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1.  Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance 
Current opinion in lipidology  2008;19(1):16-24.
Purpose of review
Based on interim results from an ongoing study, we have reported that consumption of a high-fructose diet, but not a high-glucose diet, promotes the development of three of the pathological characteristics associated with metabolic syndrome: visceral adiposity, dyslipidemia, and insulin resistance. From these results and a review of the current literature, we present two potential sequences of events by which fructose consumption may contribute to metabolic syndrome.
Recent findings
The earliest metabolic perturbation resulting from fructose consumption is postprandial hypertriglyceridemia, which may increase visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver. With insulin resistance, VLDL production is upregulated and this, along with systemic free fatty acids, increase lipid delivery to muscle. It is also possible that fructose initiates hepatic insulin resistance independently of visceral adiposity and free fatty acid delivery. By providing substrate for hepatic lipogenesis, fructose may result in a direct lipid overload that leads to triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance.
Our investigation and future studies of the effects of fructose consumption may help to clarify the sequence of events leading to development of metabolic syndrome.
PMCID: PMC4151171  PMID: 18196982
dyslipidemia; free fatty acids; fructose consumption; hepatic steatosis; insulin resistance; metabolic syndrome
2.  Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats 
The Journal of endocrinology  2014;221(1):133-144.
There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.
PMCID: PMC4457365  PMID: 24627447
Pioglitazone; type 2 diabetes; alogliptin; islet
3.  CDKAL1 and HHEX are associated with type-2 diabetes-related traits among Yup’ik people 
Journal of diabetes  2013;6(3):251-259.
Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with type-2 diabetes (T2D), mainly among individuals of European ancestry. We examined the frequency of these SNPs and their association with T2D-related traits in an Alaska Native study population with a historically low prevalence of T2D. We also investigated whether dietary characteristics that may protect against T2D, such as n-3 polyunsaturated fatty acid (n-3 PUFA) intake, modify these associations.
In 1,144 Yup’ik people, we examined 17 SNPs repeatedly identified in GWAS for individual and cumulative associations with T2D-related traits. Cumulative associations were evaluated using a genetic risk score (GRS) calculated by summing risk alleles. Associations were tested for interactions with sex, BMI, and n-3 PUFA intake.
The rs7754840 SNP in CDKAL1 is significantly associated with HbA1c (p=0.00091). The rs5015480 SNP near HHEX is significantly associated (in opposite direction to that in Europeans) with a combined fasting glucose (FG) and HbA1c measure (p=0.00046) and with HOMA-B (p=0.0014). The GRS is significantly associated with FG and combined FG & HbA1c only when the HHEX SNP is dropped from the GRS. Associations are not modified by BMI or n-3 PUFA intake.
Our results highlight the potential importance of CDKAL1 and HHEX in glucose homeostasis in this Alaska Native population with a low prevalence of T2D, and suggest that these loci should be examined in greater detail in this population.
PMCID: PMC3964139  PMID: 24112421
Alaska Native; CANHR; type-2 diabetes SNPs; glycemic traits
4.  Clinical Research Strategies for Fructose Metabolism12 
Advances in Nutrition  2014;5(3):248-259.
Fructose and simple sugars are a substantial part of the western diet, and their influence on human health remains controversial. Clinical studies in fructose nutrition have proven very difficult to conduct and interpret. NIH and USDA sponsored a workshop on 13–14 November 2012, “Research Strategies for Fructose Metabolism,” to identify important scientific questions and parameters to be considered while designing clinical studies. Research is needed to ascertain whether there is an obesogenic role for fructose-containing sugars via effects on eating behavior and energy balance and whether there is a dose threshold beyond which these sugars promote progression toward diabetes and liver and cardiovascular disease, especially in susceptible populations. Studies tend to fall into 2 categories, and design criteria for each are described. Mechanistic studies are meant to validate observations made in animals or to elucidate the pathways of fructose metabolism in humans. These highly controlled studies often compare the pure monosaccharides glucose and fructose. Other studies are focused on clinically significant disease outcomes or health behaviors attributable to amounts of fructose-containing sugars typically found in the American diet. These are designed to test hypotheses generated from short-term mechanistic or epidemiologic studies and provide data for health policy. Discussion brought out the opinion that, although many mechanistic questions concerning the metabolism of monosaccharide sugars in humans remain to be addressed experimentally in small highly controlled studies, health outcomes research meant to inform health policy should use large, long-term studies using combinations of sugars found in the typical American diet rather than pure fructose or glucose.
PMCID: PMC4013177  PMID: 24829471
5.  Associations of ghrelin with eating behaviors, stress, metabolic factors, and telomere length among overweight and obese women: Preliminary evidence of attenuated ghrelin effects in obesity? 
Appetite  2014;76:84-94.
Ghrelin regulates homeostatic food intake, hedonic eating, and is a mediator in the stress response. In addition, ghrelin has metabolic, cardiovascular, and anti-aging effects. This cross-sectional study examined associations between total plasma ghrelin, caloric intake based on 3 day diet diaries, hedonic eating attitudes, stress-related and metabolic factors, and leukocyte telomere length in overweight (n=25) and obese women (n=22). We hypothesized associations between total plasma ghrelin and eating behaviors, stress, metabolic, cardiovascular, and cell aging factors among overweight women, but not among obese women due to lower circulating ghrelin levels and/or central resistance to ghrelin. Confirming previous studies demonstrating lowered plasma ghrelin in obesity, ghrelin levels were lower in the obese compared with overweight women. Among the overweight, ghrelin was positively correlated with caloric intake, giving in to cravings for highly palatable foods, and a flatter diurnal cortisol slope across 3 days. These relationships were non-significant among the obese group. Among overweight women, ghrelin was negatively correlated with insulin resistance, systolic blood pressure, and heart rate, and positively correlated with telomere length. Among the obese subjects, plasma ghrelin concentrations were negatively correlated with insulin resistance, but were not significantly correlated with blood pressure, heart rate or telomere length. Total plasma ghrelin and its associations with food intake, hedonic eating, and stress are decreased in obesity, providing evidence consistent with the theory that central resistance to ghrelin develops in obesity and ghrelin’s function in appetite regulation may have evolved to prevent starvation in food scarcity rather than cope with modern food excess. Furthermore, ghrelin is associated with metabolic and cardiovascular health, and may have anti-aging effects, but these effects may be attenuated in obesity.
PMCID: PMC4170078  PMID: 24462487
6.  Alterations in intervertebral disc composition, matrix homeostasis and biomechanical behavior in the UCD-T2DM rat model of type 2 diabetes 
Type 2 diabetes (T2D) adversely affects many tissues, and the greater incidence of discogenic low back pain among diabetic patients suggests that the intervertebral disc is affected too. Using a rat model of polygenic obese T2D, we demonstrate that diabetes compromises several aspects of disc composition, matrix homeostasis and biomechanical behavior. Coccygeal motion segments were harvested from 6-month-old lean Sprague-Dawley rats, obese Sprague-Dawley rats, and diabetic obese UCD-T2DM rats (diabetic for 69 ± 7 days). Findings indicated that diabetes but not obesity reduced disc glycosaminoglycan and water contents, and these degenerative changes correlated with increased vertebral endplate thickness and decreased endplate porosity, and with higher levels of the advanced glycation end-product (AGE) pentosidine. Consistent with their diminished glycosaminoglycan and water contents and their higher AGE levels, discs from diabetic rats were stiffer and exhibited less creep when compressed. At the matrix level, elevated expression of hypoxia-inducible genes and catabolic markers in the discs from diabetic rats coincided with increased oxidative stress and greater interactions between AGEs and one of their receptors (RAGE). Taken together, these findings indicate that endplate sclerosis, increased oxidative stress and AGE/RAGE-mediated interactions could be important factors for explaining the greater incidence of disc pathology in T2D.
PMCID: PMC4408867  PMID: 25641259
intervertebral disc degeneration; type 2 diabetes; vertebral endplate; advanced glycation end-products; pentosidine
7.  Twenty-four Hour Endocrine and Metabolic Profiles Following Consumption of High Fructose Corn Syrup-, Sucrose- Fructose-, and Glucose-Sweetened Beverages with Meals 
We have reported that compared with glucose-sweetened beverages, consuming fructose-sweetened beverages with meals results in lower 24-h circulating glucose, insulin and leptin concentrations, and elevated triacylglycerol (TG). However, pure fructose and glucose are not commonly used as sweeteners. High fructose corn syrup (HFCS) has replaced sucrose as the predominant sweetener in beverages in the U.S.
We compared the metabolic/endocrine effects of HFCS with sucrose, and in a subset of subjects with pure fructose and glucose.
34 men and women consumed 3 isocaloric meals with either sucrose- or HFCS-sweetened beverages, and blood samples were collected over 24 hours. Eight of the male subjects were also studied when fructose- or glucose-sweetened beverages were consumed.
In 34 subjects, 24-h glucose, insulin, leptin, ghrelin and TG profiles were similar between days that sucrose or HFCS were consumed. Postprandial TG excursions after HFCS or sucrose were larger in men than women. In the men in whom the effects of 4 sweeteners were compared, the 24-h glucose and insulin responses induced by HFCS and sucrose were intermediate between the lower responses during consumption of fructose and the higher responses during glucose. Unexpectedly, postprandial TG profiles after HFCS or sucrose were not intermediate, but comparably high as after pure fructose.
Sucrose and HFCS do not have substantially different short-term endocrine/metabolic effects. In male subjects, short-term consumption of sucrose and HFCS resulted in postprandial TG responses comparable to those induced by fructose.
PMCID: PMC3037416  PMID: 18469239
glucose; fructose; high fructose corn syrup; sucrose; insulin; leptin; ghrelin; triacylglycerol; free fatty acids; postprandial hypertriacylglycerolemia; humans
8.  Changes in Post-prandial Glucose and Pancreatic Hormones, and Steady-State Insulin and Free Fatty Acids after Gastric Bypass Surgery 
Changes in the multiple mechanisms that regulate glucose metabolism after gastric bypass (RYGB) are still being unveiled.
To compare the changes of glucose and pancreatic hormones [C-peptide, glucagon and pancreatic polypeptide (PP)] during a meal test (MTT) and steady-state insulin and free fatty acid (FFA) concentrations during euglycemic–hyperinsulinemic clamp 14 days and 6 months after RYGB in morbidly obese non-diabetic patients.
Academic Medical Center, United States.
Two groups were studied at baseline and at 14 days: RYGB followed by caloric restriction (RYGB, n=12) or equivalent caloric restriction alone (Diet, n=10), to control for energy intake and weight loss. The RYGB group was studied again at 6 months, to assess the changes after substantial weight loss. During MTT we determined the early and overall changes in glucose and pancreatic hormone concentrations, and during the clamp we assessed steady-state insulin and FFA concentrations.
After 14 days, RYGB subjects had enhanced post-prandial glucose, C-peptide and glucagon responses and decreased post-prandial PP concentrations. Steady-state insulin concentrations were decreased at 14 days only in RYGB subjects, and FFA increased in both groups. Six months after RYGB and substantial weight loss, the decrease in insulin concentrations during clamp persisted, and there were further changes in post-prandial glucose and glucagon responses. FFA concentrations during clamp were significantly lower at 6 months, relative to pre-surgical values.
RYGB produces, in morbidly obese non-diabetic patients, early changes in post-meal glucose, C-peptide, glucagon and PP responses, and appears to enhance insulin clearance early after RYGB and improve insulin sensitivity in adipose tissue at 6 months post-surgery. The early changes cannot be explained by caloric restriction alone.
PMCID: PMC3896512  PMID: 24209879
Gastric bypass; gut hormones; incretins; insulin resistance; free fatty acids; insulin clearance; hyperinsulinemic euglycemic clamp; bariatric surgery; C-peptide; glucagon; glucose; type 2 diabetes
9.  Adverse metabolic effects of dietary fructose: Results from recent epidemiological, clinical, and mechanistic studies 
Current opinion in lipidology  2013;24(3):198-206.
Purpose of review
The effects of dietary sugar on risk factors and processes associated with metabolic disease remains a controversial topic, with recent reviews of the available evidence arriving at widely discrepant conclusions.
Recent findings
There are many recently published epidemiological studies that provide evidence that sugar consumption is associated with metabolic disease. Three recent clinical studies, which investigated the effects of consuming relevant doses of sucrose or high fructose corn syrup along with ad libitum diets, provide evidence that consumption of these sugars increase risk factors for cardiovascular disease (CVD) and metabolic syndrome. Mechanistic studies suggest that these effects result from the rapid hepatic metabolism of fructose catalyzed by fructokinase C, which generates substrate for de novo lipogenesis and leads to increased uric acid levels. Recent clinical studies investigating the effects of consuming less sugar, via educational interventions or by substitution of sugar-sweetened beverages for non-calorically sweetened beverages, provide evidence that such strategies have beneficial effects on risk factors for metabolic disease or on BMI in children.
The accumulating epidemiological evidence, direct clinical evidence, and the evidence suggesting plausible mechanisms support a role for sugar in the epidemics of metabolic syndrome, CVD and type 2 diabetes.
PMCID: PMC4251462  PMID: 23594708
Fructose; sucrose; high fructose corn syrup; sugar; metabolic disease
10.  Low Prepregnancy Adiponectin Concentrations Are Associated With a Marked Increase in Risk for Development of Gestational Diabetes Mellitus 
Diabetes Care  2013;36(12):3930-3937.
To examine whether circulating total and high–molecular weight (HMW) adiponectin concentrations, measured before pregnancy, are associated with subsequent risk of gestational diabetes mellitus (GDM).
This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up exam (1984–1996) with a serum sample obtained and who had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case subjects were the 256 women who developed GDM. Two control subjects were selected for each case and matched for year of blood draw, age at exam, age at pregnancy, and number of intervening pregnancies.
Compared with the highest quartile of adiponectin, the risk of GDM increased with decreasing quartile (odds ratio [OR] 1.5 [95% CI 0.7–2.9], 3.7 [1.9–7.2], and 5.2 [2.6–10.1]; Ptrend <0.001) after adjustment for family history of diabetes, BMI, parity, race/ethnicity, cigarette smoking, and glucose and insulin concentrations. Similar estimates were observed for HMW (Ptrend <0.001). The combined effects of having total adiponectin levels below the median (<10.29 mg/mL) and being overweight or obese (BMI ≥25.0 kg/m2) were associated with a sevenfold increased risk of GDM compared with normal-weight women with adiponectin levels above the median (OR 6.7 [95% CI 3.6–12.5]).
Prepregnancy low adiponectin concentrations, a marker of decreased insulin sensitivity and altered adipocyte endocrine function, is associated with reduced glucose tolerance during pregnancy and may identify women at high risk for GDM to target for early intervention.
PMCID: PMC3836148  PMID: 23990523
11.  Maternal ileal interpostion surgery confers metabolic improvements to offspring independent of effects on maternal body weight in UCD-T2DM rats 
Obesity surgery  2013;23(12):10.1007/s11695-013-1076-y.
Increasing numbers of people are undergoing bariatric surgery, of which approximately half are women in their child-bearing years. However, information on the long-term effects of maternal bariatric surgery in their children is lacking. Furthermore, since bariatric surgery is performed to reduce body weight, clinical studies have not been able to differentiate between benefits to the child due to maternal body weight loss versus other maternal postoperative metabolic changes. Therefore, we used the UCD-T2DM rat model of type 2 diabetes to test the hypothesis that maternal ileal interposition (IT) surgery would confer beneficial metabolic effects in offspring, independent of effects on maternal body weight.
Materials and Methods
IT surgery was performed on 2-month old prediabetic female UCD-T2DM rats. Females were bred 3 weeks after surgery and male pups were studied longitudinally.
Maternal IT surgery resulted in decreased body weight in offspring compared with sham offspring (P<0.05). IT offspring exhibited improvements of glucose-stimulated insulin secretion and nutrient-stimulated GLP-2 secretion (P<0.05). Fasting plasma unconjugated bile acid concentrations were 4-fold lower in IT offspring compared with sham offspring at two months of age (P<0.001).
Overall, maternal IT surgery confers modest improvements of body weight and improves insulin secretion and nutrient-stimulated GLP-2 secretion in offspring in the UCD-T2DM rat model of type 2 diabetes, indicating that this is a useful model for investigating the weight-independent metabolic effects of maternal bariatric surgery.
PMCID: PMC3855031  PMID: 24036841
12.  The good, the bad, and the unknown: Fructose and FGF21☆ 
Molecular Metabolism  2014;4(1):1-2.
PMCID: PMC4314528  PMID: 25685684
13.  Evidence for novel genetic loci associated with metabolic traits in Yup’ik people 
To identify genomic regions associated with fasting plasma lipid profiles, insulin, glucose, and glycosylated hemoglobin in a Yup’ik study population, and to evaluate whether the observed associations between genetic factors and metabolic traits were modified by dietary intake of marine derived omega-3 polyunsaturated acids (n-3 PUFA).
A genome-wide linkage scan was conducted among 982 participants of the Center for Alaska Native Health Research study. n-3 PUFA intake was estimated using the nitrogen stable isotope ratio (δ15N) of erythrocytes. All genotyped SNPs located within genomic regions with LOD scores > 2 were subsequently tested for individual SNP associations with metabolic traits using linear models that account for familial correlation as well as age, sex, community group and n-3 PUFA intake. Separate linear models were fit to evaluate interactions between the genotype of interest and n-3 PUFA intake.
We identified several chromosomal regions linked to serum apolipoprotein A2, high density lipoprotein-, low density lipoprotein-, and total cholesterol, insulin, and glycosylated hemoglobin. Genetic variants found to be associated with total cholesterol mapped to a region containing previously validated lipid loci on chromosome 19, and additional novel peaks of biological interest were identified at 11q12.2-11q13.2. We did not observe any significant interactions between n-3 PUFA intake, genotypes, and metabolic traits.
We have completed a whole genome linkage scan for metabolic traits in Native Alaskans, confirming previously identified loci, and offering preliminary evidence of novel loci implicated in chronic disease pathogenesis in this population.
PMCID: PMC3785243  PMID: 23907821
Alaska Native; metabolism; multi-point linkage genome scan
14.  Leptin concentrations in response to acute stress predict subsequent intake of comfort foods 
Physiology & behavior  2012;107(1):34-39.
Both animals and humans show a tendency toward eating more “comfort food” (high fat, sweet food) after acute stress. Such stress eating may be contributing to the obesity epidemic, and it is important to understand the underlying psychobiological mechanisms. Prior investigations have studied what makes individuals eat more after stress; this study investigates what might make individuals eat less. Leptin has been shown to increase following a laboratory stressor, and is known to affect eating behavior. This study examined whether leptin reactivity accounts for individual differences in stress eating. To test this, we exposed forty women to standardized acute psychological laboratory stress (Trier Social Stress Test) while blood was sampled repeatedly for measurements of plasma leptin. We then measured food intake after the stressor in 29 of these women. Increasing leptin during the stressor predicted lower intake of comfort food. These initial findings suggest that acute changes in leptin may be one of the factors modulating down the consumption of comfort food following stress.
PMCID: PMC3409346  PMID: 22579988
15.  Isotopic estimates of sugar intake are related to chronic disease risk factors but not obesity in an Alaska Native (Yup’ik) study population 
Sugar intake may be causally associated with chronic disease risk, either directly or by contributing to obesity. However, evidence from observational studies is mixed, in part due to the error and bias inherent in self-reported measures of sugar intake. Objective biomarkers may clarify the relationship between sugar intake and chronic disease risk. We have recently validated a biomarker of sugar intake in an Alaska Native (Yup’ik) study population that incorporates red blood cell carbon and nitrogen isotope ratios in a predictive model.
This study tested associations of isotopic estimates of sugar intake with BMI, waist circumference (WC), and a broad array of other physiological and biochemical measures of chronic disease risk in Yup’ik people.
In a cross-sectional sample of 1076 Yup’ik people, multiple linear regression was used to examine associations of sugar intake with BMI, WC and other chronic disease risk factors.
Isotopic estimates of sugar intake were not associated with BMI (P = 0.50) or WC (P = 0.85). They were positively associated with blood pressure, triglycerides, and leptin, and inversely associated with total-, HDL- and LDL-cholesterol and adiponectin.
Isotopic estimates of sugar intake were not associated with obesity, but were adversely associated with other chronic disease risk factors in this Yup’ik study population. This first use of stable isotope markers of sugar intake may influence recommendations for sugar intake by Yup’ik people; however, longitudinal studies are required to understand associations with chronic disease incidence.
PMCID: PMC3947290  PMID: 24219893
Isotopes; carbon; Isotopes; nitrogen; Chronic disease; Risk factors; Caloric sweeteners
16.  Effects of Sugar-sweetened Beverages on plasma Acylation Stimulating Protein, Leptin & Adiponectin and Metabolic Parameters 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20437.
We determined the effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity.
Design and Methods
32 overweight/obese adults consumed glucose- or fructose-sweetened beverages (25% energy requirement) with their ad libitum diets for 8 weeks, followed by sweetened beverage consumption for 2 weeks with a standardized, energy-balanced diet. Plasma variables were measured at baseline, 2, 8 and 10 weeks, and body adiposity and insulin sensitivity at baseline and 10 weeks.
Fasting and postprandial ASP concentrations increased at 2 and/or 8 weeks. ASP increases correlated with changes in late-evening triglyceride concentrations. At 10 weeks, fasting adiponectin levels decreased in both groups, and decreases were inversely associated with baseline intra-abdominal fat volume. Sugar consumption increased fasting leptin concentrations; increases were associated with body weight changes. 24-h leptin profiles increased during glucose consumption and decreased during fructose consumption. These changes correlated with changes of 24-h insulin levels.
The consumption of fructose and glucose beverages induced changes in plasma concentrations of ASP, adiponectin and leptin. Further study is required to determine if these changes contribute to the metabolic dysfunction observed during fructose consumption.
PMCID: PMC3732502  PMID: 23512943
fructose; glucose; obesity; acylation stimulating protein; leptin; adiponectin
17.  Chronic Administration of the Glucagon-Like Peptide-1 Analog, Liraglutide, Delays the Onset of Diabetes and Lowers Triglycerides in UCD-T2DM Rats 
Diabetes  2010;59(10):2653-2661.
The efficacy of liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, to prevent or delay diabetes in UCD-T2DM rats, a model of polygenic obese type 2 diabetes, was investigated.
At 2 months of age, male rats were divided into three groups: control, food-restricted, and liraglutide. Animals received liraglutide (0.2 mg/kg s.c.) or vehicle injections twice daily. Restricted rats were food restricted to equalize body weights to liraglutide-treated rats. Half of the animals were followed until diabetes onset, whereas the other half of the animals were killed at 6.5 months of age for tissue collection.
Before diabetes onset energy intake, body weight, adiposity, and liver triglyceride content were higher in control animals compared with restricted and liraglutide-treated rats. Energy-restricted animals had lower food intake than liraglutide-treated animals to maintain the same body weights, suggesting that liraglutide increases energy expenditure. Liraglutide treatment delayed diabetes onset by 4.1 ± 0.8 months compared with control (P < 0.0001) and by 1.3 ± 0.8 months compared with restricted animals (P < 0.05). Up to 6 months of age, energy restriction and liraglutide treatment lowered fasting plasma glucose and A1C concentrations compared with control animals. In contrast, liraglutide-treated animals exhibited lower fasting plasma insulin, glucagon, and triglycerides compared with both control and restricted animals. Furthermore, energy-restricted and liraglutide-treated animals exhibited more normal islet morphology.
Liraglutide treatment delays the development of diabetes in UCD-T2DM rats by reducing energy intake and body weight, and by improving insulin sensitivity, improving lipid profiles, and maintaining islet morphology.
PMCID: PMC3279561  PMID: 20622169
18.  Ileal Interposition Surgery Improves Glucose and Lipid Metabolism and Delays Diabetes Onset in the UCD-T2DM Rat 
Gastroenterology  2010;138(7):2437-2446.e1.
Background & Aims
Bariatric surgery has been shown to reverse type 2 diabetes, however the mechanisms by which this occurs remain undefined. Ileal interposition (IT) is a surgical model that isolates the effects of increasing the delivery of unabsorbed nutrients to the lower gastrointestinal tract. In this study we investigated the effects of IT surgery on glucose tolerance and diabetes onset in UCD-T2DM rats, a polygenic obese animal model of type 2 diabetes.
IT or sham surgery was performed on 4 month old male UCD-T2DM rats. All animals underwent an oral glucose tolerance test (OGTT). A subset was euthanized 2 months after surgery for tissue analyses. The remainder was followed until diabetes onset and underwent an oral fat tolerance test (OFTT).
IT surgery delayed diabetes onset by 120 ± 49 days compared with sham surgery (P< 0.05) without a difference in body weight. During OGTT, IT-operated animals exhibited lower plasma glucose excursions (P< 0.05), improved early insulin secretion (P< 0.01) and 3-fold larger plasma GLP-17–36 excursions (P< 0.001) and no difference in GIP responses compared with sham-operated animals. Total plasma PYY excursions during the OFTT were 3-fold larger in IT-operated animals (P< 0.01). IT-operated animals exhibited lower adiposity (P< 0.05), smaller adipocyte size (P< 0.05), 25% less ectopic lipid deposition, lower circulating lipids and greater pancreatic insulin content compared with sham-operated animals (P< 0.05).
IT surgery delays the onset of diabetes in UCD-T2DM rats which may be related to increased nutrient-stimulated secretion of GLP-17–36 and PYY and improvements of insulin sensitivity, β-cell function and lipid metabolism.
PMCID: PMC2883638  PMID: 20226188
Bariatric surgery; diabetes prevention; glucagon-like peptide-1; peptide-YY
19.  Fructose consumption: Recent results and their potential implications 
In addition to acquiring a better understanding of foods that may have intrinsic health benefits, increasing our knowledge of dietary components that may adversely impact health and wellness, and the levels of consumption at which these adverse effects may occur, should also be an important priority for the Foods for Health initiative. This review discusses the evidence that additional research is needed to determine the adverse effects of consuming added sugars containing fructose. Current guidelines recommend limiting sugar consumption in order to prevent weight gain and promote nutritional adequacy. However recent data suggests that fructose consumption in humans results in increased visceral adiposity, lipid dysregulation, and decreased insulin sensitivity, all of which have been associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed model for the differential effects of fructose and glucose is presented. The only published study to directly compare the effects of fructose with those of commonly consumed dietary sweeteners, high fructose corn syrup and sucrose, indicates that high fructose corn syrup and sucrose increase postprandial triglycerides comparably to pure fructose. Dose-response studies investigating the metabolic effects of prolonged consumption of fructose by itself, and in combination with glucose, on lipid metabolism and insulin sensitivity in both normal weight and overweight/obese subjects are needed.
PMCID: PMC3075927  PMID: 20388133
Fructose; glucose; visceral adiposity; insulin sensitivity; cardiovascular disease; postprandial hypertriglyceridemia; small dense low density lipoprotein
20.  Consumption of fructose-sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women 
The British journal of nutrition  2008;100(5):947-952.
Fructose consumption in the USA has increased over the past three decades. During this time, obesity, insulin resistance and the metabolic syndrome have also increased in prevalence. While diets high in fructose have been shown to promote insulin resistance and increase TAG concentrations in animals, there are insufficient data available regarding the long-term metabolic effects of fructose consumption in humans. The objective of the present study was to investigate the metabolic effects of 10-week consumption of fructose-sweetened beverages in human subjects under energy-balanced conditions in a controlled research setting. Following a 4-week weight-maintaining complex carbohydrate diet, seven overweight or obese (BMI 26.8–33.3 kg/m2) postmenopausal women were fed an isoenergetic intervention diet, which included a fructose-sweetened beverage with each meal, for 10 weeks. The intervention diet provided 15% of energy from protein, 30% from fat and 55% from carbohydrate (30% complex carbohydrate, 25% fructose). Fasting and postprandial glucose, insulin, TAG and apoB concentrations were measured. Fructose consumption increased fasting glucose concentrations and decreased meal-associated glucose and insulin responses (P=0.0002, P=0.007 and P=0.013, respectively). Moreover, after 10 weeks of fructose consumption, 14 h postprandial TAG profiles were significantly increased, with the area under the curve at 10 weeks being 141% higher than at baseline (P=0.04). Fructose also increased fasting apoB concentrations by 19% (P=0.043 v. baseline). In summary, consumption of fructose-sweetened beverages increased postprandial TAG and fasting apoB concentrations, and the present results suggest that long-term consumption of diets high in fructose could lead to an increased risk of CVD.
PMCID: PMC3038917  PMID: 18384705
Fructose; Glucose; Insulin; Hypertriacylglycerolaemia; Apolipoprotein-B
21.  Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high fructose corn syrup 
Our laboratory has investigated two hypotheses regarding the effects of fructose consumption: 1) The endocrine effects of fructose consumption favor a positive energy balance, and 2) Fructose consumption promotes the development of an atherogenic lipid profile. In previous short- and long-term studies, we demonstrated that consumption of fructose-sweetened beverages with 3 meals results in lower 24-hour plasma concentrations of glucose, insulin, and leptin in humans compared with consumption of glucose-sweetened beverages. We have also tested whether prolonged consumption of high-fructose diets could lead to increased caloric intake or decreased energy expenditure, thereby contributing to weight gain and obesity. Results from a study conducted in rhesus monkeys produced equivocal results. Carefully controlled and adequately powered long-term studies are needed to address these hypotheses. In both short- and long-term studies we demonstrated that consumption of fructose-sweetened beverages substantially increases postprandial triacylglycerol concentrations compared with glucose-sweetened beverages. In the long-term studies, apolipoproteinB concentrations were also increased in subjects consuming fructose, but not those consuming glucose. Data from a short-term study comparing consumption of beverages sweetened with fructose, glucose, high fructose corn syrup (HFCS) and sucrose, suggest that HFCS and sucrose increase postprandial triacylglycerol to an extent comparable to that induced by 100% fructose alone. Increased consumption of fructose-sweetened beverages along with increased prevalence of obesity, metabolic syndrome, and type 2 diabetes underscore the importance of investigating the metabolic consequences fructose consumption in carefully controlled experiments.
PMCID: PMC3037017  PMID: 19064538
Fructose; glucose; insulin; leptin; lipids; triacylglycerol; apolipoprotein-B
22.  Simple Anthropometrics Are More Correlated with Health Variables than Are Estimates of Body Composition in Yup’ik People 
Obesity (Silver Spring, Md.)  2013;21(9):E435-E438.
We aimed to: 1) evaluate the relationships between several indices of obesity with obesity-related risk factors; 2) compare the accuracy of body composition estimates derived from anthropometry and bioimpedance analysis (BIA) to estimates of body composition assessed by doubly-labeled water (DLW); and 3) establish equations for estimating fat mass (FM), fat-free mass (FFM), and percent body fat (PBF) in Yup’ik Eskimo people. Participants included 1056 adult Yup’ik People from 11 communities in Southwestern Alaska. In a substudy of 30 participants, we developed population-specific linear regression models for estimating FM, FFM, and PBF from anthropometrics, age, sex, and BIA against criterion measures derived from total body water assessed with DLW. These models were then used with the population cohort and we analyzed the relationships between obesity indices and several health-related and disease status variables: 1. fasting plasma lipids, 2. glucose, 3. HbA1c, 4. adiponectin, 5. blood pressure, 6) diabetes (DM), and 7) cerebrocoronary vascular disease (CCVD) which includes stroke and heart disease. The best model for estimating FM in the substudy used only three variables – sex, waist circumference (WC), and hip circumference and had multiple R2=0.9730. FFM and PBF were calculated from FM and body weight. WC and other anthropometrics were more highly correlated with a number of obesity-related risk factors than were direct estimates of body composition. We conclude that body composition in Yup’ik People can be accurately estimated from simple anthropometrics.
PMCID: PMC3748182  PMID: 23666898
Doubly labeled water; fat mass; percent body fat; lipids; blood pressure; adiponectin; diabetes; stroke; cardiovascular disease; body mass index; waist circumference; Alaska Native people
23.  Early Effects of Neutering on Energy Expenditure in Adult Male Cats 
PLoS ONE  2014;9(2):e89557.
The initial cause of post-neutering weight gain in male cats is not entirely known. There is evidence that energy intake (EI) increases rapidly post-neutering, but it is not clear if neutering also decreases energy expenditure (EE) prior to weight gain. Thus, the purpose of this study was to determine if a decrease in EE contributes to the initial shift toward positive energy balance in neutered male cats. To determine the influence of neutering on EE independent of changes in EI and body weight (BW), male cats were fed at their pre-neutering maintenance EI and EE was measured at 4 days pre-neutering, 3–4 days post-neutering, and 9 days post- neutering. Ad libitum food access was then provided for 6 months. Body composition was measured and blood samples collected for serum chemistry at pre-neutering and 7 days, 13 days and 6 months post-neutering. Total energy expenditure (TEE) adjusted for lean body mass (LBM) did not change in cats from pre-neutering to 9 days post-neutering. However, TEE adjusted for BW and resting energy expenditure adjusted for either LBM or BW showed a small, but significant (P<0.05) increase from pre-neutering to 9 days post-neutering. When allowed free choice food access, cats showed significant increases of food intake (FI) and BW. Circulating concentrations of ghrelin increased, while adiponectin levels decreased following neutering. The results of this study indicate that initial post-neutering weight gain in male cats results from increased FI and not decreased EE. Long-term control of FI should be initiated after neutering to prevent hyperphagia and weight gain in male cats.
PMCID: PMC3935885  PMID: 24586869
24.  Wilson disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease 
Hepatology (Baltimore, Md.)  2013;57(2):555-565.
Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson disease (WD) through the inhibition of S-adenosylhomocysteine hydrolase (SAHH) by copper (Cu) and the consequent accumulation of S-adenosylhomocysteine (SAH). We studied the transcript levels of selected genes related to liver injury, levels of SAHH, SAH, DNA methyltransferases genes (Dnmt1, Dnmt3a, Dnmt3b) and global DNA methylation in the tx-j mouse (tx-j), an animal model of WD. Findings were compared to those in control C3H mice, and in response to Cu chelation by penicillamine (PCA) and dietary supplementation of the methyl donor betaine to modulate inflammatory and methylation status. Transcript levels of selected genes related to endoplasmic reticulum stress, lipid synthesis, and fatty acid oxidation were down-regulated at baseline in tx-j mice, further down-regulated in response to PCA, and showed little to no response to betaine. Hepatic Sahh transcript and protein levels were reduced in tx-j mice with consequent increase of SAH levels. Hepatic Cu accumulation was associated with inflammation, as indicated by histopathology and elevated serum ALT and liver tumor necrosis factor alpha (Tnf-α) levels. Dnmt3b was down-regulated in tx-j mice together with global DNA hypomethylation. PCA treatment of tx-j mice reduced Tnf-α and ALT levels, betaine treatment increased S-adenosylmethionine and up-regulated Dnmt3b levels, and both treatments restored global DNA methylation levels. Conclusion: reduced hepatic Sahh expression was associated with increased liver SAH levels in the tx-j model of WD, with consequent global DNA hypomethylation. Increased global DNA methylation was achieved by reducing inflammation by Cu chelation or by providing methyl groups. We propose that increased SAH levels and inflammation affect widespread epigenetic regulation of gene expression in WD.
PMCID: PMC3566330  PMID: 22945834
copper; S-adenosylhomocysteine; S-adenosylhomocysteine hydrolase; inflammation; toxic-milk mouse
25.  Physiological, Pharmacological, and Nutritional Regulation of Circulating Adiponectin Concentrations in Humans 
Adiponectin is an adipocyte hormone that links visceral adiposity with insulin resistance and atherosclerosis. It is unique among adipocyte-derived hormones in that its circulating concentrations are inversely proportional to adiposity, and low adiponectin concentrations predict the development of type 2 diabetes and cardiovascular disease. Consequently, in the decade since its discovery, adiponectin has generated immense interest as a potential therapeutic target for the metabolic syndrome and diabetes.
This review summarizes current research regarding the regulation of circulating adiponectin concentrations by physiological, pharmacological, and nutritional factors, with an emphasis on human studies. In humans, plasma adiponectin concentrations are influenced by age and gender, and are inversely proportional to visceral adiposity. In vitro studies suggest that adiponectin production may be determined primarily by adipocyte size and insulin sensitivity, with larger, insulin-resistant adipocytes producing less adiponectin. While adiponectin concentrations are unchanged after meal ingestion, they are increased by significant weight loss, such as after bariatric surgery. In addition, adiponectin production is inhibited by a number of hormones, including testosterone, prolactin, glucocorticoids and growth hormone, and by inflammation and oxidative stress in adipose tissue. Smoking decreases, while moderate alcohol consumption increases, circulating adiponectin concentrations. Dietary fatty acid composition in rodents influences adiponectin production via ligand-activated nuclear receptors (PPARs); however, current evidence in humans is equivocal. In addition to PPAR agonists (such as thiazolidinediones and fibrates), a number of pharmacological agents (angiotensin receptor type 1 blockers, ACE inhibitors, and cannabinoid receptor antagonists) used in treatment of the metabolic syndrome also increase adiponectin concentrations in humans.
PMCID: PMC3190268  PMID: 18510434

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