Journal of the American College of Cardiology, Jun 1, 2006
We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family his... more We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors. BACKGROUND Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis. Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FHϩ) or with no first-degree relative with diabetes (FHϪ). Although fasting glucose was higher in FHϩ than FHϪ (5.3 Ϯ 0.1 mmol/l vs. 4.9 Ϯ 0.1 mmol/l, p Ͻ 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FHϩ (7.1 Ϯ 0.9% vs. 11.7 Ϯ 1.6%, p Ͻ 0.02), with no difference in nitroglycerin-induced endotheliumindependent vasodilatation. In the combined cohort, only FHϩ (r 2 ϭ 0.12, p Ͻ 0.02) and HbA1c (r 2 ϭ 0.14, p Ͻ 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FHϪ (p Ͻ 0.03, analysis of variance), but not in FHϩ, as even the most insulin-sensitive FHϩ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p ϭ 0.04). CONCLUSIONS Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes. (
To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-... more To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-en-Y gastric bypass (RYGB), we performed comprehensive proteomic analysis of fasting human plasma samples obtained from the SLIMM-T2D longitudinal clinical trial, which randomized obese individuals with T2D to RYGB surgery or a one-year intensive medical diabetes and weight management (DWM) program, and followed them for 3 years. Somalogic proteomic analysis was performed on plasma collected in the fasting state at baseline and during longitudinal follow-up, and proteins differentially abundant in RYGB vs. DWM at each time point were identified. The protein with highest magnitude of differential abundance at 3 years was insulin-like growth factor binding protein 2 (IGFBP2), upregulated by 2.2-fold in RYGB vs. DWM (p=4.37E-06); differences were confirmed by ELISA. IGFBP2 inversely correlated at 3 years with BMI (r=-0.74, p=5.31E-05) and HbA1c (r=-0.68, p=0.00004). Notably, IGFBP2 levels were increased at the first postoperative study visit (10% weight loss) following RYGB or at similar weight loss for the DWM group, suggesting an early weight-independent contribution. IGFBP2 is predominantly expressed in liver and upregulated after RYGB in mice (2.8-fold at 8 weeks, GSE68812). To identify IGFBP2-dependent mechanisms contributing to improved hepatic metabolism, we overexpressed mouse IGFBP2 or control vector in mouse AML12 hepatocytes, achieving a 6-fold increase in IGFPB2 protein. qPCR revealed 15-30% downregulation of lipogenic genes (e.g., Fasn, Srebp1) with a 2-fold increase in expression of genes regulating fatty acid oxidation (e.g., Ppara, Ppargc1a). Analysis of metabolism (Seahorse flux analyzer) revealed increased fatty acid oxidation (3-fold, p<0.01 for IGFBP2 vs. control). In conclusion, increased IGFBP2 expression may contribute to improved hepatic lipid oxidative metabolism, and thus induce systemic metabolic improvement after RYGB surgery. Disclosure Y. Yuchi: None. W. Cai: None. T. Takagi: None. H. Pan: None. J. Dreyfuss: None. K. Foster: None. A.H. Vernon: None. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. A. Goldfine: Employee; Self; Novartis AG. A. Hoeflich: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.
The increased prevalence of obesity has led to increased numbers of bariatric surgical procedures... more The increased prevalence of obesity has led to increased numbers of bariatric surgical procedures being performed annually. Postoperative metabolic improvements in glucose levels, blood pressure and lipids have led to recognition that surgery may prove to be a highly effective therapy for type 2 diabetes (T2D). A recent report evaluates durability of diabetes remission and metabolic improvements. Lifestyle modification, weight loss, and medical therapies are the foundation of disease management for type 2 diabetes. However, weight loss is difficult to achieve and sustain, and progressive hyperglycemia requiring additional medication use is common. Emerging data over the past few years have demonstrated that bariatric surgery may provide an additional therapeutic option, particularly in individuals early in the course of T2D. Bariatric surgeries lead to substantial and sustained weight loss for most patients, with the magnitude varying according to the procedure performed. For example, the Swedish Obesity Subjects (SOS) study, a long-term, prospective, controlled trial, demonstrated mean weight loss in surgical patients of 23% after 2 years, which was sustained at 18% by 20 years 1 . In comparison, matched controls receiving usual medical care had no significant weight change over this same interval. Furthermore, bariatric surgery is associated with improvements in obesity-related comorbidities including hypertension and dyslipidemia, and reduced incidence of myocardial infarction (29%), stroke (34%), and cancer in women (42%) 1 . Up to 80% of individuals with T2D at the time of surgery may improve glycemic control or achieve disease remission, without use of medication. Moreover, those without T2D at the time of surgery have a 73% reduction in incident diabetes 1 and may have 30-40% reductions in overall mortality . When performed at centers of excellence, these benefits are achieved with low operative mortality rates, ranging from 0.1 to 0.5% 3 , with longerterm intestinal and nutritional complications varying by procedure. Thus, bariatric surgery may represent a reasonable therapeutic approach for diabetes and weight management in patients with reasonable surgical risk who are otherwise unable to achieve or sustain health goals, a position supported by the International Diabetes
Single-cell RNA sequencing (scRNA-seq) enables molecular characterization of complex biological t... more Single-cell RNA sequencing (scRNA-seq) enables molecular characterization of complex biological tissues at high resolution. The requirement of single-cell extraction, however, makes it challenging for profiling tissues such as adipose tissue, for which collection of intact single adipocytes is complicated by their fragile nature. For such tissues, single-nucleus extraction is often much more efficient and therefore single-nucleus RNA sequencing (snRNA-seq) presents an alternative to scRNA-seq. However, nuclear transcripts represent only a fraction of the transcriptome in a single cell, with snRNA-seq marked with inherent transcript enrichment and detection biases. Therefore, snRNA-seq may be inadequate for mapping important transcriptional signatures in adipose tissue. In this study, we compare the transcriptomic landscape of single nuclei isolated from preadipocytes and mature adipocytes across human white and brown adipocyte lineages, with whole-cell transcriptome. We show that snRNA-seq is capable of identifying the broad cell types present in scRNA-seq at all states of adipogenesis. However, we also explore how and why the nuclear transcriptome is biased and limited, as well as how it can be advantageous. We robustly characterize the enrichment of nuclear-localized transcripts and adipogenic regulatory lncRNAs in snRNA-seq, while also providing a detailed understanding for the preferential detection of long genes upon using this technique. To remove such technical detection biases, we propose a normalization strategy for a more accurate comparison of nuclear and cellular data. Finally, we show successful integration of scRNA-seq and snRNA-seq data sets with existing bioinformatic tools. Overall, our results illustrate the applicability of snRNA-seq for the characterization of cellular diversity in the adipose tissue.
Bariatric surgery leads to substantial and sustained weight loss, and resolution or improvements ... more Bariatric surgery leads to substantial and sustained weight loss, and resolution or improvements in type 2 diabetes, hypertension and dyslipidemia. Cohort studies support improved longer-term mortality. Metabolic health improvements and safety vary with the specific bariatric surgery performed, likely a result of procedure-specific anatomic and physiologic changes. Recently, increased attention has focused on a syndrome of hypoglycemia with neuroglycopenia observed most commonly following Roux-en-Y gastric bypass (RYGB), which typically first presents more than 1-2 years postoperatively and occurs predominantly in the postprandial state (1, 2). Post-bariatric hypoglycemia can be life-threatening with altered consciousness, seizures, and motor vehicle accidents. Understanding the frequency of this syndrome and identifying which patients may be at risk is highly relevant given the large number of bariatric procedures performed worldwide.
Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse... more Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse model of LBW resulting from undernutrition during pregnancy. Restriction of maternal food intake from day 12.5 to 18.5 of pregnancy results in a 23% decrease in birth weight (P < 0.001), with normalization after birth. However, offspring of undernutrition pregnancies develop progressive, severe glucose intolerance by 6 months. To identify early defects that are responsible for this phenotype, we analyzed mice of undernutrition pregnancies at age 2 months, before the onset of glucose intolerance. Fed insulin levels were 1.7-fold higher in mice of undernutrition pregnancies (P ؍ 0.01 vs. controls). However, insulin sensitivity was normal in mice of undernutrition pregnancies, with normal insulin tolerance, insulin-stimulated glucose disposal, and isolated muscle and adipose glucose uptake. Although insulin clearance was mildly impaired in mice of undernutrition pregnancies, the major metabolic phenotype in young mice of undernutrition pregnancies was dysregulation of insulin secretion. Despite normal -cell mass, islets from normoglycemic mice of undernutrition pregnancies showed basal hypersecretion of insulin, complete lack of responsiveness to glucose, and a 2.5fold increase in hexokinase activity. Taken together, these data suggest that, at least in mice, primary -cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes. Diabetes 54: 702-711, 2005
Current Opinion in Endocrinology & Diabetes, Oct 1, 2006
To examine the recently recognized association between bariatric surgery-induced weight loss and ... more To examine the recently recognized association between bariatric surgery-induced weight loss and postprandial hyperinsulinemic hypoglycemia. Postprandial hypoglycemia following gastric bypass for obesity is generally considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. A rare syndrome characterized by more severe postprandial hypoglycemia and hyperinsulinemia, accompanied by diffuse pancreatic islet hyperplasia and expansion of beta-cell mass, however, has recently been identified. In our experience, the therapeutic approach to these patients is guided by the severity and frequency of hypoglycemia, and includes nutritional modification to reduce postprandial glycemic excursion and stepped medical management, including acarbose, octreotide and diazoxide. Other therapeutic agents previously used to inhibit insulin secretion or action, including calcium channel blockade, b-blockers and anticholinergics, have been minimally effective. For lifethreatening hypoglycemia refractory to medical management, partial pancreatectomy may be necessary, but hypoglycemia has recurred in some patients. These findings suggest that gastric bypass-induced weight loss may unmask an underlying beta-cell defect or contribute to pathologic islet hyperplasia. Summary Severe postprandial hyperinsulinemic hypoglycemia may be regarded as a rare, late complication of bariatric surgery. Management of these patients may require nutritional, pharmacological and, on occasion, surgical intervention. The pathophysiology remains incompletely understood.
Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication following Roux-en-Y gas... more Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication following Roux-en-Y gastric bypass (RYGB) surgery for weight management. Insulin secretion and action in response to oral and intravenous stimuli in persons with and without neuroglycopenia following RYGB are evaluated in this study. Cross-sectional cohort studies were performed at a single academic institution to assess insulin secretion and action during oral mixed meal tolerance test and intravenous glucose tolerance test (IVGTT). Insulin secretion was increased more following oral mixed meal than intravenous glucose in individuals with neuroglycopenia compared to the asymptomatic group. Reduced insulin clearance did not contribute to higher insulinemia. Glucose effectiveness at zero insulin, estimated during the IVGTT, was also higher in those with neuroglycopenia. Insulin sensitivity did not differ between groups. Increased beta-cell response to oral stimuli and insulin-independent glucose disposal may both contribute to severe hypoglycemia after RYGB.
The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the associat... more The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease. Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis. Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years. Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM. We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function. We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain. However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load. This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction. More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM. (Endocrine Reviews 31: 364 -395, 2010) I. Type 2 Diabetes Pathogenesis A. Risk factors associated with type 2 diabetes II. General Overview of Mitochondrial Biology A. The dynamic morphology of mitochondria B. Mechanisms that control mitochondrial density and capacity III. Role of Mitochondria in Tissue-Specific Contexts A. Muscle B. Adipose tissue C. Liver D. Pancreatic -cells IV. Experimental Strategies to Explore the Relationship between Mitochondrial Function and DM A. PGC-1 ␣ and  overexpression B. PGC-1 knockout models C. Other mitochondrial function defects V. Conclusions
Proceedings of the National Academy of Sciences of the United States of America, Jun 27, 2003
Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic  cell dysfun... more Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic  cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR␥ coactivator 1-␣ and- (PGC1-␣͞PPARGC1 and PGC1-͞PERC), coactivators of NRF-1 and PPAR␥-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.
Aims-Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilit... more 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 are implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who
The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type... more The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N 5 195) or medical/lifestyle therapy (N 5 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A 1c [HbA 1c ] #6.5% for 3 months without usual glucoselowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m 2 , and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA 1c (D 5 21.9 ± 2.0 vs. 20.1 ± 2.0%; P < 0.001), fasting plasma glucose (D 5 252 [2105, 25] vs. 212 [248, 26] mg/dL; P < 0.001), and BMI (D 5 28.0 ± 3.6 vs. 21.8 ± 2.9 kg/m 2 ; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used. More than 34.2 million Americans, or 10.5% of the population, have type 2 diabetes (1), and $40% have obesity (2). Obesity and type 2 diabetes cause enormous
To identify novel pathways mediating molecular mechanisms of thiazolidinediones (TZDs) in humans,... more To identify novel pathways mediating molecular mechanisms of thiazolidinediones (TZDs) in humans, we assessed gene expression in adipose and muscle tissue from six subjects with type 2 diabetes before and after 8 weeks of treatment with rosiglitazone. mRNA was analyzed using Total Gene Expression Analysis (TOGA), an automated restriction-based cDNA display method with quantitative analysis of PCR products. The expression of cell cycle regulatory transcription factors E2F4 and the MAGE protein necdin were similarly altered in all subjects after rosiglitazone treatment. E2F4 expression was decreased by 10-fold in muscle and 2.5-fold in adipose tissue; necdin was identified in adipose tissue only and increased 1.8-fold after TZD treatment. To determine whether changes were related to an effect of the drug or adipogenesis, we evaluated the impact of rosiglitazone and differentiation independently in 3T3-L1 adipocytes. While treatment of differentiated adipocytes with rosiglitazone did not alter E2F4 or necdin, expression of both genes was significantly altered during differentiation. Differentiation was associated with increased cytosolic localization of E2F4. Moreover, necdin overexpression potently inhibited adipocyte differentiation and cell cycle progression. These data suggest that changes in necdin and E2F4 expression after rosiglitazone exposure in humans are associated with altered adipocyte differentiation and may contribute to improved insulin sensitivity in humans treated with TZDs.
Background-Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profil... more Background-Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profile than expected by weight loss alone. In this study, we investigated the effect of RYGB on serum bile acid levels and their relation to clinical outcomes. Methods-We included 30 obese patients who underwent RYGB (BMI=46.1±5.9 kg/m 2 ). Clinical measurements and laboratory determinations were performed before surgery and 1 year after surgery. Fasting serum bile acids were measured by an enzymatic method and individual bile acids were quantified by HLPC-tandem mass spectrometry. Indirect calorimetry was performed to measure the rates of energy expenditure and substrate oxidation. Results-Fasting total serum bile acid levels increased twofold after RYGB (pre, 3.68±2.03 vs. post, 7.06± 9.65 μmol/l, +92 %, p=0.002). This increase in total bile acids was accompanied by a decrease in conjugated bile acids, which correlated with decreased glucose oxidation (r=0.571, p=0.002) and with increased lipid oxidation (r=-0.626, p=0.0004). The change in taurineconjugated bile acids correlated with altered DIO2 mRNA expression in adipose tissue (r= -0.498, p=0.013) potentially linking bile acid conjugation to substrate oxidation through DIO2. Conclusions-Fasting serum bile acid levels increase after RYGB. More specifically, changes in bile acid conjugation after RYGB associate with altered energy metabolism.
Best Practice & Research in Clinical Gastroenterology, Aug 1, 2014
Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids... more Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids have long been known to play important and direct roles in nutrient absorption, bile acids also serve as signaling molecules. Bile acid interactions with the nuclear hormone receptor farnesoid X receptor (FXR) and the membrane receptor G-protein-coupled bile acid receptor 5 (TGR5) can regulate incretin hormone and fibroblast growth factor 19 (FGF19) secretion, cholesterol metabolism, and systemic energy expenditure. Bile acid levels and distribution are altered in type 2 diabetes and increased following bariatric procedures, in parallel with reduced body weight and improved insulin sensitivity and glycemic control. Thus, modulation of bile acid levels and signaling, using bile acid binding resins, TGR5 agonists, and FXR agonists, may serve as a potent therapeutic approach for the treatment of obesity, type 2 diabetes, and other components of the metabolic syndrome in humans.
The World Health Organization has proclaimed obesity and type 2 diabetes (T2D) to be amongst the ... more The World Health Organization has proclaimed obesity and type 2 diabetes (T2D) to be amongst the most important threats to global public health. Roux-en-Y gastric bypass surgery leads to substantial and sustained weight loss and has become a widely-used approach to manage obesity related conditions, although physiologic mechanisms leading to metabolic improvements remain incompletely understood. Insulin sensitivity is improved post-RYGB, typically in parallel to the magnitude of weight lost ( 1 ). In contrast, insulin secretion and islet β-cell glucose sensitivity may be disproportionately increased post-RYGB ( 2 ).
To improve the power of mediation in high-throughput studies, here we introduce Highthroughput me... more To improve the power of mediation in high-throughput studies, here we introduce Highthroughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling. Trial Registration: Clinicaltrials.gov NCT01073020.
Journal of the American College of Cardiology, Jun 1, 2006
We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family his... more We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors. BACKGROUND Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis. Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FHϩ) or with no first-degree relative with diabetes (FHϪ). Although fasting glucose was higher in FHϩ than FHϪ (5.3 Ϯ 0.1 mmol/l vs. 4.9 Ϯ 0.1 mmol/l, p Ͻ 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FHϩ (7.1 Ϯ 0.9% vs. 11.7 Ϯ 1.6%, p Ͻ 0.02), with no difference in nitroglycerin-induced endotheliumindependent vasodilatation. In the combined cohort, only FHϩ (r 2 ϭ 0.12, p Ͻ 0.02) and HbA1c (r 2 ϭ 0.14, p Ͻ 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FHϪ (p Ͻ 0.03, analysis of variance), but not in FHϩ, as even the most insulin-sensitive FHϩ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p ϭ 0.04). CONCLUSIONS Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes. (
To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-... more To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-en-Y gastric bypass (RYGB), we performed comprehensive proteomic analysis of fasting human plasma samples obtained from the SLIMM-T2D longitudinal clinical trial, which randomized obese individuals with T2D to RYGB surgery or a one-year intensive medical diabetes and weight management (DWM) program, and followed them for 3 years. Somalogic proteomic analysis was performed on plasma collected in the fasting state at baseline and during longitudinal follow-up, and proteins differentially abundant in RYGB vs. DWM at each time point were identified. The protein with highest magnitude of differential abundance at 3 years was insulin-like growth factor binding protein 2 (IGFBP2), upregulated by 2.2-fold in RYGB vs. DWM (p=4.37E-06); differences were confirmed by ELISA. IGFBP2 inversely correlated at 3 years with BMI (r=-0.74, p=5.31E-05) and HbA1c (r=-0.68, p=0.00004). Notably, IGFBP2 levels were increased at the first postoperative study visit (10% weight loss) following RYGB or at similar weight loss for the DWM group, suggesting an early weight-independent contribution. IGFBP2 is predominantly expressed in liver and upregulated after RYGB in mice (2.8-fold at 8 weeks, GSE68812). To identify IGFBP2-dependent mechanisms contributing to improved hepatic metabolism, we overexpressed mouse IGFBP2 or control vector in mouse AML12 hepatocytes, achieving a 6-fold increase in IGFPB2 protein. qPCR revealed 15-30% downregulation of lipogenic genes (e.g., Fasn, Srebp1) with a 2-fold increase in expression of genes regulating fatty acid oxidation (e.g., Ppara, Ppargc1a). Analysis of metabolism (Seahorse flux analyzer) revealed increased fatty acid oxidation (3-fold, p&amp;amp;amp;lt;0.01 for IGFBP2 vs. control). In conclusion, increased IGFBP2 expression may contribute to improved hepatic lipid oxidative metabolism, and thus induce systemic metabolic improvement after RYGB surgery. Disclosure Y. Yuchi: None. W. Cai: None. T. Takagi: None. H. Pan: None. J. Dreyfuss: None. K. Foster: None. A.H. Vernon: None. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. A. Goldfine: Employee; Self; Novartis AG. A. Hoeflich: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.
The increased prevalence of obesity has led to increased numbers of bariatric surgical procedures... more The increased prevalence of obesity has led to increased numbers of bariatric surgical procedures being performed annually. Postoperative metabolic improvements in glucose levels, blood pressure and lipids have led to recognition that surgery may prove to be a highly effective therapy for type 2 diabetes (T2D). A recent report evaluates durability of diabetes remission and metabolic improvements. Lifestyle modification, weight loss, and medical therapies are the foundation of disease management for type 2 diabetes. However, weight loss is difficult to achieve and sustain, and progressive hyperglycemia requiring additional medication use is common. Emerging data over the past few years have demonstrated that bariatric surgery may provide an additional therapeutic option, particularly in individuals early in the course of T2D. Bariatric surgeries lead to substantial and sustained weight loss for most patients, with the magnitude varying according to the procedure performed. For example, the Swedish Obesity Subjects (SOS) study, a long-term, prospective, controlled trial, demonstrated mean weight loss in surgical patients of 23% after 2 years, which was sustained at 18% by 20 years 1 . In comparison, matched controls receiving usual medical care had no significant weight change over this same interval. Furthermore, bariatric surgery is associated with improvements in obesity-related comorbidities including hypertension and dyslipidemia, and reduced incidence of myocardial infarction (29%), stroke (34%), and cancer in women (42%) 1 . Up to 80% of individuals with T2D at the time of surgery may improve glycemic control or achieve disease remission, without use of medication. Moreover, those without T2D at the time of surgery have a 73% reduction in incident diabetes 1 and may have 30-40% reductions in overall mortality . When performed at centers of excellence, these benefits are achieved with low operative mortality rates, ranging from 0.1 to 0.5% 3 , with longerterm intestinal and nutritional complications varying by procedure. Thus, bariatric surgery may represent a reasonable therapeutic approach for diabetes and weight management in patients with reasonable surgical risk who are otherwise unable to achieve or sustain health goals, a position supported by the International Diabetes
Single-cell RNA sequencing (scRNA-seq) enables molecular characterization of complex biological t... more Single-cell RNA sequencing (scRNA-seq) enables molecular characterization of complex biological tissues at high resolution. The requirement of single-cell extraction, however, makes it challenging for profiling tissues such as adipose tissue, for which collection of intact single adipocytes is complicated by their fragile nature. For such tissues, single-nucleus extraction is often much more efficient and therefore single-nucleus RNA sequencing (snRNA-seq) presents an alternative to scRNA-seq. However, nuclear transcripts represent only a fraction of the transcriptome in a single cell, with snRNA-seq marked with inherent transcript enrichment and detection biases. Therefore, snRNA-seq may be inadequate for mapping important transcriptional signatures in adipose tissue. In this study, we compare the transcriptomic landscape of single nuclei isolated from preadipocytes and mature adipocytes across human white and brown adipocyte lineages, with whole-cell transcriptome. We show that snRNA-seq is capable of identifying the broad cell types present in scRNA-seq at all states of adipogenesis. However, we also explore how and why the nuclear transcriptome is biased and limited, as well as how it can be advantageous. We robustly characterize the enrichment of nuclear-localized transcripts and adipogenic regulatory lncRNAs in snRNA-seq, while also providing a detailed understanding for the preferential detection of long genes upon using this technique. To remove such technical detection biases, we propose a normalization strategy for a more accurate comparison of nuclear and cellular data. Finally, we show successful integration of scRNA-seq and snRNA-seq data sets with existing bioinformatic tools. Overall, our results illustrate the applicability of snRNA-seq for the characterization of cellular diversity in the adipose tissue.
Bariatric surgery leads to substantial and sustained weight loss, and resolution or improvements ... more Bariatric surgery leads to substantial and sustained weight loss, and resolution or improvements in type 2 diabetes, hypertension and dyslipidemia. Cohort studies support improved longer-term mortality. Metabolic health improvements and safety vary with the specific bariatric surgery performed, likely a result of procedure-specific anatomic and physiologic changes. Recently, increased attention has focused on a syndrome of hypoglycemia with neuroglycopenia observed most commonly following Roux-en-Y gastric bypass (RYGB), which typically first presents more than 1-2 years postoperatively and occurs predominantly in the postprandial state (1, 2). Post-bariatric hypoglycemia can be life-threatening with altered consciousness, seizures, and motor vehicle accidents. Understanding the frequency of this syndrome and identifying which patients may be at risk is highly relevant given the large number of bariatric procedures performed worldwide.
Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse... more Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse model of LBW resulting from undernutrition during pregnancy. Restriction of maternal food intake from day 12.5 to 18.5 of pregnancy results in a 23% decrease in birth weight (P < 0.001), with normalization after birth. However, offspring of undernutrition pregnancies develop progressive, severe glucose intolerance by 6 months. To identify early defects that are responsible for this phenotype, we analyzed mice of undernutrition pregnancies at age 2 months, before the onset of glucose intolerance. Fed insulin levels were 1.7-fold higher in mice of undernutrition pregnancies (P ؍ 0.01 vs. controls). However, insulin sensitivity was normal in mice of undernutrition pregnancies, with normal insulin tolerance, insulin-stimulated glucose disposal, and isolated muscle and adipose glucose uptake. Although insulin clearance was mildly impaired in mice of undernutrition pregnancies, the major metabolic phenotype in young mice of undernutrition pregnancies was dysregulation of insulin secretion. Despite normal -cell mass, islets from normoglycemic mice of undernutrition pregnancies showed basal hypersecretion of insulin, complete lack of responsiveness to glucose, and a 2.5fold increase in hexokinase activity. Taken together, these data suggest that, at least in mice, primary -cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes. Diabetes 54: 702-711, 2005
Current Opinion in Endocrinology & Diabetes, Oct 1, 2006
To examine the recently recognized association between bariatric surgery-induced weight loss and ... more To examine the recently recognized association between bariatric surgery-induced weight loss and postprandial hyperinsulinemic hypoglycemia. Postprandial hypoglycemia following gastric bypass for obesity is generally considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. A rare syndrome characterized by more severe postprandial hypoglycemia and hyperinsulinemia, accompanied by diffuse pancreatic islet hyperplasia and expansion of beta-cell mass, however, has recently been identified. In our experience, the therapeutic approach to these patients is guided by the severity and frequency of hypoglycemia, and includes nutritional modification to reduce postprandial glycemic excursion and stepped medical management, including acarbose, octreotide and diazoxide. Other therapeutic agents previously used to inhibit insulin secretion or action, including calcium channel blockade, b-blockers and anticholinergics, have been minimally effective. For lifethreatening hypoglycemia refractory to medical management, partial pancreatectomy may be necessary, but hypoglycemia has recurred in some patients. These findings suggest that gastric bypass-induced weight loss may unmask an underlying beta-cell defect or contribute to pathologic islet hyperplasia. Summary Severe postprandial hyperinsulinemic hypoglycemia may be regarded as a rare, late complication of bariatric surgery. Management of these patients may require nutritional, pharmacological and, on occasion, surgical intervention. The pathophysiology remains incompletely understood.
Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication following Roux-en-Y gas... more Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication following Roux-en-Y gastric bypass (RYGB) surgery for weight management. Insulin secretion and action in response to oral and intravenous stimuli in persons with and without neuroglycopenia following RYGB are evaluated in this study. Cross-sectional cohort studies were performed at a single academic institution to assess insulin secretion and action during oral mixed meal tolerance test and intravenous glucose tolerance test (IVGTT). Insulin secretion was increased more following oral mixed meal than intravenous glucose in individuals with neuroglycopenia compared to the asymptomatic group. Reduced insulin clearance did not contribute to higher insulinemia. Glucose effectiveness at zero insulin, estimated during the IVGTT, was also higher in those with neuroglycopenia. Insulin sensitivity did not differ between groups. Increased beta-cell response to oral stimuli and insulin-independent glucose disposal may both contribute to severe hypoglycemia after RYGB.
The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the associat... more The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease. Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis. Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years. Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM. We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function. We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain. However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load. This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction. More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM. (Endocrine Reviews 31: 364 -395, 2010) I. Type 2 Diabetes Pathogenesis A. Risk factors associated with type 2 diabetes II. General Overview of Mitochondrial Biology A. The dynamic morphology of mitochondria B. Mechanisms that control mitochondrial density and capacity III. Role of Mitochondria in Tissue-Specific Contexts A. Muscle B. Adipose tissue C. Liver D. Pancreatic -cells IV. Experimental Strategies to Explore the Relationship between Mitochondrial Function and DM A. PGC-1 ␣ and  overexpression B. PGC-1 knockout models C. Other mitochondrial function defects V. Conclusions
Proceedings of the National Academy of Sciences of the United States of America, Jun 27, 2003
Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic  cell dysfun... more Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic  cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR␥ coactivator 1-␣ and- (PGC1-␣͞PPARGC1 and PGC1-͞PERC), coactivators of NRF-1 and PPAR␥-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.
Aims-Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilit... more 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 are implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who
The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type... more The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N 5 195) or medical/lifestyle therapy (N 5 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A 1c [HbA 1c ] #6.5% for 3 months without usual glucoselowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m 2 , and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA 1c (D 5 21.9 ± 2.0 vs. 20.1 ± 2.0%; P < 0.001), fasting plasma glucose (D 5 252 [2105, 25] vs. 212 [248, 26] mg/dL; P < 0.001), and BMI (D 5 28.0 ± 3.6 vs. 21.8 ± 2.9 kg/m 2 ; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used. More than 34.2 million Americans, or 10.5% of the population, have type 2 diabetes (1), and $40% have obesity (2). Obesity and type 2 diabetes cause enormous
To identify novel pathways mediating molecular mechanisms of thiazolidinediones (TZDs) in humans,... more To identify novel pathways mediating molecular mechanisms of thiazolidinediones (TZDs) in humans, we assessed gene expression in adipose and muscle tissue from six subjects with type 2 diabetes before and after 8 weeks of treatment with rosiglitazone. mRNA was analyzed using Total Gene Expression Analysis (TOGA), an automated restriction-based cDNA display method with quantitative analysis of PCR products. The expression of cell cycle regulatory transcription factors E2F4 and the MAGE protein necdin were similarly altered in all subjects after rosiglitazone treatment. E2F4 expression was decreased by 10-fold in muscle and 2.5-fold in adipose tissue; necdin was identified in adipose tissue only and increased 1.8-fold after TZD treatment. To determine whether changes were related to an effect of the drug or adipogenesis, we evaluated the impact of rosiglitazone and differentiation independently in 3T3-L1 adipocytes. While treatment of differentiated adipocytes with rosiglitazone did not alter E2F4 or necdin, expression of both genes was significantly altered during differentiation. Differentiation was associated with increased cytosolic localization of E2F4. Moreover, necdin overexpression potently inhibited adipocyte differentiation and cell cycle progression. These data suggest that changes in necdin and E2F4 expression after rosiglitazone exposure in humans are associated with altered adipocyte differentiation and may contribute to improved insulin sensitivity in humans treated with TZDs.
Background-Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profil... more Background-Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profile than expected by weight loss alone. In this study, we investigated the effect of RYGB on serum bile acid levels and their relation to clinical outcomes. Methods-We included 30 obese patients who underwent RYGB (BMI=46.1±5.9 kg/m 2 ). Clinical measurements and laboratory determinations were performed before surgery and 1 year after surgery. Fasting serum bile acids were measured by an enzymatic method and individual bile acids were quantified by HLPC-tandem mass spectrometry. Indirect calorimetry was performed to measure the rates of energy expenditure and substrate oxidation. Results-Fasting total serum bile acid levels increased twofold after RYGB (pre, 3.68±2.03 vs. post, 7.06± 9.65 μmol/l, +92 %, p=0.002). This increase in total bile acids was accompanied by a decrease in conjugated bile acids, which correlated with decreased glucose oxidation (r=0.571, p=0.002) and with increased lipid oxidation (r=-0.626, p=0.0004). The change in taurineconjugated bile acids correlated with altered DIO2 mRNA expression in adipose tissue (r= -0.498, p=0.013) potentially linking bile acid conjugation to substrate oxidation through DIO2. Conclusions-Fasting serum bile acid levels increase after RYGB. More specifically, changes in bile acid conjugation after RYGB associate with altered energy metabolism.
Best Practice & Research in Clinical Gastroenterology, Aug 1, 2014
Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids... more Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids have long been known to play important and direct roles in nutrient absorption, bile acids also serve as signaling molecules. Bile acid interactions with the nuclear hormone receptor farnesoid X receptor (FXR) and the membrane receptor G-protein-coupled bile acid receptor 5 (TGR5) can regulate incretin hormone and fibroblast growth factor 19 (FGF19) secretion, cholesterol metabolism, and systemic energy expenditure. Bile acid levels and distribution are altered in type 2 diabetes and increased following bariatric procedures, in parallel with reduced body weight and improved insulin sensitivity and glycemic control. Thus, modulation of bile acid levels and signaling, using bile acid binding resins, TGR5 agonists, and FXR agonists, may serve as a potent therapeutic approach for the treatment of obesity, type 2 diabetes, and other components of the metabolic syndrome in humans.
The World Health Organization has proclaimed obesity and type 2 diabetes (T2D) to be amongst the ... more The World Health Organization has proclaimed obesity and type 2 diabetes (T2D) to be amongst the most important threats to global public health. Roux-en-Y gastric bypass surgery leads to substantial and sustained weight loss and has become a widely-used approach to manage obesity related conditions, although physiologic mechanisms leading to metabolic improvements remain incompletely understood. Insulin sensitivity is improved post-RYGB, typically in parallel to the magnitude of weight lost ( 1 ). In contrast, insulin secretion and islet β-cell glucose sensitivity may be disproportionately increased post-RYGB ( 2 ).
To improve the power of mediation in high-throughput studies, here we introduce Highthroughput me... more To improve the power of mediation in high-throughput studies, here we introduce Highthroughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling. Trial Registration: Clinicaltrials.gov NCT01073020.
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Papers by Mary Patti