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Nutrition

  • High intake of refined carbohydrate, particularly among overweight or obese women, is associated with hemorrhagic stroke risk (Am J Epidemiol [2005] 161(2):161-169) The associations of dietary carbohydrate, glycemic index, and glycemic load with stroke risk were examined among 78,779 US women who were free of cardiovascular disease and diabetes in 1980 and completed a food frequency questionnaire. During an 18-year follow-up, 1,020 stroke cases were documented (including 515 ischemic and 279 hemorrhagic). In analyses adjusting for nondietary risk factors and cereal fiber, carbohydrate intake was associated with elevated risk of hemorrhagic stroke when the extreme quintiles were compared (relative risk = 2.05, 95% confidence interval: 1.10, 3.83; ptrend = 0.02), but not with ischemic stroke. The positive association between carbohydrate intake and stroke risk was most evident among women with a body mass index of >=25 kg/m2. Likewise, dietary glycemic load was positively associated with total stroke among only those women whose body mass index was >=25 kg/m2. Cereal fiber intake was inversely associated with total and hemorrhagic stroke risk; for total stroke, relative risk = 0.66 (95% confidence interval: 0.52, 0.83; ptrend = 0.001) and for hemorrhagic stroke, relative risk = 0.51 (95% confidence interval: 0.33, 0.78; ptrend = 0.01). Findings suggest that high intake of refined carbohydrate is associated with hemorrhagic stroke risk, particularly among overweight or obese women. In addition, high consumption of cereal fiber was associated with lower risk of total and hemorrhagic stroke.

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 Ay 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.

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

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

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

Guava fruit may benefit type 2 diabetics

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

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

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-1beta 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 AUC0–240 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+ (KATP) 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 KATP currents from RINm5F cells with a half-maximally inhibitory concentration of 81 small mu, GreekM, whereas the application of norfloxacin (at concentrations up to 300 small mu, GreekM) had only minor effects on KATP currents. Block of pancreatic small beta, Greek-cell KATP 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 IKr (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 small beta, Greek-cell KATP 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 CI-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 mellitus1, 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 weight3-5, 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 compounds8, 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)

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)

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)

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)

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 

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

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

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)

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

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.

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

FDA warns Bristol-Myers Squibb about Glucophage adverse event reporting

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

Melanocyte Stimulating Hormone found to have appetite-suppressant activity

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

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

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)

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

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

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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.

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 (ge20 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 Ay 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 A1c 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 phos