Publications by authors named "Mary-Elizabeth Patti"

110 Publications

Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health.

Cell Metab 2021 Mar 19. Epub 2021 Mar 19.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. Electronic address:

Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.
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http://dx.doi.org/10.1016/j.cmet.2021.03.004DOI Listing
March 2021

Hypoglycemia After Upper Gastrointestinal Surgery: Clinical Approach to Assessment, Diagnosis, and Treatment.

Diabetes Metab Syndr Obes 2020 19;13:4469-4482. Epub 2020 Nov 19.

Research Division, Joslin Diabetes Center, Boston, MA, USA.

Context: Post-bariatric hypoglycemia (PBH) is an increasingly encountered complication of upper gastrointestinal surgery; the prevalence of this condition is anticipated to rise given yearly increases in bariatric surgical procedures. While PBH is incompletely understood, there is a growing body of research describing the associated factors, mechanisms, and treatment approaches for this condition.

Evidence Acquisition: Data are integrated and summarized from studies of individuals affected by PBH and hypoglycemia following upper gastrointestinal surgery obtained from PubMed searches (1990-2020).

Evidence Synthesis: Information addressing etiology, incidence/prevalence, clinical characteristics, assessment, and treatment were reviewed and synthesized for the practicing physician. Literature reports were supplemented by clinical experience as indicated, when published data were not available.

Conclusion: PBH can be life-altering and severe for a subset of individuals. Given the chronic nature of this condition, and sequelae of both acute and recurrent episodes, increasing provider awareness of both the condition and associated risk factors is critical for assessment, prompt diagnosis, treatment, and preoperative identification of individuals at risk.
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http://dx.doi.org/10.2147/DMSO.S233078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682607PMC
November 2020

Skeletal muscle expression of adipose-specific phospholipase in peripheral artery disease.

Vasc Med 2020 10 27;25(5):401-410. Epub 2020 Aug 27.

Heart and Vascular Center, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.

Flow-limiting atherosclerotic lesions of arteries supplying the limbs are a cause of symptoms in patients with peripheral artery disease (PAD). Musculoskeletal metabolic factors also contribute to the pathophysiology of claudication, which is manifest as leg discomfort that impairs walking capacity. Accordingly, we conducted a case-control study to determine whether skeletal muscle metabolic gene expression is altered in PAD. Calf skeletal muscle gene expression of patients with PAD and healthy subjects was analyzed using microarrays. The top-ranking gene differentially expressed between PAD and controls (FDR < 0.001) was , which encodes adipose-specific phospholipase A2 (AdPLA) and is implicated in the maintenance of insulin sensitivity and regulation of lipid metabolism. Differential expression was confirmed by qRT-PCR; was downregulated by 68% in patients with PAD ( < 0.001). Expression of was then measured in control (db/+) and diabetic (db/db) mice that underwent unilateral femoral artery ligation. There was significantly reduced expression of in the ischemic leg of both control and diabetic mice (by 51%), with significantly greater magnitude of reduction in the diabetic mice (by 79%). We conclude that AdPLA is downregulated in humans with PAD and in mice with hindlimb ischemia. Reduced AdPLA may contribute to impaired walking capacity in patients with PAD via its effects on skeletal muscle metabolism. Further studies are needed to fully characterize the role of AdPLA in PAD and to investigate its potential as a therapeutic target for alleviating symptoms of claudication.
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http://dx.doi.org/10.1177/1358863X20947467DOI Listing
October 2020

Metabolic terminology: what's in a name?

Nat Metab 2020 06;2(6):476-477

Joslin Diabetes Center, Boston, MA, USA.

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http://dx.doi.org/10.1038/s42255-020-0216-7DOI Listing
June 2020

Adjustable gastric band surgery or medical management in patients with type 2 diabetes and obesity: three-year results of a randomized trial.

Surg Obes Relat Dis 2019 Dec 16;15(12):2052-2059. Epub 2019 Apr 16.

Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.

Background: Few randomized trials have compared surgical versus lifestyle and pharmacologic approaches for type 2 diabetes (T2D) patients with mild to moderate obesity.

Objectives: This study examined resolution of hyperglycemia (A1C <6.5% and fasting glucose <126 mg/dL) 3 years after randomization to either a laparoscopic adjustable gastric band (LAGB) or 1-year diabetes and weight management (DWM) program.

Setting: University medical center, United States.

Methods: Forty T2D patients (mean ± SD: age, 51.3 ±10.0 yr; weight 109.5 ± 15.0 kg; body mass index [BMI] 36.5 ± 3.7 kg/m; HBA1C 8.2% ± 1.2%) were randomized to LAGB (n = 18) or DWM (n = 22).

Results: At 3 years, 13% of 16 patients in LAGB and 5% of 17 patients in DWM achieved resolution of hyperglycemia (P = .601), with a modestly greater reduction in antidiabetic medications in the surgical group (P = .054). Reductions from baseline in A1C were sustained at 3 years in LAGB (-.82% [95% CI: -1.62 to -.01], P = .046) compared with DWM (+.23% [95% CI: -.57 to 1.03], P = .567). The surgical group had greater weight loss (-12.0 kg [95% CI: -15.9 to -8.1] versus -4.8 [95% CI: -8.6 to -.9], P = .010). HDL-cholesterol increased more after surgery (P = .003), but changes in triglycerides, LDL-cholesterol, and blood pressure did not differ between treatments. Diabetes- and obesity-specific quality of life improved comparably with both therapies.

Conclusions: Achievement of American Diabetes Association targets for glucose, lipids, and blood pressure was similar with both treatment strategies. LAGB leads to greater sustained weight loss and higher HDL cholesterol compared with a DWM program. These findings may help guide patients with T2D and obesity when exploring options for diabetes and weight management.
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http://dx.doi.org/10.1016/j.soard.2019.03.038DOI Listing
December 2019

Association of Periconception Paternal Body Mass Index With Persistent Changes in DNA Methylation of Offspring in Childhood.

JAMA Netw Open 2019 12 2;2(12):e1916777. Epub 2019 Dec 2.

Research Division, Joslin Diabetes Center, Boston, Massachusetts.

Importance: While prenatal nutrition and maternal obesity are recognized as important contributors to epigenetic changes and childhood obesity, the role of paternal obesity in the epigenome of offspring has not been well studied.

Objectives: To test whether periconception paternal body mass index (BMI) is associated with DNA methylation patterns in newborns, to examine associations between maternal and paternal BMI and the epigenome of offspring, and to examine persistence of epigenetic marks at ages 3 and 7 years.

Design, Setting, And Participants: Project Viva is a prebirth cohort study of mothers and children including 2128 live births that enrolled mothers from April 1999 to July 2002 and followed offspring to adolescence. This study analyzed the subset of participants with available data on paternal BMI and DNA methylation in offspring blood in the newborn period, at age 3 years, and at age 7 years. Data were analyzed from July 2017 to October 2019.

Exposures: The primary exposure was paternal periconception BMI; associations were adjusted for maternal prepregnancy BMI and stratified according to maternal BMI above or below 25.

Main Outcomes And Measures: The primary outcome was genome-wide DNA methylation patterns in offspring blood collected at birth, age 3 years, and age 7 years.

Results: A total of 429 father-mother-infant triads were included. The mean (SD) periconception paternal BMI was 26.4 (4.0) and mean maternal prepregnancy BMI was 24.5 (5.2); 268 fathers had BMI greater than or equal to 25 (mean [SD], 28.5 [3.3]) and 161 had BMI less than 25 (mean [SD], 22.8 [1.8]). Paternal BMI greater than or equal to 25 was associated with increased offspring birth weight compared with paternal BMI less than 25 (mean [SD] z score, 0.38 [0.91] vs 0.11 [0.96]; P = .004). Cord blood DNA methylation at 9 CpG sites was associated with paternal BMI independent of maternal BMI (q < .05). Methylation at cg04763273, between TFAP2C and BMP7, decreased by 5% in cord blood with every 1-unit increase in paternal BMI (P = 3.13 × 10-8); hypomethylation at this site persisted at ages 3 years and 7 years. Paternal BMI was associated with methylation at cg01029450 in the promoter region of the ARFGAP3 gene; methylation at this site was also associated with lower infant birth weight (β = -0.0003; SD = 0.0001; P = .03) and with higher BMI z score at age 3 years.

Conclusions And Relevance: In this study, paternal BMI was associated with DNA methylation, birth weight, and childhood BMI z score in offspring.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.16777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991200PMC
December 2019

A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia.

J Clin Endocrinol Metab 2020 04;105(4)

Research Division, Joslin Diabetes Center, Boston, MA.

Background: Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective.

Methods: Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 μg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia.

Results: Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed.

Conclusion: A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH.

Clinical Trials Registration: NCT03255629.
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http://dx.doi.org/10.1210/clinem/dgz197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174034PMC
April 2020

Time to Dump Late Dumping Syndrome Terminology.

Obes Surg 2019 09;29(9):2985-2986

University of Colorado, Division of Endocrinology, Metabolism, and Diabetes, 12801 E. 17th Ave., MS 8106, Aurora, CO, 80045, USA.

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http://dx.doi.org/10.1007/s11695-019-04033-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008495PMC
September 2019

Paternal Nongenetic Intergenerational Transmission of Metabolic Disease Risk.

Curr Diab Rep 2019 05 24;19(7):38. Epub 2019 May 24.

Research Division, Joslin Diabetes Center and Harvard Medical School, Room 620, 1 Joslin Place, Boston, MA, 02215, USA.

Purpose Of Review: Paternal metabolic disease before conception and during spermatogenesis can adversely impact the metabolic health of offspring in later life. Here, we review the current understanding of sperm epigenetic markers as contributors to intergenerational transmission of disease risk in both human and animal studies, and review potential intervention strategies.

Recent Findings: Epidemiological studies suggest an increased risk of adverse outcomes in the offspring of fathers with obesity, diabetes, advanced age, smoking, and ancestral exposures. Potential molecular mechanisms contributing to intergenerational disease risk include genetics (DNA sequence) as well as epigenetic factors in the sperm, such as DNA methylation, chromatin and histone modification, and coding and noncoding RNAs. Potential strategies to interrupt intergenerational transmission of disease risk include increased physical activity, weight loss, bariatric surgery, cold exposure, and improved glycemic control prior to conception. Many studies suggest environmental factors experienced by fathers can program disease risk in the next generation via sperm cell-mediated transmission. Better understanding the mechanisms through which paternal metabolism influences sperm cells will help to design better intervention strategies. Future research will focus on the molecular signals that mediate the impact of paternal factors on sperm epigenetic signals and also how these affect offspring embryonic development and disease risk during adult life.
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http://dx.doi.org/10.1007/s11892-019-1163-0DOI Listing
May 2019

Trim the gut, lose the weight - and the bone.

J Clin Invest 2019 05 6;129(6):2184-2186. Epub 2019 May 6.

Vertical sleeve gastrectomy (VSG) is an effective therapeutic approach for obesity and type 2 diabetes but is associated with osteoporosis. In this issue of the JCI, Li et al. report that VSG rapidly reduces bone mass, as observed in humans, via rapid demineralization and decreased bone formation, independent of weight loss or Ca2+/vitamin D deficiency. VSG also reduces bone marrow adipose tissue, in part via increased granulocyte-colony stimulating factor (G-CSF). The interplay between VSG-mediated effects on systemic metabolism and bone biology remain to be investigated. These findings suggest novel mechanisms and therapeutic targets for bariatric surgery-induced osteoporosis.
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http://dx.doi.org/10.1172/JCI128745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546462PMC
May 2019

Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia.

Obes Surg 2019 07;29(7):2092-2099

Research Division, Joslin Diabetes Center, and Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.

Background: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB.

Methods: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics.

Results: The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 ± 141 vs. 428 ± 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 ± 70 vs. 103 ± 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH.

Conclusions: Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.
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http://dx.doi.org/10.1007/s11695-019-03845-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544487PMC
July 2019

SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms.

JCI Insight 2019 03 7;4(5). Epub 2019 Mar 7.

Section of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and cardiovascular risk in type 2 diabetes, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. Utilizing an integrated transcriptomic-metabolomics approach, we demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5' AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Given that these phenotypes mirror the effects of FGF21 to promote lipid oxidation, ketogenesis, and reduction in adiposity, we hypothesized that FGF21 is required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for SGLT2i-mediated induction of lipid oxidation and ketogenesis but is required for reduction in fat mass and activation of lipolysis. Taken together, these data demonstrate that SGLT2 inhibition triggers a fasting-like transcriptional and metabolic paradigm but requires FGF21 for reduction in adiposity.
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http://dx.doi.org/10.1172/jci.insight.123130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483601PMC
March 2019

PET-CT reveals increased intestinal glucose uptake after gastric surgery.

Surg Obes Relat Dis 2019 Apr 25;15(4):643-649. Epub 2019 Jan 25.

Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Mechanisms of metabolic improvement after bariatric surgery remain incompletely understood. Intestinal glucose uptake is increased after gastric bypass in rodents, potentially contributing to reduced blood glucose and type 2 diabetes remission.

Objective: We assessed whether intestinal glucose uptake is increased in humans after gastric surgery.

Setting: University Hospital, United States.

Methods: In a retrospective, case-control cohort study, positron emission tomography-computerized tomography scans performed for clinical indications were analyzed to quantify intestinal glucose uptake in patients with or without history of gastric surgery. We identified 19 cases, defined as patients over age 18 with prior gastric surgery (Roux-en-Y gastric bypass [n = 10], sleeve gastrectomy [n = 1], or Billroth I [n = 2] or II gastrectomy [n = 6]), and 43 controls without gastric surgery, matched for age, sex, and indication for positron emission tomography-computerized tomography. Individuals with gastrointestinal malignancy or metformin treatment were excluded. Images were obtained 60 minutes after F-fluorodeoxyglucose injection (4.2 MBq/kg), and corrected by attenuation; noncontrast low-dose computerized tomography was obtained in parallel. Fused and nonfused images were analyzed; standardized uptake values were calculated for each region by volumes of interest at the region of highest activity.

Results: Both standardized uptake values maximum and mean were significantly increased by 41% to 98% in jejunum, ascending, and transverse colon in patients with prior gastric surgery (P < .05 versus controls).

Conclusion: Intestinal glucose uptake is increased in patients with prior gastric surgery. Prospective studies are important to dissect the contributions of weight loss, dietary factors, and systemic metabolism, and to determine the relationship with increased insulin-independent glucose uptake and reductions in glycemia.
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http://dx.doi.org/10.1016/j.soard.2019.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008494PMC
April 2019

Paternal Exercise Improves Glucose Metabolism in Adult Offspring.

Diabetes 2018 12 21;67(12):2530-2540. Epub 2018 Oct 21.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA

Poor paternal diet has emerged as a risk factor for metabolic disease in offspring, and alterations in sperm may be a major mechanism mediating these detrimental effects of diet. Although exercise in the general population is known to improve health, the effects of paternal exercise on sperm and offspring metabolic health are largely unknown. Here, we studied 7-week-old C57BL/6 male mice fed a chow or high-fat diet and housed either in static cages (sedentary) or cages with attached running wheels (exercise trained). After 3 weeks, one cohort of males was sacrificed and cauda sperm obtained, while the other cohort was bred with chow-fed sedentary C57BL/6 females. Offspring were chow fed, sedentary, and studied during the first year of life. We found that high-fat feeding of sires impairs glucose tolerance and increases the percentage of fat mass in both male and female offspring at 52 weeks of age. Strikingly, paternal exercise suppresses the effects of paternal high-fat diet on offspring, reversing the observed impairment in glucose tolerance, percentage of fat mass, and glucose uptake in skeletal muscles of the offspring. These changes in offspring phenotype are accompanied by changes in sperm physiology, as, for example, high-fat feeding results in decreased sperm motility, an effect normalized in males subject to exercise training. Deep sequencing of sperm reveals pronounced effects of exercise training on multiple classes of small RNAs, as multiple changes to the sperm RNA payload observed in animals consuming a high-fat diet are suppressed by exercise training. Thus, voluntary exercise training of male mice results in pronounced improvements in the metabolic health of adult male and female offspring. We provide the first in-depth analysis of small RNAs in sperm from exercise-trained males, revealing a marked change in the levels of multiple small RNAs with the potential to alter phenotypes in the next generation.
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http://dx.doi.org/10.2337/db18-0667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245224PMC
December 2018

Epigenetics and Epigenomics: Implications for Diabetes and Obesity.

Diabetes 2018 10;67(10):1923-1931

Department of Genetics and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

The American Diabetes Association convened a research symposium, "Epigenetics and Epigenomics: Implications for Diabetes and Obesity" on 17-19 November 2017. International experts in genetics, epigenetics, computational biology, and physiology discussed the current state of understanding of the relationships between genetics, epigenetics, and environment in diabetes and examined existing evidence for the role of epigenetic factors in regulating metabolism and the risk of diabetes and its complications. The authors summarize the presentations, which highlight how the complex interactions between genes and environment may in part be mediated through epigenetic changes and how information about nutritional and other environmental stimuli can be transmitted to the next generation. In addition, the authors present expert consensus on knowledge gaps and research recommendations for the field.
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http://dx.doi.org/10.2337/db18-0537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463748PMC
October 2018

l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism.

Mol Metab 2018 11 11;17:61-70. Epub 2018 Aug 11.

Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA. Electronic address:

Objective: AMP activated protein kinase (AMPK) is recognized as an important nutrient sensor contributing to regulation of cellular, tissue, and systemic metabolism. We aimed to identify specific amino acids which could modulate AMPK and determine effects on cellular and systemic metabolism.

Methods: We performed an unbiased amino acid screen to identify activators of AMPK. Detailed analysis of cellular signaling and metabolism was performed in cultured hepatoma cells, and in vivo glucose metabolism and metabolomic patterns were assessed in both chow-fed mice and mice made obese by high-fat diet feeding.

Results: Alanine acutely activates AMP kinase in both cultured hepatic cells and in liver from mice treated in vivo with Ala. Oral alanine administration improves systemic glucose tolerance in both chow and high fat diet fed mice, with reduced efficacy of Ala in mice with reduced AMPK activity. Our data indicate that Ala activation of AMPK is mediated by intracellular Ala metabolism, which reduces TCA cycle metabolites, increases AMP/ATP ratio, and activates NH generation.

Conclusions: Ala may serve as a distinct amino acid energy sensor, providing a positive signal to activate the beneficial AMPK signaling pathway.
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http://dx.doi.org/10.1016/j.molmet.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197624PMC
November 2018

Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies.

J Clin Endocrinol Metab 2018 08;103(8):2815-2826

Research and Clinic Divisions, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts.

Context: Hypoglycemia, occurring after bariatric and other forms of upper gastrointestinal surgery, is increasingly encountered by clinical endocrinologists. The true frequency of this condition remains uncertain, due, in part, to differences in the diagnostic criteria and in the affected populations, as well as relative lack of patient and physician awareness and understanding of this condition. Postbariatric hypoglycemia can be severe and disabling for some patients, with neuroglycopenia (altered cognition, seizures, and loss of consciousness) leading to falls, motor vehicle accidents, and job and income loss. Moreover, repeated episodes of hypoglycemia can result in hypoglycemia unawareness, further impairing safety and requiring the assistance of others to treat hypoglycemia.

Objective: In this review, we summarize and integrate data from studies of patients affected by hypoglycemia after Roux-en-Y gastric bypass (RYGB) surgery, obtained from PubMed searches (1990 to 2017) and reference searches of relevant retrieved articles. Whereas hypoglycemia can also be observed after sleeve gastrectomy and fundoplication, this review is focused on post-RYGB, given the greater body of published clinical studies at present.

Outcome Measures: Data addressing specific aspects of diagnosis, pathophysiology, and treatment were reviewed by the authors; when not available, the authors have provided opinions based on clinical experience with this challenging condition.

Conclusions: Hypoglycemia, occurring after gastric bypass surgery, is challenging for patients and physicians alike. This review provides a systematic approach to diagnosis and treatment based on the underlying pathophysiology.
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http://dx.doi.org/10.1210/jc.2018-00528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692713PMC
August 2018

Metabolic Effects of Betaine: A Randomized Clinical Trial of Betaine Supplementation in Prediabetes.

J Clin Endocrinol Metab 2018 08;103(8):3038-3049

Harvard Medical School, Boston, Massachusetts.

Context: Plasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet.

Objective: To assess metabolic effects of oral betaine in obese participants with prediabetes.

Design: A 12-week, parallel arm, randomized, double-masked, placebo-controlled trial.

Setting: University-affiliated hospital.

Participants And Interventions: Persons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo.

Main Outcome Measures: Changes from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function.

Results: There was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups.

Conclusion: DMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.
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http://dx.doi.org/10.1210/jc.2018-00507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692715PMC
August 2018

Squeezing Flux Out of Fat.

Trends Endocrinol Metab 2018 04 4;29(4):201-202. Epub 2018 Feb 4.

Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA. Electronic address:

Merging transcriptomics or metabolomics data remains insufficient for metabolic flux estimation. Ramirez et al. integrate a genome-scale metabolic model with extracellular flux data to predict and validate metabolic differences between white and brown adipose tissue. This method allows both metabolic phenotyping and the identification of potential therapeutic targets for obesity.
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http://dx.doi.org/10.1016/j.tem.2018.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366633PMC
April 2018

Can reversal of RYGB also reverse hypoglycemia?

Mol Metab 2018 03 12;9:1-3. Epub 2018 Jan 12.

Research Division, Joslin Diabetes Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.molmet.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870097PMC
March 2018

Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia.

Diabetes Technol Ther 2018 02;20(2):127-139

2 Research Division, Joslin Diabetes Center , Boston, Massachusetts.

Background: Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery with limited therapeutic options. We developed an event-based system to predict and detect hypoglycemia based on continuous glucose monitor (CGM) data and recommend delivery of minidose liquid glucagon.

Methods: We performed an iterative development clinical study employing a novel glucagon delivery system: a Dexcom CGM connected to a Windows tablet running a hypoglycemia prediction algorithm and an Omnipod pump filled with an investigational stable liquid glucagon formulation. Meal tolerance testing was performed in seven participants with PBH and history of neuroglycopenia. Glucagon was administered when hypoglycemia was predicted. Primary outcome measures included the safety and feasibility of this system to predict and prevent severe hypoglycemia. Secondary outcomes included hypoglycemia prediction by the prediction algorithm, minimization of time below hypoglycemia threshold using glucagon, and prevention of rebound hyperglycemia.

Results: The hypoglycemia prediction algorithm alerted for impending hypoglycemia in the postmeal state, prompting delivery of glucagon (150 μg). After observations of initial incomplete efficacy to prevent hypoglycemia in the first two participants, system modifications were implemented: addition of PBH-specific detection algorithm, increased glucagon dose (300 μg), and a second glucagon dose if needed. These modifications, together with rescue carbohydrates provided to some participants, contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL).

Conclusions: Preliminary results indicate that our event-based automatic monitoring algorithm successfully predicted likely hypoglycemia. Minidose glucagon therapy was well tolerated, without prolonged or severe hypoglycemia, and without rebound hyperglycemia.
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http://dx.doi.org/10.1089/dia.2017.0298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771550PMC
February 2018

LETTER TO THE EDITOR.

Endocr Pract 2017 10;23(10):1275

Joslin Diabetes Center, Harvard - Research and Clinic Divisions, 1 Joslin Place, Boston MA 02215, E-mail:

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http://dx.doi.org/10.4158/1934-2403-23.10.1275DOI Listing
October 2017

Mechanisms of weight loss and improved metabolism following bariatric surgery.

Ann N Y Acad Sci 2018 01 3;1411(1):53-64. Epub 2017 Sep 3.

Research and Clinic Divisions, Joslin Diabetes Center, Boston, Massachusetts.

Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, as well as improved metabolic and overall health. Unfortunately, the cellular and physiological mechanisms by which bariatric surgery achieves weight loss have not been fully elucidated, yet are critical to understanding the central role of the intestinal tract in whole-body metabolism and to developing novel strategies for the treatment of obesity. In this review, we provide an overview of potential mechanisms contributing to weight loss, including effects on regulation of energy balance and both central and peripheral nervous system regulation of appetite and metabolism. Moreover, we highlight the importance of the gastrointestinal tract, including alterations in bile acid physiology, secretion of intestinally derived hormones, and the microbiome, as a potent mediator of improved metabolism in postbariatric patients.
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http://dx.doi.org/10.1111/nyas.13409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788713PMC
January 2018

Attenuated Effects of Bile Acids on Glucose Metabolism and Insulin Sensitivity in a Male Mouse Model of Prenatal Undernutrition.

Endocrinology 2017 08;158(8):2441-2452

Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02115.

Prenatal undernutrition and low birth weight are associated with risk of type 2 diabetes and obesity. Prenatal caloric restriction results in low birth weight, glucose intolerance, obesity, and reduced plasma bile acids (BAs) in offspring mice. Because BAs can regulate systemic metabolism and glucose homeostasis, we hypothesized that BA supplementation could prevent diet-induced obesity and glucose intolerance in this model of developmental programming. Pregnant dams were food restricted by 50% from gestational days 12.5 to 18.5. Offspring of both undernourished (UN) and control (C) dams given unrestricted diets were weaned to high-fat diets with or without supplementation with 0.25% w/w ursodeoxycholic acid (UDCA), yielding four experimental groups: C, UN, C + UDCA, and UN + UDCA. Glucose homeostasis, BA composition, liver and intestinal gene expression, and microbiota composition were analyzed in the four groups. Although UDCA supplementation ameliorated diet-induced obesity in C mice, there was no effect in UN mice. UDCA similarly lowered fasting insulin, and improved glucose tolerance, pyruvate tolerance, and liver steatosis in C, but not UN, animals. BA composition differed significantly, and liver and ileal expression of genes involved in BA metabolism (Cyp7b1, Shp) were differentially induced by UDCA in C vs UN animals. Bacterial taxa in fecal microbiota correlated with treatment groups and metabolic parameters. In conclusion, prenatal undernutrition alters responsiveness to the metabolic benefits of BA supplementation, with resistance to the weight-lowering and insulin-sensitizing effects of UDCA supplementation. Our findings suggest that BA metabolism may be a previously unrecognized contributor to developmentally programmed diabetes risk.
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http://dx.doi.org/10.1210/en.2017-00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551557PMC
August 2017

Insulin Resistance and Mitochondrial Dysfunction.

Adv Exp Med Biol 2017 ;982:465-520

Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA.

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.
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http://dx.doi.org/10.1007/978-3-319-55330-6_25DOI Listing
September 2017

Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass.

Acta Diabetol 2017 Aug 17;54(8):737-747. Epub 2017 May 17.

Research Division, Joslin Diabetes Center, and Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.

Aims: Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones is implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB + NG). We aimed to determine whether β-cell proliferation or apoptosis is altered in RYGB + NG.

Methods: We performed an observational study to analyze markers of proliferation, apoptosis, cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB + NG patients (n = 12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n = 6), and individuals with hypoglycemia due to insulinoma (n = 52).

Results: Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB + NG patients (4.5-fold increase, p < 0.001 vs. controls) and correlated with β-cell mass. Ki-67 immunoreactivity was low in both RYGB + NG and controls, but did not differ between groups. Phospho-histone H3 levels did not differ between RYGB + NG and controls. PCNA and Ki-67 were both significantly lower in both controls and RYGB + NG than insulinomas. Markers of apoptosis and cell cycle (M30, p27, and p21) did not differ between groups. PDX1 and menin exhibited similar expression patterns, while FOXO1 appeared to be more cytosolic in RYGB + NG.

Conclusions: Markers of proliferation are heterogeneous in patients with severe post-RYGB hypoglycemia. Increased β-cell proliferation in some individuals may contribute to increased β-cell mass observed in severely affected patients.
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http://dx.doi.org/10.1007/s00592-017-1001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515485PMC
August 2017

Medical nutrition therapy for post-bariatric hypoglycemia: practical insights.

Surg Obes Relat Dis 2017 May 16;13(5):888-896. Epub 2017 Jan 16.

Hypoglycemia Clinic, Joslin Diabetes Center, Boston MA; Research Division, Joslin Diabetes Center, Boston, MA; Harvard Medical School, Boston, MA. Electronic address:

Hypoglycemia is increasingly recognized as a complication of bariatric surgery. Although medications are often required, medical nutrition therapy remains the key cornerstone for successful prevention of hypoglycemia in patients with post-bariatric hypoglycemia (PBH). We provide suggested approaches to the dietary management of PBH, incorporating data from both the medical literature and extensive clinical experience in an academic referral center for PBH. The overall goal of medical nutrition therapy for PBH is to reduce postprandial surges in glucose, which often trigger surges in insulin secretion and promote subsequent hypoglycemia. Thus, strategies focus on controlled portions of low glycemic index carbohydrates, avoidance of rapidly-absorbed carbohydrates, adjustment of timing of meals and snacks, and attention to personal and cultural barriers to implementation.
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http://dx.doi.org/10.1016/j.soard.2017.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469688PMC
May 2017

Epigenetic Mechanisms of Transmission of Metabolic Disease across Generations.

Cell Metab 2017 03;25(3):559-571

Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center and Harvard Medical School, One Joslin Place, Sixth Floor, Boston, MA 02215, USA. Electronic address:

Both human and animal studies indicate that environmental exposures experienced during early life can robustly influence risk for adult disease. Moreover, environmental exposures experienced by parents during either intrauterine or postnatal life can also influence the health of their offspring, thus initiating a cycle of disease risk across generations. In this Perspective, we focus on epigenetic mechanisms in germ cells, including DNA methylation, histone modification, and non-coding RNAs, which collectively may provide a non-genetic molecular legacy of prior environmental exposures and influence transcriptional regulation, developmental trajectories, and adult disease risk in offspring.
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http://dx.doi.org/10.1016/j.cmet.2017.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404272PMC
March 2017

Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.

Mol Metab 2016 Oct 6;5(10):926-936. Epub 2016 Aug 6.

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Objective: Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear.

Methods: To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis.

Results: Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding.

Conclusions: Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034611PMC
http://dx.doi.org/10.1016/j.molmet.2016.08.001DOI Listing
October 2016

What Have Metabolomics Approaches Taught Us About Type 2 Diabetes?

Curr Diab Rep 2016 08;16(8):74

Research Division, 1 Joslin Place, Boston, MA, 02215, USA.

Type 2 diabetes (T2D) is increasing worldwide, making identification of biomarkers for detection, staging, and effective prevention strategies an especially critical scientific and medical goal. Fortunately, advances in metabolomics techniques, together with improvements in bioinformatics and mathematical modeling approaches, have provided the scientific community with new tools to describe the T2D metabolome. The metabolomics signatures associated with T2D and obesity include increased levels of lactate, glycolytic intermediates, branched-chain and aromatic amino acids, and long-chain fatty acids. Conversely, tricarboxylic acid cycle intermediates, betaine, and other metabolites decrease. Future studies will be required to fully integrate these and other findings into our understanding of diabetes pathophysiology and to identify biomarkers of disease risk, stage, and responsiveness to specific treatments.
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http://dx.doi.org/10.1007/s11892-016-0763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441387PMC
August 2016