Dialysis Treatment Is an Independent Risk Factor for Foot Ulceration in Patients With Diabetes and Stage 4 or 5 Chronic Kidney Disease

OBJECTIVE

To determine whether dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and renal impairment.

RESEARCH DESIGN AND METHODS

We performed a cross-sectional study of consecutive patients with diabetes and stage 4 or 5 chronic kidney disease (CKD) attending clinics in Manchester (U.K.). Patients were classified as either receiving dialysis therapy (dialysis) or not (no dialysis). Foot assessment included diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), prior foot ulceration and amputation, and foot self-care. Risk factors for prevalent foot ulceration were assessed by logistic regression.

RESULTS

We studied 326 patients with diabetes and CKD (mean age 64 years; 61% male; 78% type 2 diabetes; 11% prevalent foot ulceration). Compared with no dialysis patients, dialysis patients had a higher prevalence of DPN (79 vs. 65%), PAD (64 vs. 43%), prior amputations (15 vs. 6.4%), prior foot ulceration (32 vs. 20%), and prevalent foot ulceration (21 vs. 5%, all P < 0.05). In univariate analyses, foot ulceration was related to wearing bespoke footwear (odds ratio 5.6 [95% CI 2.5–13]) dialysis treatment (5.1 [2.3–11]), prior foot ulceration (4.8 [2.3–9.8], PAD (2.8 [1.3–6.0], and years of diabetes (1.0 [1.0–1.1], all P < 0.01). In multivariate logistic regression, only dialysis treatment (4.2 [1.7–10], P = 0.002) and prior foot ulceration (3.1 [1.3–7.1], P = 0.008) were associated with prevalent foot ulceration.

CONCLUSIONS

Dialysis treatment was independently associated with foot ulceration. Guidelines should highlight dialysis as an important risk factor for foot ulceration requiring intensive foot care.The lifetime risk of an individual with diabetes developing foot ulceration has been estimated to be 25% (1). Foot ulceration is a serious problem for people with diabetes, which also results in huge economic costs (2).Causal pathways to foot ulceration are multifactorial and involve combinations of physiological and mechanical factors, self-care, and treatment factors. Diabetic nephropathy has been identified to be an important risk factor for foot ulceration and amputation (3,4). Retrospective studies in patients with diabetes have shown that incident foot ulceration increases with progressive renal impairment (5), and one study reported a close temporal relation among the onset of dialysis, foot ulceration, and amputations (6).Studies reporting an association between renal failure and foot ulceration have failed to separate dialysis-treated patients from those not receiving dialysis (5,7). We therefore aimed to determine whether dialysis treatment is an independent risk factor for foot ulceration among diabetic patients with stage 4 or 5 chronic kidney disease (CKD). We hypothesized that dialysis treatment would be associated with a higher prevalence of foot ulceration after adjustment for potential confounders.     

Evaluation of Diabetic Foot Ulcer Healing With Hyperspectral Imaging of Oxyhemoglobin and Deoxyhemoglobin

OBJECTIVE

Foot ulceration remains a major health problem for diabetic patients and has a major impact on the cost of diabetes treatment. We tested a hyperspectral imaging technology that quantifies cutaneous tissue hemoglobin oxygenation and generated anatomically relevant tissue oxygenation maps to assess the healing potential of diabetic foot ulcers (DFUs).

RESEARCH DESIGN AND METHODS

A prospective single-arm blinded study was completed in which 66 patients with type 1 and type 2 diabetes were enrolled and followed over a 24-week period. Clinical, medical, and diabetes histories were collected. Transcutaneous oxygen tension was measured at the ankles. Superficial tissue oxyhemoglobin (oxy) and deoxyhemoglobin (deoxy) were measured with hyperspectral imaging from intact tissue bordering the ulcer. A healing index derived from oxy and deoxy values was used to assess the potential for healing.

RESULTS

Fifty-four patients with 73 ulcers completed the study; at 24 weeks, 54 ulcers healed while 19 ulcers did not heal. When using the healing index to predict healing, the sensitivity was 80% (43 of 54), the specificity was 74% (14 of 19), and the positive predictive value was 90% (43 of 48). The sensitivity, specificity, and positive predictive values increased to 86, 88, and 96%, respectively, when removing three false-positive osteomyelitis cases and four false-negative cases due to measurements on a callus. The results indicate that cutaneous tissue oxygenation correlates with wound healing in diabetic patients.

CONCLUSIONS

Hyperspectral imaging of tissue oxy and deoxy may predict the healing of DFUs with high sensitivity and specificity based on information obtained from a single visit.Diabetes is a major global disease that affects 194 million people worldwide and is expected to increase in prevalence to 344 million by the year 2030 (1). One major complication of diabetes is foot ulceration, which occurs in as many as 15–25% of type 1 and type 2 diabetic patients over their lifetimes (2–4). Studies show that between 2 and 6% of diabetic patients will develop a foot ulcer every year (5,6). The feet of patients with diabetes are at risk for ulceration due to a wide range of pathological conditions, the major three being peripheral neuropathy, foot deformity, and trauma, which may be exacerbated by comorbid peripheral vascular disease (4,7). If left untreated, foot ulcers lead to infection and deep-tissue necrosis (8).Foot pathology is a major source of morbidity in patients with diabetes and is a leading cause of hospitalization. Infected and/or ischemic diabetic foot ulcers (DFUs) account for about 25% of all hospital visits among patients with diabetes. Previous studies have shown that a DFU preceeds roughly 85% of all lower-extremity amputations in patients with diabetes (9,10), and more than 88,000 amputations are performed annually on diabetic patients (11). The cost to manage foot disorders is estimated at several billion dollars annually (5,12). Successful clinical management of DFUs not only has the potential to reduce the cost of caring for these patients but also to improve quality of life by reducing comorbidities.Current treatment options for DFUs include offloading to reduce pressure on the wound, wound care to prevent infections, and wound debridement to remove necrotic debris and restimulate the wound healing process (11,13,14). Even with these measures, some wounds fail to heal. Having a means to assess healing potential may help triage wounds earlier to more aggressive therapies, thereby avoiding infections and amputations.Clinical measurements of microvascular function may be an important part of DFU assessment (15–17). Hyperspectral imaging (HSI) was developed as a novel noninvasive diagnostic tool to quantify tissue oxygenation and generate anatomically relevant maps of microcirculatory changes seen in diabetic patients (18). HSI generates a map of regions of interest based on local molecular composition. With proper wavelength selection, spatial maps of molecules such as oxyhemoglobin (oxy) and deoxyhemoglobin (deoxy) can be acquired.A pilot study of 10 type 1 diabetic patients with 21 DFU sites showed that HSI identified changes in tissue oxygenation in the diabetic foot that were predictive of ulcer healing (18). The sensitivity, specificity, and positive predictive value of the healing index were 93, 86, and 93%, respectively. The goal of the current study was to test the accuracy of HSI in evaluating the healing potential of DFUs in a large number of type 1 and 2 diabetic patients.     

Diabetic Foot Prevention: A neglected opportunity in high-risk patients

OBJECTIVE

To evaluate the frequency of foot prevention strategies among high-risk patients with diabetes.

RESEARCH DESIGN AND METHODS

Electronic medical records were used to identify 150 patients on dialysis and 150 patients with previous foot ulceration or amputation with 30 months follow-up to determine the frequency with which patients received education, podiatry care, and therapeutic shoes and insoles as prevention services.

RESULTS

Few patients had formal education (1.3%), therapeutic shoes/insoles (7%), or preventative podiatric care (30%). The ulcer incidence density was the same in both groups (210 per 1,000 person-years). In contrast, the amputation incidence density was higher in the dialysis group compared with the ulcer group (58.7 vs. 13.1 per 1,000 person-years, P < 0.001). Patients on dialysis were younger and more likely to be of non-Hispanic white descent (P = 0.006) than patients with a previous history of ulcer or amputation.

CONCLUSIONS

Prevention services are infrequently provided to high-risk patients.The prevalence of foot complications is 250% higher among dialysis-treated patients than among patients without chronic kidney disease (1–3). Similarly, patients with a past ulcer history have a 34-times-greater risk of developing another ulcer (4,5). Programs to prevent foot ulcers and amputations generally involve therapeutic shoes and insoles, regular foot care, and patient education (6–8). This study evaluated the frequency of prevention services among high-risk patients.     

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.     

Importance of Time Spent Standing for Those at Risk of Diabetic Foot Ulceration

OBJECTIVE

Despite the high cumulative plantar stress associated with standing, previous physical activity reports of diabetic patients at risk of foot ulceration have not taken this activity into account. This study aimed to monitor spontaneous daily physical activity in diabetic peripheral neuropathy (DPN) patients and examine both walking and standing activities as important foot-loading conditions.

RESEARCH DESIGN AND METHODS

Thirteen DPN patients were asked to wear a body-worn sensor for 48 h. Body postures (sitting, standing, and lying) and locomotion (walking, number of steps, and postural transition) were extracted.

RESULTS

Patients daily spent twice as much time standing (13 ± 5%) as walking (6 ± 3%). They spent 37 ± 6% of time sitting and 44 ± 8% lying down. The average number of steps per day was 7,754 ± 4,087, and the number of walking episodes was 357 ± 167 with maximum duration of 3.9 ± 3.8 min.

CONCLUSIONS

The large portion of DPN patients'' time spent standing with the feet loaded requires further consideration when treating and preventing foot ulcers.Clinicians are cautious about advising extra activity in patients at risk of developing diabetic foot ulcers (DFUs). There is concern about excessive loading of the foot causing DFUs. However, the published data regarding this association are not clear.Contrary to expectations, previous studies looking at physical activity levels in individuals at high risk for DFUs have found these individuals to be less active than healthy counterparts (1–3). Maluf and Mueller (1) stratified steps per day in patients with diabetes and varying levels of foot complications. Patients with diabetic peripheral neuropathy (DPN) took ∼8,000 steps/day whereas patients with a history of DFUs took ∼5,500 steps/day (1). Armstrong et al. (4) corroborated diminished steps per day in high-risk patients, reporting ∼4,500 steps/day in this population.In trying to obtain a more complete picture of the trauma associated with physical activity of patients at high risk of DFUs, a means of calculating cumulative plantar stress from steps taken was suggested (1). Cumulative stress was described as the product of the forefoot pressure-time integral and the number of strides per day (1). Patients with a history of DFUs actually demonstrated 41% less cumulative plantar stress than control and DPN patients matched for age and BMI (1). With previous studies indicating a lower volume of total physical activity in DFU patients, variability in physical activity has been identified as a likely contributor to DFU formation (5).These previous studies assessing physical activity in patients at risk of DFUs used pedometers to measure steps per day. Until recently, it has not been possible to unobtrusively assess other types of foot loading activities, such as standing or bouts of activity using a single wearable sensor (6–8). A greater understanding of the complete physical activity of those at risk of DFUs may provide greater insight into DFU development and prevention. This study aimed to describe the quality and quantity of activities of daily living in DPN patients.     

TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.Members of the TNF receptor (TNFR)¹ superfamily play important roles in the induction of diverse signals leading to cell growth, activation, and apoptosis (1). Whether the signals induced by a given receptor leads to cell activation or death is, however, highly cell-type specific and tightly regulated during differentiation of cells. For example, the TNFRs can exert costimulatory signals for proliferation of naive lymphocytes but also induce death signals required for deletion of activated T lymphocytes (1). The cytoplasmic domains of these receptors lack intrinsic catalytic activity and also exhibit no significant homology to each other or to other known proteins. Exceptions to this include Fas(CD95) and TNFR1 that share a significant homology within an 80–amino acid region of their cytoplasmic tails (called the “death domain”; 2, 3). Therefore, it is suggested that the TNFR family members can initiate different signal transduction pathways by recruiting different types of intracellular signal transducers to the receptor complex (1).Indeed, several types of intracellular signal transducers have been identified that initiate distinct signal transduction pathways when recruited to the members of TNFR superfamily (4–19). Recent biochemical and molecular studies showed that a class of signal-transducing molecules are recruited to Fas(CD95) or TNFR1 via interaction of the death domains (2, 3, 6, 12, 17, 20). For example, Fas(CD95) and TNFR1 recruit FADD(MORT1)/RIP or TRADD/FADD (MORT1)/RIP through the interactions of their respective death domains (2, 3, 6, 12, 17, 20, 21). Clustering of these signal transducers leads to the recruitment of FLICE/ MACH, and subsequently, to cell death (13, 14).The TNFR family members can also recruit a second class of signal transducers called TRAFs (TNFR-associated factor), some of which are responsible for the activation of NF-κB or JNK (9, 20, 22). TRAF proteins were identified by their biochemical ability to interact with TNFR2, CD40, CD30, or LT-βR (4, 5, 10, 11, 15, 23–27). These receptors interact directly with TRAFs via a short stretch of amino acids within their cytoplasmic tails, but do not interact with the death domain containing proteins (4, 5, 15, 24–27). To date, five members of the TRAF family have been identified as signaling components of the TNFR family members. All TRAF members contain a conserved TRAF domain, ∼230 amino acids in length, that is used for either homo- or heterooligomerization among the TRAF family, for interactions with the cytoplasmic regions of the TNFR superfamily, or for interactions with downstream signal transducers (4, 5, 8, 10, 11, 19, 23–25, 28). In addition to the TRAF domain, most of the TRAF family members contain an NH₂-terminal RING finger and several zinc finger structures, which appear to be important for their effector functions (4, 5, 10, 11, 23–25).Several effector functions of TRAFs were revealed by recent experiments based on a transfection system. TRAF2, first identified by its interaction with TNFR2 (4), was subsequently shown to mediate NF-κB activation induced by two TNF receptors, CD40 and CD30 (9, 28–30). TRAF5 was also implicated in NF-κB activation mediated by LTβR (10), whereas TRAF3 (also known as CRAF1, CD40bp, or LAP1; references 5, 11, 24, and 25) was shown to be involved in the regulation of CD40-mediated CD23 upregulation in B cells (5). The role of other TRAF members in the TNFR family–mediated signal transduction is not clear. They may possess some effector functions as yet to be revealed, or work as adapter proteins to recruit different downstream signal transducers to the receptor complex. For example, TRAF1 is required for the recruitment of members of the cellular inhibitor of apoptosis protein (c-IAP) family to the TNFR2-signaling complex (7). In addition to the signal transduction by the TNFR family members, TRAFs may regulate other receptor-mediated signaling pathways. For example, TRAF6 is a component of IL-1 receptor (IL1R)–signaling complex, in which it mediates the activation of NF-κB by IL-1R (31). Since TRAFs form homo- or heterooligomers, it is suggested that the repertoire of TRAF members in a given cell type may differentially affect the intracellular signals triggered by these receptors. This may be accomplished by the selective interaction of TRAFs with a specific set of downstream signal transducers. Although many aspects of TRAF-mediated effector functions leading to cellular activation have been defined, it needs to be determined whether TRAF proteins will also mediate the apoptotic signals induced by the “death-domain-less” members of the TNFR superfamily (1, 27, 32–36).Here we report the isolation and characterization of a novel component of the TNFR superfamily/TRAFs signaling complex, named TRIP (TRAF-interacting protein). TRIP associates with the receptor/TRAF signaling complex, and inhibits the TRAF2-mediated NF-κB activation. Biochemical studies indicate that TRIP associates with the TNFR2 or CD30 receptor complex via its interaction with TRAF proteins, suggesting a model which can explain why the ligation of these receptors can promote different cell fates: proliferation or death.     

A New Mechanism of NK Cell Cytotoxicity Activation: The CD40–CD40 Ligand Interaction

NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2–activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2–activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.NK cells represent a distinct lineage of lymphocytes that are able to kill a variety of tumor (1), virus-infected (2), bone marrow transplanted (3), and allogeneic target cells (4). NK cells do not express T cell receptors or immunoglobulins and are apparently normal in mice with defects in the recombinase machinery (5, 6).Our knowledge about NK cell specificity has increased considerably in the last years. NK cells can probably interact with target cells by a variety of different cell surface molecules, some involved in cell adhesion, some activating the NK cytolytic program (7, 8), and other ones able to inhibit this activation by negative signaling (as reviewed in reference 9).A common feature of several inhibitory NK receptors is the capability to bind MHC class I molecules (10, 11), as predicted by the effector inhibition model within the missing self hypothesis of recognition by NK cells (12–14). Interestingly, the MHC class I receptors identified so far belong to different gene families in mouse and man; these are the p58/p70/NKAT or killer cell inhibitory receptors (KIR)¹ of the immunoglobulin superfamily in man and the Ly49 receptors of the C-type lectin family in the mouse. There is also evidence that MHC class I molecules can be recognized as triggering signals in NK cells of humans, rats as well as mice (13). The inhibitory receptors allow NK cells to kill tumor or normal cell targets with deficient MHC class I expression (12, 14). This does not exclude that other activating pathways can override inhibition by MHC class I molecules (15) and, even in their absence, there must be some activating target molecules that initiate the cytolytic program. Several surface molecules are able to mediate positive signals in NK cells. Some of these structures, like NKRP1 (16), CD69 (17), and NKG2 (18) map to the NK complex region (NKC) of chromosome 6 in mice and of chromosome 12 in humans (13). CD2 (19) and CD16 (20) molecules can also play a role in the activation pathway.NK cells resemble T cells in many respects, both may arise from an immediate common progenitor (21, 22), and share the expression of several surface molecules (23). NK cells produce cytokines resembling those secreted by some helper T cell subsets (24) and contain CD3 components in the cytoplasm (21). The expression of some surface structures, involved in TCR-dependent T cell costimulation, like CD28 in human (25), has been described on NK cells, but the functional relevance of these molecules for NK activation processes has not been fully established.Another T cell molecule of interest is CD40L, which interacts with CD40, a 50-kD membrane glycoprotein expressed on B cells (26), dendritic cells (27), and monocytes (28). CD40 is a member of the tumor necrosis factor/nerve growth factor receptor family (29) which includes CD27 (30), CD30 (31), and FAS antigen (32). Murine and human forms of CD40L had been cloned and found to be membrane glycoproteins with a molecular mass of ∼39 kD induced on T cells after activation (33). Also mast cells (34), eosinophils (35), and B cells (36) can be induced to express a functional CD40L. The CD40L–CD40 interaction has been demonstrated to be necessary for T cell–dependent B cell activation (33, 37). Mutations in the CD40L molecule cause a hyper-IgM immunodeficiency condition in man (38, 39, 40). On the other hand, CD40–CD40L interactions also orchestrate the response of regulatory T cells during both their development (41, 42) and their encounter with antigen (43, 44).NK cells have also been suggested to play a role in B cell differentiation and immunoglobulin production (45). Therefore, it was of interest to investigate whether NK cells could use a CD40-dependent pathway in their interactions with other cells. Therefore, we have investigated the ability of target cells expressing CD40 to induce activation of NK cytotoxicity.     

Corneal Confocal Microscopy: A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

OBJECTIVE

The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.

RESEARCH DESIGN AND METHODS

A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM).

RESULTS

Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm² with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm² with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74).

CONCLUSIONS

CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity.Established diabetic neuropathy leads to pain and foot ulceration. Detecting neuropathy early may allow intervention with treatments to slow or reverse this condition (1). Recent studies suggested that small unmyelinated C-fibers are damaged early in diabetic neuropathy (2–4) but can only be detected using invasive procedures such as sural nerve biopsy (4,5) or skin-punch biopsy (6–8). Our studies have shown that corneal confocal microscopy (CCM) can identify early small nerve fiber damage and accurately quantify the severity of diabetic neuropathy (9–11). We have also shown that CCM relates to intraepidermal nerve fiber loss (12) and a reduction in corneal sensitivity (13) and detects early nerve fiber regeneration after pancreas transplantation (14). Recently we have also shown that CCM detects nerve fiber damage in patients with Fabry disease (15) and idiopathic small fiber neuropathy (16) when results of electrophysiology tests and quantitative sensory testing (QST) are normal.In this study we assessed corneal sensitivity and corneal nerve morphology using CCM in diabetic patients stratified for the severity of diabetic neuropathy using neurological evaluation, electrophysiology tests, and QST. This enabled us to compare CCM and corneal esthesiometry with established tests of diabetic neuropathy and define their sensitivity and specificity to detect diabetic patients with early neuropathy and those at risk of foot ulceration.     

Role of Intrinsic Muscle Atrophy in the Etiology of Claw Toe Deformity in Diabetic Neuropathy May Not Be as Straightforward as Widely Believed

OBJECTIVE

Clawing of the toes in the diabetic neuropathic foot is believed to be caused by muscle imbalance resulting from intrinsic muscle atrophy. However, experimental data that support this mechanism are lacking. The aim of this study was to evaluate this hypothesis using magnetic resonance imaging (MRI).

RESEARCH DESIGN AND METHODS

In 20 neuropathic diabetic patients, 10 with claw toe deformity and 10 with normally aligned toes, multiple plane images of the foot and lower leg were acquired using T1-weighted spin-echo MRI. Atrophy of the intrinsic and extrinsic muscles controlling the toes was assessed using a semiquantitative 5-point atrophy scale. An intrinsic-to-extrinsic foot muscle imbalance score was derived from these atrophy scores, and correlation coefficients were established.

RESULTS

The mean ± SD intrinsic muscle atrophy score was 3.1 ± 1.1 for the toe deformity group and 2.6 ± 1.2 for the nondeformity group (not significantly different). The intrinsic muscle atrophy score was not significantly correlated with degree of toe deformity (r = −0.18). The muscle imbalance score was not significantly different between study groups and was not significantly correlated with degree of toe deformity (r = −0.14).

CONCLUSIONS

Neither intrinsic muscle atrophy nor muscle imbalance discriminated between neuropathic patients with or without claw toe deformity, suggesting that the role of these muscle factors in claw toe development may not be primary or as straightforward as previously believed. These findings shed new light on the etiology of foot deformity in diabetes and suggest a more complex nature of development, potentially involving anatomical and physiological predisposing factors.Clawing or hammering of the toes is a common foot deformity in patients with diabetes, with reported prevalence values between 32 and 46% (1,2). Both claw and hammer toes involve hyperextension of the metatarsal-phalangeal (MTP) joint as the most important structural abnormality and will be referred to as “claw toes” in this article. Claw toes in diabetic patients are associated with a distal displacement of the protective submetatarsal head fat pads and an increase of plantar foot pressures at these regions (3,4). Furthermore, in prospective analyses, claw toe deformity has been found to be a predictor of diabetic foot ulceration (5), a condition that may lead to infection or amputation. Therefore, a proper understanding of the etiology of claw toe deformity is important if we are to initiate or improve interventions for the prevention or correction of claw toe deformity with which we can reduce the risk for ulceration and further complications in this patient group.There are several theories that may explain why claw toes develop in diabetic patients. Ill-fitting footwear, in particular cramped toe boxes in patients who lack protective sensation, may externally force the toes in a clawed position (6). There are some suggestions that rupture of the plantar fascia or ligament contractures at the MTP joints may be involved (7,8). However, the most commonly reported cause of claw toe deformity is intrinsic muscle atrophy and weakness due to motor neuropathy, leading to an imbalance between intrinsic and extrinsic muscles across the MTP and interphalangeal joints (9–11). The long extrinsic flexors have a greater mechanical advantage over the extensors at the interphalangeal joints, and the extensors have a greater mechanical advantage over the flexors at the MTP joint (6,12). If the intrinsic muscles (i.e., the lumbricals and interossei) function correctly, they compensate for this mechanical advantage by flexing the MTP joint while extending the interphalangeal joints. But when the intrinsic muscles are atrophic and overpowered by the extrinsic muscles, this stabilizing action is lost, which eventually may result in clawing of the toes.Despite the existence of numerous anecdotal and observational reports on this mechanical theory of claw toe pathogenesis and despite wide acceptance of this mechanism in the diabetic foot literature, experimental data to support this theory do not exist. In addition, some reservations regarding this mechanism were provided by results from recent studies. Bus et al. performed quantitative analyses of muscle atrophy and toe deformity using magnetic resonance imaging (MRI) and concluded that intrinsic muscle atrophy does not necessarily imply claw toe deformity in the diabetic neuropathic foot (13). In agreement with these results, Andersen et al. (14) found many of their neuropathic patients with normally aligned toes to have significant degrees of atrophy of the intrinsic foot muscles. Furthermore, van Schie et al. (15) found no association between semiquantitative scores of muscle weakness and foot deformity in diabetic male patients. Therefore, even though these findings do not suggest that intrinsic muscle atrophy and muscle imbalance are no longer contributing factors in the development of toe deformity, their role may not be as straightforward as widely believed.A better understanding of the associations between muscle atrophy, imbalance, and toe deformity may be achieved with a more quantitative in vivo examination of both the foot and lower leg muscles using MRI in a group of patients with toe deformity and a matched group with normally aligned toes. Therefore, the purpose of this study was to use MRI to examine the extrinsic and intrinsic foot muscles in patients with claw toe deformity and matched patients with normally aligned toes to explore in a more objective manner the association between intrinsic muscle atrophy and claw toe deformity. Based on the current widespread beliefs, we intended to test the hypothesis that clear differences in both intrinsic muscle atrophy and muscle imbalance are present between patients with toe deformity and those without.     

Pediatric Endocrinologists' Management of Children With Type 2 Diabetes

OBJECTIVE

To understand physician behaviors and attitudes in managing children with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A survey was mailed to a nationwide sample of pediatric endocrinologists (PEs).

RESULTS

A total of 40% of PEs surveyed responded (211 of 527). Concordance with current monitoring guidelines varied widely, ranging from 36% (foot care) to 93% (blood pressure monitoring). Given clinical vignettes addressing hyperlipidemia, hypertension, and microalbuminuria, only 34% of PEs were fully concordant with current treatment guidelines. Reported barriers included concerns about patient adherence, insufficient scientific evidence about treatment, and lack of familiarity with current recommendations. Providers aged ≤45 years or in clinical practice <10 years reported significantly more aggressive management behaviors and had higher concordance with guidelines.

CONCLUSIONS

Screening and management of pediatric type 2 diabetes varied widely among PEs, suggesting opportunities for quality improvement. More aggressive management of type 2 diabetes among younger providers may be related to recent training when type 2 diabetes was more common.The incidence of type 2 diabetes in children is increasing (1), and children with type 2 diabetes are at high risk to develop diabetes-related complications, including hyperlipidemia, hypertension, and microalbuminuria (2–4). Despite limited scientific evidence, several consensus statements on the assessment and management of pediatric type 2 diabetes have been developed (4–6). Current understanding of physician management of pediatric type 2 diabetes is limited (7–10). We conducted a survey to better understand pediatric endocrinologists'' (PEs'') behaviors and attitudes related to the management of pediatric type 2 diabetes.     

Effect of Pharmacological Treatment of Depression on A1C and Quality of Life in Low-Income Hispanics and African Americans With Diabetes: A randomized, double-blind, placebo-controlled trial

OBJECTIVE

To determine whether pharmacological treatment of depression in low-income minorities with diabetes improves A1C and quality of life (QOL).

RESEARCH DESIGN AND METHODS

This was a 6-month, randomized, double-blind, placebo-controlled trial. Patients were screened for depression using Whooley''s two-question tool at a county diabetes clinic. Depression was confirmed (or not) with the Computerized Diagnostic Interview Survey (CDIS) software program, and the severity of depression was assessed monthly by the Hamilton Depression Scale (HAM-D). Depressed subjects with A1C levels ≥8.0% were randomly assigned to receive either sertraline or placebo. Diabetes care was provided by nurses following detailed treatment algorithms who were unaware of therapy for depression.

RESULTS

A total of 150 subjects answered positively to at least one question on Whooley''s questionnaire. The positive predictive value for depression diagnosed by CDIS was 69, 67, and 84% for positive answers to question 1 only, question 2 only, or both, respectively. Of the 89 subjects who entered the study, 75 completed. An intention-to-treat analysis revealed significant differences between baseline and 6 months in HAM-D and pain scores, QOL, and A1C and systolic blood pressure levels in both groups, with no differences between groups for the first three but a significantly greater decrease with sertraline in A1C and systolic blood pressure levels. Changes in HAM-D scores and A1C levels were significantly correlated in all subjects (P = 0.45 [P < 10⁻⁶]).

CONCLUSIONS

In this low-income minority population, pharmacological treatment of depression significantly improved A1C and systolic blood pressure levels compared with placebo.The prevalence of depression among people with diabetes is more than twice that of the general population (1). Coexistence of depression in persons with diabetes is associated with worse glycemic control (2), which may be due to less adherence to self-care behaviors and medications (3). Eventually, there is increased morbidity (4) and mortality (5) and higher medical costs (6).The prevalence of untreated depression in people with diabetes is higher in minorities (1). Yet, screening for and treating depression are less common in this population (7). Very little research has been published on diabetes and depression with a focus on minority populations, who have significant disparities in outcomes (8), such as higher A1C levels (9), increased rates of complications (10), and more severe depression (8).Depression is associated with worse glycemic control (2). Some studies have evaluated whether treatment of depression will improve A1C levels (11–20). However, these drug studies were open label, were of short duration, and/or were conducted in highly educated (more than high school education) Caucasian populations. Most showed that although depression was improved, A1C levels were not. We sought to determine whether use of antidepressants in a minority population with uncontrolled diabetes improved their A1C levels, quality of life (QOL), and depression compared with placebo.     

��-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.     

Anti-Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

Aromatic dicationic compounds, including bisbenzamidines and dicationically substituted bisbenzimidazoles and carbazoles, have excellent experimental anti-Pneumocystis activities (14, 40, 46, 48, 50, 51) and are also active against other microbial pathogens, including protozoan parasites (2–5, 10, 38, 41, 43, 44), fungi (45), and some viruses (25–27, 49, 53). Aromatic dications also possess other pharmacological properties, including antiinflammatory and anticoagulant activities (29–37). Two problems hindering development of these compounds as new drugs, however, are limited oral bioavailability and toxicity (24, 38, 48, 51).Recent studies of pentamidine metabolism (7–9, 21–23) have led to a novel approach to overcome the limited oral bioavailability and acute toxicity. Aromatic diamidoximes are hypothesized to be orally bioavailable prodrugs that are readily reduced by drug-metabolizing enzymes to the active aromatic amidines (19, 21, 22), resulting in excellent antimicrobial activity with reduced acute host toxicity.Amidoximes were first shown by Lamb and White to be active against experimental African trypanosomiasis (42) and then later were shown to be active against other microorganisms (1, 17, 18, 28). Although activities were often reported for both amidoximes and corresponding amidines, no mention was made in these early publications that metabolic activation was required for in vivo activity of the amidoximes. Moreover, no systematic studies were performed to determine which analogs were orally active and if the amidoxime derivatives had increased oral activity compared to the amidines. Thus, the concept of amidoximes as prodrugs of amidines was not raised in earlier studies.The hypothesis that amidoximes might be useful prodrugs resulted from research examining the metabolism of pentamidine (6–9, 21, 22). Two primary oxidative metabolites identified were the mono- and diamidoximes, formed by N-hydroxylation of pentamidine. Although the diamidoxime derivative of pentamidine has little or no activity against three protozoan parasites in vitro, both the mono- and diamidoximes were active against African trypanosomes and Leishmania spp. when given to experimental animals subcutaneously (19, 21–23, 39). The diamidoxime given orally to rats was absorbed from the gut and converted to pentamidine, a reaction subsequently shown to be catalyzed by an oxygen-independent hepatic reductase activity (21, 22). These observations led to the proposal that amidoxime derivatives, in general, are effective, orally absorbed prodrugs for all pharmacologically active amidine-containing compounds (19). However, the only amidoximes tested were derivatives of pentamidine. We recently demonstrated that two novel amidoximes of 2,5-bis[4-amidinophenyl]furan were highly active orally and intravenously (13). Moreover, Weller and coworkers demonstrated that amidoximes of potent monoamidine fibrinogen receptor antagonists greatly enhanced their oral bioavailability (54).With this promising background, we began to synthesize potential amidoxime prodrugs of our most active, least toxic diamidines. Results presented here, however, demonstrate that amidoximes are not effective prodrugs for all aromatic dicationic compounds. The nature of the linker between the two amidoxime moieties plays a key role in determining if a particular diamidoxime has oral anti-Pneumocystis activity. Diamidoxime derivatives of the very promising bisbenzimidazole and carbazole classes of dications, and bisbenzamidoximes that contain additional nitrogen atoms in the aliphatic linkers, had little or no anti-Pneumocystis activity, even though the parent diamidines had excellent intravenous activity. Variability in activity does not appear to be caused by differences in enzymatic reductase activity, since both active and inactive diamidoximes were metabolized by cell-free liver homogenates.     

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.     

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.