Effect of ranolazine on glycaemic control in patients with type 2 diabetes treated with either glimepiride or metformin.

AIM: To report the results of two phase III trials assessing the efficacy of ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy. METHODS: In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: When added to glimepiride, ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference -0.11% (95% CI -0.31, 0.1)]. CONCLUSIONS: Compared with placebo, addition of ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of ranolazine added to metformin for glycaemic control can be identified remains unclear.

Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding.

Circulating triglycerides (TGs) normally increase after a meal but are altered in pathophysiological conditions, such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high-fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food-seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking.

Obesity development in caspase-1-deficient mice.

Caspase-1 is a member of the intracellular cysteine protease family that mediates inflammation through the activation of the cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). As mice lacking IL-18 become obese and insulin resistant, and both IL-18 and IL-1ß have a role in overall energy balance, we sought to determine whether caspase-1 deficiency also causes obesity. Male and female caspase-1-deficient (caspase-1-/-) and control (wild-type (WT)) mice were fed either a high-fat (HF, 45% of kcal) or a low-fat (LF, 10% of kcal) synthetic diet starting at 6 weeks of age. Caspase-1-/- mice maintained lower but detectable levels of IL-18 compared with WT mice. Plasma IL-1ß levels were below the detection limit for both KO and WT mice. Male caspase-1-/- mice gained extra fat mass by 16 weeks on the HF diet, but not until 40 weeks on the LF diet. Female capase-1-/- mice gained more fat by 28 weeks but only on the HF diet. These data indicate that caspase-1-/- mice develop obesity with an age and sex-dependent differences, and only male mice display obesity on LF diet. Overall, this study suggests that the lower level of IL-18 in caspase-1-/- mice might be causing obesity development similarly to IL-18-deficient mice.

Adults with type 1 diabetes eat a high-fat atherogenic diet that is associated with coronary artery calcium.

AIMS/HYPOTHESIS: Coronary heart disease is the leading cause of mortality among people with type 1 diabetes. Diet is an important lifestyle factor that relates to risk of CHD. The aim of this study was to examine how diet and adherence to dietary guidelines differ between adults with and without type 1 diabetes, and their correlation with CHD risk factors and coronary artery calcium (CAC). METHODS: The study involved 571 people with type 1 diabetes and 696 controls, aged 19 to 56 years, who were asymptomatic for CHD. CAC was measured by electron-beam computed tomography. RESULTS: Compared with the controls, adults with type 1 diabetes reported a diet higher in fat, saturated fat and protein but lower in carbohydrates. Fewer than half of those with type 1 diabetes met dietary guidelines for fat and carbohydrate intake, and only 16% restricted saturated fat to less than 10% of daily energy intake. Adults with type 1 diabetes were significantly less likely to meet dietary guidelines than controls. Fat and saturated fat intakes were positively correlated, but carbohydrate intake was negatively correlated with CHD risk factors and HbA(1c). A high-fat diet and higher intake of protein were associated with greater odds of CAC, while higher carbohydrate intake was associated with reduced odds of CAC. CONCLUSIONS/INTERPRETATION: Adults with type 1 diabetes reported consuming higher than recommended levels of fat and saturated fat. High fat intake was associated with increased CHD risk factors, worse glycaemic control and CAC. An atherogenic diet may contribute to the risk of CHD in adults with type 1 diabetes.

Obesity research in the next decade.

The obesity epidemic demands more insight into genetic predisposition, mechanisms, prevention and therapeutic interventions. Opinions about how to prioritize obesity research in the next decade are many and highly varied. However, in this article I have chosen three areas of focus that arguably should be at the top of the list. These include: (1) the physiologic basis of body weight and body fat regulation; (2) epigenetic mechanisms of energy balance; and (3) the prevention of obesity. The approach needs to be translational and bi-directional with a strong emphasis on basic science including studies of relevant gene expression and animal models of energy balance. Clinical research into mechanisms can challenge the existing paradigms that could direct research back to more basic understanding or to applications to populations at risk. Communication between scientists and physicians at the far end of the spectrum needs new and ongoing emphasis.

The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Individuals with type 1 diabetes have an increased incidence of coronary artery disease (CAD) and a higher risk of cardiovascular death compared with individuals of the same age in the general population. While chronic hyperglycaemia and insulin resistance partially explain excess CAD, little is known about the potential genetic determinants of accelerated coronary atherosclerosis in type 1 diabetes. The aim of the present study was to evaluate the association of apolipoprotein A-IV (APOA4) polymorphisms with coronary artery calcification (CAC) progression, a marker of subclinical atherosclerosis. SUBJECTS AND METHODS: Two previously well-studied functional APOA4 polymorphisms resulting in the substitution of the amino acid Thr for Ser at codon 347 and Gln for His at codon 360 were genotyped in 634 subjects with type 1 diabetes and 739 non-diabetic control subjects, the participants of the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. RESULTS: The His360 allele was associated with a significantly higher risk of CAC progression among patients with type 1 diabetes (33.7 vs 21.2%, p=0.014), but not in the control subjects (14.1 vs 11.1%, p=0.42). Logistic regression analysis confirmed that the presence of the APOA4 His360 allele predicts an increased risk of progression of coronary atherosclerosis in adults with type 1 diabetes of long duration (odds ratio = 3.3, p=0.003 after adjustment for covariates associated with CAD risk). CONCLUSIONS /INTERPRETATION: This is the first report suggesting an association between the APOA4 Gln360His polymorphism and risk of CAC progression in subjects with type 1 diabetes. Additional studies are needed to explore potential interactions between APOA4 genotypes and metabolic/oxidative stress components of the diabetic milieu leading to rapid progression of atherosclerosis.

Lipid metabolism and nutrient partitioning strategies.

The increasing prevalence of overweight and obesity worldwide is daunting and requires prompt attention by the affected, health care profession, government and the pharmaceutical industry. Because overweight/obesity are defined as an excess of adipose tissue mass, all approaches in prevention and treatment must consider redirecting lipid storage in adipose tissue to oxidative metabolism. Lipid partitioning is a complex process that involves interaction between fat and other macronutrients, particularly carbohydrate. In an isocaloric environment, when fat is stored carbohydrate is oxidized and vice versa. Processes that influence fat partitioning in a manner in which weight is maintained must be modified by changes in organ-specific fat transport and metabolism. When therapy is considered, however, changes in lipid partitioning alone will be ineffective unless a negative energy balance is also achieved, i.e. energy expenditure exceeds energy intake. The intent of this review is to focus on molecules including hormones, enzymes, cytokines, membrane transport proteins, and transcription factors directly involved in fat trafficking and partitioning that could be potential drug targets. Some examples of favorably altering body composition by systemic and/or tissue specific modification of these molecules have already been provided with gene knockout and/or transgenic approaches in mice. The translation of this science to humans remains a challenging task.

Measurement of abdominal fat by CT compared to waist circumference and BMI in explaining the presence of coronary calcium.

OBJECTIVE: To evaluate the association between standard and computed tomography (CT)-based measures of obesity and subclinical atherosclerosis, defined as coronary artery calcium (CAC) by Electron Beam Computed Tomography (EBCT). DESIGN: Cross-sectional, observational study of anthropometric and CT obesity measures and presence of CAC. SUBJECTS: Participants were 383 men and 379 women, aged 20-58 y and asymptomatic for coronary artery disease (CAD). MEASUREMENTS: Intra-abdominal fat (IAF) and subcutaneous fat (SQF) were measured at the level of lumbar 2-3 and 4-5 spaces, using EBCT. Body mass index (BMI) was calculated from height and weight, and minimum waist circumference and maximum hip circumference were measured. CAC was measured by EBCT. RESULTS: In both men and women, BMI, waist circumference, IAF, and SQF were significantly related to CAC. However, BMI or waist circumference explained variation in the presence of CAC as well as IAF or SQF, univariately and after adjustment for additional cardiovascular risk factors. CONCLUSION: CT-based obesity exposure measures are not superior to BMI or waist circumference in association studies of subclinical CAD.

Sciatic nerve lipoprotein lipase is reduced in streptozotocin-induced diabetes and corrected by insulin.

The metabolic abnormalities underlying the cause of diabetic neuropathy have been the subject of much debate. Lipoprotein lipase (LPL) is a 56-kDa enzyme produced by several tissues in the body and has recently been shown in vitro to be expressed in cultured Schwann cells, where it is important in phospholipid synthesis. This suggests a role for LPL in myelin biosynthesis in the peripheral nervous system. The aim of this study was to determine if acute streptozotocin (STZ)-induced diabetes reduces the expression and regulation of sciatic nerve LPL in vivo. Adult Sprague Dawley rats were rendered diabetic via an sc injection of STZ. A decrease in sciatic nerve LPL activity was observed in the STZ-treated rats after just 2 d of diabetes and remained significantly reduced for at least 35 d. The decrease in LPL activity coincided temporally with a drop in motor nerve conduction velocity. Treatment with insulin for 4 d showed a normalization of sciatic nerve LPL activity. These results show that STZ-induced diabetes causes a decrease in LPL activity in the sciatic nerve that, as in other tissues, is reversible with insulin treatment. These data may suggest a role for LPL in the pathophysiology of diabetic neuropathy.

Dietary protein and weight reduction: a statement for healthcare professionals from the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association.

High-protein diets have recently been proposed as a "new" strategy for successful weight loss. However, variations of these diets have been popular since the 1960s. High-protein diets typically offer wide latitude in protein food choices, are restrictive in other food choices (mainly carbohydrates), and provide structured eating plans. They also often promote misconceptions about carbohydrates, insulin resistance, ketosis, and fat burning as mechanisms of action for weight loss. Although these diets may not be harmful for most healthy people for a short period of time, there are no long-term scientific studies to support their overall efficacy and safety. These diets are generally associated with higher intakes of total fat, saturated fat, and cholesterol because the protein is provided mainly by animal sources. In high-protein diets, weight loss is initially high due to fluid loss related to reduced carbohydrate intake, overall caloric restriction, and ketosis-induced appetite suppression. Beneficial effects on blood lipids and insulin resistance are due to the weight loss, not to the change in caloric composition. Promoters of high-protein diets promise successful results by encouraging high-protein food choices that are usually restricted in other diets, thus providing initial palatability, an attractive alternative to other weight-reduction diets that have not worked for a variety of reasons for most individuals. High-protein diets are not recommended because they restrict healthful foods that provide essential nutrients and do not provide the variety of foods needed to adequately meet nutritional needs. Individuals who follow these diets are therefore at risk for compromised vitamin and mineral intake, as well as potential cardiac, renal, bone, and liver abnormalities overall.

Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome.

OBJECTIVE: To examine the relationships between protease inhibitor (PI) therapy, body fat distribution and metabolic disturbances in the HIV lipodystrophy syndrome. DESIGN: Cross-sectional study. SETTING: HIV primary care practices. PATIENTS: PI-treated patients with lipodystrophy (n= 14) and PI-treated (n= 13) and PI-naive (n= 5) patients without lipodystrophy. MAIN OUTCOME MEASURES: Body composition was assessed by physical examination, dual-energy X-ray absorptiometry and computed tomography. Insulin sensitivity (SI) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. Lipid profiles, other metabolic parameters, duration of HIV infection, CD4 lymphocyte counts, HIV-1 RNA load and resting energy expenditure (REE) were also assessed. RESULTS: PI-treated patients with lipodystrophy were significantly less insulin sensitive than PI-treated patients and PI-naive patients without any changes in fat distribution (SI(22) x 10(-4) (min(-1)/microU/ml) versus 3.2 x 10(-4) and 4.6 x 10(-4) (min(-1)/microU/ml), respectively; P < 0.001). Visceral adipose tissue area and other measures of central adiposity correlated strongly with metabolic disturbances as did the percent of total body fat present in the extremities; visceral adipose tissue was an independent predictor of insulin sensitivity and high density lipoprotein cholesterol levels. REE per kg lean body mass was significantly higher in the group with lipodystrophy compared to the groups without lipodystrophy (36.9 versus 31.5 and 29.4 kcal/kg lean body mass; P < 0.001), and SI was strongly correlated with and was an independent predictor of REE in this population. CONCLUSIONS: Body fat distribution and metabolic disturbances are strongly correlated in the HIV lipodystrophy syndrome and REE is increased.

A lipoprotein-containing particle is transferred from the serum across the mammary epithelium into the milk of lactating mice.

To investigate the role of low-density lipoprotein (LDL) in the delivery of cholesterol to the mammary gland during pregnancy and lactation, we examined the distribution of radioactivity from (125)I-tyramine cellobiose-LDL injected into the tail vein of female mice at various stages of the reproductive cycle. Changes in the proportion of isotope taken up by the mammary gland largely reflected the increased weight of the gland in pregnancy and lactation. In addition, during lactation, radioactivity was found in the milk and was associated with a protein of the molecular weight of apoB-100. Quantitatively similar results were obtained with mice homozygous for disruption of the LDL receptor gene (LDLR null). Analysis of endogenous lipoproteins showed that the milk lipoprotein particles were denser than the corresponding serum lipoproteins and largely depleted of triglyceride and cholesterol. Using fluorescence microscopy we visualize the sorting of apoB protein from the LDL lipid phase at the basal surface of the mammary epithelial cell of both wild-type and LDLR-null mice. Our findings provide evidence that the mammary epithelium of the lactating mouse is able to take up LDL from the plasma by a non-LDLR-mediated process. An apoB-containing particle from which the cholesterol has been removed is transferred into milk.

Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance.

Lipoprotein lipase (LPL) plays a rate-limiting role in triglyceride-rich lipoprotein metabolism and is expressed in most tissues. Overexpression of LPL in skeletal muscle has been linked with higher plasma glucose levels suggesting insulin resistance (Jensen et al., Am J Physiol 273:R683-R689, 1997). The aim of our study was to ascertain whether the overexpression of human LPL in skeletal muscle leads to insulin resistance and to investigate the mechanism. Respiratory quotient measurements in both transgenic (MCKhLPL) and nontransgenic mice on a high-carbohydrate diet were conducted and showed a shift in fuel usage in transgenic mice when fasting but not when actively feeding. An increase in citrate and glucose 6-phosphate levels in fasted MCKhLPL mice further supports this preferential use of lipids. When challenged with an intraperitoneal injection of glucose (1 g/kg), MCKhLPL mice had a higher plasma glycemic excursion than nontransgenic mice. No differences in insulin response were observed between the two groups. Further investigation using hyperinsulinemic-euglycemic clamps revealed insulin resistance in MCKhLPL mice. Despite signs of insulin resistance, there was no associated increase in free fatty acids, hypertriglyceridemia, or hyperinsulinemia in MCKhLPL mice. In conclusion, MCKhLPL mice are insulin resistant, presumably due to increased delivery of lipoprotein-derived fatty acids to muscle.

Occasional physical inactivity combined with a high-fat diet may be important in the development and maintenance of obesity in human subjects.

BACKGROUND: A better understanding of the environmental factors that contribute to obesity is imperative if any therapeutic effect on the increasing prevalence of overweight and obesity in the United States is to be achieved. OBJECTIVE: This study examined the effect of the interaction of diet composition and physical inactivity on energy and fat balances. DESIGN: Thirty-five normal-weight and obese subjects were randomly assigned to either a 15-d isoenergetic high-carbohydrate (HC) or high-fat (HF) diet according to a crossover design. During the first 14 d, body weight and physical activity were maintained. On day 15, subjects spent 23 h in a whole-room indirect calorimeter and were fed a diet similar to that consumed during the previous 7 d while remaining physically inactive. RESULTS: Energy intakes required to maintain body weight stability during the first 14 d were similar between diets. Normal-weight and obese subjects consuming both diets had a positive energy balance on the sedentary day (day 15), suggesting that subjects were less active in the calorimeter. There was no significant effect of diet composition on total energy balance and total protein-energy balance on day 15; however, carbohydrate balance was more positive with the HC (2497.8 +/- 301.2 kJ) than with the HF (1159 +/- 301.2 kJ) diet (P = 0.0032). Most importantly, fat balance was more positive with the HF (1790.8 +/- 510.4 kJ) than with the HC (-62.8 +/- 510.4 kJ) diet (P = 0.0011). CONCLUSION: Chronic consumption of a high-carbohydrate diet could provide some protection against body fat accumulation in persons with a pattern of physical activity that includes frequent sedentary days.

Metabolic effects of rexinoids: tissue-specific regulation of lipoprotein lipase activity.

Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.