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Dietary trans-fatty acids are associated with increased risk of cardiovascular disease and have been implicated in the incidence of obesity and type 2 diabetes mellitus (T2DM). It is established that high-fat saturated diets, relative to low-fat diets, induce adiposity and whole-body insulin resistance. Here, we test the hypothesis that markers of an obese, prediabetic state (fatty liver, visceral fat accumulation, insulin resistance) are also worsened with provision of a low-fat diet containing elaidic acid (18:1t), the predominant trans-fatty acid isomer found in the human food supply. Male 8-week-old Sprague-Dawley rats were fed a 10% trans-fatty acid enriched (LF-trans) diet for 8 weeks. At baseline, 3 and 6 weeks, in vivo magnetic resonance spectroscopy (1H-MR) assessed intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content. Euglycemic-hyperinsulinemic clamps (week 8) determined whole-body and tissue-specific insulin sensitivity followed by high-resolution ex vivo 1H-NMR to assess tissue biochemistry. Rats fed the LF-trans diet were in positive energy balance, largely explained by increased energy intake, and showed significantly increased visceral fat and liver lipid accumulation relative to the low-fat control diet. Net glycogen synthesis was also increased in the LF-trans group. A reduction in glucose disposal, independent of IMCL accumulation was observed in rats fed the LF-trans diet, whereas in rats fed a 45% saturated fat (HF-sat) diet, impaired glucose disposal corresponded to increased IMCLTA. Neither diet induced an increase in IMCLsoleus. These findings imply that trans-fatty acids may alter nutrient handling in liver, adipose tissue, and skeletal muscle and that the mechanism by which trans-fatty acids induce insulin resistance differs from diets enriched with saturated fats.
Obesity (Silver Spring) 2009 Jun
PMID:Metabolic implications of dietary trans-fatty acids. 1958 78

Obesity and mild hyperglycemia are characteristic of early or "prediabetes." The associated increase in fatty acid flux is posited to enhance substrate delivery to mitochondria, leading to enhanced superoxide production that results in mitochondrial dysfunction and progressive worsening of the hyperglycemic state. We quantified superoxide production by gastrocnemius muscle, heart, and liver mitochondria in a rodent model that mimics the pathophysiology of prediabetes by administering low-dose streptozotocin to rats fed high fat (HF). Superoxide was rigorously determined indirectly as H(2)O(2) largely released from the matrix and by electron paramagnetic resonance spectroscopy that directly detects superoxide released externally. Both HF and low-dose streptozotocin mildly increased glycemia (P < .05 by 2-way analysis of variance). Matrix and external superoxide production by gastrocnemius mitochondria respiring on the complex II substrate succinate and matrix superoxide production by liver mitochondria respiring on the complex I substrates glutamate plus malate were significantly reduced by HF feeding but not affected by mild hyperglycemia. Superoxide production was not significantly altered by either treatment in heart mitochondria fueled by either complex I or II substrates. The functional status of the mitochondria was assayed as simultaneous respiration and membrane potential that were not affected by HF or mild hyperglycemia. Comparison of substrate and inhibitor effects on superoxide release implied marked differences in the redox mechanisms regulating mitochondrial superoxide production from liver mitochondria compared with muscle and heart. In summary, superoxide production from mitochondria of different insulin-sensitive tissues differs mechanistically. However, in any case, excess superoxide production as an intrinsic property of mitochondria of insulin-sensitive tissues does not result from conditions mimicking the pathophysiology of pre- or early diabetes.
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PMID:Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes. 1976 76

Worldwide, along with the increasing prevalence of obesity, the number of people with prediabetes is increasing. The diagnostic criteria for prediabetes include impaired fasting glucose, impaired glucose tolerance, and metabolic syndrome. The presence of two or more of these three criteria renders a person at high risk for future diabetes. The treatment goal of prediabetes is to prevent future development of type 2 diabetes and diabetes-related cardiovascular complications. The treatment approach is twofold: glycemic control and control of cardiovascular risk factors, mainly hypertension and hyperlipidemia. Intensive lifestyle modification is the mainstay of treatment in low-risk patients. When lifestyle modification fails and in high-risk patients, medications such as metformin and/or acarbose are recommended. For high-risk patients and those who progress despite intensive lifestyle modification, thiazolidinediones are also recommended. The goals for cardiovascular risk factor control are similar to those for patients with diabetes.
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PMID:What is the best treatment for prediabetes? 1979 2

Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes mellitus (T2DM). In obesity, the adipose cell releases nonesterified free fatty acids, hormones, adipocytokines, and other substances that are involved in insulin resistance. Under normal conditions, the pancreatic islet beta cells increase production of insulin sufficiently to maintain normal blood glucose concentrations despite insulin resistance. However, in genetically predisposed patients, the beta cells eventually become dysfunctional and T2DM develops. The development of T2DM can be delayed or sometimes prevented in individuals with obesity who are able to lose weight. Weight loss can be achieved medically with behavioral therapies that combine diet and exercise treatment or with behavioral therapies combined with weight-loss medications or weight-loss surgery. In this article, we summarize the evidence of obesity management in treating T2DM and prediabetes.
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PMID:Treating diabetes and prediabetes by focusing on obesity management. 1979 4

Insulin resistance (IR) is a consequence of obesity, and in women it is often inextricably linked with ovarian function leading to clinical reproductive manifestations such as early menarche onset, subfertility and polycystic ovary syndrome (PCOS). Likewise, the dramatic fall in oestrogen production after menopause may contribute to weight gain and changes in adipose tissue distribution. Overall, women who are obese, especially those with reproductive complications including PCOS, have been identified as specific high risk subgroups for further progression through to prediabetes, type 2 diabetes mellitus (T2DM) and potentially cardiovascular disease (CVD). This review focuses on the interrelationship between the ovarian function and obesity as well as its treatment strategies.
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PMID:Ovarian function and obesity--interrelationship, impact on women's reproductive lifespan and treatment options. 1981 76

Although women with gestational diabetes mellitus (GDM) are advised to incorporate physical activity into their lifestyle in order to reduce their risk of developing type 2 diabetes (T2DM), it is recognized that new mothers face barriers to postpartum exercise. Thus, we sought to determine whether, following the diagnosis of GDM, women indeed alter their postpartum physical activity patterns, as compared to their peers without GDM. In this prospective observational cohort study, we assessed the physical activity patterns of 238 white women (58 with GDM, 180 without GDM) in the year before pregnancy and in the year following delivery, using the Baecke questionnaire, which evaluates the following three domains of physical activity: work, sport activity, and nonsport leisure-time activity. Before diagnosis with GDM, women reported lower pregravid sport (P = 0.010) and leisure-time activity (P = 0.013), compared to their peers without GDM. By 1 year postpartum, however, there were no longer significant differences between the GDM and non-GDM groups in either sport or leisure-time activity (P = 0.078 and P = 0.957, respectively). In particular, women with GDM significantly increased their leisure-time activity over the first year postpartum (F = 10.1, P = 0.002), whereas the non-GDM group did not (F = 0.00, P = 0.984). Indeed, on multiple linear regression analysis, GDM independently predicted an increase in leisure-time activity between 1 year pregravid and 1 year postpartum (t = 2.55, P = 0.012). Furthermore, this significant relationship persisted even after adjustment for the finding of prediabetes/diabetes at 3 months postpartum (t = 2.83, P = 0.005). In conclusion, women with GDM successfully increased their leisure-time activity in the first year postpartum, reflecting an element of lifestyle change following this diagnosis.
Obesity (Silver Spring) 2010 Jul
PMID:Gestational diabetes and postpartum physical activity: evidence of lifestyle change 1 year after delivery. 1983 73

Human type 2 diabetes mellitus (T2DM) is often characterized by obesity-associated insulin resistance (IR) and beta-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in beta-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs (n = 12) received a high-fat diet that increased visceral (52%, P < 0.001) and subcutaneous (130%, P < 0.001) fat and resulted in a 31% reduction in insulin sensitivity (S(I)) (5.8 +/- 0.7 x 10(-4) to 4.1 +/- 0.5 x 10(-4) microU x ml(-1) x min(-1), P < 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30-15 mg/kg). The decrease in beta-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose >200 mg/dl during OGTT and 77-93% AIR(g) reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17-74% AIR(g) reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased beta-cell function (17-93%), and 40% lower S(I). We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes.
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PMID:Novel canine models of obese prediabetes and mild type 2 diabetes. 1984 74

Cross-sectional human studies have associated mitochondrial dysfunction to type 2 diabetes. We chose Zucker diabetic fatty (ZDF) rats as a model of progressive insulin resistance to examine whether intrinsic mitochondrial defects are required for development of type 2 diabetes. Muscle mitochondrial function was examined in 6-, 12-, and 19-week-old ZDF (fa/fa) and fa/+ control rats (n = 8-10 per group) using respirometry with pyruvate, glutamate, and palmitoyl-CoA as substrates. Six-week-old normoglycemic-hyperinsulinemic fa/fa rats had reduced mitochondrial fat oxidative capacity. Adenosine diphosphate (ADP)-driven state 3 and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated state uncoupled (state u) respiration on palmitoyl-CoA were lower compared to controls (62.3 +/- 9.5 vs. 119.1 +/- 13.8 and 87.8 +/- 13.3 vs. 141.9 +/- 14.3 nmol O(2)/mg/min.). Pyruvate oxidation in 6-week-old fa/fa rats was similar to controls. Remarkably, reduced fat oxidative capacity in 6-week-old fa/fa rats was compensated for by an adaptive increase in intrinsic mitochondrial function at week 12, which could not be maintained toward week 19 (140.9 +/- 11.2 and 57.7 +/- 9.8 nmol O(2)/mg/min, weeks 12 and 19, respectively), whereas hyperglycemia had developed (13.5 +/- 0.6 and 16.1 +/- 0.3 mmol/l, weeks 12 and 19, respectively). This mitochondrial adaptation failed to rescue the progressive development of insulin resistance in fa/fa rats. The transition of prediabetes state toward advanced hyperglycemia and hyperinsulinemia was accompanied by a blunted increase in uncoupling protein-3 (UCP3). Thus, in ZDF rats insulin resistance develops progressively in the absence of mitochondrial dysfunction. In fact, improved mitochondrial capacity in hyperinsulinemic hyperglycemic rats does not rescue the progression toward advanced stages of insulin resistance.
Obesity (Silver Spring) 2010 Jun
PMID:Adaptations in mitochondrial function parallel, but fail to rescue, the transition to severe hyperglycemia and hyperinsulinemia: a study in Zucker diabetic fatty rats. 1987 88

Whether intramuscular triglyceride (IMTG) concentration or flux is more important in the progression to type 2 diabetes is controversial. Therefore, this study examined IMTG concentration, as well as its fractional synthesis rate (FSR), in obese people with normal glucose tolerance (NGT; n = 20) vs. obese people with prediabetes (PD; n = 19), at rest and during exercise. Insulin action and secretion were assessed using an intravenous glucose tolerance test. [U-(13)C]palmitate was infused for 4 h before and throughout 1.5 h of treadmill walking at 50% VO(2(max)). IMTG concentration was measured by gas chromatograph/mass spectrometer, and FSR by gas chromatography-combustion isotope ratio mass spectrometer, from muscle biopsies taken immediately before and after exercise. Basal IMTG concentration was higher (43 +/- 5.7 vs. 27 +/- 3.9 mg/mg dry weight, P = 0.03) and FSR trended lower (0.23 +/- 0.04 vs. 0.32 +/- 0.05/h, P = 0.075), as did insulin action (S(i); 2.9 +/- 0.43 vs. 3.3 +/- 0.35 x 10(-4)/mU/ml, P = 0.07), in PD vs. NGT. IMTG concentration did not change significantly during exercise, but was no longer different in PD vs. NGT (45 +/- 7.7 vs. 37 +/- 5.8 mg/mg dry weight, P = 0.41). IMTG FSR suppressed during exercise in NGT (-81% to 0.06 +/- 0.13/h, P = 0.02), but not PD (+4% to 0.24 +/- 0.13%/h, P = 0.95). Palmitate oxidation was similar during rest (P = 0.92) and exercise (P = 0.94) between groups, but its source appeared different with more coming from muscle at rest and plasma during exercise in NGT, whereas the converse was true in PD. Altogether, higher basal IMTG concentration that is metabolically inflexible distinguishes obese people with PD from those with NGT.
Obesity (Silver Spring) 2010 Aug
PMID:Inflexibility in intramuscular triglyceride fractional synthesis distinguishes prediabetes from obesity in humans. 2003 85

The cardiometabolic syndrome has been associated with both chronic kidney disease (CKD) and cardiovascular disease (CVD). Using data from the National Kidney Foundation-Kidney Early Evaluation Program, the authors sought to investigate this association in a targeted CKD cohort. A total of 26,992 patients met eligibility criteria including age 18 years and older, diabetes, hypertension, or family history of CKD, diabetes, or hypertension and excluded those taking renal replacement therapy. Individuals were identified by Third Report of the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) criteria (dysglycemia, hypertension, and dyslipidemia) and World Health Organization criteria (obesity and proteinuria). Univariate and multivariate analyses were used to evaluate increasing components of the cardiometabolic syndrome, CKD, and CVD. On multivariate analysis there was a graded relationship between increasing components with an increased prevalence of CKD and CVD. Additionally, there was a graded trend with the stage of dysglycemia (eg, normoglycemia, prediabetes, and overt diabetes) and increasing CKD. However, there was only an increased prevalence of CVD observed in the clinically diabetic group. This trend was also observed with increasing serum glucose levels and an increasing percent of CVD and CKD up to 160 mg/dL. However, prevalent CVD increased at >140 mg/dL and prevalent CKD at >180 mg/dL. Therefore, data support that increasing metabolic components and dysglycemia are strongly associated with an increased prevalence of CKD and CVD.
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PMID:Dysglycemia predicts cardiovascular and kidney disease in the Kidney Early Evaluation Program. 2004 32


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