Biomedical subjects

Peter J Havel

Publications and source records attributed to Peter J Havel.

At least 19 recordsLinked to original sources

PubMed2006

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+ CCR7- CD45RA- effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T(CM)) cells. In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Animals↗

PubMed2006

Serum adiponectin and coronary heart disease risk in older Black and White Americans.

CONTEXT: Adiponectin may influence the risk of coronary heart disease (CHD) independently of traditional cardiovascular risk factors. OBJECTIVE: Because body composition and adiponectin levels vary by race, we examined the relationship of adiponectin with prevalent and incident CHD in a cohort of older Black and White adults. DESIGN AND SETTING: We conducted a cross-sectional and prospective cohort study at two U.S. clinical centers. PARTICIPANTS: Participants included 3075 well-functioning adults between ages 70 and 79 yr enrolled in the Health, Aging, and Body Composition study. MAIN OUTCOME MEASURES: Prevalent CHD was defined as history of myocardial infarction, coronary artery bypass graft, percutaneous coronary transluminal angioplasty, angina, or major electrocardiogram abnormalities. After excluding those with prevalent CHD, incident CHD was defined as hospitalized myocardial infarction or CHD death. RESULTS: At baseline, 602 participants (19.6%) had CHD. During 6 yr of follow-up, 262 (10.6%) incident CHD events occurred. Whites had higher median adiponectin than Blacks (12 vs. 8 microg/ml, P < 0.001). Race modified the effect of adiponectin (P for interaction was 0.002 for prevalent CHD, and P = 0.02 for incident CHD). Among Whites, an inverse association of adiponectin with CHD was explained by high-density lipoprotein and glucose. Among Blacks, a doubling of adiponectin was associated with a 40% higher risk of both prevalent CHD (odds ratio, 1.41; 95% confidence interval, 1.11-1.78) and incident CHD (hazards ratio, 1.37; 95% confidence interval, 1.01-1.87) after adjusting for explanatory variables. CONCLUSION: High circulating concentrations of adiponectin were associated with higher risk of CHD in older Blacks, even accounting for traditional CHD risk factors.

Adiponectin↗

PubMed2006

The decrease in C-reactive protein concentration after diet and physical activity induced weight reduction is associated with changes in plasma lipids, but not interleukin-6 or adiponectin.

Subclinical inflammation is a risk factor for cardiovascular disease. The mechanisms underlying increased levels of inflammatory markers and their changes in response to weight loss are not fully understood yet. It has been proposed that elevated concentrations of C-reactive protein (CRP) are mediated by cytokines produced in adipose tissue. We investigated the changes in circulating CRP after weight reduction, in relation to parameters relevant to the metabolic syndrome. Forty 25- to 35-year-old obese female volunteers participated in an intervention program of dietary education and supervised physical activity for a period of 9 weeks. Anthropological parameters and biochemical measurements (high-sensitivity CRP [hsCRP], plasma lipoproteins, interleukin 6 [IL-6], adiponectin) were analyzed before and after the intervention. Body mass index decreased by more than 7% from 31.5 +/- 4.1 to 29.1 +/- 3.9. Plasma free fatty acid (FFA) concentrations decreased by 30%, high-density lipoprotein cholesterol increased by 8%, and fasting insulin concentrations decreased by 15%. There were no significant changes in either low-density lipoprotein cholesterol or triacylglycerol concentrations. Subcutaneous and visceral adipose tissue mass decreased by 12% and 18%. High-sensitivity CRP concentrations decreased by 30%; however, mean plasma IL-6 and adiponectin concentrations remained unchanged. In linear regression analysis, the changes in plasma hsCRP concentrations were associated with baseline hsCRP concentration, change in triacylglycerols and FFA concentrations, and in waist circumference. The decrease in hsCRP concentration after weight reduction does not appear to be mediated by decreases in circulating IL-6 or adiponectin concentrations; however, change in hsCRP concentration is related to changes in waist circumference and lipid metabolism, reflected by plasma triacylglycerol and FFA levels.

Adiponectin↗

PubMed2005

Administration of Lispro insulin with meals improves glycemic control, increases circulating leptin, and suppresses ghrelin, compared with regular/NPH insulin in female patients with type 1 diabetes.

CONTEXT: Overweight and obesity are overrepresented in adolescents with type 1 diabetes mellitus (T1DM). Exogenous insulin administration often poorly reproduces normal insulin patterns and may less effectively regulate leptin and ghrelin, two hormones involved in the control of appetite and adiposity. OBJECTIVE: The objective of the study was to determine whether insulin regimens that better replicate normal insulin patterns and augment postprandial nutrient disposal may help normalize leptin and ghrelin and improve body weight regulation. DESIGN, SETTING, AND PARTICIPANTS: Ten young women with T1DM were studied in this 2-wk prospective, balanced crossover-design study at the University of California, Davis. INTERVENTION: Participants received either a single injection of regular + NPH insulin (R+N) or two mealtime injections of Lispro insulin in randomized order on 2 separate days. Meal composition and total insulin administered were the same on both treatment days. MAIN OUTCOME MEASURES: Plasma glucose, insulin, leptin, and ghrelin concentrations were monitored over the 10-h study period. RESULTS: Lispro produced two distinct mealtime peaks of insulin, compared with one prolonged rise with R+N. Lispro reduced postprandial hyperglycemia and total glucose area under the curve. Leptin increased more on the Lispro (2.7 +/- 0.7 vs. 0.7 +/- 0.5 ng/ml, P = 0.02). Ghrelin was more suppressed after lunch with Lispro (P = 0.004). CONCLUSIONS: Injection of Lispro insulin with meals produces more physiological insulin patterns, better glucose control, and improved leptin and ghrelin regulation than R+N. More closely mimicking normal insulin, leptin, and ghrelin responses to meals with fast-acting insulin may have implications for body weight regulation in T1DM.

Adolescent↗

PubMed2005

Eicosapentaenoic fatty acid increases leptin secretion from primary cultured rat adipocytes: role of glucose metabolism.

Eicosapentaenoic acid (EPA), one of the n-3 polyunsaturated fatty acids, has been shown to stimulate leptin mRNA expression and secretion in 3T3-L1 cells. However, other studies have reported inhibitory effects of EPA on leptin expression and secretion in vivo and in vitro. To determine the direct effects of EPA on basal and insulin-stimulated leptin secretion, isolated rat adipocytes were incubated with EPA in the absence and presence of insulin. EPA (10, 100, and 200 microM) increased basal leptin gene expression and secretion (+43.8%, P < 0.05; +71.1%, P < 0.01; and +73.7%, P < 0.01, respectively). EPA also increased leptin secretion in the presence of 1.6 nM insulin; however, the effect was less pronounced than in the absence of it. Because adipocyte glucose and lipid metabolism are involved in the regulation of leptin production, the metabolic effects of this fatty acid were also examined. EPA (200 microM) increased basal glucose uptake in isolated adipocytes (+50%, P < 0.05). Anaerobic metabolism of glucose, as assessed by lactate production and proportion of glucose metabolized to lactate, has been shown to be inversely correlated to leptin secretion and was decreased by EPA in both the absence and presence of insulin. EPA increased basal glucose oxidation as determined by the proportion of (14)C-labeled glucose metabolized to CO(2). Lipogenesis ((14)C-labeled glucose incorporation into triglyceride) was decreased by EPA in the absence of insulin, whereas lipolysis (glycerol release) was unaffected. The EPA-induced increase of basal leptin secretion was highly correlated with increased glucose utilization (r = +0.89, P < 0.01) and inversely related to the anaerobic glucose metabolism to lactate. EPA's effect on insulin-stimulated leptin secretion was not related to increased glucose utilization but was inversely correlated with anaerobic glucose metabolism to lactate (r = -0.84, P < 0.01). Together, the results suggest that EPA, like insulin, stimulates leptin production by increasing the nonanaerobic/oxidative metabolism of glucose.

Adipocytes↗

PubMed2005

Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes: evidence for a skeletal muscle-to-fat signaling pathway.

Interleukin-15 (IL-15) is a cytokine which is highly expressed in skeletal muscle tissue, and which has anabolic effects on skeletal muscle protein dynamics both in vivo and in vitro. Additionally, administration of IL-15 to rats and mice inhibits white adipose tissue deposition. To determine if the action of IL-15 on adipose tissue is direct, the capacity of cultured murine 3T3-L1 preadipocytes and adipocytes to respond to IL-15 was examined. IL-15 administration inhibited lipid accumulation in differentiating 3T3-L1 preadipocytes, and stimulated secretion of the adipocyte-specific hormone adiponectin by differentiated 3T3-L1 adipocytes. The latter observation constitutes the first report of a cytokine or growth factor which stimulates adiponectin production. IL-15 mRNA expression by cultured 3T3-L1 adipogenic cells and C2C12 murine skeletal myogenic cells was also examined. Quantitative real-time PCR indicated IL-15 mRNA was expressed by C2C12 skeletal myogenic cells, and was upregulated more than 10-fold in differentiated skeletal myotubes compared to undifferentiated myoblasts. In contrast, 3T3-L1 cells expressed little or no IL-15 mRNA at either the undifferentiated preadipocyte or differentiated adipocyte stages. These findings provide support for the hypothesis that IL-15 functions in a muscle-to-fat endocrine axis which modulates fat:lean body composition and insulin sensitivity.

3T3-L1 Cells↗

PubMed2005

Consuming fructose-sweetened beverages increases body adiposity in mice.

OBJECTIVE: The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose. RESEARCH METHODS AND PROCEDURES: We compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice. RESULTS: Exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern. DISCUSSION: These data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

Adipose Tissue↗

PubMed2005

Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism.

Fructose intake and the prevalence of obesity have both increased over the past two to three decades. Compared with glucose, the hepatic metabolism of fructose favors lipogenesis, which may contribute to hyperlipidemia and obesity. Fructose does not increase insulin and leptin or suppress ghrelin, which suggests an endocrine mechanism by which it induces a positive energy balance. This review examines the available data on the effects of dietary fructose on energy homeostasis and lipid/carbohydrate metabolism. Recent publications, studies in human subjects, and areas in which additional research is needed are emphasized.

Beverages↗

PubMed2004

The yellow agouti mutation alters some but not all responses to diet and exercise.

OBJECTIVE: Effects of ectopic expression of the agouti signaling protein were studied on responses to diet restriction and exercise in C57BL/6J (B6) mice and obese B6 mice congenic for the yellow agouti mutation [B6.Cg-Ay (Ay)]. RESEARCH METHODS AND PROCEDURES: Adult male Ay mice were either kept sedentary or exercised on a running wheel and fed ad libitum or diet restricted until weight matched to ad libitum-fed B6 control mice. Body composition, plasma lipids, leptin, and adiponectin were measured. mRNA levels for leptin, adiponectin, lipoprotein lipase, and pyruvate dehydrogenase kinase 4 were measured in a visceral (epididymal) and a subcutaneous (femoral) fat depot by real-time polymerase chain reaction. RESULTS: Correlations among traits exhibited one of three patterns: similar lines for B6 and Ay mice, different slopes for B6 and Ay mice, and/or different intercepts for B6 and Ay mice. Correlations involving plasma leptin, mesenteric and epididymal adipose weights, or low-density lipoprotein-cholesterol were most likely to have different slopes and/or intercepts in B6 and Ay mice. mRNA levels for leptin, Acrp30, pyruvate dehydrogenase kinase 4, and lipoprotein lipase in epididymal adipose tissue were not correlated with corresponding levels in femoral adipose tissue. DISCUSSION: The agouti protein interferes with leptin signaling at melanocortin receptors in the hypothalamus of Ay mice. Our results are consistent with the hypothesis that the melanocortin portion of the leptin-signaling pathway mediates effects primarily on certain fat depots and on some, but not all, components of cholesterol homeostasis.

Adiponectin↗

PubMed2004

Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women.

Previous studies indicate that leptin secretion is regulated by insulin-mediated glucose metabolism. Because fructose, unlike glucose, does not stimulate insulin secretion, we hypothesized that meals high in fructose would result in lower leptin concentrations than meals containing the same amount of glucose. Blood samples were collected every 30-60 min for 24 h from 12 normal-weight women on 2 randomized days during which the subjects consumed three meals containing 55, 30, and 15% of total kilocalories as carbohydrate, fat, and protein, respectively, with 30% of kilocalories as either a fructose-sweetened [high fructose (HFr)] or glucose-sweetened [high glucose (HGl)] beverage. Meals were isocaloric in the two treatments. Postprandial glycemic excursions were reduced by 66 +/- 12%, and insulin responses were 65 +/- 5% lower (both P < 0.001) during HFr consumption. The area under the curve for leptin during the first 12 h (-33 +/- 7%; P < 0.005), the entire 24 h (-21 +/- 8%; P < 0.02), and the diurnal amplitude (peak - nadir) (24 +/- 6%; P < 0.0025) were reduced on the HFr day compared with the HGl day. In addition, circulating levels of the orexigenic gastroenteric hormone, ghrelin, were suppressed by approximately 30% 1-2 h after ingestion of each HGl meal (P < 0.01), but postprandial suppression of ghrelin was significantly less pronounced after HFr meals (P < 0.05 vs. HGl). Consumption of HFr meals produced a rapid and prolonged elevation of plasma triglycerides compared with the HGl day (P < 0.005). Because insulin and leptin, and possibly ghrelin, function as key signals to the central nervous system in the long-term regulation of energy balance, decreases of circulating insulin and leptin and increased ghrelin concentrations, as demonstrated in this study, could lead to increased caloric intake and ultimately contribute to weight gain and obesity during chronic consumption of diets high in fructose.

Adult↗

PubMed2004

Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism.

Hormones produced by adipose tissue play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. This review will address the biology, actions, and regulation of three adipocyte hormones-leptin, acylation stimulating protein (ASP), and adiponectin-with an emphasis on the most recent literature. The main biological role of leptin appears to be adaptation to reduced energy availability rather than prevention of obesity. In addition to the well-known consequences of absolute leptin deficiency, subjects with heterozygous leptin gene mutations have low circulating leptin levels and increased body adiposity. Leptin treatment dramatically improves metabolic abnormalities (insulin resistance and hyperlipidemia) in patients with relative leptin deficiency due to lipoatrophy. Leptin production is primarily regulated by insulin-induced changes of adipocyte metabolism. Dietary fat and fructose, which do not increase insulin secretion, lead to reduced leptin production, suggesting a mechanism for high-fat/high-sugar diets to increase energy intake and weight gain. ASP increases the efficiency of triacylglycerol synthesis in adipocytes leading to enhanced postprandial lipid clearance. In mice, ASP deficiency results in reduced body fat, obesity resistance, and improved insulin sensitivity. Adiponectin production is stimulated by thiazolidinedione agonists of peroxisome proliferator-activated receptor-gamma and may contribute to increased insulin sensitivity. Adiponectin and leptin cotreatment normalizes insulin action in lipoatrophic insulin-resistant animals. These effects may be mediated by AMP kinase-induced fat oxidation, leading to reduced intramyocellular and liver triglyceride content. The production of all three hormones is influenced by nutritional status. These hormones, the pathways controlling their production, and their receptors are promising targets for managing obesity, hyperlipidemia, and insulin resistance.

Adipocytes↗

PubMed2004

A scientific review: the role of chromium in insulin resistance.

Chromium is an essential mineral that appears to have a beneficial role in the regulation of insulin action and its effects on carbohydrate, protein and lipid metabolism. Chromium is an important factor for enhancing insulin activity. Studies show that people with type 2 diabetes have lower blood levels of chromium than those without the disease. Insulin resistance is the common denominator in a cluster of cardiovascular disease risk factors. One out of every five Americans has metabolic syndrome. It affects 40% of people in their 60s and 70s. Insulin resistance, with or without the presence of metabolic syndrome, significantly increases the risk of cardiovascular disease. Insulin resistance is present in two serious health problems in women; polycystic ovarian syndrome (PCOS) and gestational diabetes. Several studies have now demonstrated that chromium supplements enhance the metabolic action of insulin and lower some of the risk factors for cardiovascular disease, particularly in overweight individuals. Chromium picolinate, specifically, has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type 2 diabetes. Dietary chromium is poorly absorbed. Chromium levels decrease with age. Supplements containing 200-1,000 mcg chromium as chromium picolinate a day have been found to improve blood glucose control. Chromium picolinate is the most efficacious form of chromium supplementation. Numerous animal studies and human clinical trials have demonstrated that chromium picolinate supplements are safe.

Animals↗

PubMed2003

Effects of inhibiting transcription and protein synthesis on basal and insulin-stimulated leptin gene expression and leptin secretion in cultured rat adipocytes.

We have previously reported that glucose metabolism mediates the effects of insulin to increase leptin gene expression and leptin secretion by isolated adipocytes. The aim of the present study was to investigate the role of transcription and translation in the regulation of basal and insulin-stimulated leptin production. The short-term (4 h) and long-term (24-48 h) effects of actinomycin D, a transcriptional inhibitor, and cycloheximide, an inhibitor of protein synthesis, on leptin gene expression and leptin secretion by isolated adipocytes were determined. Actinomycin D (5 microg/ml) increased both basal and insulin-stimulated (1.6 nM) leptin secretion at 4 and 24h (193+/-14.9% and 153.8+/-10.4% of respective controls at 24h, both p<0.001). Similar effects of actinomycin D were observed on basal and insulin-stimulated leptin mRNA levels. 5,6-dichlororibofuranosyl benzimidazole (DRB), another inhibitor of transcription, also increased basal (175.4+/-18.2% of control; p<0.01) and insulin-stimulated leptin secretion (141.0+/-11.1% of insulin-treated cells; p<0.05) at 24 h. The effect of actinomycin D and DRB to increase basal leptin secretion observed at 4 and 24 h was not present at 48 h when actinomycin D and DRB both markedly inhibited insulin-stimulated leptin secretion (to 36+/-16%, p<0.05 and 21.9+/-5.6% of control, for actinomycin D and DRB, respectively, both p<0.001). Neither actinomycin D nor DRB had any effect on adipocyte glucose utilization between 24 and 48 h. The observed effects of inhibitors of transcription on leptin gene expression and leptin secretion are consistent with a long-term transcriptional mechanism for insulin-stimulated glucose metabolism to increase leptin production. Cycloheximide treatment (10 microg/ml) abolished the effects of insulin to stimulate leptin secretion (29+/-11% of control, p<0.01) during the first 4 h of treatment and at all later time points, which indicate that de novo protein synthesis is required for insulin-mediated glucose metabolism to increase leptin secretion.

Adipocytes↗

PubMed2003

Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects.

We examined fasting plasma insulin, acylation-stimulating protein (ASP), leptin, adiponectin, ghrelin, and metabolic/cardiovascular risk profile before and 15 +/- 6 months after isolated Roux-en-Y gastric bypass surgery in 50 morbidly obese subjects. Average preoperative plasma lipids were mostly normal, whereas ASP, insulin, and leptin were elevated, and adiponectin and ghrelin were decreased. Postoperatively, body weight decreased significantly (-36.4 +/- 9.6%) and was best predicted by preoperative adiponectin concentration in weight-stable subjects (r = -0.59; P = 0.02). Plasma lipids and insulin resistance improved, leptin and ASP decreased (-76.3 +/- 14.6% and -35.9 +/- 52.2%; P < 0.001), and adiponectin increased (50.1 +/- 47.0%; P < 0.001). The decrease in apolipoprotein B was best predicted by the decrease in ASP (r = 0.55; P = 0.009), whereas the improved postoperative insulin sensitivity was best predicted by the increase in adiponectin (r = 0.70; P = 0.01). Despite bypassing 95% of the stomach and isolating the fundus from contact with ingested nutrients, circulating ghrelin did not decrease after surgery. In fact, plasma ghrelin increased postoperatively in the subset of subjects undergoing active weight loss (+60.5 +/- 23.2%; P < 0.001); ghrelin, however, remained unchanged in weight-stable subjects. In summary, 1) preoperative adiponectin concentrations may be predictive of the extent of weight loss; 2) changes in ASP and adiponectin are predictive of decreased apolipoprotein B and improved insulin action, respectively; and 3) plasma ghrelin increases after gastric bypass surgery in patients experiencing active weight loss.

Adiponectin↗

PubMed2003

Adiponectin is present in cord blood but is unrelated to birth weight.

OBJECTIVE: In adults, adiponectin is reduced in association with excess adiposity, type 2 diabetes, and hyperinsulinemia. We assessed whether adiponectin was 1) present in the fetal circulation, 2) altered in the fetal circulation in the presence of maternal diabetes, and 3) had relations to fetal cord blood insulin or adiposity. RESEARCH DESIGN AND METHODS: We assessed adiponectin in cord blood in a large cohort of singleton offspring of diabetic mothers (ODM; n = 134) and control mothers (n = 45). RESULTS: Adiponectin was present in cord blood and, in ODM, was higher in those delivered at later gestational ages (Spearman r = 0.18, P = 0.03). Adiponectin was slightly lower in ODM than control subjects (ODM 19.7 +/- 6.1 vs. control 21.8 +/- 5.3 micro g/ml; P = 0.04), although this difference could potentially reflect different gestational ages in the two groups (ODM 37.6 +/- 1.5 and control 40.1 +/- 1.1 weeks). In contrast to adults, adiponectin levels in the fetus were unrelated to the degree of adiposity, blood insulin, or leptin in either control subjects or ODM. CONCLUSIONS: Adiponectin is present in cord blood but does not show expected physiological relations with adiposity as observed in adults.

Adiponectin↗

PubMed2002

Differential impairment of glucagon responses to hypoglycemia, neuroglycopenia, arginine, and carbachol in alloxan-diabetic mice.

To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P <.05). In contrast, the glucagon response to arginine (0.25 g/kg intravenously [IV]) was not reduced after 1, 6, or 12 weeks of diabetes, ruling out a generalized impairment of the A-cell responses. The glucagon response to the neuroglucopenic agent, 2-deoxyglucose (2-DG; 500 mg/kg IV) was impaired, like that to insulin-induced hypoglycemia, after 6 and 12 weeks of diabetes (P <.05), suggesting that supersensitivity to the potential inhibitory effects of exogenous insulin is not the mechanism responsible for the impairment. Finally, the glucagon response to the cholinergic agonist, carbachol (0.53 micromol/kg IV), was not impaired in the diabetic animals, arguing against a defect in the A-cell's responsiveness to autonomic stimulation. The data suggest that the impairment of the glucagon response to insulin-induced hypoglycemia in alloxan diabetic mice is not due to a generalized impairment of A-cell responsiveness, to desensitization by a suppressive action of insulin, or to impairment of the A-cell response to autonomic stimuli. The remaining mechanisms which are likely to explain the late loss of the glucagon response to insulin-induced hypoglycemia include (1) a defect in the A-cell recognition of glucopenic stimuli, or (2) a defect in the autonomic inputs to the A cell that are known to be activated by glucopenic stimuli.

Animals↗

PubMed2002

Evidence that tumor necrosis factor-alpha-induced hyperinsulinemia prevents decreases of circulating leptin during fasting in rats.

Administration of tumor necrosis factor-alpha (TNF-alpha) acutely increases leptin gene expression and circulating leptin concentrations in rodents and humans. Since TNF-alpha also induces hyperinsulinemia, and because insulin is a potent stimulator of leptin production, we hypothesized that elevated plasma insulin mediates TNF-alpha-induced increases of circulating leptin. To test this hypothesis, rats were made insulin-deficient with streptozotocin (STZ) and treated with subcutaneous implants that released insulin at a constant rate and thereby "clamped" insulin levels. STZ-diabetic and nondiabetic rats were injected with TNF-alpha or vehicle; plasma leptin, insulin, and glucose concentrations were measured during an initial 12-hour postinjection period of fasting and after a subsequent 12-hour period of refeeding. Food intake during the 12 hours after fasting was assessed as a physiologic correlate of changes in leptin concentrations. In nondiabetic rats, TNF-alpha increased plasma insulin (P =.016) and prevented the fasting-induced decrease of circulating leptin (P =.004) over the initial 12 hours compared with vehicle. Food intake during the refeeding period was 30% lower (P =.008) when the nondiabetic animals were injected with TNF-alpha. In contrast, TNF-alpha did not affect leptin concentrations in STZ-diabetic animals with clamped plasma insulin levels or their food intake during the refeeding period. These results suggest that TNF-alpha-induced hyperinsulinemia likely mediates the stimulatory effect of TNF-alpha on circulating leptin in vivo. Elevated leptin levels may in turn contribute to the effect of TNF-alpha to decrease food intake.

Animals↗

PubMed2002

Fructose, weight gain, and the insulin resistance syndrome.

This review explores whether fructose consumption might be a contributing factor to the development of obesity and the accompanying metabolic abnormalities observed in the insulin resistance syndrome. The per capita disappearance data for fructose from the combined consumption of sucrose and high-fructose corn syrup have increased by 26%, from 64 g/d in 1970 to 81 g/d in 1997. Both plasma insulin and leptin act in the central nervous system in the long-term regulation of energy homeostasis. Because fructose does not stimulate insulin secretion from pancreatic beta cells, the consumption of foods and beverages containing fructose produces smaller postprandial insulin excursions than does consumption of glucose-containing carbohydrate. Because leptin production is regulated by insulin responses to meals, fructose consumption also reduces circulating leptin concentrations. The combined effects of lowered circulating leptin and insulin in individuals who consume diets that are high in dietary fructose could therefore increase the likelihood of weight gain and its associated metabolic sequelae. In addition, fructose, compared with glucose, is preferentially metabolized to lipid in the liver. Fructose consumption induces insulin resistance, impaired glucose tolerance, hyperinsulinemia, hypertriacylglycerolemia, and hypertension in animal models. The data in humans are less clear. Although there are existing data on the metabolic and endocrine effects of dietary fructose that suggest that increased consumption of fructose may be detrimental in terms of body weight and adiposity and the metabolic indexes associated with the insulin resistance syndrome, much more research is needed to fully understand the metabolic effect of dietary fructose in humans.

Animals↗