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Obesity, Leptin, K-ATP Channels and Type 2 Diabetes....


Resistin Is an Inflammatory Marker of Atherosclerosis in Humans (Circulation [2005]111:932-939.) Background— Resistin, a plasma protein, induces insulininsulin-resistant rodents and resistance in rodents. Recent reports suggest that circulating levels of resistin are elevated in obese and humans. Whereas rodent resistin is made in adipocytes,adipocyte and macrophage macrophages are a major source of human resistin. Given the convergence of function, resistin mayResults— We examined provide unique insight into links between obesity, inflammation, and atherosclerosis in humans. Methods and whether plasma resistin(CAC), a quantitative index levels were associated with metabolic and inflammatory markers, as well as with coronary artery calcification of atherosclerosis, in 879 asymptomatic subjects in the Study of Inherited Risk of Coronary Atherosclerosis. Resistin levels were positively associated with levels of inflammatoryand lipoprotein-associated phospholipase markers, including soluble tumor necrosis factor-alpha receptor-2 (P<0.001), interleukin-6 (P=0.04), Aratio and 95% confidence interval in 2 (P=0.002), but not measures of insulin resistance in multivariable analysis. Resistin levels also were associated (odds ordinal regression)1.52], P=0.03) and further control for with increasing CAC after adjustment for age, sex, and established risk factors (OR, 1.23 [CI, 1.03 to metabolic syndrome and plasma C-reactive proteinmetabolic syndrome, resistin levels (CRP) levels (OR, 1.25 [CI, 1.04 to 1.50], P=0.01). In subjects with further predicted CAC,inflammation and are predictive of whereas CRP levels did not. Conclusions— Plasma resistin levels are correlated with markers of coronary atherosclerosisinflammation, and atherosclerosis. in humans, independent of CRP. Resistin may represent a novel link between metabolic signals, Further studies are needed to define the relationship of resistin to clinical cardiovascular disease.
Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species (Am J Physiol Heart Circ Physiol [2005]288:H854-H860)Insulin resistance (IR) and associated hyperinsulinemia are major risk factors for coronary artery disease. Mechanisms linking hyperinsulinemia to coronary vascular dysfunction in IR are unclear. We evaluated insulin-induced vasodilation in isolated small coronary arteries (SCA; ~225 Ám) of Zucker obese (ZO) and control Zucker lean (ZL) rats. Vascular responses to insulin (0.1–100 ng/ml), ACh (10–9–10–5 mol/l), and sodium nitroprusside (10–8–10–4 mol/l) were assessed in SCA by measurement of intraluminal diameter using videomicroscopy. Insulin-induced dilation was decreased in ZO compared with ZL rats, whereas ACh and sodium nitroprusside elicited similar vasodilations. Pretreatment of arteries with SOD (200 U/ml), a scavenger of reactive oxygen species (ROS), restored the vasorelaxation response to insulin in ZO arteries, whereas ZL arteries were unaffected. Pretreatment of SCA with N-nitro-L-arginine methyl ester (100 Ámol/l), an inhibitor of endothelial nitric oxide (NO) synthase (eNOS), elicited a vasoconstrictor response to insulin that was greater in ZO than in ZL rats. This vasoconstrictor response was reversed to vasodilation in ZO and ZL rats by cotreatment of the SCA with SOD or apocynin (10 Ámol/l), a specific inhibitor of vascular NADPH oxidase. Lucigenin-enhanced chemiluminescence showed increased basal ROS levels as well as insulin (330 ng/ml)-stimulated production of ROS in ZO arteries that was sensitive to inhibition by apocynin. Western blot analysis revealed increased eNOS expression in ZO rats, whereas Mn SOD and Cu,Zn SOD expression were similar to ZL rats. Thus IR in ZO rats leads to decreased insulin-induced vasodilation, probably as a result of increased production of ROS by vascular NADPH oxidase, leading to decreased NO bioavailability, despite a compensatory increase in eNOS expression.
Osmotin Is a Homolog of Mammalian Adiponectin and Controls Apoptosis in Yeast through a Homolog of Mammalian Adiponectin Receptor (Molecular Cell [2005]17:171-181) The antifungal activity of the PR-5 family of plant defense proteins has been suspected to involve specific plasma membrane component(s) of the fungal target. Osmotin is a tobacco PR-5 family protein that induces apoptosis in the yeast Saccharomyces cerevisiae. We show here that the protein encoded by ORE20/PHO36 (YOL002c), a seven transmembrane domain receptor-like polypeptide that regulates lipid and phosphate metabolism, is an osmotin binding plasma membrane protein that is required for full sensitivity to osmotin. PHO36 functions upstream of RAS2 in the osmotin-induced apoptotic pathway. The mammalian homolog of PHO36 is a receptor for the hormone adiponectin and regulates cellular lipid and sugar metabolism. Osmotin and adiponectin, the corresponding “receptor” binding proteins, do not share sequence similarity. However, the ▀ barrel domain of both proteins can be overlapped, and osmotin, like adiponectin, activates AMP kinase in C2C12 myocytes via adiponectin receptors.
High intake of refined carbohydrate, particularly among overweight or obese women, is associated with hemorrhagic stroke risk (Am J Epidemiol [2005] 161(2):161-169) The associations of dietary carbohydrate, glycemic index, and glycemic load with stroke risk were examined among 78,779 US women who were free of cardiovascular disease and diabetes in 1980 and completed a food frequency questionnaire. During an 18-year follow-up, 1,020 stroke cases were documented (including 515 ischemic and 279 hemorrhagic). In analyses adjusting for nondietary risk factors and cereal fiber, carbohydrate intake was associated with elevated risk of hemorrhagic stroke when the extreme quintiles were compared (relative risk = 2.05, 95% confidence interval: 1.10, 3.83; ptrend = 0.02), but not with ischemic stroke. The positive association between carbohydrate intake and stroke risk was most evident among women with a body mass index of >=25 kg/m2. Likewise, dietary glycemic load was positively associated with total stroke among only those women whose body mass index was >=25 kg/m2. Cereal fiber intake was inversely associated with total and hemorrhagic stroke risk; for total stroke, relative risk = 0.66 (95% confidence interval: 0.52, 0.83; ptrend = 0.001) and for hemorrhagic stroke, relative risk = 0.51 (95% confidence interval: 0.33, 0.78; ptrend = 0.01). Findings suggest that high intake of refined carbohydrate is associated with hemorrhagic stroke risk, particularly among overweight or obese women. In addition, high consumption of cereal fiber was associated with lower risk of total and hemorrhagic stroke.
Interleukin-6 is a positive regulator of tumor necrosis factor -induced adipose-related protein in 3T3-L1 adipocytes" (FEBS Letters [2004] 560:153-157) Tumor necrosis factor (TNF)alpha induced adipose-related protein (TIARP) is a novel TNF-alpha-stimulated protein in adipocytes. Besides TNFalpha, interleukin (IL)-6 has recently been shown to be another adipocytokine implicated in insulin resistance. Therefore, the impact of IL-6 on TIARP gene expression in 3T3-L1 adipocytes was determined by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, TIARP mRNA expression was stimulated up to 3.8-fold by IL-6 in a dose-dependent fashion with significant stimulation detectable at effector concentrations as low as 3 ng/ml and maximal effects seen at 100 ng/ml IL-6. Induction of TIARP mRNA by IL-6 was time-dependent with significant upregulation occurring as early as 2 h after effector addition and maximal effects observed at 4 h. In parallel, TIARP protein synthesis was upregulated with maximal effects seen after 8 h of IL-6 treatment. Furthermore, the Janus kinase 2 inhibitor AG490 decreased TIARP mRNA expression. The increase of TIARP mRNA could be reversed by withdrawal of IL-6 for 24 h. Furthermore, TIARP mRNA induction by IL-6 was also seen in brown adipocytes but not in muscle and liver cells. Taken together, these results show that TIARP is acutely regulated in adipose tissue not only by TNFalphabut also by IL-6 which has been shown to be another important cytokine implicated in the pathogenesis of insulin resistance.

"PPAR coactivator 1/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity "(Proc. Natl. Acad. Sci. USA [2003], 10.1073/pnas.2135217100)A well balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure, which is typically achieved by proper physical exercise, is most effective against obesity and diabetes mellitus. Recently, peroxisome proliferator-activated receptor (PPAR) gamma, a member of the nuclear receptor, and its cofactors have been shown to be involved in lipid metabolism and in the control of energy expenditure. Here we show that PPAR gamma coactivator 1 (PGC-1) beta functions as ERRL1 (for ERR ligand 1), which can bind and activate orphan ERRs (estrogen receptor-related receptors) in vitro. Consistently, PGC-1▀/ERRL1 transgenic mice exhibit increased expression of the medium-chain acyl CoA dehydrogenase, a known ERR target and a pivotal enzyme of mitochondrial ▀-oxidation in skeletal muscle. As a result, the PGC-1▀/ERRL1 mice show a state similar to an athlete; namely, the mice are hyperphagic and of elevated energy expenditure and are resistant to obesity induced by a high-fat diet or by a genetic abnormality. These results demonstrate that PGC-1▀/ERRL1 can function as a protein ligand of ERR, and that its level contributes to the control of energy balance in vivo, and provide a strategy for developing novel antiobesity drugs

"Plasma leptin concentration is a novel and independent risk factor for CHD in WOSCOPS" (Diabetologia [2001] 44 (Suppl 1): A315. EASD 37th Annual Meeting, #1209)
Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action" (Obesity Research [2001] 9:414-417 )

"Type 2 diabetes can be delayed by changes in the lifestyles of high-risk subjects." (N Engl J Med [2001] 344:1343-50

"' Insulin is THE PRANDIAL MESSAGE" (Science [2000] 289: 2122-2125)....."

"Obesity continues to increase rapidly in the United States. To alter this trend, strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority:-The prevalence of obesity (defined as a body mass index >30 kg/m2) increased from 12.0% in 1991 to 17.9% in 1998. A steady increase was observed in all states; in both sexes; across age groups, races, educational levels; and occurred regardless of smoking status. The greatest magnitude of increase was found in the following groups: 18- to 29-year-olds (7.1% to 12.1%), those with some college education (10.6% to 17.8%), and those of Hispanic ethnicity (11.6% to 20.8%). The magnitude of the increased prevalence varied by region (ranging from 31.9% for mid Atlantic to 67.2% for South Atlantic, the area with the greatest increases) and by state (ranging from 11.3% for Delaware to 101.8% for Georgia, the state with the greatest increases).....";

"Central abdominal fat is inversely and independently related to insulin sensitivity after adjusting for total fat in women in the early postmenopausal period. Efforts to reduce either subcutaneous abdominal fat or intraabdominal fat should be helpful in reducing the risk of noninsulin-dependent diabetes mellitus in postmenopausal women....."

  Hypothesis #NDC1.00 -
Obesity + beta-cell defect => Type 2 Diabetes
- beta-cell defect => Morbid Obesity
  • Hypothesis #NDC1.01 -
    Obesity => leptin => decreased insulin secretion + increased insulin resistance => IGT
  • Hypothesis #NDC1.02 -
    IGT + beta-cell defect => Type 2 Diabetes

Obesity => Type 2 Diabetes

"How are obesity and Type 2 diabetes related?...........";

"Hopkins Study Shows Overweight Young Males are at Risk for the Development of Type 2 Diabetes...............";

"Data suggest that greater physical activity level is associated with substantial reduction in risk of type 2 diabetes, including physical activity of moderate intensity and duration. JAMA. 1999;282:1433-1439.....";

"BMI correlates with increased all-cause mortality in non-smoking Caucasian Americans (but not in non-smoking black Americans)..........";

"Peroxisome Proliferator–Activated Receptor gamma Gene Locus Is Related to Body Mass Index and Lipid Values in Healthy Nonobese Subjects .....";

Obesity => IL-6+TNF-alpha =>Leptin
"Grb10 may act as a coactivator for Akt from its ability to form a complex with Akt and its SH2 domain-dependent translocation to the cell membrane " (Molecular and Cellular Biology [2002] 22: 979-991])
"Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action (Obesity Research [2001] 9:414-417 )
Local [adipocyte] expression of TNF and plasma IL-6 are higher in subjects with obesity-related insulin resistance.(Am J Physiol -Endo/Metab [2001] 280: E745-E751)"
Tumor Necrosis Factor (TNF) impairs insulin signaling through Insulin Receptor Substrate-1 (IRS-1) by activation of a PhosphatidylInositol-3 kinase (PI-3k)/ Serine and threonine kinase c-Akt (cloned from directly transforming murine retrovirus AKT8, isolated from an AKR mouse Thymoma cell line) also known as Rac-alpha -Related to the A and C kinases - or protein kinase B-alpha (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, which is antagonized by [3' phospholipid-] Phosphatase and Tensin Homologue Deleted from Chromosome ten (PTEN/MUTATED IN MULTIPLE ADVANCED CANCERS 1-MMAC1)".....(Proc. Natl. Acad. Sci. USA, [2001] 10.1073/pnas.051042298)
Is leptin the link between obesity and insulin resistance?.....";
Leptin Levels Increase in Proportion to the Extent of Obesity.....";

Obesity => Leptin => "U-shaped" Insulin Resistance Curve
Obesity => Leptin=>Downregulated PPAR-
gamma=>Enhanced Lipolysis and Decreased Lipogenesis

"Protein Kinase C action decreases the Hill coefficient of ATP binding to cardiac KATP channels, thereby increasing their open probability at physiological ATP concentrations....." (PNAS [2000] 10:1073)

"Short-term adenovirus-induced hyperleptinemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma in epididymal fat; enzymes of fatty acid oxidation and their transcription factor, PPARalpha, normally low in adipocytes, are up-regulated, as are uncoupling proteins 1 and 2. This transformation of adipocytes from cells that store triglycerides to fatty acid-oxidizing cells is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, tumor necrosis factor alpha, and leptin, and by the appearance of the preadipocyte marker Pref-1....."

"Leptin administration to cultured rodent hepatocytes increased gluconeogenesis, decreased glycogenolysis, and decreased free fatty acid synthesis. Nevertheless, CNS injection of leptin in the same species improved measures of insulin tolerance....."(Rossetti L: Leptin regulation of hepatic glucose metabolism [Concurrent session: Leptin regulation of fuel metabolism]. 59th Annual Scientific Sessions of ADA, San Diego, CA, 1999);

"Plasma Leptin Associated with Insulin-Resistant Hypertension............";

"Leptin inhibits glycogen synthesis in the isolated soleus muscle of obese (ob/ob) mice.....";

"Low levels of leptin seem to reverse diabetes in mouse model of congenital lipodystrophy...........";

"Leptin appears to have a U-shaped effect on insulin resistance and is more active in visceral fat..................";

Obesity => Leptin => Decreases in (1) Agouti protein and (2) neuropeptide-Y =>
=> Increases in (3) melanocortin function and (4) satiety

"Hypothalamic agouti-related protein messenger ribonucleic acid [and Neuropeptide-Y mRNA] are inhibited by Leptin and stimulated by fasting.....";

"Agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, is intrically involved in leptin action.....";

"Melanocyte Stimulating Hormone appears to have appetite-suppressant activity.............";

"Leptin-associated mutations cause down-regulation of prepro-orexin gene expression.....";

Obesity => Leptin => Decreased Insulin Secretion via Opening K-ATP Channels

"Expression of the functional leptin receptor mRNA is found in pancreatic islets and directly inhibits insulin secretion.....";

"The agouti gene product stimulates pancreatic beta-cell Ca2+ signaling and insulin release..........";

"Leptin binds to VMH Kir6.2/SUR1 receptors ";

"Leptin likely suppresses insulin secretion by the activation of the same ATP-sensitive K+ channels in pancreatic beta-cells.....)";

"Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.....";

"Insulin occludes leptin activation of ATP-sensitive K+ channels in rat CRI-G1 insulin secreting cells";

"The Homeodomain of PDX-1 Mediates Multiple Protein-Protein Interactions in the Formation of a Transcriptional Activation Complex on the Insulin Promoter.....";;

Sulfonylureas - which prototypically close K-ATP channels - may also increase Leptin

"Sulfonylurea therapy is associated with increases in [insulin and] leptin levels despite weight loss.....";

"Dexamethasone stimulates leptin release from human adipocytes: unexpected inhibition by insulin.....";

  Hypothesis #NDC1.10 -
gamma is the major transcription factor for lipogenesis
  • Hypothesis #NDC1.11 -
    Downregulation of PPAR-
    gamma by leptin OVERRIDES upregulation by insulin and is the major factor responsible for post-prandial insulin resistance

Thiazolidinediones impact Leptin, PPAR-gamma, and K-ATP Channels

"Dominant negative mutations in human PPAR-gamma are associated with severe insulin resistance, diabetes mellitus and hypertension.....";

"Diazoxide- and leptin-activated K(ATP) currents show differential sensitivity to englitazone and ciclazindol in rat CRI-G1 insulin-secreting cell lines....";

"Thiazolidinediones - which decrease leptin message - appear to prevent diabetes in the hyperleptinemic db/db mouse................";

"A low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans

"Ciliary neurotrophic factor corrects obesity [and hyperinsulinemia] associated with leptin deficiency and resistance.....";

"An ascochlorin derivative, AS-6, reduces insulin resistance in the genetically obese diabetic mouse, db/db.....";

"Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes.....";

"Regulation of glucose metabolism and opening of K(ATP) channels in pancreatic beta-cells by NO.....";

"Interaction of vanadate with the cloned beta cell K(ATP) channel.....";

Mitochondrial K-ATP Channels and Cardiac Ischemia

"Diabetes or hyperglycemia impairs activation of mitochondrial KATP channels during infarction" (AJP - Heart Circ Physiol [2001] 280: Issue 4, H1744-H1750)

"Opening of sarcolemmal KATPchannels underlies ST elevation during ischemia" (Circulation Res. [2000] 87:837)

"Results suggest that mitoK-atp channels are downstream of PKC in the mechanism of infarct-size limitation by A1-receptor activation and that the anti-infarct tolerance afforded by opening of mitoK-atp channels is associated with preservation of mitochondrial function during ischemia/reperfusion.....";

"Nitric Oxide (NO) directly activates mitoK-atp channels and potentiates the ability of diazoxide to open these channels. These results provide novel mechanistic links between NO-induced cardioprotection and mitoK-atp channels.....";

"ATP-regulated K+ channel in mitochondria: pharmacology and function.....";

"Regulation of mitochondrial KATP channel by redox agents.....";

"Rat liver GTP-binding proteins mediate changes in mitochondrial membrane potential and organelle fusion.....";

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