Lee M. Kaplan

A Role for Hepatitis C Virus Infection in Type II Cryoglobulinemia

BACKGROUND Type II cryoglobulinemia is a vasculitis characterized by cryoglobulins consisting of complexes of polyclonal IgG and monoclonal IgM rheumatoid factors. The cause of these immune complexes is unknown, though both the hepatitis B (HBV) and C (HCV) viruses have been suspected. METHODS We studied 19 patients with Type II cryoglobulinemia for markers of HCV and HBV infection. Quantitative HCV antibody and RNA studies were performed on whole serum, cryoprecipitates, and supernatants. RESULTS Eight patients (42 percent) had HCV antibodies, and 16 (84 percent) had HCV RNA: Of the 19 patients, 5 (26 percent) had HBV markers, but only 1 had evidence of active HBV infection. Control serum samples from nine patients with Type I cryoglobulinemia were negative for HCV antibody and HCV RNA: There was a close, although not exclusive, association of one type of rheumatoid factor (WA) with HCV RNA: HCV antibody and HCV RNA were concentrated approximately 10-fold and 1000-fold, respectively, in the Type II cryoglobulins examined. CONCLUSIONS Type II cryoglobulinemia is strongly associated with concomitant HCV infection and a high rate of false negative serologic tests. HCV virions and HCV antigen-antibody complexes are concentrated in the cryoprecipitates, most commonly in association with the WA type of rheumatoid factor, suggesting a role for HCV in the pathogenesis of mixed cryoglobulinemia.

Common variants at 30 loci contribute to polygenic dyslipidemia

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 × 10−8), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10−15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and Adiposity

Alterations in the gastrointestinal microbiota caused by gastric bypass surgery are sufficient to trigger decreased body weight and adiposity in germ-free mouse recipients. Getting By(pass) with Help from Our Little Friends One of the most durably effective treatments for severe obesity is gastric bypass surgery. Despite its powerful effect on weight loss and remission of diabetes, the cost and associated risk of this procedure prevents its application to a large population of obese patients, prompting a search for less invasive treatments. The population structure of the trillions of microorganisms that reside in the human gut is markedly altered after gastric bypass, but the functional importance of these changes is unknown. In a new study, Liou et al. use a mouse model of gastric bypass surgery to characterize changes in the gut microbiota, both temporally and along the length of the gastrointestinal tract. Gastric bypass induced substantial, rapid, and sustained changes to the gut microbial communities that were independent of both diet and the weight loss associated with this procedure. The observed changes in this mouse model were similar to those previously observed in human gastric bypass patients. Transfer of the surgically altered microbial community to nonoperated, germ-free mice resulted in weight loss and decreased body fat. Gastric bypass was also associated with changes in the production of short-chain fatty acids, changes that were conveyed to the previously germ-free mice that received the microbiota from these operated animals. These observations demonstrate that specific alterations in the gut microbiota contribute to the beneficial effects of bariatric surgery on energy balance and obesity. They suggest new approaches to the treatment of obesity and related metabolic diseases that harness the ability of the gut microbiota to influence host metabolic physiology. Roux-en-Y gastric bypass (RYGB) results in rapid weight loss, reduced adiposity, and improved glucose metabolism. These effects are not simply attributable to decreased caloric intake or absorption, but the mechanisms linking rearrangement of the gastrointestinal tract to these metabolic outcomes are largely unknown. Studies in humans and rats have shown that RYGB restructures the gut microbiota, prompting the hypothesis that some of the effects of RYGB are caused by altered host-microbial interactions. To test this hypothesis, we used a mouse model of RYGB that recapitulates many of the metabolic outcomes in humans. 16S ribosomal RNA gene sequencing of murine fecal samples collected after RYGB surgery, sham surgery, or sham surgery coupled to caloric restriction revealed that alterations to the gut microbiota after RYGB are conserved among humans, rats, and mice, resulting in a rapid and sustained increase in the relative abundance of Gammaproteobacteria (Escherichia) and Verrucomicrobia (Akkermansia). These changes were independent of weight change and caloric restriction, were detectable throughout the length of the gastrointestinal tract, and were most evident in the distal gut, downstream of the surgical manipulation site. Transfer of the gut microbiota from RYGB-treated mice to nonoperated, germ-free mice resulted in weight loss and decreased fat mass in the recipient animals relative to recipients of microbiota induced by sham surgery, potentially due to altered microbial production of short-chain fatty acids. These findings provide the first empirical support for the claim that changes in the gut microbiota contribute to reduced host weight and adiposity after RYGB surgery.

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from κ-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates κ-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered κ-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the κ-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.

Endocrine and Nutritional Management of the Post-Bariatric Surgery Patient: An Endocrine Society Clinical Practice Guideline

OBJECTIVE We sought to provide guidelines for the nutritional and endocrine management of adults after bariatric surgery, including those with diabetes mellitus. The focus is on the immediate postoperative period and long-term management to prevent complications, weight regain, and progression of obesity-associated comorbidities. The treatment of specific disorders is only summarized. PARTICIPANTS The Task Force was composed of a chair, five additional experts, a methodologist, and a medical writer. It received no corporate funding or remuneration. CONCLUSIONS Bariatric surgery is not a guarantee of successful weight loss and maintenance. Increasingly, patients regain weight, especially those undergoing restrictive surgeries such as laparoscopic banding rather than malabsorptive surgeries such as Roux-en-Y bypass. Active nutritional patient education and clinical management to prevent and detect nutritional deficiencies are recommended for all patients undergoing bariatric surgery. Management of potential nutritional deficiencies is particularly important for patients undergoing malabsorptive procedures, and strategies should be employed to compensate for food intolerance in patients who have had a malabsorptive procedure to reduce the risk for clinically important nutritional deficiencies. To enhance the transition to life after bariatric surgery and to prevent weight regain and nutritional complications, all patients should receive care from a multidisciplinary team including an experienced primary care physician, endocrinologist, or gastroenterologist and consider enrolling postoperatively in a comprehensive program for nutrition and lifestyle management. Future research should address the effectiveness of intensive postoperative nutritional and endocrine care in reducing morbidity and mortality from obesity-associated chronic diseases.

Metabolic Surgery to Treat Type 2 Diabetes: Clinical Outcomes and Mechanisms of Action

Several gastrointestinal (GI) operations that were designed to promote weight loss can powerfully ameliorate type 2 diabetes mellitus (T2DM). Although T2DM is traditionally viewed as a chronic, relentless disease in which delay of end-organ complications is the major treatment goal, GI surgery offers a novel endpoint: complete disease remission. Ample data confirm the excellent safety and efficacy of conventional bariatric operations-especially Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding-to treat T2DM in severely obese patients. Use of experimental procedures as well as conventional bariatric operations is increasingly being explored in less obese diabetic patients, with generally favorable results, although further assessment of risk:benefit profiles is needed. Mounting evidence indicates that certain operations involving intestinal diversions improve glucose homeostasis through varied mechanisms beyond reduced food intake and body weight, for example by modulating gut hormones. Research to elucidate such mechanisms should facilitate the design of novel pharmacotherapeutics and dedicated antidiabetes GI manipulations. Here we review evidence regarding the use and study of GI surgery to treat T2DM, focusing on available published reports as well as results from the Diabetes Surgery Summit (DSS) in Rome and the World Congress on Interventional Therapies for T2DM in New York City.

The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus.

Objectives:To develop guidelines for the use of gastrointestinal surgery to treat type 2 diabetes and to craft an agenda for further research. Background:Increasing evidence demonstrates that bariatric surgery can dramatically ameliorate type 2 diabetes. Not surprisingly, gastrointestinal operations are now being used throughout the world to treat diabetes in association with obesity, and increasingly, for diabetes alone. However, the role for surgery in diabetes treatment is not clearly defined and there are neither clear guidelines for these practices nor sufficient plans for clinical trials to evaluate the risks and benefits of such “diabetes surgery.” Methods:A multidisciplinary group of 50 voting delegates from around the world gathered in Rome, Italy for the first International Conference on Gastrointestinal Surgery to Treat Type 2 Diabetes–(the “Diabetes Surgery Summit”). During the meeting, available scientific evidence was examined and critiqued by the entire group to assess the strength of evidence and to draft consensus statements. Through an iterative process, draft statements were then serially discussed, debated, edited, reassessed, and finally presented for formal voting. After the Rome meeting, statements that achieved consensus were summarized and distributed to all voting delegates for further input and final approval. These statements were then formally critiqued by representatives of several sientific societies at the 1st World Congress on Interventional Therapies for T2DM (New York, Sept 2008). Input from this discussion was used to generate the current position statement. Results:A Diabetes Surgery Summit (DSS) Position Statement consists of recommendations for clinical and research issues, as well as general concepts and definitions in diabetes surgery. The DSS recognizes the legitimacy of surgical approaches to treat diabetes in carefully selected patients. For example, gastric bypass was deemed a reasonable treatment option for patients with poorly controlled diabetes and a body mass index ≥30 kg/m2. Clinical trials to investigate the exact role of surgery in patients with less severe obesity and diabetes are considered a priority. Furthermore, investigations on the mechanisms of surgical control of diabetes are strongly encouraged, as they may help advance the understanding of diabetes pathophysiology. Conclusions:The DSS consensus document embodies the foundations of “diabetes surgery,” and represents a timely attempt by leading scholars to improve access to surgical options supported by sound evidence, while also preventing harm from inappropriate use of unproven procedures.

Gastrin-Releasing Peptide (Mammalian Bombesin) Gene Expression in Health and Disease

In recent years much attention has been focused on gastrin-releasing peptide (GRP), the mammalian homologue of bombesin, both as a neuroregulatory hormone and as a tissue-specific growth factor in normal and neoplastic tissues. This paper will analyze the distribution and role of GRP in normal mammalian tissues and examine the potential involvement of GRP in diverse pathologic processes.

Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations

BACKGROUND Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIM The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODS A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005–30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28–30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTS Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ≥40 kg/m2) and in those with class II obesity (BMI 35.0–39.9 kg/m2) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0–34.9 kg/m2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m2 for Asian patients. CONCLUSIONS Although additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.

Integrating pathway analysis and genetics of gene expression for genome-wide association studies.

Genome-wide association studies (GWAS) have achieved great success identifying common genetic variants associated with common human diseases. However, to date, the massive amounts of data generated from GWAS have not been maximally leveraged and integrated with other types of data to identify associations beyond those associations that meet the stringent genome-wide significance threshold. Here, we present a novel approach that leverages information from genetics of gene expression studies to identify biological pathways enriched for expression-associated genetic loci associated with disease in publicly available GWAS results. Specifically, we first identify SNPs in population-based human cohorts that associate with the expression of genes (eSNPs) in the metabolically active tissues liver, subcutaneous adipose, and omental adipose. We then use this functionally annotated set of SNPs to investigate pathways enriched for eSNPs associated with disease in publicly available GWAS data. As an example, we tested 110 pathways from the Kyoto Encylopedia of Genes and Genomes (KEGG) database and identified 16 pathways enriched for genes corresponding to eSNPs that show evidence of association with type 2 diabetes (T2D) in the Wellcome Trust Case Control Consortium (WTCCC) T2D GWAS. We then replicated these findings in the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) study. Many of the pathways identified have been proposed as important candidate pathways for T2D, including the calcium signaling pathway, the PPAR signaling pathway, and TGF-beta signaling. Importantly, we identified other pathways not previously associated with T2D, including the tight junction, complement and coagulation pathway, and antigen processing and presentation pathway. The integration of pathways and eSNPs provides putative functional bridges between GWAS and candidate genes or pathways, thus serving as a potential powerful approach to identifying biological mechanisms underlying GWAS findings.