Home Remedies for Hyperglycemia

Blood Sugar Miracle

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Mechanisms Of Hyperglycemiainduced Pkc Activation

Cellular DAG content can also be increased by agonist-stimulated hydrolysis of PI or PC such as PLC or PLD (11-13). Because inositol phosphate products are not increased by hyperglycemia in aortic cells and glomerular The activation of PKC by hyperglycemia may be tissue specific because it was noted in the retina (16), aorta, heart (17), and glomeruli (8,18) but not clearly demonstrated in the brain (16) and peripheral nerves (30) (Table 1). Similar increases in DAG levels and PKC activation have also been shown in multiple types of cultured vascular cells in response to increased glucose levels (Table 1) (8,16,22,31). Thus, it is likely that the DAG-PKC pathway is activated by the hyperglycemic-diabetic state in all vascular- cells. Among the various PKC isoforms in vascular cells, PKC (3 and 8 isoforms appear to be preferentially activated as shown by immunoblotting studies in aorta and heart of diabetic rats (17) and in cultured aortic smooth muscle cells exposed to high levels of...

Hyperglycemia

Subjects with the metabolic syndrome have insulin resistance as a core feature, which results in impaired glucose tolerance or frank hyperglycemia. Recently two important studies have shed further light on the importance of more intensive glycemic control4,5.The Diabetes Control and Complications Trial (DCCT) demonstrated that among patients with type 1 diabetes mellitus, compared with conventional treatment, intensive control of hyperglycemia with insulin reduced the risk of any cardiovascular disease outcome by 42 (Figure 5.2) and the risk of non-fatal myocardial infarction, stroke, or death from cardiovascular disease by 57 4. Similarly the PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROACTIVE) which assessed the benefit of piogli-tazone versus placebo in patients with type 2 diabetes mellitus and vascular disease demonstrated that piogli-tazone reduced the risk of macrovascular complications by 16 over 3 years (Figure 5.3)5. The exact mechanism by which...

Adiponectin Receptor 1 and Adiponectin Receptor

Both hyperglycemia and hyperinsulinemia decrease adipoR1 expression in skeletal muscle (54-56). On the other hand, hyperinsulinemia increases adipoR2 expression in L6 rat myotubes (56). Interestingly, hyperinsulinemia-induced suppression of adipoR1 and upregulation of adipoR2 in L6 myotubes is associated with diminished sensitivty of the cells to globular adiponectin but increased sensitivity toward full-length adiponectin.

Classification and evolution of increased cardiometabolic risk states

Figure 1.1 Schematic demonstrating where the presence of metabolic syndrome fits into the natural history of type 2 diabetes. Prior to the development of clinical overt hyperglycemia and the diagnosis of type 2 diabetes, it is observed that insulin resistance may develop in the majority of individuals, primarily associated with obesity. The development of insulin resistance in an individual will need to be compensated by hyperinsulinemia in order to maintain normal glucose tolerance. However, when the insulin secretory capacity of the p cell begins to diminish such that the pancreatic function now fails to compensate for the insulin resistance, a state of relative 'insulin deficiency' leading to hyperglycemia is observed. It is at this stage that impaired glucose tolerance and impaired fasting glucose may be present. With worsening pancreatic dysfunction and the inability to compensate fully for the degree of insulin resistance, hyperglycemia continues to increase and clinically overt...

Plasminogen Activator Inhibitor1

Although PAI-1 is primarily derived from platelets and the endothelium, it has been demonstrated that most of the elevated concentrations of this regulatory protein of the coagulation cascade in inflammatory and obese states is attributable to an upregulated expression by adipose tissue itself (12,58). Therefore, WAT represents a quantitatively relevant source of PAI-1 production, with consequently increased circulating concentrations present in obesity. Stromal cells have been shown to be the main PAI-1 producing cells in human fat, with a fivefold higher expression in the visceral than in the subcutaneous depots, which is in agreement with the strong relationship observed between circulating PAI-1 concentrations and visceral fat accumulation (59). However, whether adipose tissue itself directly contributes to circulating PAI-1, or whether it exerts an indirect effect via adipokines, such as TNF-a , IL-1 , and TGF- , to stimulate PAI-1 production by other cells has not been clearly...

Potential Therapeutic Applications

More recently, the NPY Y2 receptor has emerged as a potential player in energy homeostasis. Peripheral injection of PYY(3-36), an NPY Y2 agonist, reduced food intake and weight gain in rats and mice, but not in Y2 - - mice. Ob ob mice lacking the NPY Y2 receptor have reduced adiposity, hyperglycemia, hyperinsulinemia and have increased HPA axis activity (23). In addition, peripheral administration of PYY(3-36) to humans significantly reduced appetite and food intake (24).

Inhibitors of pyruvate dehydrogenase kinase PDHK

Increasing the activity of pyruvate dehydrogenase (PDH) by inhibiting PDHK is expected to decrease blood glucose by increasing glucose oxidation in peripheral tissues and by decreasing the supply of the gluconeogenic precursors, lactate and alanine to the liver. Dichloroacetate (DCA), a known inhibitor of PDHK was shown to reduce plasma glucose levels both in animal models of diabetes and in patients. Administration of DCA for seven days to T2D patients decreased plasma glucose, and caused marked decreases in lactate and alanine levels. However, DCA was not suitable as therapeutic agent due to its low potency, lack of specificity, poor PK, and toxicity. AZD7545, 19 is a potent rat PDHK inhibitor (IC50 0.021 mM) that increased PDH activity with an EC50 value of 0.105 mM in rat hepatocytes. Compound 19 was also found to markedly improve the 24 h glucose profile, by eliminating postprandial elevation in glucose levels, at 10 mg kg, bid, in male obese Zucker fa fa rats 15 . However, the...

Liverselective glucocorticoid receptor antagonist

The correlation between elevated hepatic glucose output and fasting hyperglycemia in type 2 diabetic patients is well established. Also, the link between elevated glucocorticoids (GCs) and their role in glucose control suggested the desirability of exploring glucocorticoid receptor antagonism as a potential therapy for T2D. However, the critical role played by GCs in the hypothalamic pituitary axis (HPA) and potential toxicities due to systemic GC antagonism, require liver-selective glucocorticoid receptor (GR) antagonism to safely treat T2D patients.

Glucagon receptor antagonists

Glucagon is a key hormone that acts as a counter regulator of the actions of insulin and, as a consequence, it contributes to insulin resistance in T2D. Glucagon is secreted by a-cells of the pancreas and it promotes hyperglycemia by increasing glycogenolysis and gluconeogenesis in liver. In T2D patients, circulating glucagon levels are normal or slightly elevated suggesting that elevated fasting glucagon levels that fail to appropriately decrease postprandially, contribute to hyperglycemia. Mice lacking glucagon receptors (GlucR 2 2 KO mice) were found to have normal glucose levels, and improved insulin sensitivity. Treatment of ob ob mice or streptotozocin (STZ) induced diabetic rats with a glucagon monoclonal antibody (Glu-mAB) normalized or slightly lowered glucose levels. Recently, similar observations were made using a specific glucagon receptor antisense oligonucleotide (GR-ASO) 28 . Bay 27-9955,25 a small molecule competitive glucagon receptor antagonist with moderate potency...

Clinical Grading Scales

Regardless of the scale used, admission clinical grade predicts mortality. However, aSAH is a complex disease, with many causes of secondary deterioration, including rebleeding, delayed ischemia from vasospasm, hydrocephalus, cerebral edema, and a host of medical complications. For this reason, a patient's worst clinical grade during the course of hospitalization has a closer correlation with outcome than the admission grade (8). In addition to clinical grade, other important predictors of mortality and poor outcome after aSAH include age, aneurysm size, rebleeding, intraventricular hemorrhage, global cerebral edema, and physiologic derangements, such as hypertension or hypotension, hypoxia, hyperglycemia, and fever (9 ).

Section Ii Cardiovascular And Pulmonary Agents

Introduction - Pharmacologic therapy of hypertension decreases overall cardiovascular morbidity and mortality, but fails to show a clear reduction in the risk of coronary heart disease (CHD) (1-4). Although many explanations have been offered for the lack of demonstrated benefit for CHD, one hypothesis in continued focus involves the unfavorable metabolic and biochemical changes caused by diuretics or (3-adrenoceptor antagonists devoid of intrinsic sympathomimetic activity (5). These drugs were used in the majority of the hypertensive clinical trials completed to date and adversely affect many of the known risk factors for CHD, including hyperlipemia, hyperglycemia and elevated plasma catecholamine levels. These potentially deleterious changes might have offset expected benefits of blood pressure reduction.

Bacterial Collagenase Model

The collagenase ICH model has been used by several investigators in mouse, rat, and pig. Their reports shed light on the pathochemical events following ICH and describe several new experimental treatments for ICH that have not been examined in the blood infusion model. Recent studies have demonstrated (i) the role of MMPs in BBB opening and edema development following collagenase-induced ICH and the effectiveness of MMP inhibitors (79,80), (i i) that select MMPs exhibit increased expression after ICH and that minocycline is neuroprotective by suppressing monocytoid cell activation and downregulating MMP-12 expression (81), and (iii) that the tripeptide macrophage microglial inhibitory factor inhibits microglial activation and results in functional improvement when given before, as well as after, the onset of collagenase-induced ICH (82,83) . Various other reports using this model have described detailed studies of the collagenase dose effect (84) , imaging features and histopathology...

Thiazolebased inhibitors

One of the first classes of 11 p-HSD 1 inhibitors to demonstrate selectivity over 11 p-HSD2 consisted of thiazole analogs. As depicted in structure 1, the general structure of active thiazoles incorporates a sulfonamide moiety at the 2-position of the thiazole ring. Two preferred compounds that have been extensively studied are BVT-2733 (2) and BVT-14225 (3). Human isozyme in vitro studies showed that compounds 2 and 3 were reasonably potent 11p-HSD1 inhibitors (IC50 3.3 and 0.05mM, respectively) and were selective vs. 11p-HSD2 (IC50> 10 mM) 21 . Although 2 was less potent in the human assay, it was more potent than compound 3 against mouse 11p-HSD1 (IC50 96 and 284nM, respectively) 21 . Both compounds were inactive at mouse 11p-HSD2 21 . Compound 2 was tested in the hyperglycemic KKAy mouse model of diabetes, and was shown to dose-dependently lower blood glucose levels, with a maximum glucose reduction of 53 (100mg kg

GLP1 agonists and dipeptidyl peptidase Iv Dppiv inhibitors

Inhibitors of DPPIV are under investigation as orally active mediators of GLP-1 levels. NVP-LAF237, 6 a potent DPPIV inhibitor, was shown to increase active GLP-1 levels, and improve glucose tolerance in rodents. Chronic treatment with 6 had no effect on weight gain in mice and rats and delayed gastric emptying in cynomolgus monkeys 9 . In humans, 6 improved hyperglycemia in T2D patients at 100 mg TID, in a 4 week study. The issues that remain to be addressed include breadth and specificity of action of 6, the durability of its effect and effects in combination with other drugs. Another DPPIV inhibitor that reached phase III clinical testing, MK431, 7 (IC50 18 nM), has excellent selectivity over other

Experimental Diabetic Neuropathy Oxidative Stress and Antioxidant Therapy

Glucose, by a process of autooxidation in the presence of decompartmenta-lized trace transitional metals, can cause lipid peroxidation (6). We have evaluated the role of hyperglycemia in lipid peroxidation in vitro, using an in vitro lipid peroxidation model, with an ascorbate-iron-EDTA system. The addition of 20 raM glucose to the incubation medium increased lipid peroxidation fourfold, confirming rapid and marked glucose-mediated autooxidative lipid peroxidation (7). Glucose autooxidation results in the production of protein reactive ketoaldehydes, hydrogen peroxide highly reactive oxidants, and the fragmentation of proteins (free radical mechanisms). Glycation and oxidation are simultaneous and inextricably linked (8).

Identify current drug therapies for hypertensive patients

Single-agent therapy is usually initiated if this is ineffective, multiple agents may be prescribed. Multiple factors determine which agents are used, including race, gender, age, and comorbidities. For instance, black patients respond better to calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and p-blockers. p-Blockers are relatively contraindicated in patients with reactive airway disease, and patients with renal artery stenosis should not receive ACE inhibitors. Diuretics produce hypokalemia and hyperglycemia. p-Blockers are not particularly effective in elderly patients. Table 28-1 reviews commonly prescribed antihypertensive medications. hyperglycemia, hypomagnesemia, hyperglycemia, hypomagnesemia,

Neurotrophins In Diabetic Neuropathy

Diabetes is associated with increases in oxidative stress in humans and in experimental animal models. Chronic hyperglycemia per se results in autoxi- dative glycation oxidation and lipid peroxidation (54-56), and hyperglycemia alone will cause lipid peroxidation of peripheral nerve in vitro (57).

Glucose And Ischemic Brain Injury

Animal studies consistently show that hyperglycemia worsens ischemic brain injury and increases the risk of hemorrhagic transformation after cerebral infarction (30-32). Observational studies show that patients with hyperglycemia at the time of stroke onset have increased morbidity and mortality and that hyperglycemia is associated with more pronounced infarct growth (33-37). Patients with hyperglycemia are also at higher risk of hem-orrhagic transformation after stroke, which can occur spontaneously or following the use of anticoagulants and fibrinolytics (38,39). Independent of the occurrence of hemorrhagic transformation, hyperglycemia is also associated with an increased risk of clinical deterioration in the days after stroke onset (40). Experimental data suggest that hyperglycemia might contribute to ischemic brain injury by several mechanisms, including increases in lactic acidosis, in blood-brain barrier (BBB) breakdown (and hence, cerebral edema), and in the release of...

Oxidative Stress In Patients With Diabetes Mellitus

Lately, considerable effort has been devoted to gain insights into the role of oxidative stress in the development and progression of late micro-and macrovascular complications in diabetes (17,23,27,28,31-34). Although hyperglycemia is an acknowledged pathogenic factor in diabetic complications, it is not known through which mechanism an excess of glucose results in tissue damage. Accumulating data support the hypothesis that oxidative stress might play an important role in the pathogenesis of late diabetic complications. Several pathways are leading to oxidative stress associated with acute or chronic hyperglycemia, such as the polyol pathway, prostanoid synthesis, glucose autoxidation, and protein glycation by increasing the production of free radicals (35-39). A close relationship of oxidative stress with glycemic control has been described, showing a significant positive correlation between malondialdehyde (MDA) and both fasting blood sugar and glycosilated hemoglobin (40)....

Hypothesis Of Advanced Glycation End Products And Its Receptor

AGE formation proceeds slowly under normal glycemic conditions but is enhanced in the presence of hyperglycemia, oxidative stress, and or conditions in which protein and lipid turnover are prolonged. For example, V-epsilon-(carboxymethyl)lysine (CML), one of the various AGE structures postulated to date, has been found to be a product of both glycoxidation (combined non-enzymatic glycation and oxidation) and lipid peroxidation reactions (53). CML and pentosidine have been shown to accumulate in diabetic kidneys in colocal-ization with a marker of lipid peroxidation (MDA), suggesting an association of local oxidative stress with the etiology of diabetic glomerular lesions (54). Evidence for an age-dependent increase in CML accumulation in distinct localizations and acceleration of this process in diabetes has been provided by immunolocalization of CML in skin, lung, heart, kidney, intestine, intervertebral discs, and particularly in arteries (55). In diabetic kidneys, AGEs were...

Impaired Glucose Metabolism and Metabolic Syndrome

Although numerous past studies show that hyperglycemia is associated with a marked increase in CVD mortality risk 5 , recent investigations have focused on the risks posed by impaired glucose metabolism (IGM), i.e., impaired fasting glucose (IFG) and or impaired glucose tolerance (IGT). In the Hoorn Study, decreased total systemic arterial compliance, increased aortic augmentation index, and decreased carotid-femoral transit time were seen in DM-2 and to a lesser extent in IGM, suggesting that either greater arterial stiffness in DM-2 or increased aortic atherosclerotic plaque reflection sites might increase augmentationindex by altering the amplitude and timing of reflected waves 6 . Increased stiffness of the muscular femoral and brachial arteries in IGM may precede elastic carotid artery stiffness in DM-2, because of decreased distension and diameter of the femoral artery coupled with increased pulse pressure. Hyperglycemia and hyperinsulinemia explained about 30 of the arterial...

Role of Oxidative Stress and Antioxidants on Adhesion Molecules and Diabetic Microangiopathy

Each cell can mobilize an armory of antioxidant defense systems. Under normal metabolic conditions, the production of free radicals and the antioxidant capacity are balanced. Hyperglycemia in diabetes mellitus is associated with an increased production of free radicals. Furthermore, observational studies indicate lower levels of antioxidants like vitamin E, vitamin C, carotene, ascor-bate, and thiols in patients with diabetes mellitus (1,2). Imbalance between free radical production and the antioxidant defense system leads to oxidative stress. In diabetic patients, oxidative stress can be demonstrated by increased levels of lipid peroxidation products (3-8). There is a body of evidence that vascular and neurological complications in patients with diabetes mellitus are a consequence of oxidative stress (9-12).

Glucose and Other Physiologic Variables

Elevated blood glucose can worsen global ischemic injury in a number of rodent models (37,113,160-163), and it is an established practice to minimize this potential variability by fasting animals prior to an insult. However, the impact of glucose level is dependent on both insult duration and occlusion efficacy. Hippocampal CA1 neuronal loss after insults of moderate duration in the gerbil appears to be insensitive to the physiologic range of glucose variation between fed and fasted states (138). Pathology can be largely unaffected even by profound hyperglycemia after insults of several minutes' duration in either rats (135) or gerbils (164), although other studies have noted increased striatal injury after occlusions as short as 4 min (165). Importantly, a threshold of approximately 12 mM glucose must be exceeded to exacerbate injury in a standard rat model of 10-min 2-VO plus hypotension (166). This permits the use of normally fed animals in most global ischemia studies, which is a...

Lipodystrophy in hivinfected subjects

Patients with LDHIV often have dyslipidemia, insulin resistance, and hepatic steatosis. Dyslipidemia in the form of hypertriglyceridemia, hypercholesterolemia, and low HDL cholesterol is much more common (50-70 ) than hyperglycemia (0-20 ) (55,56). Metabolic abnormalities may sometimes precede changes in body fat distribution.

Enhancers Of Insulin Release

Common side effects of SU therapy include hypoglycemia, as their action may occur at times when insulin is not required, and weight gain (11). Prolonged treatment with SU's also exacerbates p-cell exhaustion through over-stimulation of insulin production SU therapy is not effective when insulin receptor levels decline too far. Newer agents have attempted to address these liabilities. Repaglinide 3 and nateglinide 4 are recently introduced short acting non-sulfonylureas secretagogues which are taken prior to meals to control post-prandial glucose levels and are reported to have fewer hypoglycemic side-effects (13,14). A family of short-acting sulfonylureas, typified by 5, has recently been reported (15). Administration of 5 at 3 mg kg po lowered blood glucose levels by > 30 , 10-20 , and < 10 at 30 min, 1 hour, and 2 hours, respectively. JTT-608 6 is an insulinotropic agent which stimulates insulin release only in the presence of elevated blood glucose levels, reducing the risk of...

Inhibitors Of Hepatic Glucose Production

Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors - PDHK regulates pyruvate dehydrogenase (PDH), the enzyme which catalyzes the decarboxylation of pyruvate to acetyl-CoA. Activation of PDH increases oxidative glucose metabolism and reduced PDH activity has been linked to reduced glucose utlization in diabetes, as well as enhanced gluconeogenesis and impaired insulin secretion (33). Dichloroacetic acid, an inhibitor of PDHK, among other enzymes, has been shown to lower lactate and glucose levels in vivo (34). Two new classes of potent, specific PDHK inhibitors, represented by 13 and 14, have been reported (33,35). 13 has been shown to be orally available and while it significantly reduced lactate in normal, fasted rats, it did not lower blood glucose levels in diabetic animal models (36). Liqands for Peroxisome-Proliferator Activated Receptor y (PPARy) - PPARy, once only associated with diabetes and obesity, has recently been implicated in the transcriptional control of a wide variety of...

Endotheliumdependent Vasodilation

In physiological terms, hyperglycemia increases blood pressure and leads to endothelial dysfunction with impaired vascular reactivity (23). Hypoxia is accompanied with an influx of calcium, which might activate nitric oxide (NO) synthase followed by vasodilation and hyperemia (11) (Fig. 5). In diabetes, increased free radicals might quench NO, leading to ischemia (11,24). In vitro acetylcholine-induced vasodilation of vasculature from diabetic animals is impaired (25,26). The rate of NO synthesis in vivo compared with the rate of NO quenching is unclear. We measured the blood flow of the arteria iliaca in diabetic and nondiabetic rats. The NO-mediated stimulation by acetylcholine was impaired in diabetic rats, but in contrast to in vitro experiments, treatment

Ischemiareperfusion In Diabetes Mellitus

Microvascular dysfunction has been studied extensively in animal models. One of the most widely used models is streptozotocin-induced diabetes in the rat. In this model, rats are treated with a single toxic dose of streptozotocin, which destroys the islets of Langerhans (27). The effect of hyperglycemia on the microvasculature is then evaluated after 4-12 weeks (21,28-37). Gly-cemic control by insulin treatment can prevent the microvascular dysfunction. In diabetic humans, metabolic status is not stable, and episodes of normogly-cemia are followed by phases of hyper- and hypoglycemia. Thus, blood sugar levels vary considerably, and in consequence to the pathophysiological changes presented above, the status of oxidative stress changes and blood flow will go up and down. Therefore, it is reasonable to assume that under realistic conditions, a diabetic patient undergoes episodes of ischemia and reperfusion Figure 6 Changes in blood sugar are associated with changes in blood flow....

Disubstituted pyrimidines

A number of inhibitors utilize the pyrimidine scaffold with various substitutions at the 2 and 4 positions. Pyrimidine 8 is representative of one such series with IGF-1R activity (IC5o< 50nM) 36,37 . From this series, XL-228 (structure not disclosed) has advanced into the clinic. XL-228 is a multi-targeted protein kinase inhibitor with single-digit nanomolar activity reported for IGF-1R, IR, Src, AurA B, Fak, FGFR1,2,3 (fibroblast growth factor receptor 1,2,3), and BCR-Abl. Ph+CML and Ph+ALL patients were administered a 1-h intravenous infusion of XL-228 at a dose of 10.8mg kg on a once-weekly schedule. The dose-limiting toxicities observed included hyperglycemia and syncope 38 .

Increased intracranial pressure s and traumatic brain injury

In general hypotonic crystalloid infusions should be avoided because they may increase brain water content. Normal saline may be superior to lactated Ringer's because of the higher sodium and lower free water content. Some centers resuscitate with small volumes (4 ml kg) of hypertonic saline to minimize free water in the setting of elevated ICP. Glucose-containing solutions are avoided because of evidence of worsened neurologic outcome if ischemia occurs in the setting of hyperglycemia. Hyperglycemia (serum glucose > 180 mg dl) should be treated with insulin. Colloidal solutions are not superior to crystalloid solutions.

Metabolic Considerations in Therapeutic Hypothermia

Beyond the reported possible adverse events monitored in the two clinical trials, some metabolic perturbations might occur while patients are undergoing hypothermic therapy and rewarming to normothermic range. Hypothermia has been associated with hypokalemia, metabolic acido-sis, and hyperglycemia (70). Close monitoring and appropriate correction of these conditions is essential for patient safety. Other electrolytes, such as magnesium and phosphates, must be monitored as well. Rebound of these abnormalities with rewarming must be considered when actively normalizing temperature to normothermia.

Historical and Clinical Aspects

Before the discovery of insulin, sources of insulin exogenous to the body were not available and hypoglycemic brain damage occurred only in the context of endogenous tumors of the islets of Langerhans of the pancreas (Auer 1986). Human consumption of food had reached the point where diabetes was becoming more common, but it was then only treatable through starvation. Indeed, diabetes can metabolically be considered starvation in the midst of plenty due to the inability of glucose to enter cells, in the face of high blood glucose levels. Once insulin was discovered, it was tested in diabetes and was found to allow improved survival over the unpalatable treatment option of starvation the latter could reduce glucose loss through the urine but only slowed the diabetic process and could not stave off eventual death.

Typei Diabetes Mellitus

Sulphonylurea compounds have been shown to lower blood glucose effectively in Type-II diabetics on acute administration and chronic application as well. The mechanisms responsible for this effect are controversial and determined by the type of NIDDM, and the nature and the duration of treatment.

Pi3kakt Kinase Pathway Inhibitors In Clinical Trials

Triciribine (API-2, TCN, 28a) is a tricyclic nucleoside first reported in 1980 51 . While 28a and the corresponding 5-phosphate derivative (triciribine phosphate, TCN-P, 28b) have demonstrated antitumor activity and progressed to clinical evaluation for the treatment of several advanced solid tumors, severe side effects (e.g. hepatotoxicity and hyperglycemia) related to dosing levels ultimately limited their use 52-59 . More recently, screening of the National Cancer Institute Diversity Set identified 28a as a highly selective inhibitor of AKT, wherein cell growth was suppressed at a concentration of 50 nM 60 . While it is known that 28a blocks the AKT pathway, the mechanism by which it prevents AKT activation has not been established. Additional preclinical findings report that 28a, at a dose of 5 p.M, effectively and selectively induced apoptosis and cell growth arrest in tumor cells in which AKT was aberrantly expressed or activated, while cancer cells without this trait were not...

Vascular Blood Flow

Abnormalities in hemodynamics have been clearly documented to precede diabetic nephropathy (51,52). Elevated renal glomerular filtration rate (GFR) and modest increases in renal blood flow are characteristic findings in insulin-dependent diabetes mellitus (IDDM) patients (51,52) and experimental diabetic animals (53). Diabetic glomerular hyperfiltration is likely to be the result of hyperglycemia-induced decreases in arteriolar resistance, especially at the level of afferent arterioles (54,55), resulting in an elevation of glomerular filtration pressure. Multiple mechanisms have been proposed to explain the increases in GFR and glomerular filtration pressure, including an enhanced activity of angiotensin (56) and culturation in prostinoid productions (57-59). It is possible that the activation of DAG-PKC may also play a role in the enhancement of angiotensin actions because angiotensin mediates some of its activity by the activation of the DAG-PKC pathway (57). In addition, increases...

Hypothermia for Ischemic Stroke

However, its use is associated with several potential adverse side effects, including an increased risk of infection, coagulopathy, hypokalemia, hyperglycemia, and cardiovascular suppression. Furthermore, when hypothermia is discontinued, a rebound elevation of ICP has also been noted, which may be fatal. The timing, degree, and duration of hypothermia in ischemic stroke have not been fully worked out, nor has the safest rate of re-warming.

Vascular Permeability and Neovascularization

In the kidney, the expression of transforming growth factor-P (TGF-P) has been shown to be increased in the glomeruli of diabetic patients and experimental animals. Similar increases of TGF-p have also been reported in cultured mesangial cells exposed to high glucose levels (9). Because TGF-P can directly cause the overexpression of extracellular matrix, PKC inhibitors have been shown both to inhibit TGF-P expression by hyperglycemia and to prevent the mesangial expansion observed in diabetic nephropathy (7,9,11).

Anti Islet Autoantibody Assays

Type 1A diabetes mellitus, as defined by an expert panel of the American Diabetes Association, is characterized by the presence of antiislet autoantibodies. The presence of islet autoantibodies in individuals who otherwise seem healthy denotes an increased risk for later development of type 1A diabetes. The early expression of insulin autoantibodies (IAAs) is associated with early development of diabetes in young children and NOD mice. IAAs appear early and then disappear at approximately the time of onset of hyperglycemia in most NOD mice.

Extracellular Matrix Components

(3 antibodies significantly reduced collagen synthesis and gene expression of type (IV) collagen and fibronectin in the renal cortex of diabetic rats and in cultured mesangial cells exposed to high glucose levels. Because PKC activation can increase the production of extracellular matrix and TGF-(3 expression, it is not surprising that several reports have shown that PKC inhibitors can also prevent hyperglycemia- or diabetes-induced increases in extracellular matrix and TGF-(3 in mesangial cells or renal glomeruli (32).

Diabetes Prevention in the NOD Mouse

Keeping in mind the narrow therapeutic window between the onset of hyper-glycemia and critical P-cell mass loss, only two published therapies, antilymphocyte serum and anti-CD3 antibody (13), have been demonstrated to reverse hyperglycemia in recently diabetic NOD mice, demonstrating the difficulties in treating overtly diabetic mice.

Preparation For Carotid Stenting

Patients should be nothing by mouth (NPO) from midnight, the night before the procedure. Careful consideration should be given to which medications are taken prior to the procedure. Withholding antihypertensives could lead to uncontrolled hypertension, which could cause hemorrhagic stroke during reperfusion. Oral hyperglycemic medications are potentially associated with postprocedure lactic acidosis. On the other hand, hyperglycemia is detrimental to the ischemic brain. Therefore, preprocedural hyperglycemia should be

Origin of Oxidative Stress in Type 2 Diabetes

Suspected causative agents of the increased level of oxidative stress associated with type 2 diabetes are hyperglycemia, hyperinsulinemia, and an alteration of serum antioxidant activity (Fig. 3). 1. Hyperglycemia Hyperglycemia has been strongly implicated in the development of diabetic complications, an effect also known as glucose toxicity. The mechanisms of glucose toxicity are the subject of extensive investigation and include glucose

Can Oxidative Stress Cause Insulin Resistance

The first prospective population study undertaken to address the role of free radical stress and antioxidants in relation to the incidence of diabetes examined whether low vitamin E concentrations are a risk factor for the incidence of type 2 diabetes (92). The authors computed the levels of plasma vitamin E and the incidence of developing diabetes over a 4-year period in 944 men aged 42-60 who were determined not to have diabetes at baseline examination (92). Type 2 diabetes was defined by either a fasting blood glucose concentration of S 6.7 mM, a blood glucose concentration > 10.0 mM 2 h after a glucose load, or by a clinical diagnosis of diabetes with either dietary, oral, or insulin treatments. Forty-five men developed diabetes over the 4-year follow-up period (92). However, these 45 men also had a raised baseline body mass index, elevated blood glucose and serum fructosamine concentrations, a higher ratio of saturated fatty acids to the sum of monounsa-turated and...

Type 2 Diabetes Mellitus

Several prospective studies in numerous countries have demonstrated an elevated risk of diabetes mellitus as weight increases (75-77). The development of type 2 diabetes is associated with weight gain after age 18 yr in both men and women such that the relative risk of diabetes increases by approx 25 for each additional unit of BMI over 22 (109). Moreover, cross-sectional and longitudinal studies show that abdominal obesity is a major risk factor for type 2 diabetes (74,82,91). There is strong evidence that weight loss reduces blood glucose levels and hemoglobin A1c levels in patients with type 2 diabetes. Moreover, in three European cohorts (> 17,000 men) followed for more than 20 yr, nondiabetic men with higher blood glucose had a significantly higher risk of

Transgenic Expression of ADAR2

Ectopic expression of rat ADAR2 protein from a randomly integrated transgene in mice revealed a pronounced phenotype that was strikingly different from the neurological syndrome associated with ADAR2 deficiency or the lack of an overt phenotype in mice that cannot control ADAR2 expression by editing the ADAR2 transcript (Singh et al. 2007). Transgenic mice expressing either wild-type or editing-deficient ADAR2 isoforms displayed adult onset obesity characterized by hyperglycemia hyperleptinemia and increased adiposity. The drastic weight gain of these animals appeared to result predominantly from hyperphagia rather than a metabolic derangement (Singh et al. 2007). Interestingly, manifestation of the obese phenotype was independent of the deaminase activity of ADAR2, indicating

Definition and Prevalence of Diabetes

Diabetes mellitus, a condition characterized by hyperglycemia, is a chronic disorder of carbohydrate, lipid, and protein metabolism due to the absolute or relative lack of insulin. In 1997, there were an estimated 124 million people with diabetes worldwide, and 221 million affected people are predicted by 2010.1 While oxidative stress has also been implicated in the pathogenesis of diabetes,2 this chapter will focus on the relationship between oxidative stress and atherosclerosis in diabetes, with an emphasis on the clinical perspective. The basic mechanisms of oxidative stress are reviewed elsewhere.3-5 The presentation, diagnosis, and classification of diabetes have been reviewed elsewhere.6 Approximately 90 of cases have Type 2 diabetes, and the prevalence of both Type 1 and Type 2 diabetes is increasing,1 including a disturbing increase in Type 2 diabetes in children, usually associated with adiposity and a relatively poor prognosis with respect to the subsequent development of...

Streptozotocin Diabetic

Much less information regarding the oxidant antioxidant status is presently available for the obese Zucker rat. It should be stressed that this animal model displays only mild fasting hyperglycemia, with more severe abnormalities observed when the animal is presented with a glucose load (27,37,38). Nevertheless, Nourooz-Zadeh (39) reported that the isoprostane 8-cpi-PGF , a marker of oxidative stress, is elevated in the plasma of the diabetic Zucker rat compared with lean controls. Interestingly, these elevated levels of oxidative stress are significantly reduced with antioxidant treatment, such as a-tocopherol (39). These results concerning oxidative stress in the diabetic Zucker rat are consistent with observations of human type 2 diabetes. During a euglycemic hyperinsulinemic clamp, a significant inverse relationship has been observed between insulin action on nonoxidative glucose disposal and plasma superoxide ion, and a significant positive relationship has been seen between...

Definition and Mechanisms of Oxidative Stress

Recently, Brownlee and colleagues proposed a unifying hypothesis based on hyperglycemia hyperglycemia-induced endothelial cell mitochondrial overproduction of superoxide (O2-), which links hyperglycemia, oxidative stress, and the vascular complications of diabetes.33,34 Basically, it is suggested that excess glucose entering (for example) vascular endothelial cells via the insulin independent GLUT-1 transporter, induces mitochondrial overproduction of O2-, which then activates other pathways including protein kinase C (PKC), nuclear factor-KB (NF-kB), the polyol pathway, induces NAD(P)H oxidase, and promotes formation of AGEs and advanced lipoxidation end-products (ALEs) and (the highly pro-oxidant and long-lived) peroxynitrite.33,34,44 There is much evidence relating endothelial dysfunction and vascular damage in general and in diabetes to disturbed nitric oxide (NO) metabolism,25,44-50 and the Brownlee hypothesis is consistent with this. NO is generated from l-arginine by nitric...

Is Oxidative Stress per se Increased in Diabetes and Vascular Damage

There are many theoretical reasons why oxidative stress should be increased in diabetes, including hyperglycemia hyperglycemia-related glucose autoxidation, increased glucose flux through the polyol pathway, and activation of reduced forms of NADPH oxidase, therefore Brownlee's unifying hypothesis33,34 is appealing. There are several excellent review articles.3,39,40,45,47,49,75-77 However there are other areas of research, such as with vitamin E, in which the theory, biochemistry, cell culture and animal model data, and even human surrogate end-point data has been positive, yet human trials with hard clinical end-points of the successful interventions have not proven beneficial.78 While biochemical studies, cell culture, and

Metabolic Mechanism for OA

Hypertension was associated with the development of OA, particularly for bilateral knee disease (11,26). This study also suggested an association between bilateral knee disease and hypercholesterolemia and raised blood glucose. Similarly, after adjusting for age, slightly higher levels of plasma glucose were demonstrated in arthritic women than in normal controls (62). Nevertheless, most studies generally do not support an association between hypertension, raised serum cholesterol, glucose, and OA, and the data therefore remain inconclusive.

Physiologic Monitoring

Diabetic and hyperglycemic patients have chronic impairment of CBF, autoregulation, reduced leukocyte and erythrocyte deformability, increased thrombotic states, and endothelial cell activation. Ischemia leads to lactic acidosis and vasogenic edema, which impairs collateral flow and microcirculation. Plasma glucose > 8 mmol L after acute stroke predicts poor prognosis. Hyperglycemia is more common with insular strokes. The Glucose Insulin in Stroke Trial is under way to clarify benefits of insulin glucose infusion in acute stroke (20).

Hypoglycemic Brain Injury Epidemiology and Background

Reduced food intake does not reduce blood glucose levels below 2.8 mM, even with prolonged fasting (Auer 2004) however, reductions below 1 mM can be induced by the administration of insulin, glucagon, and drugs such as sulfonylurea derivatives. Not surprisingly, hypoglycemic brain injury occurs most frequently in diabetic patients attempting tight glucose control (Lincoln et al. 1996 Davis and Jones 1998), and consequently the risk (or fear) of hypoglycemic brain injury is the major factor limiting tight glucose control. While most diabetic patients experience moderate to severe hypoglycemia at times, very few experience hypoglycemia to the degree causing coma or brain injury. This said, the prevalence of diabetes is so high that hypoglycemic brain injury is not rare in a case series from a single hospital emergency room, there were 125 patients visits for symptomatic hypoglyce-mia in 1 year. Of these, 23 were comatose, 1 died, and 4 survivors had permanent neurological sequelae...

Counterregulatory Hormones

Glucagon Receptor Antagonists - Insulin and glucagon maintain euglycemia by balancing glucose output by the liver and peripheral disposal (91). Hyperglucagonemia is a common feature in IDDM and NIDDM patients, despite hyperglycemia (92,93). In animals with chemically induced IDDM, 70 of the hypoglycemic action of insulin can be attributed to a reduction of hyperglucagonemia, suggesting glucagon as a target for hypoglycemic therapy (94). Analogs of glucagon inhibit glucagon binding to hepatocyte receptors, and reduce hyperglycemia in animal models of IDDM (95,96). Peptidic antagonists prevent glucagon activation of adenylate cyclase, although activation of a second pathway resulting in release of inositol phosphates can still occur (97-99). Of these, des-His1-Glu9-glucagon amide enhances pancreatic insulin release, blocks effects of exogenous glucagon in rabbits, and reduces the hyperglycemia produced by endogenous glucagon in an animal model of IDDM (100). Antagonists of Glucagon and...

Peg Vs Radiological Or Surgical Gastrostomy

The focus of therapy is aimed at correcting any underlying co-morbidity such as malnutrition or hyperglycemia, loosening of the external bolster, and local measures to prevent wound breakdown (such as powdered absorbing agents or skin protectants such as zinc oxide). Placement of a larger gastrostomy tube through the same PEG tract wound tends to further dilate and distort the tract and retard wound healing, thus compounding the problem. The PEG tube may be removed for 24-48 h to permit slight wound closure prior to reinsertion of a replacement tube through the preexisting tract. This technique is most effective for PEG tube tracts that leak 1 mo following initial placement and are ineffective for patients with early tract leakage, as the majority of these patients develop poor wound healing from their underlying disease process.

Enhancers Of Insulin Action

Non-thiazolidinediones (non-TZDs) - There are now a variety of potent non-TZD PPARy ligands which exhibit antidiabetic activity in vivo, including GW-1929 26 (61,62), GI-262570 27 (63), GW-409544 (64), JTT-501 28 (65),and YM-440 (66). GW-1929 is approximately 100-fold more potent in rats than troglitazone in glucose lowering based on serum drug levels (67). The (S)-enantiomer of SB-219994 29 is considerably more potent and efficacious than its antipode (68). The phenylacetic acid derivative 30 (69) reduces hyperglycemia by 65 at 30 mg kg day in Zucker rats. The arylsulfonylamide 31 was obtained from high-throughput screening (70) and the quinoxaline L-764406 32 has been reported to be a PPARy partial agonist (71). Other Enhancers - The mechanism of insulin sensitization of the benzazine derivative 37 (73 reduction of blood glucose at 50 mg kg) (82) and azocycloalkane 38 (83) are unknown. Indoles, such as 39 lower blood glucose significantly in db db mice, reduce triglycerides, but...

Gpr119 Agonists Medicinal Chemistry

More recent patent filings describe selective GPR119 modulators comprised of a fused pyrimidinone core 30, specifically, 6-substituted and 7-substituted 48,49 . Both series of GPR119 modulators are described as being useful for treating or preventing obesity, diabetes, metabolic disease, cardiovascular disease, or a disorder related to the activity of GPR119 in a patient. Undisclosed compounds from these applications are purported to activate GPR119 and stimulate cAMP production in transfected HEK293 cells, exhibiting EC50 values ranging from about 50 nM to 14,000 nM. A mouse oGTT protocol is described for assessing the activity of these compounds in vivo, and various undisclosed fused pyrimidinone examples were reported to be effective in lowering blood glucose levels after glucose challenge.

Liverselective glucocorticoid receptor antagonists

The correlation between elevated hepatic glucose output and fasting hyperglycemia in type 2 diabetic patients is well established. Also, the link between elevated glucocorticoids (GCs) and glucose control suggested the desirability of exploring glucocorticoid receptor antagonism as a potential therapy for T2D. However, the critical role played by GCs in the hypothalamic pituitary axis (HPA) and potential toxicity due to systemic GC antagonism, suggests that liver-selective glucocorticoid receptor (GR) antagonists would be required to safely treat T2D patients.

Endothelial dysfunction

Cardiometabolic syndrome (Figure 2.7)21-23. Hyper-lipidemia, hyperglycemia, hypertension, smoking, and homocysteine have all been reported to damage the endothelium. (Studies that have treated these particular components have also shown favorable effects on endothelial dysfunction). Endothelial dysfunction leads to an imbalance in the endothelial production of favorable versus unfavorable factors. Factors such as platelet adhesion, aggregation, and thrombogenicity of the blood have been postulated to play a role. Therefore, secondary to endothelial dysfunction, circulating platelets may aggregate in particular areas, releasing cytokines and growth factors, and may initiate the inflammatory reaction. After the initial inflammatory reaction, LDL cholesterol is postulated to be more actively taken up into the vessel wall and may result in the formation of a fatty streak. Ultimately, vascular smooth muscle cells participate in the process by migrating into the intima, proliferating, and...

Carbon and nitrogencentered glucokinase activators

Compound 5 was assessed in a variety of rodent models of T2D and was effective in lowering basal blood glucose levels in addition to dampening glucose excursions during an oral glucose tolerance test (OGTT). Initial indications of participation of the liver became evident during OGTTs carried out in healthy and T2D mouse models. Compound 5 stimulated peak insulin levels at 45 min and an OGTT was carried out 120 min after oral administration of 5. While 5 was equally efficacious regardless of when the OGTT was performed, sulfonylureas were generally more effective when an OGTT was carried out concurrently with the drug-induced peak insulin levels. These results implicated activation of hepatic GK by 5, which was subsequently confirmed in a pancreatic clamp study in rats. These reports indicated improved glucose utilization in the drug-treated group. Therefore, GKAs were shown to increase the threshold of GSIR in the pancreas and also to improve glucose utilization in the liver....

Sequence Of Events During Complete And Incomplete Cerebral Ischemia

For incomplete global cerebral ischemia, this sequence of events depends on reductions of CBF below a set of thresholds inhibition of protein synthesis when CBF is below 50 of normal, suppressed electrical activity and O2 consumption when CBF is below 40 of normal, decreased ATP when CBF is below 25 of normal, and anoxic depolarization when CBF is below 20 of normal (6,7). The decrease in protein synthesis and electrical activity helps to conserve ATP for maintaining ionic homeostasis. This sequence of events is also time dependent and is delayed relative to that occurring with complete ischemia. Small, incremental improvements in CBF can forestall the loss of ATP. For example, with intracranial hypertension sufficient to reduce CBF to 15 of baseline and O+ consumption to 25 of baseline, ATP takes 12 min to fall to 35 of baseline and 30 min to fall to < 10 (8). Thus, the time course of ATP loss can be delayed more than 10-fold compared to complete ischemia, even at trickle levels of...

Histopathology Of Global Ischemia

Regions of infarction sometimes appeared in early experimental studies after long durations of global ischemia (7), particularly under conditions of elevated blood glucose (37). Partial ischemia has the potential to produce more severe pathology than a similar duration of complete ischemia, generally considered to reflect the consequences of sustained anaerobic metabolism supported by continued glucose delivery, ultimately resulting in higher lactate production and lower tissue pH (38). Watershed areas can become involved under conditions of globally impaired perfusion during recovery from cardiac arrest (1). Prolonged ischemia was also found in some early studies to result in a no reflow phenomenon (39,40), typically associated with more complete stasis during occlusion (41) or reduced blood pressure during early reperfusion (42,43). Even microinfarcts should not be detected after the short insults encountered in current models and, if they do appear, could be considered indicative...

Artificial cells containing islets

Typical results obtained by a number of groups showing that heterologous islets inside artificial cells are not immuno-rejected. They continue to function for various lengths of time in maintaininga normal blood glucose level. However, the results are not always reproducible especially in the duration of function after implantation. Fig. 8.2. Typical results obtained by a number of groups showing that heterologous islets inside artificial cells are not immuno-rejected. They continue to function for various lengths of time in maintaininga normal blood glucose level. However, the results are not always reproducible especially in the duration of function after implantation.

Leptin in type 1 autoimmune diabetes

Leptin is involved in other autoimmune conditions (17). Leptin accelerates autoimmune diabetes in female NOD LtJ mice (18). Fluctuations in serum leptin levels have also been observed in a study performed by our group in an animal model of CD4+ T-cell-mediated autoimmune disease, such as T1D. Nonobese diabetic (NOD LtJ) female mice, spontaneously prone to the development of -cell autoimmunity, have higher serum leptin levels, as compared with NOD LtJ males and nonsusceptible strains of mice, and show a serum leptin surge preceding the appearance of hyperglycemia (19). Furthermore, leptin administration early in life significantly anticipated the onset of diabetes and increased mortality and inflammatory infiltrates in beta-islets this phenomenon correlated with increased secretion of IFN-y in leptin-treated NOD mice (20). More recently, it has been found that a natural leptin receptor mutant of the NOD LtJ strain of mice (named NOD LtJ-db5J) displays reduced susceptibility to T1D...

Impaired Glucose Tolerance Impaired Fasting Glucose Insulin Resistance And Diabetes

148 Fasting Glucose High

A study of three European cohorts from the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study evaluated the relationship between hyperglycemia and mortality among non-diabetic men59. Men with fasting glucose levels in the upper 2.5 of values and upper 20 of 2-hour glucose levels after an oral glucose tolerance test demonstrated a significant increase in all-cause mortality when compared with those in lower distributions55. Men in the upper 2.5 of values for both fasting and 2-hour glucose levels were also at higher risk for cardiovascular and coronary artery disease-related death59. The Framingham Offspring Study investigated the effect of impaired glucose tolerance, impaired fasting glucose, and type 2 diabetes mellitus on the 2 diabetes, one study demonstrated a significant increase in coronary artery disease-related death and coronary events associated with HbA1c levels of greater than 7.0 compared with lower levels61. The UKPDS 23 study evaluated a...

Physiological Changes

The diabetes that develops after total pancreatectomy is particularly difficult to manage, however. Patients are exquisitely sensitive to insulin because of enhanced peripheral insulin sensitivity. Hypoglycemic episodes can be frequent, secondary to the lack of glucagon, and the counter-regulation it provides for a fall in blood glucose. Fasting and postprandial hyperglycemia is common because of unsuppressed hepatic glucose production. The paradox of hepatic resistance to insulin, and enhanced peripheral sensitivity to insulin causes difficulty in the management of postoperative diabetes. The duodenum-preserving pancreatic head resections have a lower incident of postoperative diabetes, and may actually result in improved glucose tolerance. This observation sug

What is the most common replacement fluid used in children

Procedures if glucose-containing fluids are not used, but administration of 5 glucose-containing solutions results in hyperglycemia in the majority of children. Perhaps fluid containing 1 or 2.5 glucose is best. Others still use 5 glucose solutions for maintenance but recommend nonglucose-containing BSS for third space or blood loss. In major operations it is prudent to check serial glucose levels and avoid hyperglycemia or hypoglycemia.

What challenges do spinal cordinjured patients pose

Corticosteroids have been administered to cord-injured patients, although this remains controversial universal application in this setting is dwindling. Corticosteroids are not without their own risks, including immunosuppression, hyperglycemia, and delayed wound healing.

Congenital generalized lipodystrophy from mutations in BSCL2 and AGPAT2

Patients also develop significant metabolic abnormalities very early in life. Extreme insulin resistance is a striking feature of this syndrome. Most patients have high fasting and postprandial insulin levels. Onset of DM is usually seen during pubertal years, but, occasionally, neonates may also develop hyperglycemia. Severe hypertriglyceride-mia leading to recurrent pancreatitis, low HDL cholesterol levels, and chronic steatohep-atitis are other associated features. These patients have very low levels of serum leptin and adiponectin (16). Administering recombinant leptin to these patients as a replacement therapy helped to control hyperglycemia, hypertriglyceridemia, and hepatic steato-sis (17), suggesting that hypoleptinemia may be partly responsible for the metabolic abnormalities.

Adiponectin as Insulin Sensitizing Hormone

The chronic effects of adiponectin on insulin sensitivity and energy metabolism were also investigated in adiponectin transgenic mice or adiponectin knockout (KO) mice. Scherer's group generated a transgenic mouse model with approximately threefold elevation of native adiponectin oligomers (19). The authors demonstrated that hyper-adiponectinemia significantly increased lipid clearance and lipoprotein lipase activity, and enhanced insulin-mediated suppression of hepatic glucose production, thereby improving insulin sensitivity. Kadowaki's group showed that transgenic overexpression of globular adiponectin in the genetic background of ob ob obese mice led to partial amelioration of insulin resistance, hyperinsulinemia, and hyperglycemia (20). Conflicting results have been obtained from adiponectin KO mice studies. Yamauchi et al. found no impact of adiponectin depletion on insulin sensitivity under either normal chow or after 7 mo of feeding with a high-fat diet (21). In contrast,...

Conclusion and Future Directions

The onset and progression of diabetes-related atherosclerosis is likely to involve a wide range of pathogenic mechanisms, including oxidative stress, which as suggested by Brownlee, may have a central role stemming from hyperglycemia hyper-glycemia-induced O2- production by mitochondria. Research has increased our understanding of oxidative stress in general and in diabetes, and its contribution to atherosclerosis and diabetic vascular complications. Well-validated and standardized assays of oxidative stress and damage are urgently needed. Samples for analysis must be collected and stored appropriately to avoid ex vivo oxidation, an obvious point, but one that can be difficult to achieve in large multicenter clinical trials. Knowledge of oxidative stress-related gene polymorphisms may facilitate identification and treatment of high complication risk diabetic patients and drug choice. Well-tolerated and effective drugs targeting appropriate oxidative stress pathways in appropriate...

Fetal Overnutrition Pathway

In addition to these effects of prenatal undernutrition, it is well recognized that the fetuses of diabetic mothers are born with relative obesity, suggesting a separate pathway linking prenatal nutrition with later risk of metabolic disease. Maternal hyperglycemia leads to fetal hyperglycemia and fetal hyperinsulinemia, which promotes excessive fat deposition during the third trimester. The degree of subcutaneous adiposity is increased even under conditions of subclinical maternal hyperglycemia. The increased adiposity in fetal life may then be magnified by postnatal overnutrition, and the obesity that is generated often, in turn, leads to type 2 diabetes (64).

Noncompetitive inhibitors

Deferoxamine (DFO, desferrioxamine), a bacterial siderophore isolated from Streptomyces is a potent multidentate iron binder and has been used clinically for the treatment of iron overload and toxicity. Prior to the discovery of the PHD enzymes, DFO was found to increase EPO RNA and HIF-1a levels in Hep3B cells 20 . Additionally, DFO administered intraperitoneally (i.p.) to female mice at a dose of 200 mg kg showed an increase in EPO mRNA in the kidneys after 22 h, but this effect was transient and lost upon chronic (5 day) dosing. Acclimatization to hypoxia is known to protect the heart from damage due to ischemia reperfusion (I R) injury. In rats, DFO has been shown, via HIF-1a stabilization, to simulate hypoxia and protect cardiomyocyte function after I R 21 . High blood glucose has been shown to produce a reactive metabolite, methylglyoxal, responsible for impairment of HIF-1a binding to the transcription factor p300, thus reducing gene transcription in diabetic models 22 . DFO...

Glucose Insulin and Potential Mechanisms of Vascular Stiffening

Among patients with diabetes 15 or the metabolic syndrome, arterial stiffening is observed across all age groups. In children with severe obesity, arterial wall stiffness and endothelial dysfunction are accompanied by low plasma apolipoprotein A-I levels, insulin resistance, and android fat distribution, changes that may be the main risk factors for the early events leading to atheroma formation 16 . The positive correlation between insulin resistance and central arterial stiffness and the close relationship between the extent of metabolic changes and the degree of arterial stiffness suggest that insulin resistance is a primary underlying factor. In animal models of insulin-resistant diabetes, chronic hyperglycemia and hyperinsulinemia increase local angio-tensin II production and expression of vascular Ang II type I receptors via stimulation of TGF- 1, upregulate plasminogen activator inhibitor-1, and downregulate matrix metalloprotease activity, all of which play a critical role in...

Pathways of Glucose Mediated Oxidative Stress in Diabetic Neuropathy

Diabetic distal symmetric sensorimotor polyneuropathy (DPN), the most common peripheral neuropathy in developed countries (1-3), affects up to 6070 of diabetic patients (4) and is the leading cause of foot amputation (5). The typical slowing of nerve conduction and the advancing distal symmetrical sensorimotor deficits are thought to reflect an underlying slowly progressive distal axonopathy of the dying-back type primarily affecting sensory nerve fibers (6). Improved blood glucose control substantially reduces the risk of developing DPN in insulin-dependent (type 1) diabetes (7,8), thereby strongly implicating hyperglycemia as a causative factor.

Conclusions

Taken together, there is good evidence that short- and long-term hyperglycemia cause an activation of NADPH oxidase and the formation of ROI. The endothelium has been demonstrated as one of the major sources of ROI generation. Experimental data from in vitro and in vivo studies clearly show that these ROIs are able to induce a thrombogenic transformation of the vessel wall and to be the cause for the endothelial dysfunction observed in diabetes but also in hypertension and hypercholesterolemia. Whether these cytotoxic effects are exerted by superoxide anions directly or are mediated by peroxynitrite depends on the local environment and the type of vasculature regarded. Our current knowledge is summarized in the hypothesis shown Figure 6 Current hypothesis formation of ROI by hyperglycemia and the effects of ROI on the vessel wall as cause for the development of vascular complications in diabetes. Figure 6 Current hypothesis formation of ROI by hyperglycemia and the effects of ROI on...

Resistin

The name of this adipokine was derived from the seminal observation that it induced insulin resistance in mice (40). Circulating resistin concentrations were shown to be increased in genetically obese rodents (ob ob and db db mice) as well as in high-fat-diet-induced obesity. Immunoneutralization of resistin was shown to improve hyper-glycemia and insulin resistance in high-fat-induced obese mice, whereas recombinant resistin administration impaired glucose tolerance and insulin action in normal mice. Insulin, TNF-a, epinephrine, -adrenoreceptor stimulation, and thiazolidine-diones reportedly decrease resistin gene expression. However, insulin, -adrenorecep-tor stimulation, and thiazolidinediones have been also observed to increase the expression of resistin, together with other factors such as glucose, growth hormone, and glucocorticoids (41). The real contribution of resistin in human pathophysiology remains controversial. Although resistin transcripts have been found in WAT of...

Glucose metabolism

Abnormalities in glucose tolerance are commonly noted in individuals with central obesity. As outlined in Chapter 1, it is now well accepted that the presence of insulin resistance in an individual will need to be compensated for by hyperinsulinemia in order to maintain normal glucose tolerance. In those individuals who develop diabetes, a progressive loss of the insulin secretory capacity fails to compensate for the insulin resistance and results in a progressive hyper-glycemia (see Chapter 1). Thus, an individual with obesity and insulin resistance, depending on the stage of compensation for the insulin resistance, may have euglycemia, impaired fasting glucose, impaired glucose tolerance, or overt hyperglycemia confirming the diagnosis of type 2 diabetes.

Conclusion

Proteins (glycoxidation), supporting the concept of increased oxidative stress in diabetes. Indeed, the newly introduced drug troglitazone may exert some of its protective effects by its antioxidant capacity (95). Further work is required using modern biomarkers to evaluate the extent to which agents beneficial in the treatment of diabetes, including lipoic acid (see other chapters in this volume), act by suppressing oxidative stress. Another exciting area is the prevention of the teratogenic effects of hyperglycemia Studies in rats have shown that vitamin E (96) and overexpression of CuZnSOD (97) can be beneficial.

Niacin analogs

Acipimox (5) was introduced in Europe to treat hyperlipidemia in 1985 47,48 . Acipimox is a weak agonist of GPR109A with micromolar binding and functional activity. Like niacin, acipimox raises HDL-C and triggers vasodilation in humans. However, it remains unclear whether acipimox causes mild hyperglycemia as is observed with niacin 49,50 .

Initial Assessment

INR > 1.7 (PT > 15 if no INR available) with or without chronic oral anticoagulant use* Seizure at onset of stroke (This relative contraindication is intended to prevent treatment of patients with a deficit due to postictal ''Todd's'' paralysis or with seizure due to some other CNS lesion that precludes thrombolytic therapy. If rapid diagnosis of vascular occlusion can be made, treatment may be given.) Glucose < 50 or > 400 (This relative contraindication is intended to prevent treatment of patients with focal deficits due to hypo- or hyperglycemia. If the deficit persists after correction of the serum glucose, or if rapid diagnosis of vascular occlusion can be made, treatment may be given.)

Treatment of Edema

A larger and more scientifically rigorous trial evaluating the effects of dexamethasone in primary supratentorial ICH was subsequently conducted in Thailand (27 ). This double-blinded, controlled trial randomized patients within 48 hr of the ictus. Diagnosis of ICH was confirmed by CT scan. Patients in the dexamethasone group were scheduled to receive a total of 150 mg of the drug over 9 days. Ninety-three patients were enrolled before the trial was prematurely terminated due to an excess of adverse events among patients treated with the corticosteroid. Groups were well balanced at baseline in terms of age, comorbid conditions, ICH location, and severity of initial clinical presentation. The only notable difference was a larger mean hematoma volume among patients assigned to receive dexamethasone than among those in the control group (72 vs. 59 mL). Neither mortality nor functional recovery after 21 days was different between groups. However, the rate of complications and possible...

Future Trials

Medical priorities Blood-pressure management Treatment of hyperglycemia Normalization of body temperature Prophylactic use of antiepileptic agents Safety of prophylactic anticoagulants Reversal of antithrombotic- and fibrinolytic-induced ICH Evaluation of hemostatic agents in coagulopathy-associated ICH Surgical priorities Mechanical clot removal devices Surgical targeting Perioperative imaging

Blood Glucose

The relationship of blood glucose levels and focal cerebral ischemia is complex. Elevated blood glucose levels were reported to increase (130), decrease (131), or has no effect on infarct volumes. However, the overwhelming majority of reports in the literature indicate that hyperglycemia is detrimental in focal ischemia models. In human stroke, hyperglycemia is associated with infarct expansion and worse neurologic outcome (132). Monitoring and, when necessary, controlling blood glucose levels eliminate this confounding factor.

Neuropathology

Nerve conduction studies showed markedly reduced conduction velocities in the distal nerve segments and prolonged F wave latency and proximal conduction time despite the shorter conduction pathway in diabetic rats. We suggest that the combination of hyperglycemia and ischemia results in oxidative stress and a predominantly sensory neuropathy.

Introduction

Neuropathy is a common complication of diabetes mellitus. Studies in patients and animal models have shown that endoneurial hypoxia, caused by impaired nerve blood flow, is a major factor in the etiology of diabetic neuropathy (l-4). Changes in vascular function, particularly of the endothelium, occur early after diabetes induction in experimental models, and in some preparations, this may even be partially mimicked by acute exposure to hyperglycemia (5,6). In streptozotocin-induced diabetic rats, sciatic nerve blood flow is reduced by approximately 50 within a week of diabetes induction (7,8), and this precedes changes in nerve conduction velocity (NCV). Large diameter sensory and motor fibers are particularly susceptible to endoneurial hypoxia in experimental diabetes (9,10).

Glucose Management

Between 20 and 50 of acute stroke patients are hyperglycemic at presenta-tion.137 The degree of hyperglycemia correlates with both mortality and functional outcome, even despite successful recanalization after thrombolysis. In experimental models of cerebral ischemia, hyperglycemia is shown to exacerbate ischemic neuronal injury through a variety of mechanisms. Hyperglycemia amplifies extracellular glutamate accumulation, especially in the cortex,140 impairs lipid metabolism,141 reduces perfusion to the penumbra, promotes calcium influx through NMDA receptors, cytotoxic edema, oxidative stress, and free-radical production, and increases inflammation including expression of metalloproteinases (MMPs).142 The Glucose Insulin in Stroke Trial suggests that administration of glucose, insulin, and potassium during the first 24 hours after stroke onset is safe this pilot study was underpowered to determine efficacy.143 Three studies addressing aggressive insulin therapy for euglycemia, the...

Summary

Currently, little data exist to suggest that early medical intervention, short of rtPA or aspirin administration, improves outcome after acute ischemic stroke. An organized approach to preventing complications, as demonstrated by the use of stroke units, does seem to produce better clinical outcomes. Numerous trials are underway to assess the safety and effectiveness of several different interventions, such as induced hypertension, hypothermia, aggressive insulin therapy, and administration of neuroprotective agents. Until they are completed, it seems reasonable to suggest that, in the treatment of acute ischemic stroke, measures be taken to prevent hypotension, hyperthermia, and hyperglycemia.

Pharmacotherapy

Octreotide, in a dose of 0.05-0.1 mg subcutaneously two to three times a day, has been reported to reduce blood loss from intestinal angiodysplasia. Response is fast, with the disappearance of overt bleeding and improvement in transfusion requirements as early as 24 hours after initiation of therapy. In one instance, bleeding recurred when therapy was discontinued after 6 months. No significant adverse effects other than mild hyperglycemia were noted.

Nad Nadh

Figure 3 Hyperglycemia activates the sorbitol pathway. Sorbitol oxidation increases cytosolic NADH NAD+. Increased NADH NAD+ ratios increase prostaglandin synthesis, leading to free radical production. In the mitochondria, the superoxide radical is generated by oxidation of NADH in the electron transport chain. Hyperglycemia Sorbitol pathway activity

Microalbuminuria

Suggest that the prevalence in middle-aged non-diabetics is as high as 10-15 . In a cross-sectional study of approximately 3500 Chinese subjects, the waist-to-hip ratio, systolic and diastolic pressure, serum triglyceride level, fasting plasma glucose, and homeostasis model assessment-insulin resistance (HOMA-IR) were all significantly increased in those subjects with microalbuminuria compared with normal subjects31. The prevalence of microalbuminuria was also significantly increased with an incremental rise in the number of components of the metabolic syndrome (p for trend < 0.001). However, the only independent predictors of microalbuminuria were hypertension and hyperglycemia (OR 2.15 and 1.64, respectively).

Pancreas

Experimental pancreatic injury in laboratory animals induced by streptozotocin is a standard model of inducing diabetes. Streptozotocin-induced diabetes alters serum lipidprofiles 95 , increases markers oflipid peroxidation such as hepatic thiobarbituric acid reacting substances (TBARS) and conjugated dienes 96-99 , and raises serum antibodies against MDA-protein adducts 95 , In streptozotocin-induced diabetes, treatment of rats with Vitamin E reduces blood glucose levels and reduces lipid peroxidation 98,99 , At the subcellular level, ATC supplementation improves the ability ofhepatic mitochondria to withstand ROS-induced damage in streptozotocin-induced diabetic rats 100 ,

Ocular Angiogenesis

Diabetic retinopathy is the commonest cause of visual loss in young people. Hyperglycemia leads to retinal microvascular occlusion and ischemia. The subsequent hypoxia-induced upregulation of angiogenic growth factors results in neovascularization that extends from the inner retinal surface to the vitreous gel 10 . Complications of the neovascular proliferation are the major causes for severe visual loss in diabetes through hemorrhage into the vitreous or retinal detachment 11 . Panretinal laser photocoagulation is the current conventional treatment for proliferative diabetic retinopathy. Pathological angiogenesis also occurs in tissues in the anterior segment of the eye. Neovascularization of the iris typically occurs in ischemic retinopathies like diabetic retinopathy and central retinal vein occlusion and can cause loss of vision through the associated closure of the iridocorneal drainage angle, resulting in increased intraocular pressure and glaucoma. Corneal neovascularization...

Glucose Free Solution

The next study was conducted because of an observation that hyperglycemia was associated with poor recovery after CA (26). Undertaken primarily by the Emergency Medical Services, the study compared the effect of nondextrose (0.45 NaCl n 377) and dextrose (5 n 371) solution during resuscitation. Of the 748 patients randomized, 291 patients were admitted to the hospital. Of those admitted, 141 patients received the dextrose solution and 150 received the nondextrose solution. With the patient awakening as the functional endpoint, no difference was observed between the dextrose solution arm (16.7 ) and the nondextrose arm (14.6 ). The number of patients surviving to discharge after treatment was similar, with 15.1 in the dextrose-solution arm and 13.3 in the nondextrose-solution arm (26).

Insulins

Proinsulin - Proinsulin, the physiologic precursor of active insulin, has a less pronounced, but longer duration of action than human insulin. Apparent selectivity for hepatic versus peripheral action of proinsulin (relative to insulin) has been cited as the basis for its potential use in NIDDM, where fasting hyperglycemia is attributed to high hepatic glucose output (31). This property, however, has been linked to differences in clearance rather than intrinsic selectivity (32). In one clinical study, an increased frequency of acute myocardial infarct in patients receiving proinsulin versus controls raised safety concerns and human trials have been suspended (7). reduce blood glucose after a single dose in diabetic KK mice (72,73). CP-72467, (4), is more potent than 1 in vivo and like insulin, stimulates glucose transport and glucose transporter expression in vitro (74-79). AY-31637 (5) is equipotent to ciglitazone (80). More potent thiazolidinedione analogs have been disclosed...

Stephen E Borst

Obesity and type 2 diabetes are the most common metabolic diseases in Western society, together affecting as much as half of the adult population (1). Not only is the prevalence of these conditions high, but it also continues to increase. Insulin resistance is a prediabetic condition, characterized by a failure of target organs to respond normally to insulin. Insulin resistance includes a central component (incomplete suppression of hepatic glucose output) and a peripheral component (impaired insulin-mediated glucose uptake in skeletal muscle and adipose tissue) (2). When increased insulin secretion is no longer sufficient to prevent hyperglycemia, the subject progresses from insulin resistance to type 2 diabetes. Insulin resistance is associated with other conditions such as central obesity, hypertension, and dyslipidemia, all risk factors for cardiovascular disease. The constellation of these metabolic abnormalities has been termed metabolic syndrome.

Adverse Effects

However, since there are p2 receptors in the myocardium, and since there is reflex sympathetic stimulation of the heart as a consequence of p 2 relaxation of the vasculature that supports skeletal muscles, there is always some degree of increased heart rate and cardiac output if the dosage of the p2 drug is high enough. With long-term use, hyperglycemia and hypokalemia may result. Hypokalemia does occur from direct stimulation of the sodium-potassium pump in the cell membrane, and so can occur acutely. Further hypokalemia occurs with steroid or diuretic treatment so that a hypoxemic patient could experience arrhythmias.

NaK ATPase

Na+-K+ ATPase, an integral component of the sodium pump, is involved in the maintenance of cellular integrity and functions such as contractility, growth, and differentiation (5). It is well established that Na+-K+ ATPase activity is generally decreased in the vascular and neuronal tissues of diabetic patients and experimental animals (5,86-88). However, studies on the mechanisms by which hyperglycemia inhibited Na+-K+ ATPase activity have provided some conflicting results regarding the role of PKC. Phorbol esters, activators of PKC, have been shown to prevent the inhibitory effect of hyperglycemia on Na+-K+ ATPase (5), which suggested that PKC activity might be decreased in diabetic conditions. Recently, however, we showed that elevated glucose level (20 mM) will increase PKC and cPLA2 activities, leading to increases of arachadonic acid release and PGE2 production resulting in decreases in Na+-K+ ATPase activity. Inhibitors of PKC or PLAj prevented glucose-induced reduction in...

Insulin Resistance

Hyperglycemia (NIDDM) The levels of expression of the GLUT4 glucose transporter have been analyzed in a variety of animal models of type 2 diabetes and in tissue from individuals with type 2 diabetes (for review see 18,19). GLUT4 protein content is markedly diminished in adipose tissues of human and most animal models. It has been found that GLUT4 expression in adipocytes decreases as diabetes develops in older Zucker rats (18,19), and adipose cells taken from humans with type 2 diabetes also show a reduction in GLUT4 content (20). However, this change in GLUT4 levels is restricted to adipose tissue and is not seen in skeletal muscle of these animal models of type 2 diabetes as normal expression of GLUT4 is observed in muscle of db db mice and Zucker rats (21-24). Muscle biopsies taken from individuals with type 2 diabetes also show normal skeletal muscle GLUT4 content (25). However, a small number of studies have examined the amount of GLUT4 protein on the plasma membrane of muscle...

Type 1 Diabetes

The most widely used animal model of type 1 diabetes is the streptozotocin-induced diabetic rat. Streptozotocin is a compound that causes hypersecretion of insulin from the pancreatic P-cells, resulting in their eventual dysfunction and leading to a hypoinsulinemic state (23). The streptozotocin-diabetic rat is characterized by marked postprandial hyperglycemia and by an elevation in free fatty acids without ketoacidosis (23). Skeletal muscle from the streptozotocin-diabetic rat is markedly insulin resistant for stimulation of glucose transport (24,25) and expresses a significantly reduced protein expression of the GLUT4 glucose transporter isoform (24,25).

Diabetes

Historically, strict blood glucose control in diabetics was only shown to reduce or delay the onset of microvascular disease such as retinopathy and neuropathy (Figures 8.21, 8.22 and 8.23)29. The UK Prospective Diabetes Study (UKPDS) compared conventional glucose control (fasting glucose < 15 mmol L) with an intensive strategy (< 6 mmol L) in over 4000 patients. Early data demonstrated the relationship between glycosylated hemoglobin (HbAlc) and microvascular events, and also hinted at a relationship with acute myocardial infarction rates (Figures 8.24-8.26)30. However, more recently the Diabetes Control and Complications Trial Epidemiology of Diabetes Interventions and Complications (DCCT EDIC) Study compared conventional treatment (preventing symptoms of hypoglycemia or hyperglycemia) with intensive glucose control (glucose 3.9-6.7mmol L and HbAlc < 6.05 )32. They demonstrated that, in 1400 patients over 17 years of follow-up (but a mean treatment period of 6.5 years), type 1...