excised down to the level of the deep muscle fascia from the knee to the dorsum of the foot. The wound was covered with 12-to 16/1000-inch split thickness skin grafts harvested from the ipsilateral leg. For those who underwent elective toe amputations, toe disarticulation at the metatarsalphalangeal joint was combined with removal of the articular cartilage from the metatarsal heads. Average follow-up was 3.5 years. During follow-up, 20% of the patients who underwent combined Charles procedure and elective toe amputation experienced recurrent bouts of cellulitis of the foot or leg, 50% required at least one operation for excision of crypts within the skin-grafted areas, and none required more proximal amputations. In those patients who did not undergo elective toe amputation, 83% had multiple episodes of foot or leg cellulitis and 54% underwent at least one operation for foot or leg excision of crypts, and 80% subsequently required amputation of toes secondary to chronic ulceration, infection, or drainage from web spaces. Two patients required more proximal amputation, including one below knee amputation.Comment: Those who care for patients with advanced lymphedema realize that appropriate foot hygiene is the mainstay to reduce interdigital entry lesions, but such care can be ineffective in the terminal stages of lymphedema. These patients have deformity of the toes and limited mobility. The increased weight and volume of the affected limbs prevents them from performing appropriate foot hygiene. This is an aggressive approach to the treatment of end-stage lymphedema. Nevertheless, if a decision has been made to perform a Charles procedure, the authors' data suggest the addition of toe amputations is reasonable.

Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04–1×10−17). Except for total HDL particles (r = −0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07–0.17, P = 5×10−5–1×10−19). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE±0.22 mg/dl/allele, P = 8×10−5, P interaction = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE±0.22 mg/dl/allele, P = 0.35) or metformin (β = −0.03, SEE±0.22 mg/dl/allele, P = 0.90; P interaction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE±0.012 ln nmol/L/allele, P = 0.01, P interaction = 0.01) but not in the placebo (β = −0.002, SEE±0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE±0.008 nmol/L/allele, P = 0.12; P interaction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.

Across the Diabetes Prevention Program (DPP) follow-up, cumulative diabetes incidence remained lower in the lifestyle compared with the placebo and metformin randomized groups and could not be explained by weight. Collection of self-reported physical activity (PA) (yearly) with cross-sectional objective PA (in follow-up) allowed for examination of PA and its long-term impact on diabetes prevention. RESEARCH DESIGN AND METHODS Yearly self-reported PA and diabetes assessment and oral glucose tolerance test results (fasting glucose semiannually) were collected for 3,232 participants with one accelerometry assessment 11-13 years after randomization (n 5 1,793). Mixed models determined PA differences across treatment groups. The association between PA and diabetes incidence was examined using Cox proportional hazards models. RESULTS There was a 6% decrease (Cox proportional hazard ratio 0.94 [95% CI 0.92, 0.96]; P < 0.001) in diabetes incidence per 6 MET-h/week increase in time-dependent PA for the entire cohort over an average of 12 years (controlled for age, sex, baseline PA, and weight). The effect of PA was greater (12% decrease) among participants less active at baseline (<7.5 MET-h/week) (n 5 1,338) (0.88 [0.83, 0.93]; P < 0.0001), with stronger findings for lifestyle participants. Lifestyle had higher cumulative PA compared with metformin or placebo (P < 0.0001) and higher accelerometry total minutes per day measured during follow-up (P 5 0.001 and 0.047). All associations remained significant with the addition of weight in the models. CONCLUSIONS PA was inversely related to incident diabetes in the entire cohort across the study, with cross-sectional accelerometry results supporting these findings. This highlights the importance of PA within lifestyle intervention efforts designed to prevent diabetes and urges health care providers to consider both PA and weight when counseling high-risk patients.

-Alanine and glutamine constitute the two most important nitrogen carriers released from the muscle. We studied the intracellular amino acid transport kinetics and protein turnover in nine end-stage renal disease (ESRD) patients and eight controls by use of stable isotopes of phenylalanine, alanine, and glutamine. The amino acid transport kinetics and protein turnover were calculated with a three-pool model from the amino acid concentrations and enrichment in the artery, vein, and muscle compartments. Muscle protein breakdown was more than synthesis (nmol⅐min Ϫ1 ⅐100 ml leg Ϫ1 ) during hemodialysis (HD) (169.8 Ϯ 20.0 vs. 125.9 Ϯ 21.8, P Ͻ 0.05) and in controls (126.9 Ϯ 6.9 vs. 98.4 Ϯ 7.5, P Ͻ 0.05), but synthesis and catabolism were comparable pre-HD (100.7 Ϯ 15.7 vs. 103.4 Ϯ 14.8). Whole body protein catabolism decreased by 15% during HD. The intracellular appearance of alanine (399.0 Ϯ 47.1 vs. 243.0 Ϯ 34.689) and glutamine (369.7 Ϯ 40.6 vs. 235.6 Ϯ 27.5) from muscle protein breakdown increased during dialysis (nmol ⅐ min Ϫ1 ⅐ 100 ml leg Ϫ1 , P Ͻ 0.01). However, the de novo synthesis of alanine (3,468.9 Ϯ 572.2 vs. 3,140.5 Ϯ 467.7) and glutamine (1,751.4 Ϯ 82.6 vs. 1,782.2 Ϯ 86.4) did not change significantly intradialysis (nmol ⅐ min Ϫ1 ⅐ 100 ml leg Ϫ1 ). Branched-chain amino acid catabolism (191.8 Ϯ 63.4 vs. Ϫ59.1 Ϯ 42.9) and nonprotein glutamate disposal (347.0 Ϯ 46.3 vs. 222.3 Ϯ 43.6) increased intradialysis compared with pre-HD (nmol ⅐ min Ϫ1 ⅐ 100 ml leg Ϫ1 , P Ͻ 0.01). The mRNA levels of glutamine synthase (1.45 Ϯ 0.14 vs. 0.33 Ϯ 0.08, P Ͻ 0.001) and branched-chain keto acid dehydrogenase-E2 (3.86 Ϯ 0.48 vs. 2.14 Ϯ 0.27, P Ͻ 0.05) in the muscle increased during HD. Thus intracellular concentrations of alanine and glutamine are maintained during HD by augmented release of the amino acids from muscle protein catabolism. Although muscle protein breakdown increased intradialysis, the whole body protein catabolism decreased, suggesting central utilization of amino acids released from skeletal muscle. amino acids; protein catabolism; nitrogen carriers; hemodialysis ALANINE AND GLUTAMINE play a central role in substrate recycling and interorgan nitrogen metabolism. Together, they comprise Ͻ15% of amino acid content of protein, yet they account for ϳ60% of the amino nitrogen leaving the muscle (10). In disease states, glutamine consumption exceeds the release from the muscle (19). Branched-chain amino acids (BCAA) include valine, leucine, and isoleucine. Metabolism of BCAA, alanine, glutamine, and glutamate are interrelated (Fig. 1). Ferrando et al. (16) demonstrated an inverse relationship between alanine and glutamine production in the muscle in patients with burn. The precursors for glutamine synthesis include glutamate, ␣-ketoglutarate, free ammonia, and amino nitrogen derived from catabolism of BCAA. On the other hand, pyruvate is transaminated with glutamate to generate alanine and ␣-ketoglutarate. In catabolic states, net synthesis of glutamine is decreased, but de novo alanine synthesis is increased....

ImportanceAge-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD.ObjectiveTo investigate the association between metformin use and age-related macular degeneration (AMD).Design, Setting, and ParticipantsThe Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022.InterventionsParticipants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.Main Outcomes and MeasuresPrevalence of AMD in the treatment arms.ResultsOf 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02).Conclusions and RelevanceThese data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.