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• 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; p_trend = 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; p_trend = 0.001) and for hemorrhagic stroke, relative risk = 0.51 (95% confidence interval: 0.33, 0.78; p_trend = 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.

Under conditions of nutrient satiation S6K1 negatively regulates insulin signalling (Nature AOP, published online 11 August 2004; doi:10.1038/nature02866) Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta--cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K A^y and ob/ob (also known as Lep/Lep) mice—two genetic models of obesity—have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

• Trans Fatty Acids Increase Risk Of Diabetes in Women (Am J Clin Nutr [2001] 73(6):1019-1026 )

Diet and exercise (58%) better than metformin (31%) in delaying type 2 diabetes! (NIDDK Press Release, DPT2 Results, 8 August 2001)

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

Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice (Nature Medicine [2000] 6:1115 - 1120)

• 'Big Whoop of the Year' Award goes to those weenie-wonks who had to knock-out brain insulin receptors to figure out that insulin is THE PRANDIAL MESSAGE (Science [2000] 289: 2122-2125)

Sino American Health Products, Inc., Issues a National Recall of Herbal Products Due to the Presence of the Undeclared Drugs Glyburide and Phenformin.

• It seems appropriate to question the wisdom of recommending that all Americans should replace dietary saturated fat with CHO [AJC [2000] 85:45-48]

Guava fruit may benefit type 2 diabetics

• New Sweetener (d-tagatose) Also Blunts Post-Prandial Hyperglycemia in UMd Study

Supplementation with beta-carotene for an average of 12 years has no protective effect on the risk of subsequent development of type 2 diabetes

• High-protein diets do increase individual nephron filtration rate (INFR) and affect glomeruli adversely (1) directly with individual nephron filtration rate increase and (2) inversely with total glomerular filtration rate (GFR) diminution (thus the effect is small in normal functioning kidneys and large in renal impairment)

Low-carb, High Fat Diet Improves All Major Risk Factors in Type 2 Diabetes

• Western-Diet (high in meats and fats) protective against stroke dementia: Honolulu-Asia Aging Study
  
  
  
  
  
  

Treatment

• Targeting (FABP4) aP2 may prevent and treat type 2 diabetes and atherosclerosis (doi:10.1038/nature05844) Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus (NEJM 356:1517-1526, 2007)Background The expression of interleukin-1–receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1 in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. Methods In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1–receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic–euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. Results At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. Conclusions The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov] )

• Selectively terminating Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms (Molecular Cell, 25:917-931, 23 March 2007) Akt/protein kinase B controls cell growth, proliferation, and survival. We recently discovered a novel phosphatase PHLPP, for PH domain leucine-rich repeat protein phosphatase, which terminates Akt signaling by directly dephosphorylating and inactivating Akt. Here we describe a second family member, PHLPP2, which also inactivates Akt, inhibits cell-cycle progression, and promotes apoptosis. These phosphatases control the amplitude of Akt signaling: depletion of either isoform increases the magnitude of agonist-evoked Akt phosphorylation by almost two orders of magnitude. Although PHLPP1 and PHLPP2 both dephosphorylate the same residue (hydrophobic phosphorylation motif) on Akt, they differentially terminate Akt signaling by regulating distinct Akt isoforms. Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3a through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3. Our data unveil a mechanism to selectively terminate Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms.

Higher exposure to sulfonylureas was associated with increased mortality among newly treated type 2 diabetics. Significant diabetic outcomes are dependent upon the path of control. (CMAJ[2006] 174 (2). doi:10.1503/cmaj.050748) Background: Over the past 30 years, the relation between use of sulfonylureas to treat type 2 diabetes and the risk of cardiovascular events has been vigorously debated. The purpose of this study was to determine if the risk of death changes with level of exposure to sulfonylurea drugs. Methods: This was a retrospective, inception cohort study using administrative data from Saskatchewan Health (1991– 1999). The 5795 subjects, identified by their first-ever dispensation for an oral antidiabetic agent, were grouped according to their use of such agents during follow-up. Potential subjects using insulin or combination therapy were excluded. Exposure level was defined by daily dose and degree of adherence. Separate multivariate Cox proportional-hazard models were constructed for each monotherapy group and used to calculate the risk of death associated with higher versus lower exposure category. Disease severity indicators were identified among the administrative data and entered as covariates in each model. The main outcomes were all-cause mortality and death from an acute ischemic event. Results: The mean age of the cohort members was 66.3 (standard deviation [SD] 13.4) years; 43.4% were female; and their mean duration of follow-up was 4.6 (SD 2.1) years. First-generation sulfonylureas were used exclusively by 120 subjects; glyburide, by 4138; and metformin, by 1537. A greater risk of death was associated with higher daily doses of the first-generation sulfonylureas (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.0–4.7) and glyburide (HR 1.3, 95% CI 1.2–1.4), but not metformin (HR 0.8, 95% CI 0.7–1.1). Similar associations were observed for death caused by an acute ischemic event. Interpretation: Higher exposure to sulfonylureas was associated with increased mortality among patients newly treated for type 2 diabetes. The same relation was not observed with metformin. This implies that the manner in which blood glucose concentration is lowered may be as important as achieving recommended glucose targets.

• Insulin + N-alpha-Deoxycholyl-l-lysyl-methylester (Insulin/DCK) Formulation Can be Absorbed in the Intestine and is Biologically Efficacious (Diabetologia [2005]48:405-411) Aims/hypothesis  The development of an orally active insulin formulation will offer great advantages over conventional injectable insulin therapy in the treatment of patients with diabetes mellitus. Since insulin absorption in the intestine is restricted by the natural physiological characteristics of insulin, we developed a small synthetic compound, N-alpha-deoxycholyl-l-lysyl-methylester (DCK), as an insulin carrier to enhance oral delivery. Methods   Streptozotocin-induced diabetic rats orally received single doses of insulin (42 U/kg) or insulin/DCK formulation (10, 21, 30 and 42 U/kg) under fasting conditions. Blood glucose levels and plasma insulin concentrations were measured for 6 h following the administration of the agents. An OGTT was also performed immediately after the administration of the oral insulin/DCK formulation. Results  The administration of 21, 30 and 42 U/kg (based on insulin activity) of insulin/DCK formulation reduced plasma glucose levels by up to 33.0% (median; range 30.6–70.2%), 78.5% (39.4–86.8%) and 75.2% (67.0–87.4%), respectively, compared with baseline levels. Furthermore, plasma insulin concentrations were observed to rapidly increase. In the OGTT, the insulin/DCK formulation reduced the AUC_0–240 for glucose by 30.8% (22.3–54.9%) (p<0.01), and stabilized glycaemia for up to 4 h. Conclusions/interpretation  The results of this study demonstrate that the insulin/DCK formulation can be absorbed in the intestine and that it is biologically efficacious. We therefore suggest that this oral formulation could be used as an alternative to injectable insulin with enhanced clinical effects

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.

• PTEN may be a promising target for therapeutic intervention for type 2 diabetes (Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0308617100) In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes.

Fluoroquinolones differ markedly in their potencies to inhibit K⁺ channel activity (Life Sciences [2003] 73:429-435)
In patients administered lomefloxacin alterations in blood glucose concentrations have been observed in some cases and lomefloxacin has previously been shown to augment insulin release from rat pancreatic islets at micromolar concentrations. The aim of the present study was to compare the effects of two structurally related fluoroquinolones, lomefloxacin and norfloxacin, on ATP-sensitive K⁺ (K_ATP) currents from the clonal insulinoma cell line RINm5F using the whole-cell configuration of the patch-clamp technique. The application of lomefloxacin concentration-dependently blocked K_ATP currents from RINm5F cells with a half-maximally inhibitory concentration of 81 M, whereas the application of norfloxacin (at concentrations up to 300 M) had only minor effects on K_ATP currents. Block of pancreatic -cell K_ATP currents could be mediated by interaction of lomefloxacin either with the regulatory subunit (SUR1) or with the pore-forming subunit (Kir6.2). We favour the latter hypothesis, since some fluoroquinolones have recently been shown to block the pore-forming subunit of the cardiac rapid delayed rectifier K⁺ current I_Kr (which is encoded by HERG (human ether-a-go-go-related gene)). Thus, as demonstrated for cardiac HERG channels in previous studies and for pancreatic -cell K_ATP channels in the present study, fluoroquinolones differ markedly in their potencies to inhibit K⁺ channel activity.

• GlaxoSmithKline's diabetes drug wins US approval(Ananova 11 Oct 2002) GlaxoSmithKline's combination diabetes drug, Avandamet, has been approved by the US Food and Drug Administration.Avandamet is a combination of GSK's existing diabetes drug Avandia and metformin for the treatment of type 2, adult-onset diabetes. Type 2 diabetes affects an estimated 16 million Americans and 150 million people worldwide. Metformin is the generic version of Glucophage, the long-established diabetes drug marketed by Bristol-Myers Squibb of the US and Germany's Merck. Generic metformin was launched in the US in January.GSK says the combination helps patients manage their type 2 diabetes for longer. Many patients are already taking both Avandia and Glucophage. Avandamet will be commercially available in the US in about a month, GSK says. "The approval of Avandamet represents a significant opportunity for our diabetes franchise, and we intend to realise the full potential of this exciting new combination product," says GSK chief executive JP Garnier.In the second quarter of this year, Avandia sales rose 4% to £222 million worldwide. City analysts were expecting the FDA to approve Avandamet either before the end of the year or in the first quarter of 2003. Max Herrmann, analyst at ING Charterhouse, says the drug will help sales of the Avandia franchise reach £1.5 billion by 2006."Shares in Glaxo are up 46p at £13.17 in morning trading, still some way off their high so far this year of £17.80. The group was hit in May when the remaining patents protecting antibiotic Augmenting from generic competition were thrown out by a US court. Analysts have since voiced fears that a similar fate may await Glaxo's top-selling antidepressant Paxil.

The peripheral insulin-sensitizing effect of exendin-4 (in contrast to the insulinotropic effect) does not involve the GLP-1 receptor pathway.  Biochemical Pharmacology [2002] 63::993-996)  The insulinotropic agent, exendin-4, is a long-acting analogue of glucagon-like peptide-1 (GLP-1) which improves glucose tolerance in humans and animals with diabetes, but the underlying mechanisms and the effects of exendin-4 on peripheral (muscle/fat) insulin action are unclear. Previous in vivo and clinical studies have been difficult to interpret because of complex, simultaneous changes in insulin and glucagon levels and possible effects on hepatic metabolism. Thus, the comparative effects of exendin-4 and GLP-1 on insulin-stimulated 2-[³H]deoxyglucose (2-DOG) uptake were measured in fully differentiated L6 myotubes and 3T3-adipocytes, including co-incubation with inhibitors of the PI-3-kinase (wortmannin) and mitogen-activated protein (MAP) kinase (PD098059) pathways. In L6 myotubes, there was a concentration-dependent and PI-3-kinase-dependent increase in insulin-stimulated 2-DOG uptake with exendin-4 and GLP-1, e.g. for exendin-4 the C_I-200 value (concentration of insulin required to increase 2-DOG uptake 2-fold) decreased from 1.3±1.4×10^-7 M (insulin alone, n=16) to 5.9±1.3×10^-8 M (insulin+exendin-4 0.1 nM, n=18, P<0.03). A similar insulin-sensitizing effect was observed with exendin-4 in 3T3-adipocytes, but GLP-1 had no effect on adipocyte insulin sensitivity. In conclusion, this is the first direct evidence showing that exendin-4 increases insulin-stimulated glucose uptake in muscle and fat derived cells via a pathway that involves PI-3-kinase activation. Furthermore, the contrasting responses of exendin and GLP-1 in 3T3-adipocytes suggest that the peripheral insulin-sensitizing effect of exendin-4 (in contrast to the insulinotropic effect) does not involve the GLP-1 receptor pathway.

• Merck's small molecular insulin mimetics reduce food intake and body weight and prevent development of obesity (Nature Medicine [2002] 8:179-183) Obesity and insulin resistance are major risk factors for a number of metabolic disorders, such as type 2 diabetes mellitus^{1, 2}. Insulin has been suggested to function as one of the adiposity signals to the brain for modulation of energy balance. Administration of insulin into the brain reduces food intake and body weight^3-5, and mice with a genetic deletion of neuronal insulin receptors are hyperphagic and obese⁶. However, insulin is also an anabolic factor; when administered systemically, pharmacological levels of insulin are associated with body weight gain in patients⁷. In this study, we investigated the efficacy and feasibility of small molecule insulin mimetic compounds^{8, 9} to regulate key parameters of energy homeostasis. Central intracerebroventricular (i.c.v.) administration of an insulin mimetic resulted in a dose-dependent reduction of food intake and body weight in rats, and altered the expression of hypothalamic genes known to regulate food intake and body weight. Oral administration of a mimetic in a mouse model of high-fat diet-induced obesity reduced body weight gain, adiposity and insulin resistance. Thus, insulin mimetics have a unique advantage over insulin in the control of body weight and hold potential as a novel anti-obesity treatment.

In obese women, endothelial activation correlates with visceral body fat and weight loss represents a safe method for downregulating the inflammatory state and ameliorating endothelial dysfunction. (Circulation [2002; 10:1161)

• An insulin-sensitive phosphatidylinositol 3-kinase/Akt pathway promotes carcinogenesis via translocation of Mdm2 from the cytoplasm to the nucleus (PNAS [2001] 98 11598-11603) The Mdm2 oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. To regulate p53, Mdm2 must gain nuclear entry, and the mechanism that induces this is now identified. Mitogen-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, the Akt/PKB serine-threonine kinase, results in phosphorylation of Mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus. Pharmacological blockade of PI3-kinase/Akt signaling or expression of dominant-negative PI3-kinase or Akt inhibits nuclear entry of Mdm2, increases cellular levels of p53, and augments p53 transcriptional activity. Expression of constitutively active Akt promotes nuclear entry of Mdm2, diminishes cellular levels of p53, and decreases p53 transcriptional activity. Mutation of the Akt phosphorylation sites in Mdm2 produces a mutant protein that is unable to enter the nucleus and increases p53 activity. The demonstration that PI3-kinase/Akt signaling affects Mdm2 localization provides insight into how this pathway, which is inappropriately activated in many malignancies, affects the function of p53.

Transcriptional coactivator PGC-1 controls hepatic gluconeogenesis (Nature [2001] 413: 131 - 138)

• IKK-ß May Underly the Inflammatory Etiology of the Dysmetabolic Syndrome (Science [2001] 293:1673-1677)

GLP-1 or exendin-4 applied during the neonatal diabetic period exert both short- and long-term beneficial effects on ß-cell mass recovery and glucose homeostasis (Diabetes [2001] 50:1562-157)

• Short-term reduction of HbA_1c levels does not appear to affect endothelial function in patients with type 2 diabetes and previously poorly regulated glycaemic control. (Intern Med J [2001] 31: 322328)

Insulin Inhibits the Expression of Intercellular Adhesion Molecule-1 by Human Aortic Endothelial Cells through Stimulation of Nitric Oxide (The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 7 2572-2575)

• Inositol Phosphoglycans (IPGs) are Involved in the
  Reversal of Type 2 Diabetes in Mice by Products of Malaria Parasites (Mol Genetics Metab [2001] 73: 248-258)

Atenolol = less morbidity + equivalent mortality vs. captopril in UKPDS (Diabetic Medicine [2001] 18 (6), 438-444)

• SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo (Nature409, 92 - 97 (2001) Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo

Insulin resistance in lipoatrophic mice is completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone (Nature Medicine [2000] 7:941-946)

• Metformin prevents pancreatic cancer in hamsters (GASTROENTEROLOGY [2001] 120:1263-1270)

Pharmacological manipulation of Acetyl-CoEnzymeA Carboxylase-2 (ACC-2) may lead to loss of body fat in the context of normal caloric intake(Science [2001] 291:2613-2616 

• Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean (Nature [2000] 406:415 - 418 )

Rosiglitazone Improves beta-Cell Function as Measured by Proinsulin/Insulin Ratio in Patients with Type 2 Diabetes (ADA 60th meeting [2000], Abs #495)

• Pexiganan cream 1% provides a high clinical response rate for infected diabetic foot ulcers (ADA 60th meeting [2000], Abs #517)

CD26 worsens blood glucose regulation by proteolytically inactivating GLP-1 thereby decreasing insulin secretion (Proc. Natl. Acad. Sci. USA[2000], 10.1073)

• Once-Daily Glargine Insulin Approved for Injection (Lantus-tm) (24 April 2000, FDA Label)

American Ginseng (Panax quinquefolius L) Reduces Postprandial Glycemia in Nondiabetic Subjects and Subjects With Type 2 Diabetes Mellitus  (Arch Int Med [2000]:Vol 160 No. 7)

• Beta-blockers inhibit insulin secretion increasing risk of diabetes [while improving survival]The New England Journal of Medicine [2000] 342 (#13)

Rezulin Removed from US market after FDA CDER Woodcock Meeting 4PM Tuesday 21 March

• Avandia Approved for Marketing in the EU

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 intra-abdominal fat should be helpful in reducing the risk of noninsulin-dependent diabetes mellitus in postmenopausal women.

• Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Long-Acting GLP-I agonist Exendin-4 Stimulates Both -Cell Replication and Neogenesis, Resulting in Increased beta-Cell Mass and Improved Glucose Tolerance in Diabetic Rats

• Glucagon-Like Peptide 1 and Exendin-4 Convert Pancreatic AR42J Cells Into Glucagon- and Insulin-Producing Cells

FDA warns Bristol-Myers Squibb about Glucophage adverse event reporting

• Jacuzzis may 'help control [type 2]diabetes'

GLP-1 is able to normalize plasma glucose in all type 2-diabetic patients studied thus far

• Mitsubishi Chemical Corp. in agreement with Johnson & Johnson for licensing MCC-555 ((+)-5-[[6-(2-fluorobenzyl)-oxy-2-naphy]methyl]-2-4-thiazolidinedione), a unique and very potent thiazolidinedione, in the US

Melanocyte Stimulating Hormone found to have appetite-suppressant activity

• Actos ®(pioglitazone) approved for monotherapy or combination with insulin, metformin, and SFU's. Side effects include significant edema and weight gain as well as anemia. Avoid in heart failure and in combination with statins it may induce CPK elevations and rhabdomyolysis. Additional benefit includes triglyceride reductions.

Ultralong-Acting Insulin (Glargine®) as Effective as but Safer than NPH in Type 2 Diabetics

• FDA approves Avandia (Rosiglitazone) but significant weight gain and increases in LDL-cholesterol with this new thiazolidinedione may impede utilization

Type 2 Diabetics eventually need insulin for good control (UKPDS)

• Buccally-Administered Insulin Seen as Effective Post-Prandially in Early Phase II Trials

Insulinomimetic [L-783,281] found in Pseudomassaria fungi growing deep in the African rain forests near Kinsasha by investigators from Merck Research Laboratories can be given orally (but necessary clinical trials mean marketing is at least 3-4 years away)

• D-Chiro-inositol (discovered by Dr. Joseph Larner at the University of Virginia Department of Biochemistry) is another naturally occurring agent which significantly reduces insulin resistance 

Nitrendipine Significantly Reduces Total Mortality in Elderly Diabetics with Systolic Hypertension (160-219/<95) in a SubAnalysis of the SHET Trial by Finnish Researchers

Monitoring

• Noninvasive monitoring now feasible also using ultrasound technology"(Nature Medicine [2000] 6:347-350)

Watch-Like Device -Approved 9 May 2000 (!) - Will Check Blood Sugars Painlessly

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• • No Needle Prick Needed for Experimental Home Diabetes Monitoring Check

The device goes before an FDA Advisory Committee meeting on December 6th 1999. If approved the device could be on the market as early as April, 2000.

• National Survey Reveals Few Patients
  Understand Underlying Cause of Disease
  
  
  
  
  
  
  

Pathogenesis

The Inflammation Link: Association between psoriasis, diabetes mellitus, and atherosclerosis - A case-control study(JAAD 56: 629-634 ,April 2007) Background Previous reports demonstrated an association between psoriasis and other diseases including heart failure and diabetes mellitus.Objectives Our aim was to describe the association between psoriasis, diabetes mellitus, and atherosclerosis in Israel. Methods A cross-sectional study was performed utilizing the database of Maccabi Healthcare Services (MHS), a large health provider organization in Israel. Case patients were defined as subjects who were diagnosed with psoriasis. Patients with diabetes and atherosclerosis were identified by using the MHS diabetes and cardiovascular registries, respectively. The control group included MHS enrollees without psoriasis. The proportion of diabetes and atherosclerosis among case and control groups was compared. Chi-square tests were used to compare categorical parameters. Logistic regression models were used for multivariate analyses. Results The study included 46,095 patients with psoriasis (case patients) and 1,579,037 subjects without psoriasis (control patients). The age-adjusted proportion of diabetes was significantly higher in psoriasis patients as compared with the control group (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.1-1.48). The age-adjusted proportion of atherosclerosis was significantly higher in psoriasis patients as compared with the control group (OR 1.28, 95% CI 1.04-1.59). In patients with psoriasis, a multivariate logistic regression model demonstrated an association between diabetes and the multiple use of very potent topical steroids (P < .05) or use of systemic medication for psoriasis (methotrexate, cyclosporine or acitretin) (P < .001). A similar model demonstrated an association between atherosclerosis and the use of phototherapy (P < .001). Limitations Our study was based on a computerized database. The diagnosis of psoriasis was based on digitally transmitted data. Therefore overestimation (false-positive cases) and underestimation (false-negative cases) of psoriasis patients may exist, thereby being a source for information bias. A second limitation is selection bias that may occur due to the possibility that reporting of both psoriasis and associated illnesses is higher in individuals who are seeking medical care. A third limitation concerns the causal effect between occurrence of psoriasis and atherosclerosis or diabetes. The dataset of MHS records diagnoses only from 1997 and does not record the date of disease onset. Conclusions Our study supports previous reports for an association between psoriasis and atherosclerosis and psoriasis and diabetes. Further study is needed to support this observation.

• PHLPP: A Phosphatase that Directly Dephosphorylates Akt, Promotes Apoptosis, and Suppresses Tumor Growth (Molecular Cell, 18:13-24, 01 April 2005) Akt/protein kinase B critically regulates the balance between cell survival and apoptosis. Phosphorylation of Akt at two key sites, the activation loop and the hydrophobic motif, activates the kinase and promotes cell survival. The mechanism of dephosphorylation and signal termination is unknown. Here, we identify a protein phosphatase, PH domain leucine-rich repeat protein phosphatase (PHLPP), that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1), triggering apoptosis and suppressing tumor growth. The effects of PHLPP on apoptosis are prevented in cells expressing an S473D construct of Akt, revealing that the hydrophobic motif is the primary cellular target of PHLPP. PHLPP levels are markedly reduced in several colon cancer and glioblastoma cell lines that have elevated Akt phosphorylation. Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth. These data are consistent with PHLPP terminating Akt signaling by directly dephosphorylating and inactivating Akt.

Insulin resistance measured by the euglycaemic insulin clamp predicts subsequent CHD in elderly men. Proinsulin provides a better prediction of CHD than insulin. (Diabetologia [2005]48:1432-0428 (Online))  Aims/hypothesis  The association between CHD and insulin sensitivity (Si) measured by the euglycaemic insulin clamp has not been examined previously. Earlier studies found a relationship between CHD and elevated plasma insulin, an analysis that may have been confounded by co-determination of proinsulin, which has evolved as a stronger predictor of CHD. The aim was to determine the longitudinal relationships between Si, intact proinsulin, 32–33 split proinsulin, specific insulin and subsequent CHD. Methods  This was a population-based cohort study of 815 men in Uppsala, Sweden, aged 70 years at baseline with a follow-up of up to 10 years. Baseline insulin sensitivity was determined by euglycaemic insulin clamp. Fasting proinsulin, 32–33 split proinsulin and specific insulin concentrations were analysed using specific two-site immunometric assays. CHD was taken as diagnosed, if stated (in the event of death) on the Cause of Death Registry, or for subjects hospitalised for the first time with CHD, if CHD was recorded in the Hospital-Discharge Registry. The associations were analysed using Cox's proportional hazards, presented as hazard ratios (HRs) with their 95% CIs for a one-SD increase in the predictor. Results  In multivariate analysis, Si (HR:0.80, CI:0.65–0.97) adjusted for serum cholesterol, systolic blood pressure, fasting plasma glucose, BMI and smoking predicted CHD. Intact proinsulin (HR:1.18, CI:1.01–1.38), adjusted as the model above, predicted CHD, whereas 32–33 split proinsulin (HR:1.13, CI:0.95–1.35) or specific insulin (HR:1.07, CI:0.89–1.30) did not. Conclusions/interpretation  Insulin resistance measured by the euglycaemic insulin clamp predicts subsequent CHD in elderly men. Proinsulin provides a better prediction of CHD than insulin.

• 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.

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 ß barrel domain of both proteins can be overlapped, and osmotin, like adiponectin, activates AMP kinase in C2C12 myocytes via adiponectin receptors.

• Elevated fasting serum glucose levels and a diagnosis of diabetes are independent risk factors for several major cancers - particularly Ca of the Pancreas - and the risk tends to increase with an increased level of fasting serum glucose (JAMA [2005] 293: 194-202) Context  Diabetes is a serious and costly disease that is becoming increasingly common in many countries. The role of diabetes as a cancer risk factor remains unclear. Objective  To examine the relationship between fasting serum glucose and diabetes and risk of all cancers and specific cancers in men and women in Korea. Design, Setting, and Participants  Ten-year prospective cohort study of 1 298 385 Koreans (829 770 men and 468 615 women) aged 30 to 95 years who received health insurance from the National Health Insurance Corp and had a biennial medical evaluation in 1992-1995 (with follow-up for up to 10 years). Main Outcome Measures  Death from cancer and registry-documented incident cancer or hospital admission for cancer. Results  During the 10 years of follow-up, there were 20 566 cancer deaths in men and 5907 cancer deaths in women. Using Cox proportional hazards models and controlling for smoking and alcohol use, the stratum with the highest fasting serum glucose (>=140 mg/dL [>=7.8 mmol/L]) had higher death rates from all cancers combined (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.22-1.37 in men and HR, 1.23; 95% CI, 1.09-1.39 in women) compared with the stratum with the lowest level (<90 mg/dL [<5.0 mmol/L]). By cancer site, the association was strongest for pancreatic cancer, comparing the highest and lowest strata in men (HR, 1.91; 95% CI, 1.52-2.41) and in women (HR, 2.05; 95% CI, 1.43-2.93). Significant associations were also found for cancers of the esophagus, liver, and colon/rectum in men and of the liver and cervix in women, and there were significant trends with glucose level for cancers of the esophagus, colon/rectum, liver, pancreas, and bile duct in men and of the liver and pancreas in women. Of the 26 473 total cancer deaths in men and women, 848 were estimated as attributable to having a fasting serum glucose level of less than 90 mg/dL. For cancer incidence, the general patterns reflected those found for mortality. For persons with a diagnosis of diabetes or a fasting serum glucose level greater than 125 mg/dL (6.9 mmol/L), risks for cancer incidence and mortality were generally elevated compared with those without diabetes. Conclusion  In Korea, elevated fasting serum glucose levels and a diagnosis of diabetes are independent risk factors for several major cancers, and the risk tends to increase with an increased level of fasting serum glucose.

^{Inflammation and cancer: the long reach of Ras (Nature Medicine [2005] 11:20-21)} For decades cancer biologists have thought of oncogenes in terms of their ability to prompt tumor growth and survival, acting within the cancer cell. That viewpoint is now changing to take into account data showing that oncogenes influence inflammation. Insights now emerge from work on Ras and the proinflammatory mediator interleukin-8, produced by tumor-infiltrating immune cells.

• The relative risk of type 2 in heavy smokers was 1.53, 95% CI: 1.14–2.05, while current smokers had relative risks of 0.17, 95% CI: 0.04–0.78 for type 1 diabetes (Diabetologia [2005] 47:1953-1956) Aims/hypothesis  We compared the association between smoking habits and later occurrence of type 2 diabetes on the one hand and between smoking and diabetes with autoimmunity on the other hand.Methods  We used data from a prospective study of 11-year cumulative incidence of diabetes in the Nord-Trøndelag Health Survey.Results  Confirming previous reports, heavy smoking (20 cigarettes per day) carried an increased relative risk (RR) of type 2 diabetes (n=738, RR=1.64, 95% CI: 1.12–2.39). In contrast, smoking reduced the risk of latent autoimmune diabetes in adults (LADA) and of traditional type 1 diabetes (LADA n= 81, RR=0.25, 95% CI: 0.11–0.60; type 1 diabetes, n=18, RR=0.17, 95% CI: 0.04–0.73).Conclusions/interpretations  The results indicate that nicotine influences autoimmune processes in human diabetes.

Circulating Mononuclear Cells In The Obese Found To Be In Proinflammatory State, Contributing To Diabetes And Heart Disease (Circulation [2004] 110:1564-1571) Background— In view of the increase in plasma concentrations of proinflammatory mediators tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and C-reactive protein (CRP) in obesity, we investigated whether peripheral blood mononuclear cells (MNC) from obese subjects are in a proinflammatory state. Methods and Results— MNC were prepared from fasting blood samples of obese (n=16; body mass index [BMI]=37.7±5.0 kg/m²) and normal-weight control (n=16; BMI=23.8±1.9 kg/m²) subjects. Nuclear factor kB (NF-kB) binding to DNA in nuclear extracts was elevated (P<0.05) and the inhibitor of NFkB-ß (IkB-ß) was significantly lower (P<0.001) in the obese group. Reverse transcription–polymerase chain reaction revealed elevated levels of migration inhibitor factor (MIF), IL-6, TNF-a, and matrix metalloproteinase-9 (MMP-9) mRNA expression in the obese subjects (P<0.05). Plasma concentrations of MIF, IL-6, TNF-a, MMP-9, and CRP were also significantly higher. Plasma glucose, insulin, and free fatty acids (FFAs) were measured, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Plasma FFA concentration related significantly to BMI, IL-6, and TNF-a mRNA expression and plasma CRP levels but not to HOMA-IR. On the other hand, the inflammatory mediators were significantly related to BMI and HOMA-IR. Conclusions— These data show (1) for the first time that MNC in obesity are in a proinflammatory state with an increase in intranuclear NF-kB binding, a decrease in IkB-ß, and an increase in the transcription of proinflammatory genes regulated by NF-kB; (2) that plasma FFAs are a modulator of inflammation; and (3) that insulin resistance is a function of inflammatory mediators.

• Under conditions of nutrient satiation S6K1 negatively regulates insulin signalling (Nature AOP, published online 11 August 2004; doi:10.1038/nature02866) Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta--cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K A^y and ob/ob (also known as Lep/Lep) mice—two genetic models of obesity—have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

Oxidative stress induces insulin resistance by activating the nuclear factor-kB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase (Diabetologia [2004] 47: 794 - 805) Aims/hypothesis  Oxidative stress is associated with diabetes, hypertension and atherosclerosis. Insulin resistance is implicated in the development of these disorders. We tested the hypothesis that oxidative stress induces insulin resistance in rats, and endeavoured to identify mechanisms linking the two. Methods  Buthionine sulfoximine (BSO), an inhibitor of glutathione synthase, was administered to Sprague-Dawley rats and 3T3-L1 adipocytes. Glucose metabolism and insulin signalling both in vivo and in 3T3-L1 adipocytes were examined. In 3T3-L1 adipocytes, the effects of overexpression of a dominant negative mutant of inhibitory kB (IkB), one role of which is to block oxidative-stress-induced nuclear factor (NF)-kB activation, were investigated. Results  In rats given BSO for 2 weeks, the plasma lipid hydroperoxide level doubled, indicating increased oxidative stress. A hyperinsulinaemic-euglycaemic clamp study and a glucose transport assay using isolated muscle and adipocytes revealed insulin resistance in BSO-treated rats. BSO treatment also impaired insulin-induced glucose uptake and GLUT4 translocation in 3T3-L1 adipocytes. In BSO-treated rat muscle, adipose tissue and 3T3-L1 adipocytes, insulin-induced IRS-1 phosphorylation in the low-density microsome (LDM) fraction was specifically decreased, while that in whole cell lysates was not altered, and subsequent translocation of phosphatidylinositol (PI) 3-kinase from the cytosol and the LDM fraction was disrupted. BSO-induced impairments of insulin action and insulin signalling were reversed by overexpressing the dominant negative mutant of IkB, thereby suppressing NF-kB activation. Conclusions/interpretation  Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-kB activation is likely to be involved in this process.

• Endothelial dysfunction predicts type 2 diabetes in women independent of other known risk factors, including obesity and subclinical inflammation.(JAMA [2004] 291:1978-1986) Context  Endothelial dysfunction occurs in diagnosed type 2 diabetes mellitus but may also precede development of diabetes. Objective  To determine whether elevated plasma levels of biomarkers reflecting endothelial dysfunction (E-selectin; intercellular adhesion molecule 1 [ICAM-1]; and vascular cell adhesion molecule 1 [VCAM-1]) predict development of type 2 diabetes in initially nondiabetic women. Design and Setting  Prospective, nested case-control study within the Nurses' Health Study, an ongoing US study initiated in 1976. Participants  Of 121 700 women initially enrolled, 32 826 provided blood samples in 1989-1990; of those free of diabetes, cardiovascular disease, or cancer at baseline, 737 developed incident diabetes by 2000. Controls (n = 785) were selected according to matched age, fasting status, and race. Main Outcome Measure  Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels of E-selectin, ICAM-1, and VCAM-1. Results  Baseline median levels of the biomarkers were significantly higher among cases than among controls (E-selectin, 61.2 vs 45.4 ng/mL; ICAM-1, 264.9 vs 247.0 ng/mL; VCAM-1, 545.4 vs 526.0 ng/mL [all P values <=0.004]). Elevated E-selectin and ICAM-1 levels predicted incident diabetes in logistic regression models conditioned on matching criteria and adjusted for body mass index (BMI), family history of diabetes, smoking, diet score, alcohol intake, activity index, and postmenopausal hormone use. The adjusted relative risks for incident diabetes in the top quintile vs the bottom quintiles were 5.43 for E-selectin (95% confidence interval [CI], 3.47-8.50), 3.56 for ICAM-1 (95% CI, 2.28-5.58), and 1.12 for VCAM-1 (95% CI, 0.76-1.66). Adjustment for waist circumference instead of BMI or further adjustment for baseline levels of C-reactive protein, fasting insulin, and hemoglobin A_1c or exclusion of cases diagnosed during the first 4 years of follow-up did not alter these associations. Conclusion  Endothelial dysfunction predicts type 2 diabetes in women independent of other known risk factors, including obesity and subclinical inflammation.

Higher iron stores (reflected by an elevated ferritin concentration and a lower ratio of transferrin receptors to ferritin)
are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors (JAMA [2004] 291:711-717) Context  Type 2 diabetes is a common manifestation of hemochromatosis, a disease of iron overload. However, it is not clear whether higher iron stores predict the development of type 2 diabetes in a healthy population. Objective  To examine plasma ferritin concentration and the ratio of the concentrations of transferrin receptors to ferritin in relation to risk of type 2 diabetes. Design, Setting, and Participants  Prospective nested case-control study within the Nurses' Health Study cohort. Of the 32 826 women who provided blood samples during 1989-1990 and were free of diagnosed diabetes, cardiovascular disease, and cancer, 698 developed diabetes during 10 years of follow-up. The controls (n = 716) were matched to cases on age, race, and fasting status; and on body mass index (BMI) for cases in the top BMI decile. Main Outcome Measure  Incident cases of type 2 diabetes. Results  Among cases, the mean (SD) concentration of ferritin was significantly higher (109 [105] vs 71.5 [68.7] ng/mL for controls; P<.001 for difference) and the mean (SD) ratio of transferrin receptors to ferritin was significantly lower (102 [205] vs 141 [340], respectively; P = .01). In conditional logistic regression stratified on the matching factors and controlled for BMI and other diabetes risk factors, the multivariate relative risks [RRs] of incident type 2 diabetes across increasing quintiles of ferritin were 1.00, 1.09 (95% confidence interval [CI], 0.70-1.70), 1.26 (95% CI, 0.82-1.95), 1.30 (95% CI, 0.83-2.04), and 2.68 (95% CI, 1.75-4.11) (P<.001 for trend). The RRs across increasing quintiles of transferrin receptors to ferritin ratio were 2.44 (95% CI, 1.61-3.71), 1.00 (95% CI, 0.64-1.56), 1.13 (95% CI, 0.73-1.74), 0.99 (95% CI, 0.64-1.53), and 1.00 (P = .01 for trend). Further adjustment for an inflammatory marker (C-reactive protein) did not change the results appreciably. The associations persisted within strata defined by levels of BMI, menopausal status, alcohol consumption, and C-reactive protein. Conclusion  Higher iron stores (reflected by an elevated ferritin concentration and a lower ratio of transferrin receptors to ferritin) are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors.

• ADP-ribosylation factor 6 regulates insulin secretion through plasma membrane phosphatidylinositol (Proc. Natl. Acad. Sci. USA, [2003] 10.1073/pnas.2232129100) 4,5-bisphosphate ADP-ribosylation factor 6 (ARF6) is a small GTP-binding protein that regulates peripheral vesicular trafficking and actin cytoskeletal dynamics, and it has been implicated as critical to regulated secretion. Expression of a dominant-inhibitory ARF6 mutant, ARF6(T27N), impaired glucose-, depolarization-, and gamma-thio-GTP-stimulated insulin secretion in the pancreatic ß-cell line, MIN6. In response to depolarization, MIN6 cells expressing ARF6(T27N) displayed an unaltered initial fast phase but an impaired subsequent slow phase of insulin secretion. Actin cytoskeletal disassembly with latrunculin A enhanced insulin secretion, whereas stabilization with jasplakinolide inhibited secretion, consistent with the actin cytoskeleton serving as a barrier to exocytosis in these cells. ARF6(T27N) led to a depolarization-dependent reduction in the levels of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] with a time course that paralleled the inhibition of secretion. Moreover, blockade of PI(4,5)P₂-dependent events by expression of a lipid-binding protein resulted in inhibition of depolarization-induced secretion in a manner identical to ARF6(T27N). These results indicate that ARF6 is required to sustain adequate levels of PI(4,5)P₂ during periods of increased PI(4,5)P₂ metabolism such as regulated secretion.

Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR (J. Clin. Invest.[2003]112:1223-1233 doi:10.1172/JCI200317222) Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2^–/– murine embryo fibroblast cultures display early senescence with overexpression of p21^CIP1/WAF1 that is rescued by loss of TP53. Tsc2^–/–TP53^–/– cells, as well as tumors from Tsc2^+/– mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2^–/–TP53^–/– cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2^–/–TP53^–/– and Tsc1^–/– cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFR-a and PDGFRß expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRß in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.

• Tumor Necrosis Factor-alpha Inhibits Insulin’s Stimulating Effect on Glucose Uptake and Endothelium-Dependent Vasodilation in Humans (Circulation [2003]108:1815) Background— Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Methods and Results— Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220±44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by N^G-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha was smaller (P<0.001); TNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. ^f Conclusion— These results support the concept that TNF-^alpha could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.

The insulin/IGF-I pathway controls yeast, nematode, fruit fly, and rodent life spans and is related to the aging process in humans (Am J Physiol Endocrinol Metab [2003] 285:10.1152, E1064-E1071) Although the underlying mechanisms of longevity are not fully understood, it is known that mutation in genes that share similarities with those in humans involved in the insulin/insulin-like growth factor I (IGF-I) signal response pathway can significantly extend life span in diverse species, including yeast, worms, fruit flies, and rodents. Intriguingly, the long-lived mutants, ranging from yeast to mice, share some important phenotypic characteristics, including reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-I plasma levels. Such genetic homologies and phenotypic similarities between insulin/IGF-I pathway mutants raise the possibility that the fundamental mechanism of aging may be evolutionarily conserved from yeast to mammals. Very recent findings also provide novel and intriguing evidence for the involvement of insulin and IGF-I in the control of aging and longevity in humans. In this study, we focus on how the insulin/IGF-I pathway controls yeast, nematode, fruit fly, and rodent life spans and how it is related to the aging process in humans to outline the prospect of a unifying mechanism in the genetics of longevity.

• Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle (PNAS [2003] 100:11110-11115) We have shown previously that mice with a targeted disruption in the stearoyl-CoA desaturase 1 gene (SCD1^-/-) have increased insulin sensitivity compared with control mice. Here we show that the SCD1^-/- mice have increased insulin signaling in muscle. The basal tyrosine phosphorylation of the insulin receptor and insulin receptor substrates 1 and 2 are elevated. The tyrosine phosphorylation of insulin-like growth factor-1 receptor was similar between SCD1^+/+ and SCD1^-/- mice. The association of insulin receptor substrates 1 and 2 with the alpha-p85 subunit of phosphatidylinositol 3-kinase as well as the phosphorylation of Akt-Ser-473 and Akt-Thr-308 are also elevated in the SCD1^-/- mice. Interestingly, the mRNA levels, protein mass, and activity of the protein-tyrosine phosphatase-1B implicated in the attenuation of the insulin signal are reduced in the SCD1^-/- mice, whereas the levels of the leukocyte antigen-related protein phosphatase are similar between two groups of mice. The content of glucose transporter 4 in the plasma membrane and basal as well as insulin-mediated glucose uptake are increased in the SCD1^-/- mice. In addition, the muscle glycogen content and the activities of glycogen synthase and phosphorylase are increased in the SCD1^-/- mice. We hypothesize that loss of SCD1 function induces increased insulin signaling at least in part by a reduction in the expression of protein-tyrosine phosphatase 1B. SCD1 could be a therapeutic target in the treatment of diabetes.

Transcriptional corepressor Ct-BP could serve as a metabolic (redox) sensor (Proc. Natl. Acad. Sci. USA [2003]10:1073) Carboxyl-terminal binding protein (CtBP) is a transcriptional corepressor originally identified through its ability to interact with adenovirus E1A. The finding that CtBP-E1A interactions were regulated by the nicotinamide adeninine dinucleotides NAD⁺ and NADH raised the possibility that CtBP could serve as a nuclear redox sensor. This model requires differential binding affinities of NAD⁺ and NADH, which has been controversial. The structure of CtBP determined by x-ray diffraction revealed a tryptophan residue adjacent to the proposed nicotinamide adenine dinucleotide binding site. We find that this tryptophan residue shows strong fluorescence resonance energy transfer to bound NADH. In this report, we take advantage of these findings to measure the dissociation constants for CtBP with NADH and NAD⁺. The affinity of NADH was determined by using fluorescence resonance energy transfer. The binding of NADH to protein is associated with an enhanced intensity of NADH fluorescence and a blue shift in its maximum. NAD⁺ affinity was estimated by measuring the loss of the fluorescence blue shift as NADH dissociates on addition of NAD⁺. Our studies show a >100-fold higher affinity of NADH than NAD⁺, consistent with the proposed function of CtBP as a nuclear redox sensor. Moreover, the concentrations of NADH and NAD⁺ required for half-maximal binding are approximately the same as their concentrations in the nuclear compartment. These findings support the possibility that changes in nuclear nicotinamide adenine dinucleotides could regulate the functions of CtBP in cell differentiation, development, or transformation.

• Autonomic Nervous System (ANS) dysfunction may be associated with the development of diabetes in healthy adults (Circulation. [2003]107:2190.)Background- Autonomic nervous system (ANS) dysfunction has been correlated with fasting insulin and glucose, independent of clinically diagnosed diabetes. We tested whether men and women (aged 45 to 64 years) from the Atherosclerosis Risk In Communities study (n=8185) with ANS dysfunction, estimated by high heart rate (HR) and low HR variability (HRV), were at increased risk for developing type 2 diabetes.Methods and Results- Supine HR and HRV indices were measured for 2 minutes at baseline; indices were divided into quartiles for analyses. From 1987 to 1998 (mean follow-up 8.3 years), there were 1063 cases of incident diabetes. The relative risk (RR) of developing diabetes for participants with low-frequency (LF) power (0.04 to 0.15 Hz) HRV in the lowest quartile (<7.7 ms²) compared with the highest quartile (>=38.9 ms²) was 1.2 (95% CI 1.0-1.4) after adjustment for age, race, sex, study center, education, alcohol drinking, current smoking, prevalent coronary heart disease, physical activity, and body mass index. Participants in the uppermost (>72.7 bpm) versus the lowest (<=60.1 bpm) quartile of HR had a 60% increased risk (95% CI 33%-92%) of developing diabetes. Results were similar when the sample was restricted to participants with normal fasting glucose (glucose <6.1 mmol/L) at baseline (n=7192) or when adjusted for baseline glucose (HR quartile 4 versus quartile 1, RR=1.4, 95% CI 1.2-1.7). Conclusions- These findings suggest that ANS dysfunction may be associated with the development of diabetes in healthy adults

Enalapril significantly reduces the incidence of diabetes in patients with left ventricular dysfunction, especially those with impaired FPG. (Circulation [2003] 107:1291.) Background— Diabetes mellitus is a predictor of morbidity and mortality in patients with heart failure. The effect of angiotensin-converting enzyme (ACE) inhibitors on the prevention of diabetes in patients with left ventricular dysfunction is unknown. The aim of this retrospective study was to assess the effect of the ACE inhibitor enalapril on the incidence of diabetes in the group of patients from the Montreal Heart Institute enrolled in the Studies of Left Ventricular Dysfunction (SOLVD). Methods and Results— Clinical charts were evaluated for fasting plasma glucose (FPG) levels by blinded reviewers. A diagnosis of diabetes was made when a FPG >=126 mg/dL (7 mmol/L) was found at 2 visits (follow-up, 2.9±1.0 years). Of the 391 patients enrolled at the Montreal Heart Institute, 291 were not diabetic (FPG <126 mg/dL without a history of diabetes), 153 of these were on enalapril and 138 were on placebo. Baseline characteristics were similar in the 2 groups. Forty patients developed diabetes during follow-up, 9 (5.9%) in the enalapril group and 31 (22.4%) in the placebo group (P<0.0001). By multivariate analysis, enalapril remained the most powerful predictor for risk reduction of developing diabetes (hazard ratio, 0.22; 95% confidence intervals, 0.10 to 0.46; P<0.0001). The effect of enalapril was striking in the subgroup of patients with impaired FPG (110 mg/dL [6.1 mmol/L] <=FPG <126 mg/dL) at baseline: 1 patient (3.3%) in the enalapril group versus 12 (48.0%) in the placebo group developed diabetes (P<0.0001). Conclusions— Enalapril significantly reduces the incidence of diabetes in patients with left ventricular dysfunction, especially those with impaired FPG.

• ^{Plasma Brain Natriuretic Peptide (BNP) and Norepineprine (NE) Correlate with Morbidity & Mortality in CHF(Circulation [2003] 107:1278.)}

Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity (NEJM [2002] 346:802-810) Background Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents.Methods All subjects underwent a two-hour oral glucose-tolerance test (1.75 mg of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose. Results Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance. Conclusions Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.

• Defective Akt activation is associated with glucose- but not glucosamine-induced insulin resistance (Am J Physiol [2002] 282: e497-506) 3T3-L1 adipocytes develop insulin-resistant glucose transport upon preincubation with high glucose or glucosamine, provided insulin (0.6 nM) is present during preincubation. Insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity is unaffected (30). Total cellular IRS-1, PI 3-kinase, or Akt concentrations were unchanged. Akt activation in subcellular fractions was assessed by immunoblotting with two phospho-Akt-specific antibodies. Upon acute 100 nM insulin stimulation, plasma membrane (PM)-associated phospho-Akt was highest in cells preincubated in low glucose with no insulin, less in high glucose with no insulin, even less in low glucose+insulin, and lowest in high glucose+insulin. Only high glucose+insulin caused insulin-resistant glucose transport. Acute insulin stimulation increased total PM-Akt about twofold after preincubation without insulin in low or high glucose. Preincubation with 0.6 nM insulin decreased Akt PM translocation by ~25% in low and ~50% in high glucose. Preincubation with glucosamine did not affect Akt phosphorylation or translocation. Conclusions: chronic exposure to high glucose or insulin downregulates acute insulin-stimulated Akt activation, acting synergistically distal to PI 3-kinase. Maximal insulin activates more Akt than required for maximal glucose transport stimulation. Insulin resistance may ensue when PM-associated phospho-Akt decreases below a threshold. High glucose and glucosamine cause insulin resistance by different mechanisms in 3T3-L1 adipocytes.

Inflammation may be an etiologic factor for diabetes in women  (American Journal of Epidemiology [2002]155: 57-64) Emerging data suggest that inflammation may play a role in the etiology of diabetes mellitus. Because few prospective studies have addressed this issue, the author examined the relation between leukocyte count and erythrocyte sedimentation rate and diabetes incidence using data from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (from 19711975 to 19921993). Of 8,352 participants included in the analysis, 878 developed incident diabetes during the approximately 20-year follow-up. After adjustment for age, smoking status, systolic blood pressure, cholesterol concentration, use of antihypertensive medication, recreational exercise, nonrecreational activity, alcohol use, and body mass index, the hazard ratios from proportional hazards for participants with a leukocyte count of 9.1 x 10⁹/liter compared with participants with a leukocyte count of 5.7 x 10⁹/liter were 1.33 (95% confidence interval (CI): 0.81, 2.19) for men and 1.68 (95% CI: 1.21, 2.34) for women. The adjusted hazard ratios for participants with an erythrocyte sedimentation rate of 26 mm/hour compared with participants with an erythrocyte sedimentation rate of 5 mm/hour were 1.85 (95% CI: 0.97, 3.54) for men and 0.83 (95% CI: 0.47, 1.44) for women. These results provide limited support to the hypothesis that inflammation is an etiologic factor for diabetes.

• Increased resistin expression in abdominal fat could explain the increased risk of type 2 diabetes associated with central obesity  (Lancet [2002] 359)  Resistin, an adipocyte-derived cytokine, causes insulin resistance and glucose intolerance in mice. We investigated whether resistin expression was higher in human abdominal adipose tissue than other adipose tissue depots. We extracted RNA from 32 adipose tissue samples (13 subcutaneous abdominal, seven omentum, six thigh, and six breast). Quantitative PCR was used to determine resistin mRNA expression. Resistin mRNA concentrations were similar in both the subcutaneous abdominal and omental depots. The abdominal depots showed a 418% increase in resistin mRNA expression compared with the thigh. Increased resistin expression in abdominal fat could explain the increased risk of type 2 diabetes associated with central obesity.

Increased adipocyte 11 HSD-1 activity mimics visceral obesity and the metabolic syndrome.(Science [2001] 294: 2071-2072)The adverse metabolic consequences of obesity are best predicted by the quantity of visceral fat. Excess glucocorticoids produce visceral obesity and diabetes, but circulating glucocorticoid levels are normal in typical obesity. Glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD-1). We created transgenic mice overexpressing 11ß HSD-1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11ß HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.

• Women with long or highly irregular menstrual cycles have a significantly increased risk for developing type 2 DM that is not completely explained by obesity. (JAMA [2001] 286:2421-2426) Context  Although oligomenorrhea has been associated cross-sectionally with insulin resistance and glucose intolerance, it is not known whether oligomenorrhea is a marker for increased future risk of type 2 diabetes mellitus (DM).Objective  To prospectively assess risk of type 2 DM in women with a history of long or highly irregular menstrual cycles.Design and Setting  The Nurses' Health Study II, a prospective observational cohort study.Participants  A total of 101 073 women who had no prior history of DM and who reported their usual menstrual cycle pattern at age 18 to 22 years on the baseline (1989) questionnaire.Main Outcome Measure  Incident reports of DM, with follow-up through 1997, compared among women categorized by menstrual cycle length (5 categories).Results  During 564 333 person-years of follow-up, there were 507 cases of type 2 DM. Compared with women with a usual cycle length of 26 to 31 days (referent category) at age 18 to 22 years, the relative risk (RR) of type 2 DM among women with a menstrual cycle length that was 40 days or more or was too irregular to estimate was 2.08 (95% confidence interval [CI], 1.62-2.66), adjusting for body mass index at age 18 years and several other potential confounding variables. The RR of type 2 DM associated with long or highly irregular menstrual cycles was greater in obese women, but was also increased in nonobese women (at body mass indexes at age 18 years of <25, 25-29, and >30 kg/m2, RRs were 1.67 [95% CI, 1.14-2.45], 1.74 [95% CI, 1.07-2.82], and 3.86 [95% CI, 2.33-6.38], respectively).Conclusion  Women with long or highly irregular menstrual cycles have a significantly increased risk for developing type 2 DM that is not completely explained by obesity.

Ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals. (JAMA. [2001]286:1882-1885)  Context  Type 2 diabetes is a growing clinical and public health problem. Preventive efforts related to lifestyle modification are not always successful; therefore, alternative prevention strategies need to be studied. Objective  To investigate the effectiveness of ramipril, an angiotensin-converting enzyme inhibitor, in preventing diabetes among high-risk persons. Design, Setting, and Participants  The randomized, controlled Heart Outcomes Prevention Evaluation trial of 5720 patients older than 55 years without known diabetes but with vascular disease who were followed up for a mean of 4.5 years. The study included 267 hospitals in 19 countries and was conducted between 1994 and 1999.Intervention  Patients were randomly assigned to receive ramipril, up to 10 mg/d (n = 2837), or placebo (n = 2883).Main Outcome Measure  Diagnosis of diabetes determined from self-report at follow-up visits every 6 months, compared between the 2 groups.Results  One hundred and two individuals (3.6%) in the ramipril group developed diabetes compared with 155 (5.4%) in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.51-0.85, P<.001). Similar results were noted when different diagnostic criteria were used; in the ramipril group, the RR for diagnosis of diabetes and hemoglobin A_1c greater than 110% was 0.60 (95% CI, 0.43-0.85), for initiation of glucose-lowering therapy, 0.56 (95% CI, 0.41-0.77), and for both, 0.51 (95% CI, 0.34-0.76). These effects were also consistently seen in several subgroups examined.Conclusions  Ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals. Because these results have important clinical and public health implications, this hypothesis requires prospective confirmation.                                       

• Disruption of Sur2-containing KATP channels [?hyperpolarization -ed]enhances insulin-stimulated glucose uptake in skeletal muscle (PNAS [2001] 98 11760-11764) ATP-sensitive potassium channels (K_ATP) are involved in a diverse array of physiologic functions including protection of tissue against ischemic insult, regulation of vascular tone, and modulation of insulin secretion. To improve our understanding of the role of K_ATP in these processes, we used a gene-targeting strategy to generate mice with a disruption in the muscle-specific K_ATP regulatory subunit, SUR2. Insertional mutagenesis of the Sur2 locus generated homozygous null (Sur2^-/-) mice and heterozygote Sur2^+/-) mice that are viable and phenotypically similar to their wild-type littermates to 6 weeks of age despite, respectively, half or no SUR2 mRNA expression or channel activity in skeletal muscle or heart. Sur2^-/- animals had lower fasting and fed serum glucose, exhibited improved glucose tolerance during a glucose tolerance test, and demonstrated a more rapid and severe hypoglycemia after administration of insulin. Enhanced glucose use was also observed during in vivo hyperinsulinemic euglycemic clamp studies during which Sur2^-/- mice required a greater glucose infusion rate to maintain a target blood glucose level. Enhanced insulin action was intrinsic to the skeletal muscle, as in vitro insulin-stimulated glucose transport was 1.5-fold greater in Sur2^-/- muscle than in wild type. Thus, membrane excitability and K_ATP activity, to our knowledge, seem to be new components of the insulin-stimulated glucose uptake mechanism, suggesting possible future therapeutic approaches for individuals suffering from diabetes mellitus

Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action (Obesity Research [2001] 9:414-417 ) Objective: Plasma concentrations of interleukin-6 (IL-6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL-6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes. Research Methods and Procedures: Fasting plasma IL-6 concentrations (enzyme-linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men). Results: Fasting plasma IL-6 concentrations were positively correlated with percentage of body fat (r = 0.26, p = 0.049) and negatively correlated with M (r = -0.28, p = 0.031), but were not related to acute insulin response (r = 0.13, p = 0.339). After adjusting for percentage of body fat, plasma IL-6 was not related to M (partial r = -0.23, p = 0.089). Discussion: Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL-6 and insulin action seems to be mediated through adiposity.

• IKK-ß May Underly the Inflammatory Etiology of the Dysmetabolic Syndrome (Science [2001] 293:1673-1677)

MI Presaged by Increased HbA1c (European Heart Journal [2001] 22:1102-1110)

• Increased PAI-1 in the arterial wall associates with diabetes. (Arteriosclerosis, Thrombosis, and Vascular Biology. [2001]21:1378-1382.)

Diabetes and ischemic heart disease interact to accelerate the progression of myocardial dysfunction(JACC [2000] 38:421-428)

• Acrp30 is a potent insulin enhancer linking adipose tissue and whole-body glucose metabolism. (Nature medicine[2001] 7:947-953)

Elevated levels of CRP and IL-6 predict the development of type 2 DM. These data support a role for inflammation in diabetogenesis. (JAMA. [2001] 286:327-334)

• Tissue-specific deletion of Foxa2 in pancreatic cells results in hyperinsulinemic hypoglycemia (Genes Dev. [2001] 15:1706-1715)

Glycemic Control is Without Effect upon Hepatic Lipase in Type 1 Diabetes (ADA 61st SS, Abstract #2197-PO, June 2001)

• Gamma Globulin Levels Predict Type 2 Diabetes in the Pima Indian Population (ADA 61st SS, Abstract #154-OR, June 2001)

Insulin Resistance Is More Predictive Than Glycaemia of Coronary Heart Disease in a Randomized Controlled Trial of Farglitazar (ADA 61st SS, Abstract #2159-PO, June 2001)

• Elevated White Blood Cell Count Predicts Type 2 Diabetes in Pima Indians (ADA 61st SS, Abstract #2266-PO, June 2001)

·Dyslipidemia Is Predictive of Macrovascular Events in Type 2 Diabetes While Glycemia Is Not (ADA 61st SS, Abstract #1910-PO, June 2001)

• · Pre-DM subjects may have an increased risk of CVD even prior to the onset of DM (ADA 61st SS, Abstract #118-OR, Sunday, 24 June 2001 )

UCP2 correlates with leptin levels and may be a a key component of ß-cell glucose sensing (Cell [2001] 105: 745-755)

• ·Losing Weight Returns Compromised T-Cell Function To Normal Via Reduced a-TNF (Clin Endocrinol [2001] 54(3):347-354 )

MSH/ACTH[4-10] reduces adiposity, leptin, and insulin (JCEM [2000] 86:1144-1148)

• Leptin significantly increases Hormone Sensitive Lipase activity in J774.2 macrophages (Diabetes [2001] 50:955-961)

Increased plasminogen activator inhibitor activity and diabetes predict subsequent coronary events in patients with angina pectoris" (Ann Med [2001] 33:206-212)

• 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 aPhosphatidylInositol-3kinase (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 Aand Ckinases - 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-MMAC.....(Proc. Natl. Acad. Sci. USA, [2001] 10.1073/pnas.051042298

• The hormone resistin links obesity to diabetes (Nature {2001] 409: 307-312)

·Overweight children have higher concentrations of C-reactive protein and higher white blood cell counts than normal weight children, indicating low-grade systemic inflammation, which may predict future cardiovascular disease and diabetes (Pediatrics [2001] 107:e13)

• Obesity, but only in individuals with a family history of diabetes or hypertension, strongly associates with the Insulin Resistance Syndrome (Genetic Epidemiology [2000] 19: 395-409)

Pravastatin is the latest of anti-atherosclerotic agents to be shown to delay glucose excursions as well the development of Type 2 Diabetes Mellitus (Circulation.2001 103:357)

• Appetite-Stimulating Gene Found on Chromosome 19 and 100% Homologous in Humans and Rats is 81% Homomologous in Earthworms (EASD Symposium on AP, Wednesday 20 Sep 2000)

Factors associated with abnormal glucose metabolism may play an important role in the etiology of pancreatic cancer (JAMA [2000]283:2552-2558)

• HCV-infected subjects are four times more likely to have type 2 diabetes than those without HCV(DG News, 14 April 2000)

Targeted Overactivity of beta- Cell K_ATP Channels Induces Profound Neonatal Diabetes (Cell [2000]:100,534-654)

• Growth hormone therapy in children is associated with a *6-fold* higher risk of type 2 diabetes (34·4/100000 years) AND the type 2 diabetes does NOT resolve after GH therapy is stopped (Lancet [2000] 355:610-613)

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

• Peroxisome ProliferatorActivated Receptor gamma Gene Locus Is Related to Body Mass Index and Lipid Values in Healthy Nonobese Subjects

Short-term, adenovirus-vectored 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

• (a) Human PPAR gamma mRNA expression is most abundant in adipose tissue, but lower level expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma2/gamma1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity

• Higher BMI is associated with higher CRP concentrations, even among young adults aged 17 to 39 years - these findings suggest a state of low-grade systemic inflammation in overweight and obese persons

• 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). Conclusions  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.

Leptin binds to VMH Kir6.2/SUR1 receptors(J Physiol. [1999]1 ( Pt 2):439-52)
1. Patch-clamp recordings were made from rat ventromedial hypothalamic neurones in slices of brain tissue in vitro. In cell-attached recordings, removal of extracellular glucose or metabolic inhibition with sodium azide reduced the firing rate of a subpopulation of cells through the activation of a 65 pS channel that was blocked by the sulphonylureas tolbutamide and glibenclamide.
2. In whole-cell patch-clamp recordings, in the absence of ATP in the electrode solution, glucose-receptive neurones gradually hyperpolarized due to the induction of an outward current at -60 mV. This outward current and the resultant hyperpolarization were blocked by the sulphonylureas tolbutamide and glibenclamide.
3. In recordings where the electrode solution contained 4 mM ATP, this outward current was not observed. Under these conditions, 500 microM diazoxide was found to induce an outward current that was blocked by tolbutamide.
4. In cell-attached recordings diazoxide and the active fragment of leptin (leptin 22-56) reduced the firing rate of glucose-receptive neurones by the activation of a channel with similar properties to that induced by removal of extracellular glucose.
5. Reverse transcription followed by the polymerase chain reaction using cytoplasm from single glucose-receptive neurones demonstrated the expression of the ATP-sensitive potassium (KATP) channel subunits Kir6.1 and SUR1 but not Kir6.2 or SUR2.
6. It is concluded that glucose-receptive neurones within the rat ventromedial hypothalamus exhibit a KATP channel current with pharmacological and molecular properties similar to those reported in other tissues.

PMID: 10050011 [PubMed - indexed for MEDLINE]

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

Type 2 Diabetes in whites, but not blacks, is inversely associated with serum magnesium levels

• Beta Cell Failure Gets Almost All Type 2 Diabetics In Time

Plasma Leptin Associated with Insulin-Resistant Hypertension

• The agouti gene product stimulates pancreatic ß-cell Ca²⁺ signaling and insulin release

Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity

• Insulin resistance in Sicilians (and in "transient perinatal diabetes") has been linked to the PC-1 region of Chromosome 6[but in Mexican- Americans it has been variously linked to Chromosomes 2, 6, 10q, 15, the SUR-1 receptor, and TRP64ARG beta 3AR ]

The allele frequency of the PPAR gamma 2 missense mutation Pro12Ala variant is 0.12 in Caucasian Americans, 0.10 in Mexican Americans, 0.08 in Samoans, 0.03 in African Americans, 0.02 in Nauruans, and 0.01 in Chinese

• C-Reactive Protein Strongly Associates with Measures of Obesity, Insulin Resistance, and Subclinical Atherosclerosis in Healthy, Middle-Aged Women

Low levels of leptin appear to reverse diabetes in mouse model of congenital lipodystrophy

• Leptin differentially produced in subcutaneous and omental fat and has a U-shaped dose-response curve significantly inhibiting insulin actionin omental adipocytes

Might inflammatory markers (particularly orosomucoid) predict Type 2 Diabetes?

• Adipose-Cells secrete IL-6 which correlates with BMI, TNF-alfa, insulin resistance, markers of endothelial dysfunction, and the inflammatory marker C-Reactive Protein (CRP)

Leptin induces IL-1 which causes fever and anorexia in rats

• The Kidney is probably as important as the Liver in Gluconeogenesis

In men, overweight at 25 years of age strongly predicts diabetes risk in middle age

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