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Control is good and less expensive....

"Intensive blood glucose control in patients with type 2 diabetes significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications"BMJ [2000]320:1373-1378
"The diabetes attributable risk for dementia of 8.8% suggests that diabetes may contribute to the clinical syndrome in a substantial proportion of all dementia patients.....";
Glycemic control is subject to intervention. Better control may decrease hospitalization among people with diabetes.
Thus, there is considerable potential for reducing health care costs
"Poor diabetic perioperative glycemic control is a risk factor for infectious complications...........";
"Stress Worsens Diabetic Control and Treatment of Depression Improves Diabetic Control............";
"Jacuzzis may *help control [type 2] diabetes*..........";
"ADA recommends admission of all diabetics who are badly out of control.....";

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

"Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action (Obesity Research [2001] 9:414-417 )
"Type 2 diabetes can be delayed by changes in the lifestyles of high-risk subjects." (N Engl J Med [2001] 344:1343-50
"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)";
"Obesity continues to increase rapidly in the United States. To alter this trend, strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority:-The prevalence of obesity (defined as a body mass index >30 kg/m2) increased from 12.0% in 1991 to 17.9% in 1998. A steady increase was observed in all states; in both sexes; across age groups, races, educational levels; and occurred regardless of smoking status. The greatest magnitude of increase was found in the following groups: 18- to 29-year-olds (7.1% to 12.1%), those with some college education (10.6% to 17.8%), and those of Hispanic ethnicity (11.6% to 20.8%). The magnitude of the increased prevalence varied by region (ranging from 31.9% for mid Atlantic to 67.2% for South Atlantic, the area with the greatest increases) and by state (ranging from 11.3% for Delaware to 101.8% for Georgia, the state with the greatest increases).....";
"Central abdominal fat is inversely and independently related to insulin sensitivity after adjusting for total fat in women in the early postmenopausal period. Efforts to reduce either subcutaneous abdominal fat or intraabdominal fat should be helpful in reducing the risk of noninsulin-dependent diabetes mellitus in postmenopausal women....."

  Hypothesis #NDC1.00 -
Obesity + beta-cell defect => Type 2 Diabetes
- beta-cell defect => Morbid Obesity
  • Hypothesis #NDC1.01 -
  • The SUR-1/Kir6.2 complex is the Leptin Receptor [CONFIRMED]
    Hypothesis #NDC1.02 -
    • Obesity => leptin => decreased insulin secretion + increased insulin resistance => IGT
  • Hypothesis #NDC1.03 -
    IGT + beta-cell defect => Type 2 Diabetes

Obesity => Type 2 Diabetes
"How are obesity and Type 2 diabetes related?...........";
"Hopkins Study Shows Overweight Young Males are at Risk for the Development of Type 2 Diabetes...............";
"Data suggest that greater physical activity level is associated with substantial reduction in risk of type 2 diabetes, including physical activity of moderate intensity and duration. JAMA. 1999;282:1433-1439.....";
"BMI correlates with increased all-cause mortality in non-smoking Caucasian Americans (but not in non-smoking black Americans)..........";
"Peroxisome Proliferator–Activated Receptor gamma Gene Locus Is Related to Body Mass Index and Lipid Values in Healthy Nonobese Subjects .....";
Obesity => IL-6+TNF-alpha =>Leptin
"Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action (Obesity Research [2001] 9:414-417 )
Local [adipocyte] expression of TNF and plasma IL-6 are higher in subjects with obesity-related insulin resistance.(Am J Physiol -Endo/Metab [2001] 280: E745-E751)"
Tumor Necrosis Factor (TNF) impairs insulin signaling through Insulin Receptor Substrate-1 (IRS-1) by activation of a PhosphatidylInositol-3 kinase (PI-3k)/ Serine and threonine kinase c-Akt (cloned from directly transforming murine retrovirus AKT8, isolated from an AKR mouse Thymoma cell line) also known as Rac-alpha -Related to the A and C kinases - or protein kinase B-alpha (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, which is antagonized by [3' phospholipid-] Phosphatase and Tensin Homologue Deleted from Chromosome ten (PTEN/MUTATED IN MULTIPLE ADVANCED CANCERS 1-MMAC1)".....(Proc. Natl. Acad. Sci. USA, [2001] 10.1073/pnas.051042298)
"Is leptin the link between obesity and insulin resistance?.....";
"Leptin Levels Increase in Proportion to the Extent of Obesity.....";
Obesity => Leptin => Decreased Insulin Secretion via Opening K-ATP Channels
"Targeted Overactivity of beta- Cell KATP Channels Induces Profound Neonatal Diabetes (Cell [2000]:100,534-654).....";
"Expression of the functional leptin receptor mRNA is found in pancreatic islets and directly inhibits insulin secretion.....";
"The agouti gene product stimulates pancreatic beta-cell Ca2+ signaling and insulin release..........";
"Leptin suppresses insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells.....";
"Leptin binds to VMH Kir6.2/SUR1 receptors ";
"Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.....";
"Insulin occludes leptin activation of ATP-sensitive K+ channels in rat CRI-G1 insulin secreting cells";
"The Homeodomain of PDX-1 Mediates Multiple Protein-Protein Interactions in the Formation of a Transcriptional Activation Complex on the Insulin Promoter.....";;
Sulfonylureas - which prototypically close K-ATP channels - may also increase Leptin
"Sulfonylurea therapy is associated with increases in [insulin and] leptin levels despite weight loss.....";
"Dexamethasone stimulates leptin release from human adipocytes: unexpected inhibition by insulin.....";Obesity => Leptin => "U-shaped" Insulin Resistance Curve
Obesity => Leptin=>Downregulated PPAR-
gamma=>Enhanced Lipolysis and Decreased Lipogenesis
"Short-term adenovirus-induced hyperleptinemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma in epididymal fat; enzymes of fatty acid oxidation and their transcription factor, PPARalpha, normally low in adipocytes, are up-regulated, as are uncoupling proteins 1 and 2. This transformation of adipocytes from cells that store triglycerides to fatty acid-oxidizing cells is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, tumor necrosis factor alpha, and leptin, and by the appearance of the preadipocyte marker Pref-1....."
"Leptin administration to cultured rodent hepatocytes increased gluconeogenesis, decreased glycogenolysis, and decreased free fatty acid synthesis. Nevertheless, CNS injection of leptin in the same species improved measures of insulin tolerance....."(Rossetti L: Leptin regulation of hepatic glucose metabolism [Concurrent session: Leptin regulation of fuel metabolism]. 59th Annual Scientific Sessions of ADA, San Diego, CA, 1999);
"Plasma Leptin Associated with Insulin-Resistant Hypertension............";
"Leptin inhibits glycogen synthesis in the isolated soleus muscle of obese (ob/ob) mice.....";
"Low levels of leptin seem to reverse diabetes in mouse model of congenital lipodystrophy...........";
"Leptin appears to have a U-shaped effect on insulin resistance and is more active in visceral fat..................";
Obesity => Leptin => Decreases in (1) Agouti protein and (2) neuropeptide-Y =>
=> Increases in (3) melanocortin function and (4) satiety
"Hypothalamic agouti-related protein messenger ribonucleic acid [and Neuropeptide-Y mRNA] are inhibited by Leptin and stimulated by fasting.....";
"Agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, is intrically involved in leptin action.....";
"Melanocyte Stimulating Hormone appears to have appetite-suppressant activity.............";
"Leptin-associated mutations cause down-regulation of prepro-orexin gene expression.....";

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

Thiazolidinediones impact Leptin, PPAR-gamma, and K-ATP Channels
"Dominant negative mutations in human PPAR-gamma are associated with severe insulin resistance, diabetes mellitus and hypertension.....";
"Diazoxide- and leptin-activated K(ATP) currents show differential sensitivity to englitazone and ciclazindol in rat CRI-G1 insulin-secreting cell lines....";
"Thiazolidinediones - which decrease leptin message - appear to prevent diabetes in the hyperleptinemic db/db mouse................";
"A low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans

"Ciliary neurotrophic factor corrects obesity [and hyperinsulinemia] associated with leptin deficiency and resistance.....";
"An ascochlorin derivative, AS-6, reduces insulin resistance in the genetically obese diabetic mouse, db/db.....";
"Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes.....";
"Regulation of glucose metabolism and opening of K(ATP) channels in pancreatic beta-cells by NO.....";
"Interaction of vanadate with the cloned beta cell K(ATP) channel.....";
Mitochondrial K-ATP Channels and Cardiac Ischemia
"Diabetes or hyperglycemia impairs activation of mitochondrial KATP channels during infarction" (AJP - Heart Circ Physiol [2001] 280: Issue 4, H1744-H1750)
"Opening of sarcolemmal KATPchannels underlies ST elevation during ischemia" (Circulation Res. [2000] 87:837)
"Serum leptin is elevated in patients with coronary artery disease"

"Either glyburide or mitochondrial K(ATP) channel blocker 5-hydroxydecanoate abolish cardioprotection by YM934 in a concentration-dependent manner" J Pharmacol Exp Ther [1999] 291(2):710-716
"Results suggest that mitoK-atp channels are downstream of PKC in the mechanism of infarct-size limitation by A1-receptor activation and that the anti-infarct tolerance afforded by opening of mitoK-atp channels is associated with preservation of mitochondrial function during ischemia/reperfusion.....";
"Nitric Oxide (NO) directly activates mitoK-atp channels and potentiates the ability of diazoxide to open these channels. These results provide novel mechanistic links between NO-induced cardioprotection and mitoK-atp channels.....";
"ATP-regulated K+ channel in mitochondria: pharmacology and function.....";
"Regulation of mitochondrial KATP channel by redox agents.....";
"Rat liver GTP-binding proteins mediate changes in mitochondrial membrane potential and organelle fusion.....";

Mitochondrial Membranes , Mg++, Malate/Oxaloacetate Translocators, Gluconeogenesis, and, Ketoacidosis....

  Hypothesis #NDC2.00 - Gluconeogenic Hormones affect Malate/Oxaloacetate Translocators or Shuttles in the mitochondrial membranes to result in (1) Increased cytoplasmic levels of OAA and
(2) Decreased
mitochondrial levels of malic acid.

  • Hypothesis #NDC2.01 - Gluconeogenic hormones - particularly AVP - directly inhibit Malic Enzyme (malate dehydrogenase) in both mitochondrial matices and cytosol.
  • Hypothesis #NDC2.02 - Insulin enhances lipogenesis by increasing mitochondrial membrane permeability to citrate and over-riding inhibition of Malic Enzyme
  • Hypothesis #NDC2.03 - Lipolysis (FFA-CoA -oxidation) results in increased mitochondrial NADH(H+) to NAD+ ratios thus further inhibiting the already endergonic conversion of malate => oxaloacetate
  • Hypothesis #NDC2.04 - Malate/Oxaloacetate Translocators (MOT) are dependent on [Mg++]'s with lower levels resulting in (1) Increased cytoplasmic levels of OAA and (2) Decreased mitochondrial levels of malic acid

"Type 2 Diabetes in whites, but not blacks, is inversely associated with serum magnesium levels................";
"Mg2+ control of respiration in isolated rat liver mitochondria.....";

  • Hypothesis #NDC2.05 - Increased cytoplasmic levels of OAA are gluconeogenic and insulin-antagonistic
  • Hypothesis #NDC2.06 - Mitochondrial levels of malic acid which are decreased
    can result in decreased mitochondrial respiration

"The role of malate in regulating the rate of mitochondrial respiration in vitro.....";
"The role of malate in hormone-induced enhancement of mitochondrial respiration.....";
"Sources of intramitochondrial malate.....";
"Pyruvate/malate antiporter in rat liver mitochondria.....";
"Fumarate permeation in rat liver mitochondria: fumarate/malate and fumarate/phosphate translocators.....";
"Oxaloacetate permeation in rat kidney mitochondria: pyruvate/oxaloacetate and malate/oxaloacetate translocators.....";
"Oxaloacetate uptake into rat brain mitochondria and reconstruction of the malate/oxaloacetate shuttle.....";
"Capacity of the malate/oxaloacetate shuttle for transfer of reducing equivalents across the envelope of leaf chloroplasts.....";
"Aminooxyacetic acid inhibits the malate-aspartate shuttle in isolated nerve terminals and prevents the mitochondria from utilizing glycolytic substrates.....";
"Suppression of the mitochondrial oxidation of (-)-palmitylcarnitine by the malate-aspartate and alpha-glycerophosphate shuttles.....";
"Dehydroepiandrosterone and related steroids inhibit mitochondrial respiration in vitro.....";
"Regulation of oxalacetate metabolism in liver mitochondria. Evidence for nicotinamide adenine dinucleotide-malate dehydrogenase equilibrium and the role of phosphoenolpyruvate carboxykinase in the control of oxalacetate metabolism in intact guinea pig and rat liver mitochondria.....";
"Gluconeogenesis in vitro. Formation of glucose 6-phosphate from malate by a cell-free rat-liver system consisting of cytosol and mitochondria.....";
"Effect of alloxan on the transport of dicarboxylate, tricarboxylate, pyruvate and glutamate in isolated mouse liver mitochondria.....";
"Transport of malate and citrate into rat brain mitochondria under hypoxia and anesthesia.....";

  • Hypothesis #NDC2.07 - Vasopressin is the most potent gluconeogenic hormone in this context and can -
    in the absence of sufficient insulin-induced compensation - virtually abolish mitochondrial levels of OAA.
    This results in inability to metabolize Acetyl-CoA-SH and severe ketosis with acidosis
  • Hypothesis #NDC2.08 - Dehydration (through vomiting and/or diarrhea and/or sweating and/or hypodipsia)
    is the major pathophysiologic cause of DKA
    (acting through significantly increased ADH-Vasopressin release)
  • Hypothesis #NDC2.09
    On one level, adaptation to ongoing maximal leptin-enhanced lipolysis may confer some degree of resistance to ketosis
    Hypothesis #NDC2.10
    On another level, leptin may compete with vasopressin to maintain mitochondrial levels of OAA

"Vasopressin increases cytosolic sodium concentration in hepatocytes and activates calcium influx through cation-selective channels.....";
"Ketogenesis in isolated rat-liver mitochondria. IV. Oxaloacetate decarboxylation: consequences for metabolic calculations.....";
"Type I and II models of diabetes produce different modifications of K+ currents in rat heart: role of insulin.....";
"DKA can occur in patients classified as Type 2 based on previous insulin dose or subsequent oral Rx (Hispanics were mainly type 2 (47%), with 34% type 1 and 19% unknown. Whites were predominantly type 1 (80%), with 17% type 2 and 3% unknown. African Americans showed a slight preponderance of type 1 (53%), with a large number of type 2 patients (44%) and 3% unknown).....";

Inositols and and Insulin Resistance
"Insulin resistance, a result of reduced synthesis of prostaglandylinositol cyclic phosphate, a mediator of insulin action?
Regulation of cyclic PIP synthetase activity by oral antidiabetic and antihypertensive drugs
"Phosphoinositides decrease ATP sensitivity of the cardiac ATP-sensitive K(+) channel. A molecular probe for the mechanism of atp-sensitive inhibition.....";
"D-chiro-inositol effective in reducing insulin resistance................";
"Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity.................";

Genetic Markers of Insulin Resistance
"Insulin resistance in Sicilians has been linked to the PC-1 region of Chromosome 6 [but in Mexican-Americans it has been variously linked to Chromosomes 2,6,10,15,the SUR-1 receptor, and TRP64ARG";

Inflammation, and Type 2 Diabetes....
"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......";
"Could Type 2 Diabetes be an inflammatory disease? (Adipocyte IL-6 correlates with BMI, insulin resistance,endothelial dysfunction, TNF-alpha, AND CRP)..........";
"Leptin induces IL-1 which causes fever and anorexia in rats.....";
"C-Reactive Protein is Strongly-Associated With Measures of Obesity, Insulin Resistance, and Subclinical Atherosclerosis in Healthy, Middle-Aged Women...........";

Postprandial Metabolism and Atherosclerosis Risk....

Plasma leptin concentration is a novel and independent risk factor for CHD in WOSCOPS (Diabetologia [2001] 44 (Suppl 1): A315. EASD 37th Annual Meeting, #1209)
"Insulin treatment in type 2 diabetes induces profound metabolic modifications of lipoprotein, resulting in significant decrease of the intravascular residence time of very low density lipoprotein, intermediate density lipoprotein and low density lipoprotein particles. This is likely to make these particles less harmful. [Diabetologia (2000) 43: 27-35]....."
"In normal glucose tolerant offspring of type 2 diabetics, PAI-1 activity was correlated with plasma PAI-1 antigen level (r = 0.40, P = 0.02), fibrinogen (r = 0.45, P = 0.01), and HDL cholesterol (r = –0.36, P = 0.04). However, tPA antigen level, fasting and postload plasma glucose and insulin, total cholesterol, triglycerides, WHR, and BMI did NOT correlate with PAI-1 activity.....";
"Perturbed handling of postprandial triglycerides in normolipidemic CAD patients involves the accumulation of apo C-I–rich large VLDL particles and the generation of small, apo C-I– and cholesterol-rich VLDL remnants.....";
"Fasting Insulinemia Appears to Associate with Measures of BOTH Increased (t-PA antigen) AND Decreased (PAI-1 antigen) Fibrinolytic Potential.....";
"Diabetic subjects have significantly (P<0.001) more increased Dicarboxylic Acid (DA) excretion in urine than corresponding healthy subjects. The yields of DA's in each group decreased in the order adipic>suberic>sebacic acid. Being stable and easily detectable compounds, DA's may be considered potential markers of oxidative attack on PUFA in diabetes.....";
"Data suggest that LDL particle size should probably be added to the cluster of risk factors that characterize the insulin resistance syndrome. The association of 'insulin resistance' and LDL particle diameter, however, is not mediated directly through the level of insulinemia but via alterations in lipid metabolism.....";
"The greatest cost savings in diabetes care is to be had from reducing cardiovascular complications............";
"The American Heart Association has conceded - *Diabetes is now recognized as a major risk factor for coronary heart disease*...........";
"Should we recognize another class of diabetes called *Prandial Diabetes* with different risk factors? Why? The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease.........";
"A Common Mutation of the Insulin Receptor Substrate-1 Gene Is A Risk Factor for Coronary Artery Disease .....";
"Gender Difference in Postprandial Lipemia:-Importance of Visceral Adipose Tissue Accumulation.....";
"Postprandial hypertriglyceridemia - [NOT particle size] - along with Proinsulin - [NOT insulin] - and LDL-cholesterol -[NOT small-dense LDL] - found to correlate with atherosclerosis.............";
"*Nonfasting* Serum Glucose and Insulin Concentrations Significantly Increases the Risk of Stroke..........";
"IGT correlates with increased CHD, CHD-related, AND total mortality in Japanese-Americans..............";
"Fiber consumption predicts (fasting and postprandial) insulin levels, weight gain, and other CVD risk factors more strongly than total or saturated fat consumption. .....";
"Even though *secondarily* associating with increased cardiovascular disease in the elderly, higher fasting plasma insulin appears to correlate with *improved survival* in that population..........";
"Hypertension in Pima Diabetics Correlates with Renal Disease and NOT with Cardiovascular Disease............";
"HDL's from poorly controlled diabetics are abnormal and do not inhibit LDL-oxidation or Apo-A1 fragmentation in vitro............";
"NHLBI Investigators Identify HDL (*Good Cholesterol*) Gene................";
"Proteinuria Is an Independent Risk Factor for Ischemic Stroke in Non-Insulin-Dependent Diabetes Mellitus.............";
"Homocysteine a significant risk factor for atherosclerosis post-menopause..........";
"Silent Myocardial Ischemia with significant lesions occurs in 20.9% of type 2 diabetic male patients who are totally asymptomatic for CHD............";
"Effects of exercise on decreasing atherosclerosis may be due to inhibition of cytokine release................";
"Intensive Insulin Therapy Saves Lives in Acute MI's (The DIGAMI Study)....................";

"Diabetes-Related Lower-Extremity Amputations Disproportionately Affect Blacks and Mexican Americans.............";
"*Legs for Life* offers free vascular screenings for PVD (peripheral vascular disease) nationwide this month..........";

High Carbohydrate Diets and Atherosclerosis Risk....

"It seems appropriate to question the wisdom of recommending that all Americans should replace dietary saturated fat with CHO [AJC (2000) 85:45-48]....";
"Low-Cholesterol and High-Fat Diets Reduce Atherosclerotic Lesion Development in ApoE-Knockout Mice.....";"
"Protein-Rich Diets May Reduce Heart Disease Risk............";
"The Western-Diet Results in Insulin-Resistance, but not Atherosclerosis in LDL-Receptor Deficient Mice with Hypercholesterolemia
(But high fructose diets do result in increased atherosclerosis in the same model)...............
"Low Carb, High Fat Diet Appears to Improve Major Risk Factors in 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).....";
Western-Diet (high in meats and fats) protective against stroke dementia: Honolulu-Asia Aging Study.....";

Therapeutic Interventions into Diabetic Atherosclerosis....

"Marine omega-3 fatty acids improve large artery endothelium-dependent dilation in subjects with hypercholesterolemia without affecting endothelium-independent dilation (JACC 35:265-270, 2000)....."
"PPAR-gamma activators inhibit expression of VCAM-1 and ICAM-1 in activated endothelial cells and significantly reduce monocyte/macrophage homing to atherosclerotic plaques. These findings suggest that PPAR-gamma activators, currently used in treatment of type 2 diabetes, may have beneficial effects in modulating inflammatory responses in atherosclerosis.....";
"Results extend previous findings in patients with DM to a larger cohort, confirming the benefit of cholesterol lowering with simvastatin treatment on CHD events. In addition, significant decreases in total mortality, major coronary events, and revascularizations were observed in simvastatin-treated patients with impaired fasting glucose levels. These results strongly support the concept that cholesterol lowering with simvastatin therapy improves the prognosis of patients with elevated fasting glucose levels (above 6.0 mmol/L [above 110 mg/dL]) or DM and known CHD......";
"Lipid-lowering therapy generally should be more aggressively applied to patients with diabetes and/or at the time of coronary heart disease (CHD) diagnosis.....";
"Eicosapentaenoic Acid and Docosahexaenoic Acid Block Serotonin-Induced Smooth Muscle Cell Proliferation........."
"Fish Oils Safe and Effective in Angiographic Placebo-Controlled Trials of Coronary Artery Regression and in MI Survival "
"Alcohol use inversely associated with coronary mortality in older onset diabetics............";
"Nitrendipine Improves Diabetic Mortality in the Elderly with Systolic Hypertension..............";
"Gemfibrozil lowers CHD events but again fails to affect total mortality [this time in CHD patients with low HDL and even despite an expected high total mortality from CHD in this population....... ";
"ADA recommends treatment of all diabetics as though they have coronary disease by NCEP II guidelines........";
"Aggressive Cholesterol Lowering after CABG Shows Angiographic Benefit but FAILS to show a Significant Clinical Benefit in Diabetics...........";
"Reo-Pro and half-dose TPA are as effective as angioplasties in acute myocardial infarctions..............";
"EAS Study rates Lipitor More Effective Than Zocor or Baycol in reaching target goals............";
"Stents help diabetic patients who require coronary revascularization..........";
"Use of Reo-Pro with Stents Improves Diabetic Survival..............";
"Treatment with ramipril, an ACE inhibitor, can significantly reduce the risk of heart attack, stroke, cardiovascular death and kidney disease in high-risk people with diabetes...........";
"An isoflavone dietary supplement, P-081, derived from red clover, significantly increases HDL cholesterol levels in postmenopausal women not taking estrogen Rx.........";
"Compared with placebo, long-term use of cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent claudication........";

Therapy of Type 2 Diabetes....

"Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia.....";
Guava fruit may benefit type 2 diabetics.....";
Long-Acting GLP-I agonist Exendin-4 Stimulates Both beta-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 .....";
NDC recommends metformin as first line MONOTHERAPY therapy in the OBESE (BMI>30) type 2 patient but also recommends caution when using metformin combination with sulfonylurea agents.......";
"Bristol-Myers Squibb warned about Glucophage adverse event reporting.............";
"FDA foolishly rejects important new antibiotic................";
"GLP-1 is able to normalize plasma glucose in all type 2-diabetic patients studied. This analysis underlines the great therapeutic potential of GLP-1.....";
"Actos (pioglitazone) approval in Type 2s as monotherapy or in combination with metformin, insulin, or SFU's cautioned by edema, weight gain, and anemia but heartened by lowering triglycerides.................";
"Avandia (Rosiglitazone) approval by FDA cautioned by LDL increase, edema, anemia, and weight-gain.............";
"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............;
"D-chiro-inositol effective in reducing insulin resistance................";
"Beta Cell Failure Gets Almost All Type 2 Diabetics In Time.............";
"Type 2 diabetics will eventually require insulin for good control.........";

Etiology of Type 1 Diabetes...and the IL-4 Pathway....

"Natural Killer (NK) Cells Associate with Destructive Autoimmunity in Type 1 Models (Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0402065101)"
IL-12 locally produced by islet-infiltrating cells plays a critical role in the development of type 1 diabetes" (J Autoimmunity [2001]16:97-104)
hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.Proc. Natl. Acad. Sci. USA, [2001] 98, Issue 7, 3988-3991"
pDNA vaccination is an effective strategy to prevent IDDM - IL-4 was also required for disease prevention (The Journal of Immunology[2001] 166: 2122-2132)"
"Some patients with idiopathic type 1 diabetes have a nonautoimmune, fulminant disorder characterized by the absence of insulitis and of diabetes-related antibodies, a remarkably abrupt onset, and high serum pancreatic enzyme concentrations. (N Engl J Med 2000;342:301-7.).....";
"Blocking interaction between CD44, hyaluronic acid prevents type 1 diabetes in NOD mice.....";
Genetic Abnormality in Diabetic Mice May Answer Why Autoimmune Disease Are More Common in Women .....";
"The Human ENSA Gene That Encodes alpha-Endosulfine, a Regulator of beta-Cell KATP Channels, has been localized to an area of Chromosome 14 with IDDM susceptibility-linkage (IDDM11)..............";
"An insulin peptide fragment has been identified as an autoantigen in the NOD [Non-Obese Diabetic] mouse model..........";
"Focus of attack in Type 1 diabetes may be *stiff-man* antigen GAD.........";
"In identical twins discordant for type 1 diabetes the diabetic siblings appeared to secrete NO interleukin-4.......";
"IL-13 reduces incidence of Type 1 diabetes in NOD mice...........";
"Interleukin-4 appears to prevent insulitis and the development of Type 1 diabetes in the NOD mouse model.....";

Therapy of Type 1 Diabetes....

"Still More Participants Needed for Natiowide Study to Prevent Type 1 Diabetes.....(call 1-800-425-8361)";
Long-Acting GLP-I agonist Exendin-4 Stimulates Both beta-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 .....";
"The Insulin Gene has successfully been transfected into diabetic rat livers and significantly improves glycemia..............";
"MCV group is now the second to have transfected the insulin gene into hepatocytes.....";
"Ultralong-acting Insulin (Glargine) Safer but as Effective as NPH in Types 1 and 2 diabetics........";
"Basal-Bolus (Ultralente/Regular) Insulin Regimen Highly Effective with Carbohydrate Counting in Type 1 Diabetes............";
"Orally administered amidated pectin insulin (PI) hydrogel beads sustain plasma concentrations of insulin in streptozotocin (STZ) diabetic rats..............";
"Oral insulinomimetic found in the African rainforests (shades of *The Medicine Man* - eh?)..........";

Diabetic Monitoring and Microvascular Complications (and Atherosclerosis?....)

"Coronary Disease in Type 1's Correlates with Depression, NOT Glucose. Lower Extremity Arterial Disease, however, DOES Correlate with Blood Glucose in Type 1's.....";
"Presence of more severe retinopathy or visual impairment in diabetic patients is a risk indicator for increased risk of ischemic heart disease death. Presence of these ocular conditions may identify individuals who should be under care for cardiovascular disease......";
"Children and young adults with insulin dependent diabetes continue to be at increased risk for death from diabetic ketoacidosis.....";
"Early renal function decline is 3 times more likely to develop in blacks than whites and potentially modifiable factors,
including lower socioeconomic status, suboptimal health behaviors, and suboptimal control of glucose levels.............";
"Inhibitor of Diabetic Proliferative Retinopathy Unmasked............";
"Watch Sensor Apparently Effective in Monitoring Blood Sugars Non-Invasively Recommended for Approval..........";
"Data suggest that persons with type 1 diabetes may not judge correctly when their BG level is too low to permit safe driving
and may consider driving with a low BG level even when they are aware of the low level.
Health care professionals should counsel their patients about the risk of driving with hypoglycemia
and the importance of measuring BG level before driving.............";
"Conservative Therapy WITHOUT AMPUTATION Safe and Effective for Diabetic Foot Ulcers and Osteomyelitis.............";
"Foot Surgery in Diabetes Leads to Increased Degenerative Changes.........";
"Gabapentin not superior to amitriptylline in small, under-powered, cross-over study of pain relief in 28 diabetic neuropathic patients.............";
"Diabetes common (3x-increased) in hospitalized bipolar patients............";
"Parent-Teen Integration into the Diabetic Team Affects Outcomes Positively...........";

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