Poor Glycemic Control Is an Independent Risk Factor for Low HDL Cholesterol in Patients With Type 2 Diabetes

OBJECTIVE

To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia.

RESEARCH DESIGN AND METHODS

We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides <400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors.

RESULTS

A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1–1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1–1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05–1.18], P = 0.00017).

CONCLUSIONS

Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with type 2 diabetes (1,2). Several studies have shown that aggressive comprehensive management of the mixed dyslipidemia associated with the metabolic syndrome and type 2 diabetes is needed to reduce the increased cardiovascular risk (3,4). Despite this evidence, treatments do not completely address all the components of diabetic dyslipidemia and therapeutic targets are still not achieved (5). Nearly half of type 2 diabetic patients have low levels of HDL cholesterol (5), a key component of diabetes-related dyslipidemia and a strong independent risk factor for CVD. HDL cholesterol is inversely correlated with cardiovascular risk, even when LDL cholesterol has been reduced with statin therapy (6–7).An inverse relationship between HDL cholesterol and A1C levels has been described in type 2 diabetic patients (8,9). It is unclear, however, whether this relationship is partly dependent on obesity and/or hypertriglyceridemia, which are known determinants of low HDL cholesterol and frequently found in patients with poorly controlled diabetes. This study was designed to test the hypothesis that glycemic control is independently associated with HDL cholesterol in patients with type 2 diabetes.     

Development and Validation of a Uremic Pruritus Treatment Algorithm and Patient Information Toolkit in Patients With Chronic Kidney Disease and End Stage Kidney Disease

ContextUremic pruritus (UP) affects up to half of all patients with kidney disease and has been independently associated with poor patient outcomes. UP is a challenging symptom for clinicians to manage as there are no validated guidelines for its treatment.ObjectivesThe study aimed to develop and validate an algorithm and patient information toolkit for the treatment of UP in patients with kidney disease.MethodsThe study involved a literature search and development of an initial draft algorithm, followed by content and face validation of this algorithm. Validation entailed three rounds of interviews with six nephrology clinicians per round. Participants assessed the relevance of each component of the algorithm and then rated a series of statements on a scale of 1-5 to assess face validity of the algorithm. After each round, the content validity index (CVI) of each algorithm component was calculated, and the algorithm was revised by the study team in response to findings. This process was followed by a second study that developed and validated a patient information pamphlet and video.ResultsAlgorithm validation participants were affiliated with three institutions and included seven physicians, four registered nurses, three nurse practitioners, three pharmacists, and a dietician. The average CVI of the algorithm components across all three rounds was 0.89, with 0.80 commonly cited as the lower acceptable limit for content validation. More than 78% of participants rated each face validity statement as “Agree” or “Strongly Agree”. For the patient information tools, five clinicians and 15 patients were included in validation. The average CVI was 1.00 for both tools, and the average face validity was 92%.ConclusionA treatment algorithm and patient information toolkit for managing UP in patients with kidney disease were developed and validated through expert review. Further research will be conducted on implementation of the treatment algorithm and evaluating patient-reported outcomes.     

Clostridium difficile Infection in Patients With Chronic Kidney Disease

ObjectiveTo examine the rate of Clostridium difficile infection (CDI) and hospital-associated outcomes in a national cohort of hospitalized patients with chronic kidney disease (CKD) and assess the impact of long-term dialysis on outcome in these patients.Patients and MethodsData for January 1, 2005, through December 31, 2009 were obtained from the National Hospital Discharge Survey, which includes information on patient demographics, diagnoses, procedures, and discharge types. Data collected and analyzed for this study included age, sex, race, admission type (urgent or emergent combined vs elective), any colectomy diagnosis, length of stay, type of discharge, and mortality. International Classification of Diseases, Ninth Revision, Clinical Modification codes were utilized to identify CKD patients and CDI events. Weighted analysis was performed using JMP version 9.ResultsAn estimated 162 million adults were hospitalized during 2005-2009, and 8.03 million (5%) had CKD (median age, 71 years). The CDI rate in CKD patients was 1.49% (0.119 million) compared with 0.70% (1.14 million) in patients without CKD (P<.001). Patients with CKD who were undergoing long-term dialysis were more than 2 times as likely to develop CDI than non-CKD patients and 1.33 times more likely than CKD patients not undergoing dialysis (all P<.001). In a weighted multivariate analysis adjusting for sex and comorbidities, patients with CKD and CDI had longer hospitalization, higher colectomy rate (adjusted odds ratio [aOR], 2.30; 95% confidence interval [CI], 2.14-2.47), dismissal to a health care facility (aOR, 2.22; 95% CI, 2.19-2.25), and increased in-hospital mortality (aOR, 1.55; 95% CI, 1.52-1.59; all P<.001) as compared with CKD patients without CDI. Patients with CKD who were undergoing long-term dialysis did not have worse outcomes as compared with CKD patients who were not undergoing long-term dialysis.ConclusionThese data suggest that patients with CKD have a higher risk of CDI and increased hospital-associated morbidity and mortality. Future prospective studies are needed to confirm these findings and to identify effective CDI prevention in CKD patients, who appear to have an increased risk of CDI acquisition.     

High Levels of Foot Ulceration and Amputation Risk in a Multiracial Cohort of Diabetic Patients on Dialysis Therapy

OBJECTIVE

To evaluate the prevalence of lower-limb complications in a multiracial cohort of patients with diabetes receiving dialysis.

RESEARCH DESIGN AND METHODS

This work was a cross-sectional study of lower-limb complications in dialysis-treated patients with diabetes in the U.K. and U.S.

RESULTS

We studied 466 patients (139 U.K.; 327 U.S.). The prevalence of lower-limb complications was high (foot ulcers 12%, neuropathy 79%, peripheral arterial disease 57%, history of foot ulceration 34%, and prior amputation 18%), with no significant ethnic variation, except that foot ulcers were more common in whites than in patients of African descent (P = 0.013). Ninety-five percent of patients were at high risk of lower-limb complications. Prior amputation was related to foot ulcer history, peripheral arterial disease, and hemodialysis modality in multivariable analysis. Prevalent ulceration showed independent associations with foot ulcer history and peripheral arterial disease, but not with ethnicity.

CONCLUSIONS

All patients with diabetes receiving dialysis are at high risk of lower-limb complications independent of ethnic background.Among individuals with diabetes, significant ethnic differences in lower-limb complications have been identified in the U.K. (1) and the U.S. (2). Previous studies linking renal impairment or end-stage renal disease to lower-limb complications have been retrospective and have not considered ethnicity (3,4). We aimed to establish the prevalence of lower-limb complications by ethnic group in dialysis-treated diabetic patients.     

Peginesatide to Manage Anemia in Chronic Kidney Disease Patients on Peritoneal Dialysis

♦ Background:

Peginesatide is a novel, synthetic, peptide-based pegylated erythropoiesis-stimulating agent that is designed specifically to stimulate the erythropoietin receptor. The purpose of the present study was to assess, for the first time, the efficacy and safety of peginesatide in chronic kidney disease (CKD) patients receiving peritoneal dialysis (PD) and previously on epoetin treatment.

♦ Methods:

In this open-label multicenter study, 59 PD patients with CKD were converted from epoetin (alfa or beta) to once-monthly peginesatide. Doses were titrated to maintain hemoglobin levels between 10 g/dL and 12 g/dL during the 25 weeks of the study. The primary endpoint was change from baseline in mean hemoglobin values during the evaluation period (weeks 20 – 25).

♦ Results:

The mean hemoglobin value during the evaluation period was 11.3 ± 1.07 g/dL, and the mean change from baseline was 0.10 ± 1.15 g/dL (95% confidence limits: −0.24, 0.44 g/dL). During the evaluation period, most patients maintained hemoglobin levels between 10 g/dL and 12 g/dL (63.0%) and within ±1.0 g/dL of baseline (60.9%). The median weekly epoetin dose at baseline was 96.0 U/kg, and the median starting peginesatide dose was 0.047 mg/kg. Forty-three patients (72.9%) completed the study. Six patients (10.2%) received red blood cell transfusions. The observed adverse event profile was consistent with underlying conditions in the PD patient population. The most common adverse event was peritonitis (20.3%), a complication commonly associated with PD. Four deaths occurred during the study (2 related to septic shock, and 1 each to myocardial ischemia and myasthenia gravis).

♦ Conclusions:

In this study, once-monthly peginesatide maintained hemoglobin levels in PD patients after conversion from epoetin.     

The Effect of Iron and Erythropoietin Treatment on the A1C of Patients With Diabetes and Chronic Kidney Disease

OBJECTIVE

To examine the effect of intravenous iron and erythropoietin-stimulating agents (ESAs) on glycemic control and A1C of patients with diabetes and chronic kidney disease (CKD).

RESEARCH DESIGN AND METHODS

This was a prospective study of patients with type 2 diabetes and CKD stage IIIB or IV undergoing intravenous iron (group A) and/or ESA (group B). Full blood profiles were determined over the study period. Glycemic control was monitored using A1C, seven-point daily glucose three times weekly, and continuous glucose monitoring (CGM).

RESULTS

There were 15 patients in both group A and group B. Mean A1C (95% CI) values fell in both groups (7.40% [6.60–8.19] to 6.96% [6.27–7.25], P < 0.01, with intravenous iron and 7.31% [6.42–8.54] to 6.63% [6.03–7.36], P = 0.013, ESA). There was no change in mean blood glucose in group A (9.55 mmol/l [8.20–10.90] vs. 9.71 mmol/l [8.29–11.13], P = 0.07) and in group B (8.72 mmol/l [7.31–10.12] vs. 8.78 mmol/l [7.47–9.99], P = 0.61) over the study period. Hemoglobin and hematocrit values significantly increased following both treatments. There was no linear relationship found between the change in A1C values and the rise of hemoglobin following either treatment.

CONCLUSIONS

Both iron and ESA cause a significant fall in A1C values without a change to glycemic control in patients with diabetes and CKD. At the present time, regular capillary glucose measurements and the concurrent use of CGM remain the best alternative measurements of glycemic control in this patient group.A1C is the most widely accepted and used method of assessing chronic glycemia in patients with diabetes. It is formed by the irreversible binding of glucose to hemoglobin over the lifespan of the erythrocyte (1,2).Patients with chronic kidney disease (CKD) are commonly anemic due to a variety of reasons, including functional or absolute iron deficiency and erythropoietin insufficiency (3,4). Treatment of anemia in patients with CKD using iron replacement therapy and erythropoietin-stimulating agents (ESAs) has resulted in significant improvements to quality of life and the correction of anemia without the need for blood transfusions (3–5).There are several studies (6–9) that show a fall of A1C in patients treated with ESA and iron therapy. These studies are mostly in patients already receiving hemodialysis and those without diabetes. The effect of the lowering of the A1C values following either treatment has been postulated to be secondary to the formation of new erythrocytes in the blood stream, causing a change of proportion of young to old cells, and also from an alteration in the red-cell glycation rates (10,11).Despite this, a comprehensive analysis of the relationship between glycemic control and A1C changes in patients undergoing both iron and ESA therapy has never been performed using robust methods, such as seven-point daily capillary glucose monitoring (7PGM) or using CGM devices. Thus, any class effect that iron therapy and ESA may have on A1C values could in fact represent a parallel change to glycemic control along with the currently postulated physiological changes. Furthermore, the effect of the fall in A1C following these two therapies has not been well studied in patients not already on hemodialysis.This study therefore sought to establish how intravenous iron and ESA therapy influence A1C values in patients with type 2 diabetes and CKD not on hemodialysis. Robust monitoring of blood glucose was performed throughout the study period to determine if the anticipated fall in A1C was a true reflection of glycemic control.     

Serum Lipopolysaccharide Activity Is Associated With the Progression of Kidney Disease in Finnish Patients With Type 1 Diabetes

OBJECTIVE

The aim of the study was to investigate whether serum lipopolysaccharide (LPS) activities are associated with the progression of kidney disease in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

For this prospective study, we chose 477 Finnish patients with type 1 diabetes, who were followed for 6 years. At the baseline visit, 239 patients had a normal albumin excretion rate (normoalbuminuria) and 238 patients had macroalbuminuria. Patients were further divided into nonprogressors and progressors based on their albumin excretion rate at follow-up. Eighty normoalbuminuric patients had developed microalbuminuria, and 79 macroalbuminuric patients had progressed to end-stage renal disease. Serum LPS activity was determined with the Limulus amoebocyte lysate chromogenic end point assay.

RESULTS

Serum LPS activity was significantly higher in the macroalbuminuric group than in the normoalbuminuric group (P < 0.001). Notably, normoalbuminuric progressor patients had a significantly higher LPS activity at baseline than normoalbuminuric nonprogressor patients (median 49 [interquartile range 34–87] vs. 39 [29–54] EU/ml; P = 0.001). The normoalbuminuric progressor patients exhibited features of the metabolic syndrome with higher triglyceride concentrations and lower estimated glucose disposal rate. A high LPS-to-HDL ratio was associated with the progression of kidney disease in both groups. Insulin resistance (P < 0.001) and serum LPS activity (P = 0.026) were independent risk factors of disease development, when A1C was removed from the regression analysis.

CONCLUSIONS

High serum LPS activity is associated with the development of diabetic nephropathy in Finnish patients with type 1 diabetes.Diabetic nephropathy is one of the leading causes of death in patients with type 1 diabetes worldwide. It has been estimated that approximately one-third of patients with type 1 diabetes develop chronic kidney disease during their lifetime (1). Patients with diabetic nephropathy experience dyslipidemia and macrovascular complications, which in turn increases the risk of cardiovascular death (2,3). Although renal dysfunction is often associated with a long duration of diabetes, poor glycemic control, and genetic susceptibility, the etiology of the complication is largely unknown. Recent studies have demonstrated that patients with type 1 diabetes have elevated levels of proinflammatory markers in the serum (4). It should also be noted that type 1 diabetic patients are more prone to infections than nondiabetic subjects (5).Bacterial infections induce a systemic inflammatory response, which may cause severe organ damage or even death. Bacterial endotoxins/lipopolysaccharides (LPSs) play a central role in acute and chronic inflammations. LPS triggers the innate immune response characterized by cytokine release and immune system activation. LPS is a unique glycolipid located at the outer membrane of Gram-negative bacteria. These potentially harmful bacteria may colonize in different parts of the body including the oral mucosa and gastrointestinal, genitourinary, and respiratory tracts (6).Bacterial infections may be life-threatening, especially in patients who require dialysis or who have undergone kidney transplantation. In such patients with end-stage renal disease (ESRD), sepsis increases the risk of mortality >100-fold compared with that for the general population (7). Several studies have shown that periodontitis is relatively common among patients with diabetes and impaired kidney function (8–10). Periodontitis refers to inflammation of the supporting tissue of the teeth and is often caused by Gram-negative bacteria. Bacterial infections are also associated with other forms of kidney disease, e.g., IgA nephropathy, the most common form of glomerulonephritis in the world (11). In addition, bacterial endotoxins have been commonly used to induce acute kidney failure in laboratory animals. Given the close association between periodontitis and kidney disease on one hand and periodontitis and Gram-negative bacteria on the other, it can be hypothesized that LPS triggers not only inflammation in patients with periodontitis but also the process that leads to diabetic nephropathy. Thus, we studied whether serum LPS activity is associated with the development of kidney disease in Finnish patients with type 1 diabetes.     

Cognitive Function Is Not Associated With Recurrent Foot Ulcers in Patients With Diabetes and Neuropathy

OBJECTIVE

To study whether there is an association between cognitive impairment and the relapse rate of foot ulcers in diabetic patients and those with previous foot ulcers.

RESEARCH DESIGN AND METHODS

This single-center prospective study assessed the association of cognitive function and risk for ulcer relapse in 59 patients with diabetes (mean age 65.1 years, diabetes duration 16.5 years, and A1C 7.4%), peripheral neuropathy, and a history of foot ulceration. Premorbid and current cognitive functions were measured (multiple-choice vocabulary test [Lehrl], number-symbol test, mosaic test [HAWIE-R], and trail-making tests A and B [Reitan]). Prevalence of depression was evaluated retrospectively (diagnoses in patient files or use of antidepressive medication). Patients were re-examined after 1 year.

RESULTS

Three patients (5%) died during follow-up (one of sepsis and two of heart problems). The remaining 56 patients (48%) developed 27 new foot ulcerations (78% superficial ulcerations [Wagner stage 1]). Characteristics of patients with and without ulcer relapse were not different. In a binary logistic regression analysis, cognitive function is not predictive of foot reulceration.

CONCLUSIONS

Cognitive function is not an important determinant of foot reulceration.Diabetic patients and those with a history of foot ulcers are at risk for foot reulceration (1,2). Although cognitive function is known to be impaired in patients with diabetes compared with that in nondiabetic control subjects (3), no studies have examined the potential role of cognitive impairment, an important factor for educational success (4), in the development or recurrence of diabetic foot ulcers. Our hypothesis is that cognitive function is associated with the relapse rate of foot ulcers in patients with diabetes and previous foot ulcers.     

Implementation of Cluster-Based Management Strategies for Patients With Chronic Kidney Disease

Chronic kidney disease is a critical public health problem and health economic burden. This research adopted the clustering analysis method, which was used to divide 259 patients into 3 subgroups of patients, based on the situational leadership management. The goal was to discover the needs for patient management and a self-management support strategy applied to clinical care. At the same time, the aim was to constantly improve the ability of self-management for patients with chronic kidney disease to improve their physical and mental health, to realize the diversification of slow disease management, and customization of care.     

Hepatitis C and Treatment in Patients with Chronic Kidney Disease

Hepatitis C virus (HCV) is associated with increased mortality and morbidity in patients with chronic kidney disease (CKD). The early detection and treatment of Hepatitis C associated with kidney disease is paramount to preventing the progressive loss of kidney function. HCV treatment until the advent of direct acting anti-viral agents (DAAs) was limited to interferon and ribavirin. Interferon and ribavirin treatment resulted in only modest success but with frequent adverse events and poor tolerability. Furthermore, interferon and ribavirin could not be used in certain patient populations including those with advanced CKD, were on dialysis, or those who have received a kidney transplant. DAAs have now made treatment possible in these sub-groups with a sustained viral response (SVR) of 90–100% and minimal side effects. DAAs have helped increase transplant rates by allowing for the use of HCV positive kidneys in recipients who are HCV negative. Although the choice of DAAs should be carefully considered and based on patient characteristics, concomitant medications, and HCV genotype.     

Mental Health and Relational Self-Management Experiences of Patients with Type 2 Diabetes and Stage 3 Chronic Kidney Disease

Self-management (SM) behaviors reduce disease burden from advancing diabetic kidney disease. From a parent study about patients’ transition experience to SM, this study report presents coping resources that support SM and barriers from two focus group interviews (n = 6). Ethnographic analysis identified two patterns: (a) mental health self-management characterized by coping, and (b) relational self-management characterized by social support. Practice implications include focused assessment of perceived social support and social network, dating advisement, and workplace management. Future study considerations include inquiry about diabetes and dating relationships and workplace resources for SM support.     

Relationship Between Retinal Blood Flow and Renal Function in Patients With Type 2 Diabetes and Chronic Kidney Disease

OBJECTIVE

To study the relationship between retinal microcirculation and renal function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Using a laser Doppler velocimetry system, we obtained the retinal blood flow (RBF) values by simultaneously measuring the retinal vessel diameter and blood velocity. To determine if the RBF is affected in the presence of renal dysfunction, we also evaluated the renal function using the estimated glomerular filtration rate calculated by age and serum creatinine level.

RESULTS

We recruited 169 eyes of 169 consecutive Japanese patients with type 2 diabetes, no or minimal diabetic retinopathy, and normo/microalbuminuria (mean age ± SD, 59.0 ± 11.1 years). We divided the patients into four groups based on the stage of chronic kidney disease (CKD) (non-CKD, n = 99; CKD stage 1, n = 22; stage 2, n = 27; stage 3, n = 21). We found significant (P = 0.035) decreases in RBF with decreased vessel diameter (P = 0.017) but no difference in blood velocity (P = 0.54) in stage 3 CKD compared with the non-CKD group. Multiple regression analysis showed that the CKD stage was significantly (P = 0.02) and independently associated with decreased RBF.

CONCLUSIONS

Our results indicated that the vessel diameter and RBF in the retinal arterioles decrease in patients with type 2 diabetes with stage 3 CKD, suggesting that impaired renal function might be associated with decreased RBF, probably via constriction of the retinal arterioles, in early-phase diabetic retinopathy.Although both retinopathy and nephropathy are major diabetic microvascular complications, few studies have examined the relationship between retinal structural changes and renal functions in patients with diabetes. Thickening of the basement membrane in the retinal and glomerular capillary vessels has been reported in late-stage diabetic retinopathy and nephropathy (1), suggesting that retinopathy and nephropathy share similar microvascular pathological pathways related to abnormal glucose metabolism and other processes, e.g., inflammation and endothelial dysfunction. Those findings support the clinical recommendation to monitor renal function in patients with diabetes who have signs of retinopathy. A growing body of evidence suggests that several cardiovascular risk factors are associated with the stage of chronic kidney disease (CKD) (2), which accelerates progression of atherosclerosis and increases the propensity to oxidative stress (3). Moreover, diabetes per se is the leading cause of the incidence and prevalence of CKD (4). Although we recently reported that retinal blood flow (RBF) decreases in patients with type 2 diabetes without retinopathy and with mild retinopathy using a retinal laser Doppler velocimetry (LDV) system (5), it is unclear whether renal dysfunction is associated with impaired retinal microcirculation in patients with diabetes.Recent ophthalmic epidemiologic studies have also reported that narrowing of the retinal arterioles is associated with CKD independent of diabetes and hypertension (6) and that patients with moderate CKD were three times more likely to develop early age-related macular degeneration compared with subjects with no or mild CKD (7), suggesting that renal dysfunction might have some effect on ocular disorders. However, no study has examined the relation between renal dysfunction and retinal microcirculation in type 2 diabetes. The current study examined the effect of renal dysfunction, evaluated by grading the CKD, on the retinal microcirculation in patients with type 2 diabetes, especially the early stages of retinopathy and nephropathy.     

Thyroid Status and Death Risk in US Veterans With Chronic Kidney Disease

Objective

Given that patients with non–dialysis-dependent chronic kidney disease (NDD-CKD) have a disproportionately higher prevalence of hypothyroidism compared with their non-CKD counterparts, we sought to determine the association between thyroid status, defined by serum thyrotropin (TSH) levels, and mortality among a national cohort of patients with NDD-CKD.

Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin

OBJECTIVETo investigate the associations of metformin, serum vitamin B₁₂, calcium supplements, and cognitive impairment in patients with diabetes.RESULTSParticipants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B₁₂, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]).CONCLUSIONSMetformin use was associated with impaired cognitive performance. Vitamin B₁₂ and calcium supplements may alleviate metformin-induced vitamin B₁₂ deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B₁₂ and calcium use on cognition in older people with diabetes who are taking metformin.In 2010, more than 346 million people had diabetes worldwide. Recent studies from the U.K. (1) and Italy (2) reported that the adult prevalence of diabetes was approximately 4.2%. In the U.S., the prevalence of diabetes in the adult population may be as high as 14% when undiagnosed cases are included (3). The prevalence of diabetes may be higher in some developing nations: in the developing region of southern China it was reported to be 21.7% in 2010 (4). The prevalence of diabetes is more than 20% in some Pacific Island nations, reaching 47% in 22- to 64-year-old American Samoans (5).In diabetes, hyperglycemia activates the cellular signaling protein kinase C, which induces production of the vasoconstrictor protein endothelin-1. Excess intracellular glucose is converted to sorbitol by the enzyme aldose reductase. When intracellular levels of glucose are high, this process exhausts the energy substrate NADPH, resulting in oxidative stress. High intracellular sorbitol levels cause osmotic stress and cell death. These biochemical changes in hyperglycemia are a proposed mechanism for macrovascular and microvascular complications and neuropathy (6–8). Diabetes is associated with a faster rate of cognitive decline in those with mild cognitive impairment (MCI) (9) and an increased risk for developing Alzheimer disease (AD) (10).Approximately 90% of patients with diabetes have type 2 diabetes (1). The biguanide metformin is a first-line treatment for type 2 diabetes, increasing glucose uptake in muscle while reducing liver gluconeogenesis (the synthesis of glucose from amino acids). These effects are mediated by activation of the cellular signaling protein AMP–activated protein kinase (11).Metformin first became available in the U.K. in 1958 and entered the Canadian market in 1971, but it has been available in the U.S. only since 1995. In a survey of 65,000 U.S. war veterans (12), metformin use among those with diabetes increased from 29% in 2000 to 63% in 2005. Among 242 Australian veterans who had diabetes, metformin was used by 75% in 2005 but decreased to 57% in 2009 (13).The rate of vitamin B₁₂ deficiency among patients who are taking metformin is reported to approach 30% (14–16). A drug interaction between metformin and the cubilin receptor inhibits the uptake of vitamin B₁₂ from the distal ileum, lowering serum vitamin B₁₂ levels. In a long-term, randomized, placebo-controlled trial, metformin therapy in type 2 diabetes was associated with a 19% reduction in serum vitamin B₁₂ concentrations compared with placebo (17). In a case-control study, Wile and Toth (18) reported that metformin use was associated with reduced vitamin B₁₂ levels and more severe peripheral neuropathy in patients with diabetes.In a prospective trial, calcium supplements were reported to reverse the drug interaction that causes vitamin B₁₂ deficiency induced by metformin (19). The clinical significance of alleviating metformin-induced vitamin B₁₂ malabsorption by calcium supplementation has not been previously investigated. By correcting vitamin B₁₂ levels in patients with diabetes who use metformin, calcium supplements may help to preserve cognitive function. In addition, neuronal signaling in memory and learning involves a calcium-mediated process, so calcium supplementation may also have a direct effect on the brain. Calcium dysregulation is the subject of one proposed theory for age-related cognitive changes and AD (20). The risks and potential benefits of calcium supplementation on cognition and for alleviating vitamin B₁₂ malabsorption merit further investigation.The amyloid plaques seen in the brains of patients with AD are formed by aggregation of Aβ peptides. In cell cultures, Chen and colleagues (21) reported that activation of AMP–activated protein kinase by metformin increased the expression of β-secretase, an enzyme that increases the formation of Aβ peptides. One recent case-control study that included 14,172 participants 65 years of age or older reported that taking metformin over the long term increased the risk of AD (odds ratio [OR] 1.71 [95% CI 1.12–2.60]) (22).Recent studies of murine models of diabetes indicate that metformin may attenuate irregularities in phosphorylation of tau proteins (23) or may facilitate neuroneogenesis (24) and so may be of benefit to those with AD. In 25,393 patients older than 50 years with type 2 diabetes, metformin was reported to reduce the risk of dementia by 24% (hazard ratio 0.76 [95% CI 0.58–0.98]) (25). The purpose of our study was to investigate the associations of metformin, serum vitamin B₁₂ levels, and cognition in a sample of patients with diabetes.     

Association of Race/Ethnicity,Inflammation, and Albuminuria in Patients With Diabetes and Early Chronic Kidney Disease

OBJECTIVE

African Americans (AAs) and Hispanics have higher diabetes and end-stage renal disease but similar or lower early chronic kidney disease (CKD) compared with whites. Inflammation plays a critical role in the pathogenesis of diabetes-related CKD. We postulated that in contrast to the general population, AAs and Hispanics have a higher prevalence of early diabetic CKD and systemic inflammatory markers compared with whites.

RESEARCH DESIGN AND METHODS

We analyzed the National Health and Nutrition Examination Survey 1999–2008 of 2,310 diabetic patients aged ≥20 years with fasting plasma glucose (FPG) ≥126 mg/dL. We performed multiple linear regression among patients with early CKD (urinary albumin excretion [UAE] ≥30 μg/mL and estimated glomerular filtration rate ≥60 mL/min/1.73 m²) to test the relationship between UAE and C-reactive protein (CRP) by race/ethnicity, adjusting for demographics, diabetes duration, FPG, hemoglobin A_1c, uric acid, white blood cell count, medication use, cardiovascular disease, and related parameters.

RESULTS

In patients with diabetes, the prevalence of early CKD was greater among Hispanics and AAs than whites (P < 0.0001). AAs had higher adjusted odds ratio (AOR) for CRP ≥0.2 mg/dL (AOR 1.81 [95% CI 1.19–2.78]), and Hispanics had higher AOR for UAE ≥30 μg/mL (AOR 1.65 [1.07–2.54]). In a regression model adjusted for confounding variables, there was a significant association between UAE and CRP in the mid-CRP tertile (CRP 0.20–0.56 mg/dL, P = 0.001) and highest CRP tertile (CRP ≥0.57 mg/dL, P = 0.01) for Hispanics, but only in the mid-CRP tertile (P = 0.04) for AAs, compared with whites.

CONCLUSIONS

AAs and Hispanics with diabetes have a higher prevalence of early CKD compared with whites, which is significantly associated with UAE and/or CRP.     

Impact of Chronic Kidney Disease on Survival After Amputation in Individuals With Diabetes

OBJECTIVE

To identify factors that influence survival after diabetes-related amputations.

RESEARCH DESIGN AND METHODS

We abstracted medical records of 1,043 hospitalized subjects with diabetes and a lower-extremity amputation from 1 January to 31 December 1993 in six metropolitan statistical areas in south Texas. We identified mortality in the 10-year period after amputation from death certificate data. Diabetes was verified using World Health Organization criteria. Amputations were identified by ICD-9-CM codes 84.11–84.18 and categorized as foot, below-knee amputation, and above-knee amputation and verified by reviewing medical records. We evaluated three levels of renal function: chronic kidney disease (CKD), hemodialysis, and no renal disease. We defined CKD based on a glomerular filtration rate <60 ml/min and hemodialysis from Current Procedural Terminology (CPT) codes (90921, 90925, 90935, and 90937). We used χ² for trend and Cox regression analysis to evaluate risk factors for survival after amputation.

RESULTS

Patients with CKD and dialysis had more below-knee amputations and above-knee amputations than patients with no renal disease (P < 0.01). Survival was significantly higher in patients with no renal impairment (P < 0.01). The Cox regression indicated a 290% increase in hazard for death for dialysis treatment (hazard ratio [HR] 3.9, 95% CI 3.07–5.0) and a 46% increase for CKD (HR 1.46, 95% CI 1.21–1.77). Subjects with an above-knee amputation had a 167% increase in hazard (HR 2.67, 95% CI 2.14–3.34), and below-knee amputation patients had a 67% increase in hazard for death.

CONCLUSIONS

Survival after amputation is lower in diabetic patients with CKD, dialysis, and high-level amputations.Diabetes is the most common underlying cause of nontraumatic amputation in the U.S. and Europe (1–4). Of the 120,000 amputations performed in the U.S. every year, 40–70% are in individuals with diabetes. Among individuals with end-stage renal disease receiving dialysis, the incidence of amputation is about 10 times higher than in the general diabetic population (5).The in-hospital and 30-day mortality after amputation in people with diabetes is higher than in people with coronary artery bypass graft surgery, breast cancer, or stroke (6–8). However, there is little published data that report the long-term survival after amputation and even less data regarding patients with chronic kidney disease (CKD). The purpose of this study was to identify differences in the proportion of amputations and survival after lower-extremity amputation in individuals with diabetes and CKD and to identify risk factors for survival after an amputation.