). The optimal threshold score for risk of incident neuropathy was ≤5 sensate stimuli out of 8, with 72% sensitivity, 64% specificity, positive and negative likelihood ratios of 2.5 and 0.35, and positive and negative predictive values of 87 and 46%, respectively (χ² = 20.7, P < 0.001). Area under the ROC curve was significantly greater for the monofilament examination compared with that for other simple sensory tests.

CONCLUSIONS

A simple threshold of ≤5 sensate stimuli out of 8 discriminates 4-year risk of diabetic neuropathy with acceptable operating characteristics. Although there are limitations in its specificity for prediction of future neuropathy onset, the monofilament examination is appropriate as a simple diabetic neuropathy screening instrument generalizable to the clinical setting.The diffuse injury to peripheral nerves, defined as diabetic sensorimotor polyneuropathy but commonly referred to as “diabetic neuropathy,” has exceptionally high incidence (1) and is observed in up to 50% of people with diabetes when evaluated using objective tests such as nerve conduction studies (2). It represents a progressive, diffuse, and length-dependent process of nerve injury, involving factors other than simple exposure to hyperglycemia (1). It begins with a long subclinical latency period whose identification and management is challenging; notwithstanding, it is important to identify neuropathy in its earliest stages because it may progress to produce extreme morbidity and health care costs (3,4). Valid identification at early stages will probably provide the best opportunity for effective intervention.At present, underdiagnosis of diabetic neuropathy is a fundamental issue: it impedes the benefits of early identification, impedes the emphasis on early management necessary to improve glycemic control, and impedes the prevention of neuropathy-related sequelae (5). That practice recommendations for screening, such as examination with the monofilament or vibration tuning fork, are not being systematically carried out contributes to the issue of underdiagnosis and may be related to challenges with applicability of a screening test in clinical practice (6). Whereas measurement of microalbuminuria and funduscopic examinations serve as objective tests for incipient nephropathy and retinopathy in type 1 diabetes, evidence for the validity of a comparably objective test is lacking for neuropathy.The Semmes-Weinstein 10-g monofilament examination is a simple, practical, and accurate tool for diabetic neuropathy screening. It involves a hand-held calibrated nylon thread that buckles once it has delivered a force of 10 g; in this way, when applied to the skin surface, it provides a standardized measure of a patient''s ability to sense a point of pressure. Although first studied as a specific prognostic indicator for skin infection, ulceration, and amputation (7,8), it has been studied for identification of diabetic neuropathy (9–12). In the study with the highest level of evidence for identifying the presence of diabetic neuropathy, a score of 7 or 8 correct responses out of 8 was associated with 78% sensitivity, whereas a score of ≤3 correct responses was associated with 96% specificity (10,12). The monofilament examination became part of clinical practice guidelines on the basis of this concurrent validity (13).The most relevant question is whether the monofilament score can represent incipient nerve injury before the development of clinically recognized diabetic neuropathy; that is, does the monofilament examination have sufficient predictive validity? Guided by this consideration, we monitored for a mean of 4 years patients with diabetes but without neuropathy for the future onset of diabetic neuropathy through the Toronto Diabetic Neuropathy Cohort (10,12). To our knowledge, it represents the only prospective observational study designed to assess the predictive validity (the validity in identifying future risk of neuropathy onset) of a simple screening test for diabetic neuropathy.     

Serum Levels of the Adipokine Chemerin in Relation to Renal Function

OBJECTIVE

To investigate serum levels of the adipokine chemerin in patients on chronic hemodialysis (CD) as compared with control patients with a glomerular filtration rate (GFR) >50 ml/min.

RESEARCH DESIGN AND METHODS

Chemerin was quantified by ELISA in control patients (n = 60) and CD patients (n = 60) and correlated with clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation, in both groups.

RESULTS

Median serum chemerin levels were more than twofold higher in CD patients (542.2 μg/l) compared with subjects with a GFR >50 ml/min (254.3 μg/l) (P < 0.001). Furthermore, GFR, as assessed by the original Modification of Diet in Renal Disease formula, independently predicted circulating chemerin concentrations in multiple regression analyses in both control patients (P < 0.05) and CD patients (P < 0.01).

CONCLUSIONS

We demonstrate that markers of renal function are independently related to circulating chemerin levels.Recently, chemerin has been identified as a novel adipocyte-secreted factor playing a crucial role in adipocyte differentiation and insulin signaling (1–4). Several studies have quantified circulating chemerin in humans. Thus, two reports found an independent association between chemerin and markers of inflammation (5,6). Furthermore, correlations between circulating chemerin and metabolic syndrome–related parameters have been described (6–8). In contrast to other adipokines (9–12), no data have been published so far about the relation of chemerin to renal function.     

Pathophysiology of Neuropathic Pain in Type 2 Diabetes: Skin denervation and contact heat�Cevoked potentials

OBJECTIVE

Neuropathic pain due to small-fiber sensory neuropathy in type 2 diabetes can be diagnosed by skin biopsy with quantification of intra-epidermal nerve fiber (IENF) density. There is, however, a lack of noninvasive physiological assessment. Contact heat–evoked potential (CHEP) is a newly developed approach to record cerebral responses of Aδ fiber–mediated thermonociceptive stimuli. We investigated the diagnostic role of CHEP.

RESEARCH DESIGN AND METHODS

From 2006 to 2009, there were 32 type 2 diabetic patients (20 males and 12 females, aged 51.63 ± 10.93 years) with skin denervation and neuropathic pain. CHEPs were recorded with heat stimulations at the distal leg, where skin biopsy was performed.

RESULTS

CHEP amplitude was reduced in patients compared with age- and sex-matched control subjects (14.8 ± 15.6 vs. 33.7 ± 10.1 μV, P < 0.001). Abnormal CHEP patterns (reduced amplitude or prolonged latency) were noted in 81.3% of these patients. The CHEP amplitude was the most significant parameter correlated with IENF density (P = 0.003) and pain perception to contact heat stimuli (P = 0.019) on multiple linear regression models. An excitability index was derived by calculating the ratio of the CHEP amplitude over the IENF density. This excitability index was higher in diabetic patients than in control subjects (P = 0.023), indicating enhanced brain activities in neuropathic pain. Among different neuropathic pain symptoms, the subgroup with evoked pain had higher CHEP amplitudes than the subgroup without evoked pain (P = 0.011).

CONCLUSIONS

CHEP offers a noninvasive approach to evaluate the degeneration of thermonociceptive nerves in diabetic neuropathy by providing physiological correlates of skin denervation and neuropathic pain.Type 2 diabetic neuropathy is frequently complicated with neuropathic pain, suggesting the involvement of small-diameter thermonociceptive nerves (1). Two approaches have been developed for the diagnosis of small-fiber sensory neuropathy: psychophysical assessments by measuring thermal thresholds on quantitative sensory testing (2,3) and pathological evaluations by quantifying intra-epidermal nerve fiber (IENF) density in punch skin biopsies (4–6). These examinations provide psychophysical and neuropathological evidence of small-diameter thermonociceptive nerve degeneration and serve as the definition of small-fiber sensory neuropathy (7,8). These two tests are sensitive in detecting the negative symptoms of diabetic neuropathy, for example, the elevation of thermal thresholds (9). However, the neurophysiological correlates of these tests with positive symptoms such as neuropathic pain are limited, and the physiological consequences of thermonociceptive nerve involvements in diabetic neuropathy have rarely been explored.In recent years, several groups, including our own, have established contact heat–evoked potential (CHEP) as a clinically feasible approach to examine the physiology of thermonociceptive nerves (10,11). CHEP, by activating Aδ fibers, can be recorded at the vertex for clinical use (12). Thus, CHEPs provide a noninvasive technique to objectively evaluate the physiology of thermonociceptive nerve dysfunctions. This approach raises the possibility of whether CHEP can be a noninvasive diagnostic tool complementary to IENF density and thermal thresholds and whether CHEP parameters can reflect the neurophysiological correlates of reduced IENF density in diabetic neuropathy. Additionally, since the CHEP amplitude parallels the perceived intensity of heat pain in normal subjects (11,13), a further critical issue is whether CHEP could demonstrate positive symptoms or signs of neuropathic pain in diabetic neuropathy. These include the spontaneous forms, such as a burning sensation, and the evoked forms, such as hyperalgesia to thermal stimuli.To address the above issues, our study investigated the following: 1) the changes in CHEP and its diagnostic role in diabetic neuropathy, 2) the correlations of CHEP with the skin innervation and thermal thresholds, and 3) the relationship of CHEP and neuropathic pain in diabetic neuropathy.     

Large-Fiber Dysfunction in Diabetic Peripheral Neuropathy Is Predicted by Cardiovascular Risk Factors

OBJECTIVE

Diabetic large–nerve fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, amputation, and mortality. Thus, determination of modifiable risk factors is of great clinical importance.

RESEARCH DESIGN AND METHODS

We assessed 1,407 patients with type 1 diabetes and a normal VPT participating in the EURODIAB Prospective Complications Study, at baseline mean ± SD age of 32.7 ± 10.2 years with diabetes duration of 14.7 ± 9.3 years and follow-up of 7.3 ± 0.6 years. VPT was measured using biothesiometry on the right big toe and medial malleolus. An abnormal result was defined as >2 SD from the predicted mean for the patient s age.

RESULTS

An abnormal VPT was associated with an increased incidence of gangrene, amputation, foot ulceration, leg bypass or angioplasty, and mortality (P ≤ 0.02). The incidence of abnormal VPT was 24% over the 7.3-year follow-up. Duration of diabetes and A1C significantly influenced the incidence of abnormal VPT (P < 0.0001). After correction for these, established risk factors for cardiovascular disease (CVD), including male sex (P = 0.0004), hypertension (P < 0.0001), total cholesterol (P = 0.002), LDL cholesterol (P = 0.01), smoking (P < 0.0001), weight (P < 0.0001), and diabetes complications (retinopathy [P = 0.0001], nephropathy [P = 0.01], and autonomic neuropathy [P = 0.001]), were all found to be significant risk factors. A previous history of CVD doubled the incidence of abnormal VPT.

CONCLUSIONS

This prospective study indicates that cardiovascular risk factors predict development of large-fiber dysfunction, which may account for the high mortality rate in patients with an abnormal VPT, and emphasizes the importance of early determination of VPT to detect subclinical neuropathy and to address cardiovascular risk factors.Chronic diabetic peripheral neuropathy (DPN) is a slowly progressive process, the pathogenesis of which is poorly understood. However, we do know that large-fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, lower-limb amputation, and mortality (1–3). One consequence of these clinical complications is a massive economic burden, estimated in 2001 to be $10.9 billion in the U.S. (4,5). Early in the natural history of DPN, patients are usually asymptomatic. Thus, reliable identification of individuals in the early stages of the neuropathic process is required so that more rigorous modification of risk factors and foot care education can be implemented. The best method to identify such patients is still a matter of some debate (6–9).In patients with type 2 diabetes, the prevalence of an abnormal VPT has been shown to be 11.4% (10), and the incidence of an abnormal VPT was 19.9% over a 12-year period (11). Some investigators have used absolute values of VPT as predictors of foot ulceration. In one study, a VPT >25 V was associated with a sevenfold increase in ulcer risk, compared with that of individuals with a VPT <15 V (12). Another study showed an incidence of 7.2% of first foot ulceration within 1 year in patients with a VPT ≥25 (13). In addition, a cutoff of 25 V has been shown to be a more sensitive way of detecting patients at risk of foot ulceration than the 10-g monofilament (14). Small-fiber dysfunction may be determined by measuring thermal thresholds, but in terms of discriminating between patients with and without ulceration, it does not seem to provide any additional value above measurement of VPT (15).Thus, ample evidence exists to highlight the clinical importance of an abnormally high VPT, but as yet there is little evidence to identify the risk factors involved in its development. Poor glycemic control is associated with an abnormal VPT even at diagnosis in patients with type 2 diabetes (16). Evidence also suggests that height is a determinant of VPT (10,17). Importantly, VPT is known to increase with age (18,19). The majority of research regarding large-fiber dysfunction, as measured by VPT, has been conducted in patients with type 2 diabetes. In this study, we have examined the incidence of abnormal VPT in a large cohort of patients with type 1 diabetes to identify possible modifiable risk factors.     

Dietary Patterns and Risk for Diabetes: The Multiethnic Cohort

OBJECTIVE

The high diabetes incidence among Japanese Americans and Native Hawaiians cannot be explained by BMI. Therefore, we examined the influence of three dietary patterns of “fat and meat,” “vegetables,” and “fruit and milk” on diabetes risk in the Hawaii component of the Multiethnic Cohort with 29,759 Caucasians, 35,244 Japanese Americans, and 10,509 Native Hawaiians.

RESEARCH DESIGN AND METHODS

Subjects aged 45–75 years completed a baseline food frequency questionnaire. After 14 years of follow-up, 8,587 subjects with incident diabetes were identified through self-reports or health plan linkages. Risk was assessed using Cox regression stratified by age and adjusted for ethnicity, BMI, physical activity, education, total energy, smoking, alcohol intake, marital status, and hypertension.

RESULTS

Fat and meat was significantly associated with diabetes risk in men (hazard ratio 1.40 [95% CI 1.23–1.60], P_trend < 0.0001) and women (1.22 [1.06–1.40], P_trend = 0.004) when extreme quintiles were compared. Except in Hawaiian women, the magnitude of the risk was similar across ethnic groups although not always significant. After stratification by BMI, fat and meat remained a predictor of disease primarily among overweight men and among overweight Japanese women. Vegetables lowered diabetes risk in men (0.86 [0.77–0.95], P_trend = 0.004) but not in women, whereas fruit and milk seemed to be more beneficial in women (0.85 [0.76–0.96], P_trend = 0.005) than in men (0.92 [0.83–1.02], P_trend = 0.04).

CONCLUSIONS

Foods high in meat and fat appear to confer a higher diabetes risk in all ethnic groups, whereas the effects of other dietary patterns vary by sex and ethnicity.Native Hawaiians have extremely high rates of obesity and diabetes, but despite their relatively low body weight, individuals with Japanese ancestry are also disproportionately affected by diabetes (1). Among the >44,000 Japanese Americans, 14,000 Native Hawaiians, and 35,000 Caucasians in the Hawaii component of the Multiethnic Cohort (MEC), a previous analysis had found diabetes incidence rates of 15.5, 12.5, and 5.8 per 1,000 person-years, respectively, that could not be explained by BMI (2). Dietary patterns have been identified as additional predictors of disease but have only rarely been investigated prospectively among non-Caucasian populations (3–5). The most commonly identified patterns are the so-called “western,” “unhealthy,” or “conservative” pattern (3–11), which is high in meat, high-fat foods, and sweets, and the “prudent” or “healthy” pattern, rich in fruit and vegetables (3–8,10,12,13). With the goal to contribute to the prevention of diabetes, we examined the effect of three dietary patterns, “fat and meat,” “vegetables,” and “fruit and milk,” which had been previously identified in the MEC, on diabetes risk (14).     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

Heart rate variability and sensorimotor polyneuropathy in type 1 diabetes

OBJECTIVE

Reduced heart rate variability (HRV) is classically viewed as an early phenomenon in diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the characteristics of HRV across the spectrum of clinical DSP in type 1 diabetes.

RESEARCH DESIGN AND METHODS

Eighty-nine diabetic subjects and 60 healthy volunteers underwent assessment of RR interval variation (RR_var) during deep breathing and clinical and electrophysiological examination. We examined the distribution of age-standardized RR_var across the spectrum of clinical DSP, identified variables associated with RR_var in multivariate regression, and compared RR_var with validated measures of neuropathy.

RESULTS

Age-standardized RR_var had a significant, step-wise, inverse relationship with ordinal categories of increasing DSP severity (β = −5.4, P < 0.0001) among subjects with diabetes. Case subjects with DSP had substantially lower age-standardized RR_var compared with diabetic control subjects without DSP (β = −5.2, P < 0.01), although there was substantial overlap of RR_var between diabetic case subjects and control subjects and the healthy volunteer cohort. In multivariate analysis, advanced age was independently associated with lower RR_var in both healthy volunteers and diabetic subjects, whereas higher glycated hemoglobin A_1c and systolic blood pressure were independently associated with lower RR_var in diabetic subjects. RR_var had a significant association with validated measures of large and small fiber neuropathy.

CONCLUSIONS

HRV may be a biomarker for clinical DSP and is associated cross-sectionally with both early and late measures of neuropathy. The low HRV observed in some control subjects without DSP and in most case subjects with severe DSP may signify that HRV has different prognostic implications in these groups, requiring further longitudinal study.Decreased heart rate variability (HRV)—the instantaneous beat-to-beat variation in heart rate during respiration—has long been identified as an early marker of autonomic neuropathy in diabetes, often preceding any other manifestation of neuropathy (1). Since these first observations, the classic dogma has been that decreased HRV is an early, asymptomatic finding in diabetic polyneuropathy (2). In normal individuals, heart rate varies significantly throughout the respiratory cycle—increasing with inspiration and decreasing with expiration—in a phenomenon known as sinus arrhythmia (3). These physiologic changes are mediated by sympathetic and parasympathetic nerves in the autonomic nervous system. Pathophysiologically, decreased HRV is thought to reflect impaired parasympathetic innervation of the vagus nerve, the longest autonomic nerve, in a length-dependent fashion akin to injury of peripheral somatic nerves in diabetic sensorimotor polyneuropathy (DSP) (4).HRV during deep breathing is one of several cardiovascular autonomic reflex tests (CARTs) that are part of the gold standard diagnostic criteria for cardiac autonomic neuropathy (CAN) (5), a clinical condition characterized by dysfunction of the autonomic innervation of the cardiovascular system (6). Although the isolated finding of decreased HRV is considered sufficient criterion for possible or early CAN, a second abnormal CART is required for a definite or confirmed diagnosis (5). HRV can be assessed by a variety of metrics, categorized into “time” and “frequency” domains, but HRV with deep breathing in the time domain remains the most commonly used CART and has the greatest specificity for CAN (4).Recently, several large prospective studies have demonstrated that CAN, defined by HRV criteria, is an independent predictor of cardiovascular disease (CVD) (7,8) and mortality in diabetes (9–12). Intervention trials have shown that intensive glycemic control and a strategy aimed at lifestyle change with pharmacological correction of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria decrease the incidence and progression of CAN (13–15).To date, several studies have explored the relationship between HRV and microvascular complications of diabetes (16,17). Decreased HRV has been associated with new onset renal impairment (16) as well as cardiovascular mortality in patients with diabetic nephropathy (17). However, the nature of the relationship between HRV and DSP has not been well established (18).In light of this question and the early diagnostic value of HRV in autonomic neuropathy, we aimed to cross-sectionally evaluate HRV among type 1 diabetic participants in the Toronto Diabetic Early Neuropathy Cohort (19) to determine whether it can serve as a biomarker for DSP based on the gold-standard definition (20). To further elucidate the temporal and pathophysiological relationship underlying decreased HRV, we compared it with validated measures of peripheral neuropathy including functional large fiber sensory and motor measures, as well as functional and morphological small fiber measures.     

Sex and Racial/Ethnic Differences in Cardiovascular Disease Risk Factor Treatment and Control Among Individuals With Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

To examine sex and racial/ethnic differences in cardiovascular risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).

RESEARCH DESIGN AND METHODS

This study was an observational study examining mean levels of cardiovascular risk factors and proportion of subjects achieving treatment goals.

RESULTS

The sample included 926 individuals with diabetes. Compared with men, women were 9% less likely to achieve LDL cholesterol <130 mg/dl (adjusted prevalence ratio 0.91 [0.83–0.99]) and systolic blood pressure (SBP) <130 mmHg (adjusted prevalence ratio 0.91 [0.85–0.98]). These differences diminished over time. A lower percentage of women used aspirin (23 vs. 33%; P < 0.001). African American and Hispanic women had higher mean levels of SBP and lower prevalence of aspirin use than non-Hispanic white women.

CONCLUSIONS

Women with diabetes had unfavorable cardiovascular risk factor profiles compared with men. African American and Hispanic women had less favorable profiles than non-Hispanic white women.Population-based health survey data suggest that sex and racial/ethnic disparities are present in diabetes process of care measures and cardiovascular risk factor control (1–9). Available data also indicate that sex-specific race/ethnicity differences are present in cardiovascular risk factor control, but these data are limited to Medicare and Veterans'' Hospital patient populations (5,10–13). We therefore performed analyses of participants with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine sex and sex-specific racial/ethnic differences in cardiovascular risk factor treatment and control.     

Lifestyle counseling in routine care and long-term glucose, blood pressure, and cholesterol control in patients with diabetes

OBJECTIVE

In clinical trials, diet, exercise, and weight counseling led to short-term improvements in blood glucose, blood pressure, and cholesterol levels in patients with diabetes. However, little is known about the long-term effects of lifestyle counseling on patients with diabetes in routine clinical settings.

RESEARCH DESIGN AND METHODS

This retrospective cohort study of 30,897 patients with diabetes aimed to determine whether lifestyle counseling is associated with time to A1C, blood pressure, and LDL cholesterol control in patients with diabetes. Patients were included if they had at least 2 years of follow-up with primary care practices affiliated with two teaching hospitals in eastern Massachusetts between 1 January 2000 and 1 January 2010.

RESULTS

Comparing patients with face-to-face counseling rates of once or more per month versus less than once per 6 months, median time to A1C <7.0% was 3.5 versus 22.7 months, time to blood pressure <130/85 mmHg was 3.7 weeks versus 5.6 months, and time to LDL cholesterol <100 mg/dL was 3.5 versus 24.7 months, respectively (P < 0.0001 for all). In multivariable analysis, one additional monthly face-to-face lifestyle counseling episode was associated with hazard ratios of 1.7 for A1C control (P < 0.0001), 1.3 for blood pressure control (P < 0.0001), and 1.4 for LDL cholesterol control (P = 0.0013).

CONCLUSIONS

Lifestyle counseling in the primary care setting is strongly associated with faster achievement of A1C, blood pressure, and LDL cholesterol control. These results confirm that the findings of controlled clinical trials are applicable to the routine care setting and provide evidence to support current treatment guidelines.Diabetes is increasingly common in the U.S. and worldwide (1,2). Elevated blood glucose, blood pressure, and LDL cholesterol are associated with increased risk for micro- and macrovascular complications, and their reduction decreases the risk (3–8). Nevertheless, most patients with diabetes do not have A1C, blood pressure, and LDL cholesterol under control (9,10).American and European guidelines widely recommend diet, exercise, and weight counseling with follow-up for patients with diabetes (11,12). Many short-term randomized clinical trials have shown that intensive lifestyle counseling interventions of up to 1 year in duration can lead to lower blood glucose (13–16) and blood pressure (17–21), but long-term data on the efficacy of lifestyle counseling are lacking (22–24). Furthermore, clinical trials typically involve resource-intensive interventions that may not be feasible in routine care, and the efficacy of lifestyle counseling in everyday clinical practice remains questionable (25–27). Consequently, further evidence is needed to establish that lifestyle counseling as practiced in routine care improves the outcomes of patients with diabetes.We therefore conducted a retrospective study of over 30,000 patients with diabetes and hyperglycemia, hypertension, and/or hyperlipidemia who received care in a primary care setting to test the hypothesis that higher rates of lifestyle counseling in routine care are associated with better diabetes control.     

One-year results of a community-based translation of the Diabetes Prevention Program: Healthy-Living Partnerships to Prevent Diabetes (HELP PD) Project

OBJECTIVE

Although the Diabetes Prevention Program (DPP) and the Finnish Diabetes Prevention Study (FDPS) demonstrated that weight loss from lifestyle change reduces type 2 diabetes incidence in patients with prediabetes, the translation into community settings has been difficult. The objective of this study is to report the first-year results of a community-based translation of the DPP lifestyle weight loss (LWL) intervention on fasting glucose, insulin resistance, and adiposity.

RESEARCH DESIGN AND METHODS

We randomly assigned 301 overweight and obese volunteers (BMI 25–40 kg/m²) with fasting blood glucose values between 95 and 125 mg/dL to a group-based translation of the DPP LWL intervention administered through a diabetes education program (DEP) and delivered by community health workers (CHWs) or to an enhanced usual-care condition. CHWs were volunteers with well-controlled type 2 diabetes. A total of 42.5% of participants were male, mean age was 57.9 years, 26% were of a race/ethnicity other than white, and 80% reported having an education beyond high school. The primary outcome is mean fasting glucose over 12 months of follow-up, adjusting for baseline glucose.

RESULTS

Compared with usual-care participants, LWL intervention participants experienced significantly greater decreases in blood glucose (−4.3 vs. −0.4 mg/dL; P < 0.001), insulin (−6.5 vs. −2.7 μU/mL; P < 0.001), homeostasis model assessment of insulin resistance (−1.9 vs. −0.8; P < 0.001), weight (−7.1 vs. −1.4 kg; P < 0.001), BMI (−2.1 vs. −0.3 kg/m²; P < 0.001), and waist circumference (−5.9 vs. −0.8 cm; P < 0.001).

CONCLUSIONS

This translation of the DPP intervention conducted in community settings, administered through a DEP, and delivered by CHWs holds great promise for the prevention of diabetes by significantly decreasing glucose, insulin, and adiposity.The Diabetes Prevention Program (DPP) and the Finnish Diabetes Prevention Study (FDPS) demonstrated that the incidence of type 2 diabetes could be reduced by almost 60% in patients with prediabetes through weight loss resulting from changes in diet and physical activity (1,2). Despite these promising findings, the prevalence of type 2 diabetes continues to increase (3). Furthermore, although diabetes mortality has declined 8.3% in the last decade, diabetes-related complications continue to increase, resulting in rising disease burden (4).Several recent translations (5–13) of the DPP and FDPS have demonstrated encouraging effects across diverse settings, including primary care settings (6,9,11–13), cardiac rehabilitation programs (10), churches (8), YMCAs (5), and health care facilities (7). The personnel who implemented the intervention included nurses (6,11,12), registered dietitians and exercise physiologists (7,10), health care professionals (9,13), volunteer medical personnel (8), and YMCA trainers (5). Evaluating these translated interventions is challenging because of the differences in outcome measures, sample sizes, and study designs. Although these interventions typically produced ~6% weight loss, the studies tended to have small sample sizes, often did not include comparison conditions, and lacked randomized allocation to treatment conditions. No translational study to date has reported significant reductions in blood glucose in individuals with prediabetes. Therefore, additional translational research is needed that uses innovative, cost-effective systems to deliver effective lifestyle interventions targeting patients at risk for diabetes. Numerous studies have tested the use of community health workers (CHWs) in the management of diabetes (14), but no studies to date have tested the use of CHWs in implementing lifestyle interventions designed to prevent diabetes.This report presents the first-year results of the Healthy-Living Partnerships to Prevent Diabetes (HELP PD) Project on glucose, insulin resistance, and adiposity (15). The HELP PD project was designed to translate the methods of the DPP into the community via key modifications to enhance feasibility and dissemination: the delivery of a group-based lifestyle weight loss (LWL) intervention via a partnership between an existing community-based diabetes education program (DEP) and CHWs.     

Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE

To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders.

RESULTS

Unadjusted mean HbA_1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA_1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA_1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA_1c >9%; P = 0.005) but not with average HbA_1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time.

CONCLUSIONS

This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.The Diabetes Control and Complications Trial (DCCT) showed that improved metabolic control reduces the risk of long-term complications in both adult and adolescent patients with type 1 diabetes (1,2). The observational follow-up study of the DCCT (the Epidemiology of Diabetes Interventions and Complications [EDIC] study) further proved that good glycemic control had persistent beneficial effects on long-term complications (3). Based on the results of the DCCT/EDIC study, it was recommended to optimize glycemic control as early and close to normal as possible in all patients with type 1 diabetes in order to prevent development and progression of microvascular complications.Diabetes treatment has been intensified in pediatric and adolescent patients during the past 15 years. Insulin therapy has changed from twice-daily injection regimen to intensified therapy with multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII). This has been reported from single-center and multicenter studies (4–10). In the 1990s, mainly an increased use of MDI was observed, whereas since 2000, pump therapy increased considerably, paralleled by a decrease in MDI therapy (11). With the intensification of insulin regimen, the frequency of daily self-monitoring of blood glucose (SMBG) increased continuously (5,10–12), as close glucose monitoring is a precondition for intensified insulin therapy with an appropriate dose adjustment. Likewise, the use of short-acting insulin analogs has continuously increased since the mid-1990s and the use of long-acting analogs since 2000 (4,5,10).Despite these far-ranging changes in diabetes therapy, the anticipated improvement in metabolic control in children and adolescents with type 1 diabetes has not been achieved in all settings. The multicenter Hvidoere studies did not observe any improvement in glycemic control during 1995–2005 (6–8). Other studies, however, reported a significant decrease in average HbA_1c level over the past two decades (4,5,10,11,13). Concordantly, several studies indicated a notable increase in the proportion of children and adolescents with good metabolic control (HbA_1c <7.5 or <8%) over the past years (11,13).In the DCCT study, the tradeoff with intensified insulin therapy was a marked increase in episodes of severe hypoglycemia (2). Several studies reported a higher hypoglycemia risk with lower HbA_1c level (4,6,7,10,14), but others did not (15,16). Results on the trend of severe hypoglycemic events over the past 15 years are also inconsistent (4,5,8,9,11).The aim of this study was to give a current update on the temporal trend of metabolic control in German and Austrian children and adolescents over the past 15 years (1995–2009), to identify potential determinants of metabolic control, and to analyze the simultaneous trend of severe hypoglycemic and diabetic ketoacidotic events.     

Central Processing of Gut Pain in Diabetic Patients With Gastrointestinal Symptoms

OBJECTIVE

To evaluate the brain''s responses to painful visceral and somatic stimuli in diabetic patients with gastrointestinal symptoms.

RESEARCH DESIGN AND METHODS

The sensitivity to electrical esophageal and median nerve stimulations was assessed in 15 healthy volunteers and 14 type 1 diabetic patients with autonomic neuropathy and gastrointestinal symptoms using a euglycemic-hyperinsulinemic clamp. Evoked brain potentials were recorded.

RESULTS

Patients had reduced sensitivity to esophageal (48%; P < 0.001) and median nerve (80%; P < 0.001) stimulations. They also had increased (8.8%; P = 0.007) and nonreproducible (P = 0.006) latencies of evoked potentials in response to esophageal stimulations, with 26% reduction in amplitude (P = 0.011). No potential differences were seen to median nerve stimulations. In diabetic patients, the topographic location of the first peak in potentials was more central (P < 0.001) and gastrointestinal symptoms correlated with characteristics of brain potentials (P = 0.049).

CONCLUSIONS

This study supports that diabetes induces changes in peripheral visceral nerves as well as in the central nervous system.Gastrointestinal symptoms are more prevalent in diabetic individuals than in the general population (1,2). The pathogenesis is undoubtedly multifactorial, including motor dysfunction, glycemic control, psychological factors, etc. (3,4). However, diabetic autonomic neuropathy (DAN) seems to play a central role (1,3,5). The aim of this study, in healthy control subjects and patients with long-standing diabetes and gastrointestinal symptoms, was to describe the following: 1) the sensory thresholds for electrical esophageal and median nerve stimulation and 2) the evoked brain potentials (EPs) recorded with a high-resolution electroencephalogram system.     

Patient Race/Ethnicity and Patient-Physician Race/Ethnicity Concordance in the Management of Cardiovascular Disease Risk Factors for Patients With Diabetes

OBJECTIVE

Patient-physician race/ethnicity concordance can improve care for minority patients. However, its effect on cardiovascular disease (CVD) care and prevention is unknown. We examined associations of patient race/ethnicity and patient-physician race/ethnicity concordance on CVD risk factor levels and appropriate modification of treatment in response to high risk factor values (treatment intensification) in a large cohort of diabetic patients.

RESEARCH DESIGN AND METHODS

The study population included 108,555 adult diabetic patients in Kaiser Permanente Northern California in 2005. Probit models assessed the effect of patient race/ethnicity on risk factor control and treatment intensification after adjusting for patient and physician-level characteristics.

RESULTS

African American patients were less likely than whites to have A1C <8.0% (64 vs. 69%, P < 0.0001), LDL cholesterol <100 mg/dl (40 vs. 47%, P < 0.0001), and systolic blood pressure (SBP) <140 mmHg (70 vs. 78%, P < 0.0001). Hispanic patients were less likely than whites to have A1C <8% (62 vs. 69%, P < 0.0001). African American patients were less likely than whites to have A1C treatment intensification (73 vs. 77%, P < 0.0001; odds ratio [OR] 0.8 [95% CI 0.7–0.9]) but more likely to receive treatment intensification for SBP (78 vs. 71%, P < 0.0001; 1.5 [1.3–1.7]). Hispanic patients were more likely to have LDL cholesterol treatment intensification (47 vs. 45%, P < 0.05; 1.1 [1.0–1.2]). Patient-physician race/ethnicity concordance was not significantly associated with risk factor control or treatment intensification.

CONCLUSIONS

Patient race/ethnicity is associated with risk factor control and treatment intensification, but patient-physician race/ethnicity concordance was not. Further research should investigate other potential drivers of disparities in CVD care.There are well-documented racial disparities in diabetes prevalence and mortality. African Americans and Hispanics have higher diabetes prevalence, death rates, and higher rates of serious complications (1). Even after controlling for access to care and socioeconomic status, diabetes disparities in the U.S. persist (1). There are also widely recognized disparities in cardiovascular risk factors associated with diabetes. African American and Hispanic patients with diabetes are less likely to meet glucose, cholesterol, or blood pressure targets (2).The evidence surrounding whether insured patients of color receive worse care for diabetes and cardiovascular disease (CVD) risk factor control is mixed (3–6). Studies have found significant disparities in the likelihood of receipt of medications (7) and medication intensification (8,9). However, several studies have shown that minority patients received equal or better quality processes of care such as screening and medication intensification (4,10–12).Interpersonal barriers resulting from language or cultural differences between patients and physicians may explain a portion of diabetes management disparities (13,14). Physicians engage in less patient-centered communication with patients of color than with white patients (15). Patient race/ethnicity has been associated with physicians'' assessment of patient intelligence, feelings of affiliation toward the patient, and beliefs about the patients'' likelihood of risk behavior and adherence with medical advice (16,17).Patient-physician race/ethnicity concordance (the patient and health care provider having the same race/ethnicity) may help bridge interpersonal barriers in care for minority patients (18). Race/ethnicity concordance is associated with increased patient trust in the physician (19) and health services utilization and satisfaction (20). However, evidence that race/ethnicity concordance is an important factor in the quality of health care is mixed (21). No studies have examined the association among race/ethnicity concordance, cardiovascular disease processes of care, and levels of intermediate outcomes.The purpose of this study was to examine the association of patient race/ethnicity and patient-physician race/ethnicity concordance on CVD risk factor levels and treatment intensification in a large cohort of diabetic patients in an integrated delivery system.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

No Difference in Small or Large Nerve Fiber Function Between Individuals With Normal Glucose Tolerance and Impaired Glucose Tolerance

OBJECTIVE

To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS

Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.

RESULTS

There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.

CONCLUSIONS

Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.A high prevalence of impaired glucose tolerance (IGT) in individuals with idiopathic neuropathy has been reported (1), but whether neuropathy already exists in the prediabetic stage, i.e., IGT, is unknown (2,3). In a population-based study, neuropathy was marginally more common in IGT than in normoglycemic controls (4), but others reported no difference in measures of neuropathy between IGT and normal glucose tolerance (NGT) (5,6).When addressing the question of whether “IGT neuropathy” truly exists, objective measures of nerve dysfunction are frequently crude and focused on large nerve fibers, and small nerve fiber dysfunction is often overlooked (1,4,6).Thus, our aim was to study measures of both small and large nerve function in well-characterized normoglycemic, IGT, and type 2 diabetic (T2D) individuals.     

Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms

OBJECTIVE

To test if knowledge of type 2 diabetes genetic variants improves disease prediction.

RESEARCH DESIGN AND METHODS

We tested 40 single nucleotide polymorphisms (SNPs) associated with diabetes in 3,471 Framingham Offspring Study subjects followed over 34 years using pooled logistic regression models stratified by age (<50 years, diabetes cases = 144; or ≥50 years, diabetes cases = 302). Models included clinical risk factors and a 40-SNP weighted genetic risk score.

RESULTS

In people <50 years of age, the clinical risk factors model C-statistic was 0.908; the 40-SNP score increased it to 0.911 (P = 0.3; net reclassification improvement (NRI): 10.2%, P = 0.001). In people ≥50 years of age, the C-statistics without and with the score were 0.883 and 0.884 (P = 0.2; NRI: 0.4%). The risk per risk allele was higher in people <50 than ≥50 years of age (24 vs. 11%; P value for age interaction = 0.02).

CONCLUSIONS

Knowledge of common genetic variation appropriately reclassifies younger people for type 2 diabetes risk beyond clinical risk factors but not older people.A genetic risk score built with 18 type 2 diabetes genetic loci predicted new diabetes cases (1), though it did not add to common diabetes clinical risk factors that usually appear during adulthood (1–3). In recent years, the number of genetic loci convincingly associated with diabetes has doubled (4–10). Here, we test two hypotheses: an updated genetic risk score incorporating a larger number of common diabetes-associated single nucleotide polymorphisms (SNPs) improves ∼8-year risk prediction of diabetes beyond common clinical diabetes risk factors; and the predictive ability is better in younger subjects in whom early preventive strategies could delay diabetes onset (11).