Significant Increase In Insulin Resistance Research Articles

Changes in insulin resistance following antidepressant treatment mediate response in major depressive disorder.

Insulin resistance (IR) is a potential predictor of antidepressant treatment response. We assess changes in IR after antidepressant treatment and whether these changes have any effect on treatment response. Also, to see whether changes in IR mediates relationship between C-reactive protein (CRP) and antidepressant efficacy. This is a secondary analysis of an 8-week, open-label clinical trial with 95 adults experiencing a major depressive episode. Response to vortioxetine was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). Generalized estimating equation models were utilized for this intent-to-treat analysis. When adjusted for age, sex, and body mass index, there was a significant increase in IR following treatment in the overall sample (p = 0.035). This finding was detected in treatment non-responders (p = 0.019), whereas it was not observed in responders (p = 0.329). Mediation analysis revealed that change in IR during treatment was responsible for change in MADRS as well as the relationship between baseline CRP and treatment response. Exacerbation of IR during antidepressant treatment mediated non-response. Conversely in treatment responders IR reduced. Like previous studies, baseline CRP moderated treatment response. This relationship was also mediated by changes in IR. These findings further elucidate the role of IR in terms of antidepressant response as well as potentially explain inflammation's relationship with the latter.

Over Expression of FOXO1 in Subcutaneous Fatty Tissue and its Response to Resistance Training in High Fat Diet and Type 2 Diabetic Rat

Objective: Forkhead box proteins and Forkhead box transcription factor O1 (FOXO1) in particular, mediate insulin signaling pathways and glucose homeostasis. This study aimed to compare FOXO1 expression in subcutaneous adipose (SA) tissue between obese rats with and without type 2 diabetes (T2D) and its response to resistance training in T2D.
 Materials and Methods: 21 male wistar rats (220±20 g) were obese by 6 weeks high fat diet (HFD) and randomly assigned to either non-diabetes (n=7) or two T2D groups (control and exercise groups, n=7 in each case). Fasting glucose, insulin, insulin resistance and FOXO1 expression were compared between non-diabetes and diabetes groups. All variables were also assigned after resistance training in the form of climbing a ladder (6 weeks/5 times weekly) in exercise compare with control groups. Data were compared by ANOVA, independent and paired t-test methods (P<0.05).
 Results: Induction of diabetes resulted in significant increase in insulin resistance, glucose, and FOXO expression in SA tissue and a decrease in insulin compared to obese health rats (P< 0.0001). A significant decrease in fasting insulin (P< 0.0001), insulin resistance (P< 0.0001) and FOXO1 expression in SA tissue (P< 0.0001) and increase in insulin (P: 0.002) were observed by resistance training compared to control diabetes rats.
 Conclusion: Based on our results, improving insulin resistance and glucose in response to resistance training in obese diabetic rats may be rooted in decreased insulin expression following these exercises.

Coronary microvascular dysfunction is only detectable in type 2 diabetes in the presence of obesity

Abstract Background Heart failure (HF) is a leading cardiovascular complication of type 2 diabetes (T2D). Coronary microvascular dysfunction (CMD) precedes HF in diabetes and carries important prognostic information. CMD is also evident in metabolically healthy obese individuals without diabetes or hypertension. Whether diabetes causes CMD in the absence of obesity is uncertain. The interrelation among visceral adiposity and CMD has not been assessed previously. Objectives We sought to better understand the links between visceral and epicardial adipose tissue (VAT and EAT respectively) distribution, insulin resistance with myocardial perfusion, energetics and function in asymptomatic lean (LnT2D) and overweight/obese T2D patients (ObT2D) without cardiovascular disease. Methods 62 participants [27 Ob-T2D, 15 Ln-T2D, and 20 overweight controls] were recruited. Subjects underwent cardiac and abdominal magnetic resonance imaging and 31P-magnetic resonance spectroscopy, for measurements of EAT and VAT areas, rest and adenosine stress myocardial blood flow (MBF), cardiac function and phosphocreatine to ATP ratio (PCr/ATP). Fasting blood samples were taken for plasma homeostasis model assessment of insulin resistance (HOMA-IR) index calculations. Results The biochemical characteristics and multiparametric MR results are given in Table 1 and results of Pearson's regression analysis in the entire study population are given in Table 2. Stress MBF was lowest in ObT2D, while rest MBF was highest in LnT2D. Left ventricular ejection fraction (LVEF) and myocardial PCr/ATP were similarly reduced in diabetes groups. In the absence of obesity, there was no significant increase in VAT, EAT or HOMA-IR in T2D patients compared to controls. BMI and VAT, negatively correlated with LVEF, and strain parameters. PCr/ATP correlated with LVEF, but not HOMA-IR. BMI, EAT and VAT all correlated significantly with HOMA-IR, and HOMA-IR correlated with cardiac functional parameters. There was no association between HOMA-IR and myocardial perfusion. Conclusions In this study CMD was only evident in ObT2D patients, with normal rest and stress MBF in LnT2D patients. Despite normal perfusion and no significant increase in insulin resistance, LVEF and myocardial PCr/ATP were similarly reduced in LnT2D and ObT2D, and PCr/ATP correlated with LVEF. This suggests that alterations in cardiac energy metabolism are mechanistically more relevant for the pathophysiology of diabetic cardiomyopathy in LnT2D patients. In the absence of correlation between insulin resistance and myocardial perfusion, factors like inflammation and altered adipokine profile may play important roles for the pathophysiology of CMD in ObT2D patients. A better understanding of the underlying pathophysiological mechanisms of diabetic cardiomyopathy in LnT2D and ObT2D may help to develop contemporary tailored treatment and prevention strategies to tackle excess heart failure risk. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): BHFWellcome trust Table 1Table 2

Impact of Dairy Food Intake on Glucose Homeostasis: A Randomized Controlled Trial (P08-039-19)

ObjectivesThe consumption of dairy foods, both low-fat and full-fat, tends to be associated with better metabolic health and lower type 2 diabetes risk in most observational studies. We aimed to test the effects of diets rich in either low-fat or full-fat dairy products on glucose tolerance and its key determinants, compared to a diet limited in dairy. We hypothesized that diets rich in dairy, particularly full-fat dairy, would improve glucose homeostasis. MethodsSeventy-two men and women with the metabolic syndrome first completed a 4-week wash-in period during which they limited their dairy intake to no more than 3 servings of skim milk per week. Participants were then randomized to either continue the limited dairy diet or switch to a diet containing 3.3 servings per day of either low-fat or full-fat milk, yogurt, and cheese, for 12 weeks. Glucose tolerance and its key determinants (insulin sensitivity, beta-cell function, liver fat content, low-grade inflammation) were assessed before and after the 12-week intervention period. ResultsIn primary per protocol analyses (n = 67), repeated measures analysis of variance revealed no treatment effect on glucose tolerance, as measured by the area-under-the-curve glucose in a 3-hour oral glucose tolerance test (P = 0.340). However, intervention effects were seen for the homeostasis model assessment insulin resistance index (P = 0.004 overall), and post hoc tests showed a significant increase in insulin resistance in the low-fat dairy group (mean ± SD + 0.8 ± 1.4, adjusted P = 0.03) and the full-fat dairy group (+ 1.3 ± 1.7, adjusted P = 0.003) compared to the limited dairy group (-0.2 ± 1.1). These effects were unchanged in secondary analyses adjusted for moderate changes in fat mass. ConclusionsIn this 12-week dietary intervention study, we detected no evidence for our hypothesis that dairy consumption improves glucose tolerance. Unexpectedly, insulin resistance increased in individuals consuming diets rich in either low-fat or full-fat dairy products, compared to participants who limited their dairy intake. Funding SourcesThis work was supported by the National Dairy Council, Dairy Farmers of Canada, the Dutch Dairy Association (NZO), Dairy Australia, and the French Dairy Interbranch Organization (CNIEL).

Fluconazole, a Fungal Cytochrome P450 Enzyme Inhibitor: The Potential Role in Augmenting Hepatotoxicity and Hyperinsulinemia Induced by Dexamethasone in Rats

Insulin resistance (IR) is a widespread health problem characterized by failure of cell responses to insulin. IR increases the risk of fungal infections. Long-term administration of dexamethasone is a therapeutic need accompanied IR and fungal infections. Fluconazole is the first-line antifungal therapy that inhibit fungal cytochrome P450 (CYP450) enzyme. It has a hepatotoxic effect and moderate inhibitory effect on multiple CYP450 enzymes that could affect the pharmacokinetics of drugs used to treat insulin resistance such as metformin. This study aims to evaluate the effect of administration of fluconazole on liver function, CYP450 concentration and level of insulin resistance induced by dexamethasone and high fat diet. Insulin resistance in rats was induced by dexamethasone (0.1mg/kg/day s.c) (DEX) for 2 weeks, after eight weeks of high fat diet (HFD) until the end of the experiment. Oral administration of fluconazole (20, 40 mg/kg) (FLU20, 40) was started concomitantly with DEX for 2 weeks. Metformin (400mg/kg) (MET) was used as a reference treatment for IR and administered orally for 2 weeks with DEX and FLU (20, 40). Concomitant administration of FLU either 20mg/kg or 40 mg/kg with DEX showed significant increase in IR, AST and ALT compared by that caused by DEX alone or with MET. FLU showed a significant decrease in serum CYP450 that elevated by DEX. Massive fibrosis was noticed in histological assessments of liver tissues of HFD+DEX+FLU (20, 40) groups. In conclusion administration of FLU in case of IR induced by HFD+DEX resulted in deterioration of liver functions and decrease in the therapeutic efficacy of MET.

COMPARISON OF METABOLIC PROFILE OF OBESE NON-DIABETIC PATIENTS WITH CORONARY ARTERY DISEASE DEPENDING ON ATORVASTATIN DOSE

Introduction:Cardiovascular diseases (CVD) are one of the most important medical-biological and social problems in Ukraine and in the world because coronary artery disease (CAD) is a major cause of death and disability. Overweight and obesity are risk factor of CVD and type 2 diabetes mellitus (T2DM). Although statins have been shown to be beneficial in secondary prevention of CVD in a number of trials, current reports of increased risk of T2DM with statin use raise concerns. The aim: To compare the metabolic profile and therapeutic targets of non-diabetic obese patients with CAD depending on the dose of atorvastatin. Materials and methods: The study included 107 patients (82 men and 25 women) with CAD and abdominal obesity. Patients were divided into two groups: those taking 20 mg and 40 mg of atorvastatin daily correspondingly. Glucose, insulin, HbA1c, HOMA-IR, lipids, hs-CRP and anthropometric parameters were measured for each subject. Results: For patients with CAD and obesity, who had taken atorvastatin in a 40-mg dose, we observed a significant increase in insulin resistance and impaired fasting glucose. Also we found a reliable correlation between the carbohydrate and lipid spectrum. These parameters reflect the mechanism of the formation of metabolic disorders as a result of intensive statin therapy. Сonclusions: Despite of the beneficial reductions in LDL and total cholesterol, atorvastatin treatment on a dose 40 mg resulted in significant increase of fasting glucose, insulin levels and insulin resistance pertaining to those patients.

Uncaria tomentosa (cat claw) Counteracts Chronic Fipronil-induced Endocrine Disruption Induced Insulin Resistance and Hepatic Damage in Male Albino Rats

The current study investigated the ability of Uncaria tomentosa (cat claw) to counteract fipronil (FIP) induced metabolic abnormalities. A total of 20 male adult albino rats were randomly divided into 4 groups (5 rats each). Control rats received only dis. water, Uncaria group was treated by dietary Uncaria 5g/kg, fipronil group rats treated with 3.23 mg/kg of FIP, and fipronil and Uncaria co-treated group was given 3.23 mg/kg FIP with 5g/kg dietary Uncaria. The doses were given every day for consecutive 12 weeks. Body weight, food intake and food conversion ratio (FCR) were determined. Blood samples were collected for estradiol and lipid profile estimation. Plasma liver enzymes were assayed. .Glucose and insulin were determined for Homa IR calculation. Liver tissues and abdominal fat were fixed for histopathological examinations. FIP-treated rats had no influence on body weight gain however, it increased (P<0.05) the food conversion ratio than other groups. Estradiol level was significantly (P<0.05) reduced by FIP however Uncaria ameliorated this decrease. Rats administrated FIP exhibited significantly higher cholesterol, triglycerides (TG), low-density lipoproteins (LDL) and liver enzymes (AST, and ALT) more than those in the other groups while it decreased (P<0.05) high-density lipoproteins (HDL). FIP produced a significant increase in insulin resistance (HOMA-IR) that was ameliorated by Uncaria. The liver of FIP-treated rats revealed vacuolar degeneration, lymphocytic infiltration and focal necrosis. Moreover, FIP increased diameter of fat cells. Uncaria combated FIP induced insulin resistance, liver damage and adiposity. Cat claw could effectively protect against metabolic disruption induced by FIP.

Effect of Anthelmintic Treatment on Insulin Resistance: A Cluster-Randomized, Placebo-Controlled Trial in Indonesia.

Emerging evidence suggests that helminth infections are associated with lower insulin resistance (IR). Current deworming programs might remove this helminth-associated protective effect. Therefore, we evaluated the anthelmintic treatment effect on changes in IR. We conducted a double-blind, household-cluster-randomized, placebo-controlled clinical trial on Flores island, Indonesia, an area endemic for soil-transmitted helminths (STHs). All subjects received 4 rounds of albendazole or matching placebo with 3-month intervals, for 3 consecutive days. The primary outcome was the change in homeostatic model assessment of IR in those aged >16 years. An intention-to-treat analysis was performed involving all subjects and ad hoc in the helminth-infected subjects. We examined 797 (in 329 households) and 872 (in 353 households) subjects, who were assigned randomly into the albendazole and placebo arms, respectively. Albendazole was associated with a significant reduction in STH prevalence, total immunoglobulin E (IgE), and eosinophil count. Whereas albendazole had no effect on IR (estimated treatment effect, 0.006 [95% confidence interval, -.010 to .021]; P = .48) at the community level, it was associated with a significant increase in IR (estimated treatment effect, 0.031 [95% confidence interval, .004 to .059]; P = .04) (P value for interaction = .01) among helminth-infected subjects as detected by microscopy. Pathway analysis suggested that this might in part be due to an increased body mass index or a reduced eosinophil count. Anthelmintic treatment reduces STH prevalence, total IgE, and eosinophil count but has no effect on IR at the community level. In helminth-infected subjects, treatment significantly increases IR, highlighting the need for metabolic health monitoring with ongoing deworming programs. ISRCTN 75636394.

High salt intake does not aggravate glucose dysregulation and dyslipidemia induced by estrogen-progestin oral contraceptive

BackgroundEstrogen-progestogen combined oral contraceptive (OC) use has been associated with increased cardiometabolic risk factors, including glucose dysregulation, dyslipidemia, hypertension, and pro-inflammatory state. However, the effect of a high-salt diet on these risk factors during OC use is not yet investigated. We therefore hypothesized that a high-salt diet would increase cardiometabolic risk factors in female rats treated with a combination of OC steroids, levonorgestrel (L) and ethinylestradiol (EE), and that elevated plasma levels of pro-inflammatory markers are associated with the cardiometabolic effects. MethodsFemale Wistar rats were given (p.o.) vehicle, high-dose (1.0μg EE plus 5.0μgL) or low-dose (0.1μg EE plus 0.5μgL) OC with or without a high-salt diet (8%) daily for 8 weeks. Insulin resistance (IR) was estimated using the homeostatic model of assessment (HOMA). ResultsResults showed that OC treatment or high salt diet led to significant increases in insulin resistance, plasma insulin, total cholesterol (TC), triglyceride (TG), TC/HDL-cholesterol, uric acid levels, and decreased glucose tolerance. OC treatment but not a high-salt diet resulted in increased plasma C-reactive protein and TG/HDL-cholesterol. However, a high-salt diet did not aggravate the effects of OC treatment. ConclusionThe results from the present study indicate that glucose dysfunction and dyslipidemia induced by OC use, but not those induced by increased dietary salt are associated with elevated plasma C-reactive protein. Besides, increased dietary salt does not worsen abnormal cardiometabolic impact of OC use.

Adiposity-independent hypoadiponectinemia as a potential marker of insulin resistance and inflammation in schizophrenia patients treated with second generation antipsychotics

ObjectiveThe purpose of this study was to explore body fat independent effect of second generation antipsychotics (SGAs) on measures of glucose and adipokine homeostasis, and markers of inflammation. MethodEight non-diabetic men with schizophrenia (age: 55±3years, BMI: 29.7±1.2kg/m2) on SGAs were studied after an overnight fast. DXA and single-cut CT of abdomen were respectively used for the assessment of total body and abdominal fat. Blood samples were collected for measurements of glucose, insulin, leptin, adiponectin, C-reactive protein (CRP), and TNF-α. Data in schizophrenic subjects were compared to eight age (55±2.8years) and BMI (29.6±1.1kg/m2) matched healthy men. ResultsThe results were significant for markedly decreased serum adiponectin in schizophrenia patients (4.6±0.9 vs 11.1±1.5ng/mL, p=0.001). Lower levels of adiponectin in schizophrenia men were associated with significant increases in insulin resistance (4.2±0.7 vs 1.7±0.4, p=0.004), CRP (3.5±1.2 vs 1.2±0.3, p=0.037), and leptin (12±1.4 vs 8.5±1.4ng/mL, p=0.05). Various measures of adiposity, including fat mass index (FMI) and abdominal fat were not different in the two study groups. ConclusionsThese findings in the context of comparable age and total body/abdominal fat mass are assumed to be either disease specific, and/or treatment inflicted. The definitive invoking etiology and a presumptive role of hypoadiponectinemia in the development of insulin resistance and increased risk of inflammation warrant future investigation.

Study of markers of atherosclerosis including insulin resistance in patients with chronic renal failure

Objectives: The present study was designed to assess the markers of atherosclerosis including Insulin resistance (IR) in na?ve patients with chronic renal failure (CRF). Methods: Eighty consecutive na?ve patients with CRF were taken up for study. They were divided into non-diabetic group, Group A (N = 50) and diabetic group, Group B (N = 30). Twenty healthy individuals were taken as controls, Group C (N = 20). Patients undergoing renal replacement therapy, having chronic liver disease and with concomitant acute or chronic infection were excluded from the study. Routine hemogram, fasting plasma glucose, fasting serum insulin ,lipid profile, renal function tests, C-reactive protein (CRP), serum uric acid levels, ultrasound of abdomen and ultrasound B scan for carotid intima medial thickness (CIMT) were done for all patients and control. The data collected were analyzed to inter-correlate the parameters using SPSS 16. Results: On comparing parameters between the three groups, values of HOMA-IR, CRP, uric acid, VLDL and CIMT were significantly higher in Groups A and B than Group C whereas values of HOMA-B, HDL and LDL were lower in both groups A and Bas compared to group C. HOMA-IR had significant negative correlation with creatinine clearance (Crcl) (r = -0.449, p = 0.01) in Group A and (r = -0.483, p = 0.007) in Group B. HOMA-IR had significant positive correlation with CIMT (r = 0.413, p = 0.03) in Group A and (r = 0.581, p = 0.001) in Group B. Crcl had significant negative correlation with CIMT(r = -0.375, p = 0.007) in Group A and (r = -0.705, p = 0.001) in Group B. Crclnegatively correlated with C-reactive protein (r = -0.460, p = 0.001) in Group A and (r = 0.431, p = 0.01) in Group B. HOMA-B positively correlated with Crcl (r = 0.667, p = 0.001) and also with CIMT (r = -0.531, p = 0.003) among Group B individuals. Conclusion: There is a significant increase in insulin resistance (IR) and β cell dysfunction in patients with CRF. Also IR linearly increases with reduction in renal function. CRP and uric acid are also significantly increased, reflecting the existence of a chronic inflammatory milieu in these patients. All these factors contribute to accelerated atherosclerosis, signifying CRF per se is independent risk factor for atherosclerosis.

Association of visceral and subcutaneous fat with glucose intolerance, insulin resistance, adipocytokines and inflammatory markers in Asian Indians (CURES-113)

Objectives: The aim of the study was to assess the association between visceral and subcutaneous fat with glucose intolerance, adipocytokines, inflammatory markers and carotid IMT in Asian Indians. Design and methods: Subjects with NGT ( n = 85), IGT ( n = 49) and T2DM ( n = 93) were randomly selected from CURES. Total abdominal, visceral and subcutaneous fat were measured using Helical CT scan. Adiponectin, hs-CRP, TNF-alpha, oxidized LDL, visfatin and leptin and IMT and insulin resistance were assessed. Results: Total abdominal fat ( p = 0.041) and the visceral fat ( p = 0.039) but not subcutaneous fat progressively increased from NGT, IGT and T2DM subjects. With increasing quartiles of visceral fat, there was a significant increase in insulin resistance ( p = 0.040); significant decrease in adiponectin ( p = 0.043) and increase in TNF-alpha ( p = 0.028), hs-CRP ( p = 0.043), OX-LDL ( p = 0.034) and visfatin ( p = 0.040), and carotid IMT ( p = 0.047) was observed. Conclusion: Visceral fat levels increased with increasing glucose intolerance and are associated with decreased levels of adiponectin and increased levels of hs-CRP, TNF-alpha, oxidized LDL, visfatin, HOMA-IR and IMT.

17β-Estradiol treatment is unable to reproduce p85α redistribution associated with gestational insulin resistance in rats

Maternal metabolic adaptations are essential to ensure proper fetal development. According to changes in insulin sensitivity, pregnancy can be divided into two periods: early pregnancy, characterized by an increase in maternal insulin sensitivity, and late pregnancy, in which there is a significant increase in insulin resistance. The aims of the present work were two-fold: firstly, the molecular mechanisms associated with the development of pregnancy-related insulin resistance in peripheral tissues, mainly retroperitoneal adipose tissue and skeletal muscle, were studied in pregnant rats at 6, 11, and 16 days gestation. Secondly, the role of 17β-estradiol in this process was elucidated in an animal model consisting of ovariectomized rats treated with 17β-estradiol to mimic plasma gestational levels. The results support the conclusion that retroperitoneal adipose tissue plays a pivotal role in the decrease in insulin sensitivity during pregnancy, through a mechanism that involves p85α redistribution to the insulin receptor and impairment of Glut4 translocation to the plasma membrane. Treatment with 17β-estradiol did not reproduce the molecular adaptations that occur during pregnancy, suggesting that other hormonal factors presents in gestation but absent in our experimental model are responsible for p85α redistribution to the insulin receptor.

Growth and Growth Hormone Therapy in Subjects With Mulibrey Nanism

Mulibrey nanism is a monogenic disorder with prenatal-onset growth restriction, mild dysmorphic features, and a strong tendency for insulin resistance but no major neurologic handicap. Growth hormone therapy has been shown to promote short-term growth in children born small for gestational age, but the experience with long-term therapy is insufficient. Growth in patients with mulibrey nanism has not been analyzed previously in detail. We evaluated the natural growth pattern and long-term impact of growth hormone treatment in the largest cohort of subjects with mulibrey nanism to date. The study included 72 living subjects followed up to 30 years. Thirty (18 female) were treated with recombinant human growth hormone for a median period of 5.7 years. Patients were reviewed at baseline and every 6 to 12 months during the therapy. Evaluation included assessment of height, weight, and pubertal status and laboratory analyses. Glucose metabolism was evaluated by oral glucose-tolerance test. The patients were born small for gestational age with immature craniofacial features. They experienced a continuous deceleration in height (median decrement of 1.1 SDS) and weight for height (median reduction of 17%) in infancy followed by an incomplete catch-up growth lasting up to school age. The final adult height averaged 136 cm in girls and 150 cm in boys. Growth hormone treatment improved the prepubertal growth but had only little impact on adult height (+5 cm). The treated subjects showed earlier bone maturation and growth arrest but not a significant increase in insulin resistance. On the contrary, the subjects who were treated with growth hormone were slimmer and had less metabolic syndrome as young adults. The patients with mulibrey nanism showed a distinct postnatal growth pattern. The growth hormone treatment was safe and induced a good short-term effect, but the impact on the adult height remained modest.

TheAPOB-516C/T polymorphism is associated with differences in insulin sensitivity in healthy males during the consumption of diets with different fat content

Several apo B polymorphic sites have been studied for their potential use as markers for CHD in the population and for potential gene-diet interactions. Our aim was to determine whether the presence of the -516C/T polymorphism in the APOB gene promoter modifies insulin sensitivity to dietary fat. We studied fifty-nine healthy volunteers (thirty men and twenty-nine women, thirty-six homozygotes for the -516C allele (C/C) (nineteen males and seventeen females) and twenty-three heterozygotes for the -516T allele (C/T) (eleven males and twelve females)). Subjects consumed three diets during the feeding study, 4 weeks each: an SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate (CHO)-rich diet (30 % fat, 55 % CHO) or a MUFA-rich diet (38 % fat, 22 % MUFA) following a randomised cross-over design. For each diet, we investigated peripheral insulin sensitivity with the insulin suppression test. Male carriers of the -516T allele showed a significantly greater decrease in steady-state plasma glucose concentrations when changing from the SFA-rich diet (9.18 (sd 1.35) mmol/l) to the MUFA (6.55 (sd 0.74) mmol/l) or the CHO (6.31 (sd 0.93) mmol/l) diets than did those who were homozygous for the C allele (P = 0.040). Furthermore, C/T subjects presented higher plasma NEFA values after consumption of the SFA diet compared with the MUFA and CHO diets (P = 0.001). This effect was not observed in females (P = 0.908). Our findings show that male carriers of the -516T allele, C/T, have a significant increase in insulin resistance after consumption of all diets, but the difference is more exaggerated after the SFA diet compared with the MUFA- and CHO-rich diets.

Plasma leptin: Associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease

Background and aim Leptin, an adipocyte-derived protein, regulating food intake and metabolism has been implicated in the development of coronary heart disease. We have examined the relationship between leptin and vascular risk factors including insulin resistance, metabolic, inflammatory and haemostatic risk factors. Methods and results The study was carried out in 3640 non-diabetic men aged 60–79 years drawn from general practices in 24 British towns and who were not on warfarin. Leptin was strongly positively correlated with waist circumference ( r = 0.58; p < 0.0001). Leptin concentrations decreased significantly with increasing physical activity and were lowered in cigarette smokers and elevated in men with pre-existing coronary heart disease and stroke; alcohol intake showed no association with leptin concentration. After adjustment for waist circumference and these lifestyle factors, increased leptin was independently associated with significant increases in insulin resistance, triglycerides, inflammatory markers (interleukin-6, C-reactive protein, fibrinogen, plasma viscosity), coagulation factor VIII, endothelial markers von Willebrand factor, tissue plasminogen activator, and fibrin D-dimer levels; and a decrease in HDL-cholesterol. No association was seen between leptin and blood pressure, total cholesterol, glucose or white cell count after adjusting for waist circumference. Further adjustment for insulin resistance abolished the relationships between leptin and triglycerides and HDL-cholesterol, weakened the associations with the haemostatic factors although they remained significant, but made minor differences to the associations with inflammatory markers. Conclusion Plasma leptin is associated with insulin resistance, inflammation and disturbances in haemostasis independent of waist circumference, suggesting possible pathways by which leptin may influence risk of cardiovascular disease.

Effect of Behavioral Interventions on Insulin Sensitivity and Atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit

A previous study suggested that insulin metabolic variables play a role in the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. The present study sought to determine: 1) if young, individually caged WHHLs are insulin-resistant relative to New Zealand white (NZW) rabbits and 2) whether dietary or exercise interventions can improve insulin sensitivity and slow the development of atherosclerosis in these animals. Forty-two WHHLs were assigned to a dietary, exercise, or control condition, and 12 NZWs were used as a comparison control group. The intervention ran from 3 to 7 months of age, and all animals received an intravenous glucose tolerance test at the beginning and end of the intervention. WHHLs were insulin-resistant relative to NZWs at 3 months of age. Whereas the dietary intervention was effective in controlling insulin resistance, WHHLs in the exercise group without dietary restriction and the control group exhibited significant increases in insulin resistance. No intervention significantly influenced the progression of atherosclerosis. Young WHHLs are insulin-resistant during an early period when atherosclerosis is developing rapidly. Dietary restriction, but not exercise without weight control, is effective in controlling insulin metabolic variables in the WHHL model. Although dietary intervention can reduce cardiovascular risk factors such as insulin resistance, it is not effective in slowing the development of atherosclerosis in these genetically dyslipidemic animals. Similarly, exercise training, without dietary control, does not influence the progression of disease in WHHLs.

Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance.

Our primary objective was to evaluate changes in energy expenditure and body composition in women with normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM). A secondary objective was to examine the relationship between maternal leptin and nutrient metabolism. Fifteen obese women, eight with NGT and seven with GDM, were evaluated before conception (P), at 12-14 wk (E), and at 34-36 wk (L). Energy expenditure and glucose and fat metabolism were measured using indirect calorimetry. Basal hepatic glucose production was measured using [6,6-2H2]glucose and insulin sensitivity by euglycemic clamp. There was a significant increase (6.6 kg, P = 0.0001) in fat mass from P to L. There was a 30% (P = 0.0001) increase in basal O2 consumption (VO2, ml/min). There were no significant changes in carbohydrate oxidation during fasting or storage from P to L. There was, however, a significant (P = 0.0001) 150% increase in basal fat oxidation (mg/min) from P to L. Under hyperinsulinemic conditions, there were similar 25% increases in VO2 (P = 0.0001) from P to L in both groups. Because of the significant increases in insulin resistance from P to L, there was a significant (P = 0.0001) decrease in carbohydrate oxidation and storage. There was a net change from lipogenesis to lipolysis, i.e., fat oxidation (30-40 mg/min, P = 0.0001) from P to L. Serum leptin concentrations had a significant positive correlation with fat oxidation at E (r = 0.76, P = 0.005) and L (r = 0.72, P = 0.009). Pregnancy in obese women is associated with significant increases in fat mass and basal metabolic rate and an increased reliance on lipids both in the basal state and during the clamp. These modifications are similar in women with NGT and GDM. The increased reliance on fat metabolism is accompanied by a concomitant decrease in carbohydrate metabolism during hyperinsulinemia. The increase in fat oxidation may be related to increased maternal serum leptin.

Changes in the atherogenic risk factor profile according to degree of weight loss

Background: The atherogenic risk factor profile in obese subjects is characterised by hypertension, reduced high density lipoprotein (HDL) cholesterol, increased low density lipoprotein (LDL) cholesterol and triglycerides, and insulin resistance....

What's new in … Diabetes prevention and delivery of care

The worldwide prevalence of diabetes mellitus is projected to reach 5.4% (300 million individuals) by 2025, and the evolving pandemic of childhood obesity in Western countries has caused a significant increase in insulin resistance and type 2 diabetes. The potential societal impact is enormous, and growing appreciation of the scale of the problem is reflected in increasingly frequent public pronouncements by Western political leaders. There is an urgent need to develop and deploy systems for preventing the development of diabetes in individuals at risk, and for effective delivery of complex care to those who develop the condition.