Home Remedies for Hyperglycemia

Blood Sugar Miracle

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Hyperglycemia and glucose transporter GLUT1

Hyperglycemia (an increased blood D-glucose concentration) is the most important symptom exhibited by diabetic patients, and this has severe effects on the development of diabetic retinopathy (Cai & Boulton, 2002). At the inner BRB, the retinal endothelial cells express facilitative glucose transporter, GLUT1 that recognizes hexoses and dehydroascorbic acid (DHA) as substrates (Vera et al., 1993). GLUT1 mainly mediates the influx transport of D-glucose across the inner BRB. GLUT1 exhibits an asymmetrical localization at the inner BRB, and the abluminal expression of GLUT1 protein is 2- and 3-times higher than that on the luminal membrane (Takata K et al., 1992 Fernandes et al., 2003), suggesting that GLUT1 suppresses glucose accumulation in the retinal interstinal fluid. Regarding the influx permeability rate, the blood-to-retina transport is 544 and 2440 microL (min- g retina) for D-glucose and DHA, respectively (Puchowicz et al., 2004 Hosoya et al., 2004). DHA is the oxidized...

HyperglycemiaDRG CategoT 463

I I yperglycemia exists when the blood glucose level is greater than 110 mg dL. Normal blood glucose levels can be maintained between 70 and 110 mg dL when there is an adequate balance between insulin supply and demand. In acutely ill individuals, hyperglycemia is usually not diagnosed until a random test of serum glucose level shows an increase above the 150 to 200 mg dL range. Glucose is the most important carbohydrate in body metabolism. It is formed from the breakdown of polysaccharides, especially starch, and is absorbed from the intestines 440 Hyperglycemia Insulin is produced by the beta cells of the pancreas, which are stimulated to release it when the blood glucose level rises. Insulin transports glucose, amino acids, potassium, and phosphate across the cell membrane. Insufficient production or ineffective use of insulin causes an elevated blood glucose level (hyperglycemia), which promotes water movement into the bloodstream from the interstitial space and intracellular...

Hyperglycemia

There are very few reports regarding the development of diabetes or worsening of preexisting diabetes in patients with renal cell carcinoma (Elias 2005 Palgon et al. 1986 Jobe et al. 1993 Callewaert et al. 1999). In one case, the patient was diagnosed with a preexisting insulin-dependent diabetes mellitus that became uncontrollable by insulin therapy. The patient underwent partial nephrectomy because of a histological papillary type and the control of his glycemia improved immediately and insulin need became identical to the premor-bid situation (Callewaert et al. 1999). The other three case reports did not have any history of diabetes melli-tus and the hyperglycemia resolved following nephrec-tomy. The mechanism for this syndrome is unclear and none of these patients had evidence of metastatic disease or family history of diabetes. No specific etiology was found, but the possibility of ectopic glucagon production was considered. Hypothetically, diabetes could develop in patients with...

Poly ADPribose Polymerase PARP

Poly (ADP-ribose) Polymerase (PARP) is a nuclear enzyme residing as an inactive form which gets activated after the cell receives the DNA damaging signals. Increased intracellular glucose generates increased ROS in the mitochondria, which induces DNA strand breaks, thereby activating PARP. Once activated, PARP depletes its substrate, NAD+ molecule, by breaking into nicotinic acid and ADP-ribose, slowing the rate of glycolysis and mitochondrial function. By inhibiting mitochondrial superoxide or ROS production with either MnSOD or UCP-1, prevented both modification of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by ADP-ribose and reduction of its activity by hyperglycemia Du X, 2003 . PARP was found to decrease the GAPDH activity, activate the polyol and PKC pathways, increases intracellular AGE formation and activates hexosamine pathway flux which trigger the production of reactive oxygen and nitrogen species, playing a role in the pathogenesis of endothelial dysfunction and...

Diabetic Nerve Disease

If you have elevated blood glucose for a long time, many different nerves in your body can get damaged a condition known as neuropathy. In the following sec- The vagus nerve regulates the heart rate, and when it gets injured due to high blood glucose levels the heart rate is fast even at rest. The fast heart rate by itself is not necessarily harmful, unless the person also has coronary artery disease. In this case, the neuropathy can increase the risk of serious heart rhythm problems and even death. Therefore, people with diabetes who have autonomic neuropathy affecting the heart should be evaluated by a cardiologist to determine the extent of heart disease.

Advance Glycation End Products

Extended exposure of proteins to hyperglycemia can result in nonenzymatic reactions, in which the condensation of glucose with primary amines forms Schiff bases. These products can rearrange to form Amadori products and advanced glycation end-products (AGE). The glycation process occurs both intracellularly and extracellularly. It has been reported that the glycation modification target to intracellular signaling molecules and extracellular structure proteins alike, and furthermore, alter cellular functions. Multiple forms of proteins subjected to glycation have been identified with W -(carboxymethyl)lysine (CML), pentosidine, and pyralline being the major form of AGEs presented in diabetic states.

Oxidative stress and diabetic retinopathy

Diabetic retinopathy pathogenesis is multifactorial, and the precise mechanisms are unclear. Several mechanisms have been proposed, including enhanced free radical production ROS (Brownlee et al., 1998 Koya & King 1998). Oxidative stress is increased in the retina in diabetes, and it is considered to play an important role in the development of retinopathy (Manikanth et al., 2010 Armstrong et al., 1998). It has been already proved that oxidative stress and hyperglycemia are central to chronic pathogenesis of diabetic retinopathy (Turk 2010). Increased levels of free radicals have a direct effect on in vivo protein. Oxidative stress induced modification of proteins is initiated mainly by reactions with hydroxyl radical however, the course of the oxidation process is determined by the availability of oxygen and superoxide radical or its protonated form (HO2'). Collectively, these ROS can lead to oxidation of amino acid residue side chains, cross-linking of soluble and or...

Activation of the Polyol Pathway

Increased activity of the polyol pathway has been documented in culture studies using vascular cells exposed to diabetic level of D-glucose and in animals with diabetes (58,59). In these studies, hyperglycemia has been shown to increase the activity of aldose reduc-tase and enhances the reduction of glucose to sorbitol, then further oxidized to fructose by sorbitol dehydrogenase. Abnormality in the polyol pathway has been suggested to cause vascular damage in the following ways (a) osmotic damage by the accumulation of sorbitol (58) (b) induction of oxidative stress by increasing nicotinamide adenine dinucleotide phosphate (NADP) NAD+ ratio and the activation of Na+ K+ adenosine triphosphate (ATP)ase (59) and (c) reduction of NO in the vasculature by decreasing cellular NADPH, a cofactor used by aldose reductase to reduce glucose to sorbitol (60). Multiple studies have shown that inhibition of aldose reductase, the key enzyme in the

Vascular Permeability and Neovascularization

Increased vascular permeability is another characteristic vascular abnormality in diabetic patients and animals, in which increased permeability can occur at as early as 4-6 weeks' duration of diabetes, suggesting endothelial cell dysfunctions (139). Because the vascular barrier is formed by tight junctions between endothelial cells, the increase in permeability as a result of the abnormalities in the endothelial cells. The activation PKC can directly increase the permeability of albumin and other macromolecules through barriers formed by endothelial cells, probably by phosphorylating the cytoskeletal proteins forming the intercellular junctions (140-142). Recently, PKC- 1 overexpression in human dermal microvascular endothelial cells has been reported to enhance phorbol ester-induced increase in permeability to albumin (143). Thus, the actions of phorbol ester and hyperglycemia in endothelial-barrier functions are mediated in part through activation of PKC- 1 isoform.

Vascular nitric oxide defficiency origin in diabete

In diabete, hyperglycemia may actvate PKC isoform bll in endothelial cells, what reduces calcium ingress in cells and, consequently, nitric oxide synthesis (15). Besides, PKC promotes superoxide generation in endothelial cells and it quenches in a reaction that produces the toxic radical peroxynitrite (15). This way, overactivation of PKC mediated by hyperglycemia may reduce the synthesis or accelerate the loss of nitric oxide (15). Hyperglycemia also provides a substrate increase for endothelial aldose reductase (15). Such enzyme generates sorbitol from glucose in a reaction that oxidizes NADPH - and, this way, decreases disponibility of reducing co-factor for NO sintase (16). Glycated tissue proteins (whose levels increase as a consequence of hyperglycemia) may generate superoxide in a non-enzymatic reaction that needs transition metal catalysis such factor also contributes to NO deficiency associated to hyperglycemia (15). Besides, AGEs may also extinguish NO directly (15).

Basement Membrane Thickening and Extracellular Matrix Expansion

Histologically, increases in type IV and VI collagen, fibronectin and laminin and decreases in proteoglycans are observed in the mesangium of diabetic patients with nephropathy and probably in the vascular endothelium in general (152,153). These effects can be replicated in mesangial cells incubated in increasing glucose levels that were prevented general PKC inhibitors (154-156). Additionally, increased expression of transforming growth factor (TGF)- P has been implicated in the development of mesangial expansion and basement membrane thickening in diabetes. Because PKC activation can increase the production of ECM and TGF-P, it is not surprising that several reports have shown that PKC inhibitors can also prevent hyperglycemia- or diabetes-induced increases in ECM and TGF-P in mesangial cells or renal glomeruli (98).

Effects over diabetic complications

A recent report showed that all alterations induced by hyperglycemia - including aldose redutase, PKC and AGEs increases - are reversed by inhibiting free radicals production induced by glucose (25). Such fact gives the possibility that, by blocking glucose induced oxidative stress, it may also be possible to prevent lesions caused by other pathways (25).

Advanced glycoxidation endproducts metabolism

Other intracellular protective systems also help to limit the accumulation of reactive AGE intermediates. Methylglyoxal is first converted by glyoxalase-I to S-D-lacto-ylglutathione in the presence of reduced glutathione as an essential cofactor, and then converted to D-lactate by glyoxalase-II. The significance of such systems is supported by studies in which overexpression of glyoxalase-I prevented hyperglycemia-induced AGE formation and increased macromolecular endocytosis (47). These systems, however, could still be overwhelmed by high AGE conditions such as diabetes, renal failure, or sustained excess dietary AGE intake.

Effect of MnSOD over hiperglycemic memory

A paradox in diabetes is called hiperglycemic memory and refers to a persistent progression of microvascular alterations induced by hyperglycemia during subsequent periods of normal glycemic homeostasis (34). That outstanding phenomenon occurred in eyes of diabetic dogs during a post-hyperglycemic period of euglycemia (34). Eyes were hystologically normal during 2,5 years before exposition to elevated and sustained glycemia (34). But, after a subsequent period of 2,5 years of normal glycemia, eyes developed severe retinopathy (34). Worsening of retinopathy, in spite of sustained normoglycemia, was also related in rats with streptozocin induced diabetes implicating that an isolated good glycemic control does not stop diabetic microangiopathy progression in its late stage (34). As it was suggested by Brownlee and cols., superoxide mitochondrial production induced by hyperglycemia (oxidative stress) may provide an explanation for development of complications during post-hyperglycemia...

Initial and Preoperative Management

Anemia should be corrected to a hemoglobin greater than 10 g dl. Coagulopathy (raised international normalized ratio INR , PT and PTT, or platelets < 100,000) should be diagnosed preoperatively and platelets should be given intraoperatively if the patient is severely thrombocytopenic. Diabetic patients usually have severe hyperglycemia, which should be corrected with a glucose-insulin sliding scale. Electrolyte abnormalities must be corrected as far as possible, without incurring unnecessary delay of surgical debride-ment.

Protein Kinase C PKC

In the diabetic retina, cellular accumulation of diacylglycerol which activates PKC to translocate into plasma membrane and to acquire phosphorylation activities has been documented (Dempsey et al., 2000 Newton, 1997 Xia et al., 1994). Hyperglycemia induced the activation of PKC is associated with the pathologic changes of diabetic retinopathy. The exact mechanism of PKC induced vascular leakage in diabetic retinopathy still remains unclear, but PKC, especillay -isoform is considered as a key mediator of VEGF induced BRB disruption and retinal neovascularization (Aiello et al., 1997 Xia et al., 1996). Recently, it is reported that PKC8 is also associated with the pathogenesis of diabetic retina through inducing the decrement of endothelial tight junction protein (ZO-1, 2) expression and subsequent vascular hyperpermeability in diabetic retina (Kim et al., 2010a). In addition, PKC mediated occludin phosphorylation is reported to participate in the VEGF stimulated vascular leakage...

Apoptosis In Autonomic Neurons

For insulin and IGF-I and that failure of these protective systems may account for the severity of autonomic dysfunction in type 1 diabetes (106,109). In support of this concept, differences in neuroaxonal dystrophy have been observed in different animal models of autonomic neuropathy two models of type 1 diabetes, the streptozotocin diabetic and BB W rat develop marked hyperglycemia and concomitant deficiency in both circulating insulin and IGF-I. These type 1 animals develop neuroaxonal dystrophy in nerve terminals in the prevertebral sympathetic ganglia and the distal portions of noradrenergic ileal mesenteric nerves. In contrast, the Zucker diabetic fatty rat, an animal model of type 2 diabetes, despite developing severe hyperglycemia comparable with that in the STZ- and BB W-diabetic rat models does not develop neuroaxonal dystrophy. Unlike the type 1 models of diabetes, the Zucker diabetic fatty rats have significant hyperinsulinemia and normal levels of plasma IGF-I (109).

Underlying Metabolic Abnormalities In Type 1 And Type 2

Several hyperglycemia-induced pathways have been invoked as the pathogenetic basis for DPN, such as Fig. 1. Scheme of pathogenetic pathways involved in type 1 and type 2 DPN. Note that some of the early key metabolic abnormalities such as Na+ K+-ATPase and NO activities as well as oxidative stress are influenced both by hyperglycemia and insulin C-peptide deficiencies. This is also true for some of the mechanisms involved in the structural phase with the exception of nodal paranodal degeneration, which appears to be a direct consequence of impaired insulin action. Fig. 1. Scheme of pathogenetic pathways involved in type 1 and type 2 DPN. Note that some of the early key metabolic abnormalities such as Na+ K+-ATPase and NO activities as well as oxidative stress are influenced both by hyperglycemia and insulin C-peptide deficiencies. This is also true for some of the mechanisms involved in the structural phase with the exception of nodal paranodal degeneration, which appears to be a...

Polycystic Ovarian Syndrome

PCOS is a common disorder of premenstrual women characterized by hyperandrogenism, chronic anovulation, menstrual irregularity, hyperinsulin-emia, and often (for which it is a major cause) infertility (106,107). Prevalence estimates range from 5 to 10 of menstruating females. It was first reported in 1980 that women with PCOS had hyperinsulinemia, suggesting the presence of insulin resistance (108-110). Subsequently, many women with PCOS were found to have subtle acanthosis nigricans, a skin darkening often associated with insulin resistance. Women with chronic anovulation and hyperandrogenemia (111,112) without secondary causes were found to have glucose intolerance and elevated insulin levels (55). That PCOS is associated with insulin resistance and hyperglycemia following an oral glucose tolerance test (OGTT) was first demonstrated by Dunaif in 1987 (109). Forty percent of PCOS patients who are also obese have IGT or frank type 2 diabetes, and this remains consistent despite ethnic...

Hyperosmolality mediated by GLUT1

For all cells in the body, it is important to maintain a physiologically optimal osmolality. Sorbitol, a popular sweetener, works as a common organic osmolyte in cells. In the retinal cells, it is known that the cellular polyol pathway is responsible for sorbitol production from D-glucose (Vinores et al., 1993). The rate-limiting enzyme involved in sorbitol production is aldose reductase encoded by the AR2 gene located on 7q35 which is thought to be a possible susceptible region for diabetic retinopathy (Patel et al., 1996). Under diabetic conditions, hyperglycemia enhances the intracellular accumulation of sorbitol because of the increased GLUTl-mediated facilitative D-glucose transport to the retina and stimulated cellular aldose reductase activity (Iannello et al., 1999). The elevated concentration of sorbitol causes hyperosmolality which stimulates lactate production and intracellular water and reduces the uptake of O2 (Stevens et al., 1993 Lim et al., 2001). Therefore, GLUT1 is...

Antiplatelet therapy and diabetes

Considered together, data acquired in vitro and in vivo suggest that platelets from subjects with diabetes are hypersensitive to diverse agonists. Unfortunately, currently available antiplatelet therapy does not restore normal responsiveness to platelets from subjects with diabetes. In animal preparations simulating selected aspects of diabetes, platelets remain hypersensitive to thrombin despite administration of aspirin (67). This observation suggests that the hypersensitivity is not a reflection of generation of thromboxane A2, and that the treatment of subjects with diabetes with aspirin (as is being done often inferentially) is unlikely to decrease platelet reactivity to the level typical of that seen with platelets from nondiabetic subjects. Because hyperglycemia per se appears to increase platelet reactivity, improved glycemic control is a critical component of the anti-thrombotic regimen.

Effects of growth hormone and insulinlike growth factor 1 deficiency on ageing and longevity

Abstract Present knowledge on the effects of growth hormone (GH) insulin-like growth hormone (IGF)1 deficiency on ageing and lifespan are reviewed. Evidence is presented that isolated GH deficiency (IGHD), multiple pituitary hormone deficiencies (MPHD) including GH, as well as primary IGF1 deficiency (GH resistance, Laron syndrome) present signs of early ageing such as thin and wrinkled skin, obesity, hyperglycemia and osteoporosis. These changes do not seem to affect the lifespan, as patients reach old age. Animal models of genetic MPHD (Ames and Snell mice) and GH receptor knockout mice (primary IGF1 deficiency) also have a statistically significant higher longevity compared to normal controls. On the contrary, mice transgenic for GH and acromegalic patients secreting large amounts of GH have premature death. In conclusion longstanding GH IGF1 deficiency affects several parameters of the ageing process without impairing lifespan, and as shown in animal models prolongs longevity. In...

Primary Nursing Diagnosis

Medication management Hyperglycemia management Nutrition management Electrolyte management Electrolyte monitoring Fluid resuscitation Intravenous therapy If the patient has hyperglycemia because of diabetes mellitus or HNKS, management is based on the severity of her or his symptoms. Because HNKS is associated with extraordinarily high levels of glucose (some reports describe levels higher than 1000 mg dL), the patient usually 442 Hyperglycemia requires volume resuscitation followed by an insulin infusion. Often patients receive intermittent SC or IV doses of insulin as well. This should be done cautiously, however, because if the serum glucose level is reduced too rapidly, fluid shifts into the central nervous system, leading to cerebral edema and death. No matter what the diagnosis, once the glucose level and the patient are stabilized, a full workup to determine the cause and long-term treatment is needed to prevent recurrences of hyperglycemia. Current thinking with...

Macrovascular Disease And Diabetes An Overview

As opposed to the clear influence of hyperglycemia in the development of microvas-cular complications in diabetes, hyperglycemia plays a less strong role in the development of macrovascular disease, in particular CAD, as shown by the UKPDS (10). Thus, the risk for macrovascular disease in diabetes seems to rely to a considerable degree on other associated abnormalities, such as hypertension, dyslipidemia, altered fibrinolysis, and obesity, all components of the insulin resistance syndrome (44). Endothelial dysfunction activation, detected in most of the clinical abnormalities associated to the insulin resistance syndrome, is now considered a precocious event in the clinical history of both micro- and macrovascular complications, contributing to the initiation and progression of the vascular damage in diabetes.

What are the Cellular Effects of the Non Antioxidant Properties of the Tocopherols

The mechanism by which vitamin E produces cellular events could be in principle related to the known radical chain breaking properties of the molecule. This would imply that regulation of certain cellular functions is controlled by the production and elimination of lipid soluble free radicals and that vitamin E serves as a radical scavenger. The biological difficulty of controlling the propagation of radical chain reactions makes this mechanism improbable. Furthermore, if this were the mechanism of action of the tocopherols, other similar radical chain braking molecules, and in particular the eight natural tocopherol analogues, would act analogously this is however often not the case. Thus, it can be assumed that a-tocopherol modulates cellular behavior by specific interactions with enzymes, structural proteins, lipids and transcription factors. Similarly, troglitazone, an antidiabetic drug of the thiazolidinedione class, acts as an insulin sensitizer and improves hyperglycemia....

Monocyte Chemoattractant Protein MCP1

MCP-1 contributes to the recruitment of inflammatory cells (monocytes monocyte derived macrophage microglia) in injured tissue and ROS injury may play a role in DR and retinal detachment10'. MCP-1 is a potential angiogenic factor in the proliferative phase of DR and is associated with proliferation DR107.Hyperglycemia increases the expression of MCP-1 in vascular EC63 and AGE-induced ROS generation induced the MCP-1 gene and mRNA expression63. Recently, aqueous samples in humans with DR have revealed higher levels of MCP-1 and VEGF when compared to nondiabetic subjects and authors further state that inflammatory changes may precede the development of neovascularization in proliferative DR108.

Oxidative Stress Antioxidants And Lipid Peroxidation

Interestingly, in nerve and dorsal root ganglia of the streptozotocin-induced diabetic rat, no changes occur in the levels of antioxidant enzyme mRNAs, including glutathione peroxidase, and both Cu-Zn- and Mn-dependent superoxide dismutase (the cytosolic and mitochondrial forms, respectively, of this enzyme), whereas the expression of catalase mRNA is increased (Kishi et al. 2000). Several of the antioxidant enzyme genes undergo upregulation of expression in non-neural diabetic tissues and in endothelial cells cultured in high glucose (Ceriello et al. 1996 Khanna et al. 1996 Reddi and Bollineni 1997). This increase of gene expression could reflect an effort to mount an adaptive response to hyperglycemia-mediated oxidative stress and resultant nonenzymatic protein glycation or other free-radical-mediated damage, which causes inactivation of the existing antioxi-dant enzyme population.

Cranial Diabetic Neuropathy

Spontaneous complete recovery invariably occurs within an average 2-3 months, independently of the quality of control of hyperglycemia. Aberrant regeneration and synkinesis, which are so common after facial nerve palsy of different origin, do not disturb recovery of diabetic ophthalmoplegia.

Positron Emission Tomography

Liver metastases have been reported in the setting of intrahepatic cholestasis (56). False-negative results can occur in the setting of hyperglycemia. Of concern, some studies have also shown that false-negative results may occur in early-stage pancreatic cancers (55,57).

Physiologic effects of nitric oxide on the vascular system

Hyperglycemia and endothelium-derived vasocative substances. Hyperglycemia decreased the bioavailability of nitric oxide (NO) and prostacyclin (PGI2) and increased the synthesis of vasoconstrictor prostanoids and endothelin (ET-1) via multiple mechanisms (see text). PLC, phospholipase C DAG, diacylglycerol PKC, protein kinase C eNOS, endothelial nitric oxide synthase Thr, thrombin NAD(P)H Ox, nicotinamide adenine dinucleotide phosphate oxidase O2-, superoxide anion OONO-, peroxynitrite MCP, monocyte chemoattractant protein-1 NFkb, nuclear factor K b TNF, tumor necrosis factor Ils, interleukins COX-2, cyclooxygense-2. (Reproduced with permission from ref. 127.) Fig. 1. Hyperglycemia and endothelium-derived vasocative substances. Hyperglycemia decreased the bioavailability of nitric oxide (NO) and prostacyclin (PGI2) and increased the synthesis of vasoconstrictor prostanoids and endothelin (ET-1) via multiple mechanisms (see text). PLC, phospholipase C DAG, diacylglycerol PKC,...

Calciphylaxis Calcific Uremic Arteriolopathy

Vascular calcification, the hallmark of calciphylaxis, is a complex process regulated by many factors. Medial arterial calcification is a feature characteristic of both diabetes mellitus and end-stage renal disease. This calcification involves a phenotype switch of the vascular myofibroblast to one of an osteoprogenitor, a process influenced by osteotropic hormones and inhibitors. In pathologic states, the end result is vascular calcification. Local para-crine control of the process involves bone morphogenetic protein-2, parathyroid hormone-related peptide, osteo-pontin, osteoprotegerin, Pit-1 (a sodium-dependent phosphate cotransporter), and matrix Gla protein, all of which respond to various metabolic and inflammatory stimuli (summarized in Figure 35.1) (9,10). Osteopontin production likely contributes to mineralization, and can be induced by hyperglycemia, uremia, and hyperphosphate-mia, all common features in patients with calciphylaxis (9). Matrix Gla protein (MGP) may be...

Clinical Significance

The incidence of insulin resistance without overt hyperglycemia is unknown, but overt hyperglycemia occurs in about 15 of patients treated with thiazide diuretics. The incidence of hyperglycemia caused by loop diuretics is lower because these agents tend to cause less potassium wastage than thiazides. Glucose concentrations are mildly elevated (120-150 mg dl) in most cases however, severe hyperglycemia with glycosuria can be precipitated even by mild to moderate (25-50 mg day) doses of thiazides.

Vascular cell maintenance

Conditions such as the progression of proliferative diabetic retinopathy. Remodeling of the basement membrane is an important element in the development of neovascularization. E2 plays a role in the control of the extracellular cytokines FGF-2 and PAI-1 which maintain some control over this process (Albuquerque et al. 1998 Rubanyi and Kauffman 1998). It is well known that pericyte and endothelial cell communication plays an important role in the health of retinal capillaries (Hall 2006). It is also well known that pericyte loss is one of the first damaging effects of hyperglycemia. The fact that sex hormones can work to protect pericytes further links the role of sex hormones to the cell responses to diabetes. Furthermore, as discussed previously, sex hormones and their cognate receptors are well known to populate the retina of humans.

Abnormalities in coagulation

Attention has been directed at fibrinogen levels and dynamics in diabetes for a variety of reasons. The most important one is the fact that the plasma level of fibrinogen has been shown to be an independent risk factor for thrombotic events in population-based studies (260-262). In diabetes, plasma fibrinogen levels are found to be elevated, particularly in patients with hyperglycemia (263-265). Insulin deficiency leads to an increase in fibrinogen synthesis in IDDM, and infusion of insulin will decrease the fibrinogen synthetic rate (266). Interestingly, fibrinogen survival is decreased in diabetes, and this abnormality can be reversed by administration of insulin or by administration of heparin, suggesting that intravascular fibrin formation may be taking place (262). Exercise may also affect plasma fibrinogen and it has been shown that exercise conditioning will lower plasma fibrinogen levels in NIDDM individuals (267). The above findings suggest that there may be increased fibrin...

Therapies For Microvascular Insufficiency

Protein kinase C (PKC) and diacylglycerol (DAG) are intracellular signaling molecules that regulate vasculature by endothelial permeability and vasodilation. The PKC isozymes are a family of 12 related serine threonine kinases (25) whose normal function is the activation of essential proteins and lipids in cells essential for cell survival. PKC-P is expressed in the vasculature (26,27) and belived to be involved in cell proliferation, differentiation, and apoptosis. PKC is activated by oxidative and osmolar stress, both of which are a consequence of the dysmetabolism of diabetes. Increased polyol pathway activity and pro-oxidants bind to the catalytic domain of PKC and it is disin-hibited. PKC-P overactivation is induced by hyperglycemia or fatty acids through receptor-mediated activation by phospholipase C. It is hypothesized that AGEs and oxidants produced by nonenzymatic glycation and the polyol pathway, respectively, increase the production of DAG (28). Increased DAG and calcium...

Gastroduodenal Dysfunction The Gastroparesis Syndrome

Endoneurial Blood Flow

Acute hyperglycemia might play an important pathogenetic role (23). Antral motility decreases with postprandial glucose levels more than 9.7 mmol L (2). In 10 patients with type 1 diabetes mellitus and sensory motor neuropathy, Flowaczny and coworkers (24) showed that when plasma glucose concentrations were controlled by permanent iv administration of insulin, gastric emptying rates were near normal. Nevertheless, although achieving and sustaining normoglycemia is undoubtedly important, in clinical practice symptomatic patients with gastroparesis still require prokinetic therapy for satisfactory results (2). However, to further complicate matters, it has been shown that the accelerating effect of prokinetics, such as cisapride and erithromycin is in turn significantly dampened by hyperglycemia (25). Thus, good glycemic control is an inevitable premise to successful management of diabetic gastroparesis. Treatment of diabetic gastroparesis has two facets one, treatment of autonomic...

Somatic theories of sleep function

Some of the other changes in human metabolism observed after sleep deprivation appear to be strongly influenced by circadian mechanisms or may reflect side-effects of sleep deprivation rather than sleep per se. For example, cortisol release is under circadian control 9 , is known to increase after sleep deprivation 70 , and has been linked to some of the metabolic disturbances reported after sleep deprivation 71 . Sleep deprivation is also known to reduce cortical metabolism 72 , which may contribute to elevated blood glucose following restricted sleep 8 . If indeed the fundamental purpose of sleep is to regulate blood glucose, using the brain as a glucose sponge seems a rather inelegant way to do it.

Mechanisms responsible for the overexpression of pai1 in diabetes

A combination ofhyperinsulinemia, hypertriglyceridemia, and hyperglycemia increases the concentration of PAI-1 in blood in normal subjects (99). Although neither the infusion of insulin with euglycemia maintained by euglycemic clamping nor the infusion of triglycerides without induction of hyperinsulinemia in normal subjects increases the concentration of PAI-1 in blood, the induction of hyperglycemia, hypertriglyceridemia, and hyperinsulinemia by infusion of glucose plus emulsified triglycerides plus heparin (to elevate blood FFAs) does increase concentrations of PAI-1 in blood. Of note, the infusion of insulin under euglycemic clamp conditions results in a marked decrease in the concentration of blood triglycerides and FFAs. Thus, results of the infusion studies demonstrate that the combination of hyperinsulinemia, hyperglycemia, and hypertriglyceridemia is sufficient to increase expression of PAI-1 in healthy subjects. However, results in these studies do not answer the question of...

Fecal Incontinence in Peripheral Neuropathies

Diabetes mellitus is the most common cause of polyneuropathy in developed countries. Diabetic neuropathy is a chronic symmetrical sensorimotor polyneuropathy that usually begins after years of hyperglycemia and is frequently associated with autonomic neuropathy and bowel, bladder, and sexual dysfunction. Severe diabetic autonomic neuropathy (DAN) is almost always associated with insulin-dependent diabetes. Symptoms of autonomic involvement include impairment of sweating and of vascular reflexes, constipation, nocturnal diarrhea and fecal incontinence, atonic bladder, sexual impotence, and occasionally postural hypotension. The pathogenetic mechanism of the constipation is uncertain, but autonomic neuropathy causing parasympathetic denervation is likely to be implicated. Diarrhea typically occurs at night or after meals, is a more troublesome complication of diabetes, and may be an isolated symptom of autonomic dysfunction. It is usually chronic, but it is intermittent and alternates...

Volume Depletion and Increased Catecholamines

Volume depletion may reduce both renal blood flow and glomerular filtration rate, thereby reducing the filtered load of glucose and promoting hyperglycemia. In addition, it has been postulated that reduction in blood pressure and flow to muscle, the primary site of insulin-mediated glucose uptake, may be attributed to volume depletion. Thus volume depletion could reduce tissue sensitivity to insulin indirectly by limiting delivery to muscle bed. Increased plasma catecholamine levels accompanying volume depletion may increase glycogenolysis, thereby increasing glucose input. However, most patients with diuretic-induced glucose intolerance have mild hyperglycemia and are not markedly volume depleted. Moreover, if dietary sodium intake is increased during diuretic therapy, volume depletion and increased catecholamine levels can be prevented. Thus, these catecholamines probably play a minor role in producing hyperglycemia except in patients with severe volume depletion. Therefore, other...

Oxidative and Nitrosative Stress in Diabetes Induced Vascular Dysfunction

Superoxide anion may quench NO, thereby reducing the efficacy of a potent endothe-lium-derived vasodilator system that participates in the homeostatic regulation of the vasculature, and evidence suggests that during hyperglycemia, reduced NO availability exists (64). Hyperglycemia-induced superoxide generation contributes to the increased expression of NAD(P)H oxidase, which in turn generate more superoxide anion. Hyperglycemia also favors, through the activation of NF-kB an increased expression of iNOS, which may increase the generation of NO (65,66). Superoxide anion interacts with NO, forming the strong oxidant peroxynitrite (ONOO-), which attacks various biomolecules, leading to among other processes the production of a modified amino acid, nitrotyrosine (67). Although nitrotyrosine was initially considered a specific marker of peroxynitrite generation, other pathways can also induce tyrosine nitration. Thus, nitrotyrosine is now generally considered a collective index of reactive...

Autonomic Regulation Of Cardiovascular Function

The best known manifestation of early dysautonomia in human diabetic neuropathy is a loss of cardiovagal function (7). Similar abnormalities have been described after several months of diabetes in experimental diabetic neuropathy (EDN). In a study of Yucatan miniature pigs, blood pressure (BP) and heart rate where recorded telemetrically (8). After 3 months of diabetes induced with streptozotocin (STZ), there was a marked reduction in respiratory sinus arrhythmia. Beyond 3 months, the impairment of cardiovagal function became more pronounced and was associated with increased resting heart rate. Similar observations were reported in spontaneous diabetes in the WBN Kob rat (9). Florid hyperglycemia was present by 8-9 months, at which time there was a loss of the circadian rhythm of the heart rate and BP with a loss of the nocturnal fall in BP. Sympathetic failure is typically preceded by evidence of sympathetic overactivity, and much of the resting tachycardia is sympathetic in origin.

Role For Vascular Vs Nonvascular Mechanisms

The most impressive evidence for dissociation of NBF and nerve conduction changes has recently been generated in two studies in animal models of type 2 diabetes (28,29). In type 2 BBZDR Wor rats, neurovascular defects were not accompanied by sensory nerve conduction slowing or hyperalgesia (28). Furthermore, in type 2 Zucker diabetic fatty rats development of motor nerve conduction deficit at 12-14 weeks of age markedly preceded decrease in sciatic endoneurial nutritive blood flow (at 24-28 weeks of age 29 ). In contrast, in Zucker rats with impaired glucose tolerance, but absent fasting hyperglycemia (a model of the initial stage of type 2 diabetes) neurovascular dysfunction developed earlier than motor nerve conduction deficit (at 24-28 weeks of age and 32 weeks of age, respectively 29 ).

Melpomeni Peppa md Jaime Uribarri md and Helen Vlassara md

Two landmark clinical studies, the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study, showed that intensive control of hyperglycemia could reduce the occurrence or progression of retinopathy, neuropathy and nephropathy in patients with type 1 and type 2 diabetes (2,3). Although these studies reinforce the important role of hyperglycemia in the pathogenesis of diabetic complica- tions, the identification of the mechanisms by which hyperglycemia exerts these effects remains limited (4). It is well known that long-term hyperglycemia leads to the formation of advanced glycation or glycoxidation end-products (AGEs), which mediate most of the deleterious effects of hyperglycemia and seem to play a significant role in the pathogenesis of diabetic complications (5,6). AGEs, together with the interrelated processes of oxidative stress and inflammation, may account for many of the complications of diabetes (5,6). Evidence for this emerges not only...

Activation of the Dagpkc Pathway

DAG can be generated from multiple pathways. Agonist-induced formation of DAG depends mainly on hydrolysis of phosphatidylinositol by phospholipase C (84). However, this mechanism is most likely minimally involved in diabetes, because inositol phosphate products were not found to be increased by hyperglycemia in aortic cells and glomerular mesangial cells (85,86). When the fatty acids in DAG were analyzed (87), DAG induced by high-glucose condition has predominantly palpitate- and oleic- acid-enriched composition, whereas DAG generated from hydrolysis of phosphatidylinositol has the composition of 1-stearoly-2-arachidonyl-,SW-glycerol (88). In labeling studies using 6-3H - or U-14C - glucose, we have shown that elevated glucose increase the incorporation of glucose into the glycerol backbone of DAG in aortic endothelial cells (87), aortic SMCs (89), and renal glomeruli (90). These facts indicate that the increased DAG levels in high-glucose condition are mainly derived from the de...

Adjusting Your Insulin for Time Changes

The body's sensitivity to insulin varies throughout the day and night. You are most insulin sensitive early in the night and most resistant early in the morning. These changes in insulin sensitivity are due to the daily fluctuations in the levels of hormones, particularly cortisol. The internal body clock that regulates these hormones gets cues from environmental light and temperature. When you go to a different time zone, the body clock and the hormones reset to the new light-dark cycle. This resetting process takes time and explains why you feel jet-lagged. The challenge for people who are on insulin is to figure out how to adjust basal insulin levels while the body is getting used to being in the new time zone. The solution is to make sure that you have a safe basal rate and to use bolus insulin doses to cover any high blood glucose levels

Mechanism of Hypokalemia Induced Glucose Intolerance

The precise molecular mechanism of hypokalemia-induced glucose intolerance is not completely understood however, the bulk of clinical and experimental evidence indicates that glucose-mediated beta cell insulin release plays a major role. Studies in normal volunteers have shown that thiazide-induced potassium deficiency sufficient to produce sustained hypokalemia is associated with decreased glucose utilization and subnormal plasma insulin response to hyperglycemia of 125 mg dl (hyperglycemic glucose clamp). However, glucose uptake is normal under these circumstances, indicating that tissue resistance is not the major cause of impaired glucose uptake. Furthermore, the plasma insulin response to hyperglycemia (an estimate of beta cell sensitivity) is directly related to the degree of body potassium deficit. Moreover, the impairment in plasma insulin response to hyperglycemia can be completely prevented by coadministration of potassium with thiazides in an amount sufficient to prevent...

Potential preventive and therapeutic options Oral Hypoglycemic Agents

The cornerstone of DM therapy is optimal glycemic control, because hyperglycemia is the basis of all the metabolic disturbances that occurs in the disease. As shown previously, both in vivo and in vitro elevated glucose levels have been shown to cause abnormal endothelium-dependent relaxation. Lower glucose levels also result in a decrease in insulin levels, which consequently may also improve endothelial function. Therefore, therapy should be directed toward lowering glucose levels and increasing insulin sensitivity.

Cellular response to insulin

Complex molecular events in insulin signaling and insulin synthesis secretion has given increasing information on the polygenic diseases that manifest as IGT and type 2 diabetes. The cellular effects of insulin have been generally agreed on for type 2 diabetes (Fig. 2). Specifically, all patients with type 2 diabetes have two defects impaired insulin release by the pancreatic p-cell and resistance to the cellular response to insulin, or insulin resistance. All treatments for type 2 diabetes are directed at improving one of these two defects. In many patients with type 2 diabetes, there are decreases in insulin secretion over time, such that initial treatment of hyperglycemia can be successfully managed by diet exercise or use of a single oral hypoglycemic agent. Over time, patients often need the addition of a second agent, then a third, and finally exogenous insulin injections. For IGT the defects are not as clearly defined. Some authors feel that insulin resistance is the initiating...

Gender Ethnicracial And Life Span Considerations

When assessing vital signs, you may note hypertension, a common complication in diabetic patients. Palpate the peripheral pulses to determine their strength, regularity, and symmetry. During the neurological examination, use an ophthalmoscope to evaluate the patient for retinopathy or cataracts. Assess the patient for any signs and symptoms of hypoglycemia or hyperglycemia (Table 2).

Studies In Man Cognition And Dementia

Although quite a few studies have looked at neuropsychological test performance and school achievement in children with diabetes, this remains an area of some controversy (36). Some studies report that children with type 1 diabetes perform more poorly than control subjects on measures of intelligence, attention, processing speed, long-term memory, and executive skills (37,38), whereas other studies report that test performances are within the normal range (39). However, the observation that children with an early onset of diabetes (e.g., before the age of 6) are at increased risk for slowing of intellectual development is quite consistent (36,40). This increased vulnerability of younger children may be attributable to an increased sensitivity of the developing brain to the adverse effects of both hypo- and hyperglycemia (40,41). However, uncertainty remains as to the disease variables that are related to impaired cognitive performance (43). This is likely to be largely because of...

Therapeutic implications

Consideration of the derangements in platelet function, the coagulation system, and the fibrinolytic system and their contributions to exacerbation of macrovascular disease in type 2 diabetes gives rise to several therapeutic approaches. Empirical use of aspirin (160-325 mg per day in a single dose) seems appropriate in view of the high likelihood that covert CAD is present even in asymptomatic people with type 2 diabetes and the compelling evidence that prophylactic aspirin reduces the risk of heart attack when CAD is extant. Because many of the derangements contributing to a prothrombotic state in diabetes are caused by hyperglycemia, rigorous glycemic control is essential. Accordingly, the use of diet, exercise, oral hypoglycemic agents, insulin sensitizers, and if necessary insulin itself is appropriate to lower HbA1c to 7 . Because other derangements contributing to a prothrombotic state such as attenuation of fibrinolysis appear to be related to insulin resistance and...

Treatment Of Painful Diabetic Neuropathy

A number of studies have confirmed the major contribution of prolonged hyperglycemia in the pathogenesis of neuropathy and neuropathic pain (30-33). More recent studies in patients with idiopathic painful neuropathies further support the relationship between hyperglycemia and painful neuropathy. In the study of Singleton et al. (34), impaired glucose tolerance was more common in patients with idiopathic painful neuropathy than the general population. Thus, achieving near normoglycemia should be the primary aim in both the prevention of and the first step in the management of generalized peripheral neuropathy.

Discharge And Home Healthcare Guidelines

Reinforce the need for small, frequent meals. Warn against overeating at any one meal, which places too great a demand on the pancreas, and stress limiting caffeine and alcohol. Instruct the patient to inspect her or his stools daily and report to the physician any signs of steatorrhea. Teach the patient and family the care related to surgically induced diabetes symptoms and appropriate treatment for hypoglycemia and hyperglycemia, procedure for performing blood glucose monitoring, administration of insulin injections. Teach the patient or significant other to change the dressing over the abdominal incision and empty the drains daily (if present).

Insulin Resistance Introduction

Thiazide diuretics remain the cornerstone of antihypertensive therapy and have been shown to reduce morbidity and mortality in hypertensive populations throughout the world. However, their use has been associated with a high incidence of endocrine disturbances including glucose intolerance. Glucose intolerance induced by thiazide diuretics was first reported in the late 1950s. Since then a variety of thiazides as well as loop diuretics have been reported to cause mild glucose intolerance, overt hyperglycemia, and rarely nonketotic hyperosmolar states. More recently, the clinical importance of insulin resistance in relation to cardiovascular morbidity has been identified. It is now known that insulin resistance is a risk factor for cardiovascular disease, including myocardial infarction. The fact that many untreated lean and obese hypertensives exhibit underlying tissue resistance to insulin indicates that this may be a predisposing factor to glucose intolerance and development of...

Insulindependent Diabetes Mellitus Introduction

Insulin-dependent diabetes mellitus (IDDM) is a metabolic disorder caused by a deficiency of insulin. The deficiency is thought to occur in those individuals who are genetically predisposed to the disease and who have experienced a precipitating event, commonly a viral infection or environmental change, that causes an autoimmune condition affecting the beta cells of the pancreas. It is treated by injection of insulin and regulation of diet and activity that maintain body functions. Complications that occur from improper coordination of these include hypoglycemia and hyperglycemia which, if untreated, lead to insulin shock or ketoacidosis. Long-term effects of the disease include neuropathy, nephropathy, retinopathy, atherosclerosis, and microangiopathy.

Additional Nursing Diagnoses Risk For Injury

Related to (Specify hyperglycemia or hypoglycemia.) Defining Characteristics (Specify hyperglycemia fatigue, irritability, headache, abdominal discomfort, weight loss, polyuria, polydipsia, polyphagia, dehydration, blurred vision hypoglycemia nervousness, sweating, hunger, palpitations, weakness, dizziness, pallor, behavior changes, uncoordinated gait.) Goal Client will not experience injury from hyperglycemia or hypoglycemia. Outcome Criteria hyperglycemia, blood glucose level, urinary glucose and ketones, pH and electrolyte levels. Provides information about complication caused by increased glucose levels resulting from improper diet, an illness, or omission of insulin administration glucose is unable to enter the cells, and protein is broken down and converted to glucose by the liver, causing the hyperglycemia fat and protein stores are depleted to provide energy for the body when carbohydrates are not able to be used for energy. Provides insulin replacement to maintain normal...

Prevention and Treatment of Diuretic Induced Hypokalemia

The first approach to preventing diuretic-induced hypokalemia is to use the lowest dose possible (Table 1). With regard to thiazide diuretics, the majority of the blood pressure lowering effect is seen at doses of 12.5-25 mg day. At higher doses, further blood pressure lowering is minimal, but rather, metabolic side-effects such as hypokalemia, hyperglycemia, and hypercholesterolemia become more prevalent.

Inhibitors of AGE Production

The production of AGE, as a result of prolonged exposure of proteins to chronic hyperglycemia, can result in direct quenching of NO and increasing the oxidative stress. Conversely, hyperglycemia, which increases oxidative stress, can convert even elevated levels of NO to peroxynitrite, which is deleterious to vascular function (179). A decrease in oxidative stress can restore vascular function rather than increase the NO supply. Prolonged hyperglycemia and hypercholesterolemia both cause a depletion of tetrahydrobiopterin (BH4), an essential cofactor for NOS, resulting in an uncoupling of eNOS and lowered production of NO (180). Studies using both diabetic animal models (113) and hypercholesterolemic patients (112) have demonstrated that tetrahydrobiopterin

Diabetesinduced Neuropathology

Although neuronal vacuolation and mitochondrial disruption have been suggested to result from hyperglycemia-induced oxidative stress (26,28,34), these changes may be a feature of poor fixation. Moreover, aging-associated oxidative mitochondrial damage involves effaced cristae in an otherwise intact, not ballooned, organelle (35).

Effects of the Renin Angiotensin System on Insulin Signaling

Gabriely I, Yang XM, Cases JA, Ma XH, Rossetti L, Barzilai N. Hyperglycemia modulates angiotensinogen gene expression. Am J Physiol Regul Integr Comp Physiol 2001 281 R795-R802. 71. Amiri F, Venema VJ, Wang X, Ju H, Venema RC, Marrero MB. Hyperglycemia enhances angiotensin II-induced janus-activated kinase STAT signaling in vascular smooth muscle cells. J Biol Chem 1999 274 32382-32386.

Pathophysiology Of Microvascular Disease And Endothelial Dysfunction In Diabetes

Although microvascular diabetic complications have been well-characterized there is still uncertainty regarding the mechanisms that lead to their development. In the past two main pathogenic hypotheses have been proposed the metabolic hypothesis and the hypoxic hypothesis (11,12). According to the metabolic hypothesis, hyperglycemia is directly responsible of end-organ damage and development of complications through

Pigmented Epithelial Derived Factor PEDF

In the study of Zhi59 et al ,diabetic rats and control animals were randomly assigned to receive perindopril or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without perindopril. The results showed the VEGF-to-PEDF ratio was increased in the retina of diabetic rats perindopril lowered the increased VEGF-to-PEDF ratio in diabetic rats and ameliorated the retinal damage. In BRECs, perindopril lowered the hyperglycemia-induced elevation of VEGF-to-PEDF ratio by reducing mitochondrial ROS and the decreased ROS production was a result of perindopril induced upregulation of PPARY and UCP-2 expression59.

Individuals with chronic disease

Diabetes leads to susceptibility to infection in later stages of the disease because of persistent hyperglycemia (Umpierrez and Kitabchi, 2003 Maldonado et al., 2004) or loss of microcirculation efficiency (Dinh and Veves, 2005). Salmonella (Acheson and Hohmann, 2001), Listeria monocytogenes (Nolla-Salas et al., 2002 Chougle and Narayanaswamy, 2004) and Toxoplasma gondii (Yamamoto et al., 2003) have been isolated from infected tissues of patients with advanced diabetes. Elderly who are diabetic are especially prone to infections in general (Rajagopalan, 2005), which may include foodborne infections.

Secretomotor Function

Cardone et al. (29), in a detailed and careful study of the sweat response in STZ-induced diabetes in the rat, reported decreased sweating that paralleled severity of hyperglycemia. The pilocarpine-induced sweat responses in the hind foot pads of groups of control and streptozocin diabetic rats, in good and in poor glycemic control and with a crossover design after 20 weeks of diabetes, were evaluated with the silicone mold sweat test to determine the number of sweat droplets per group of foot pads. The sweat response was dose dependent and reproducible, disappearing with denervation and reappearing with reinnervation. In the good glycemic controlled group, the sweat response was not different from that of the control group for up to 136 days. In the poor controlled group, the sweat response became reduced (p < 0.005) at 16 days and progressively worsened 40 of baseline values at 14 weeks (p < 0.001). After restoring euglycemia in the poor control group, a normal sweat response...

Spinal Neurochemistry In Diabetes

It has been previously speculated that decreased excitatory neurotransmitter input to the spinal cord as a result of a hyperglycemia-induced shift in the phenotype of primary afferents could lead to a sensitized postsynapse through upregulation of receptors for the excitatory neurotransmitter glutamate and the modulating neuropeptides substance P and CGRP. This hypothesis was prompted by the observation that whereas peripherally-evoked spinal release of substance P is reduced in diabetic rats, direct delivery of substance P to the spinal cord of diabetic rats elicits a protracted hyperalgesic response (52,65). The biological precedent for such a mechanism is seen in skeletal muscle, which responds to denervation and loss of cholinergic excitatory input by increasing the amount of ACH receptor protein and progressing to a state of denervation hypersensitivity (see ref. 72). Of the few studies published to date, ligand binding experiments have reported increased binding of substance P...

Therapies Targeted To Metabolic Pathways

Hyperglycemia has been shown in a number of studies to cause oxidative stress in tissues that are susceptible to the complications of diabetes, including peripheral nerves. In turn, the oxidative stress leads to the generation of free radicals that can attack the lipids, proteins, and nucleic acids of the affected tissues directly, compromising physiological function. The end result is the loss of axons and disruption of the microvascu-lature in the peripheral nervous system (Fig. 2). It has been shown that there is an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant moieties were reduced in patients with diabetic peripheral

The Kallikrein Kinin Pathway

Abnormalities in the kallikrein kinin pathway have been found recently in the DCCT Echo Dobutamine International Cooperative cohort of type 1 diabetes (47) and increased expression of B2-kinin receptors has been described in the vessel wall of diabetic animals (48). Interestingly hyperglycemia, which is known to induce endothelial dysfunction as a result of its ability to promote endothelial cell toxicity, has also been shown to up-regulate the expression of kinin receptors in VSMC (49). Thus, in diabetes, the abnormalities in the kallikrein kinin system by modulating vascular fibrosis play an important role in the development of arteriosclerosis.

Endothelium Dependent Vasodilation in Animal Models

Similarly, in an animal model of type 2 diabetes, the Zucker rat, which is characterized by hyperglycemia because of insulin resistance, abnormal endothelium-dependent va-sodilation is also seen (46). The early vascular dysfunction that occurs in type 1 diabetic animal models can be prevented by insulin therapy (50,51). The abnormal endothelial cell function that develops appears to be as a result of hyperglycemia rather than any other metabolic disturbance. This has been demonstrated by in vitro incubation experiments in which isolated arteries exposed to elevated glucose concentrations have similar decreases in endothelium-dependent vasodilation (52,53). This effect does not seem to be as a result of the hyperosmolarity because similar concentrations of mannitol have no effect on endothelium-dependent relaxation (52). The decreased endothelium-dependent vasodi-lation that occurs may be as a result of decreased synthesis or release of NO, decreased Endothelial cell dysfunction in...

Increased Nitric Oxide Inactivation Decreased Bioavailability andor Breakdown of Nitric Oxide

Prolonged hyperglycemia results in an alternative metabolism of glucose through the polyol pathway in which glucose is oxidized to sorbitol. This reaction is coupled with the oxidation of NADPH to NADP+, generating free radicals. The second step is the oxidation of sorbitol to fructose, which is coupled with the reduction of NAD+ to NADH (109,110). The increased cytolosic NADH NAD+ results in an altered redox state, which may alter the availability of tetrahydrobiopterin, an essential cofactor for NOS. If tetrahydrobiopterin is depleted, NO production is decreased (111,112). Tetrahydro-biopterin supplementation has been shown to improve impaired endothelium-dependent vasodilation in diabetic animals (113).

Vascular Contractility and Blood Flow

Abnormalities in hemodynamic have been documented to precede diabetic nephropa-thy. Elevated renal glomerular filtration rate and modest increases in renal blood flow are characteristic finding in IDDM patients and experimental diabetic animals with poor glycemic control (128-131). Diabetic glomerular filtration is likely to be the result of hyperglycemia-induced decreases in arteriolar resistance, especially at the level of afferent arteriole, resulting in an elevation of glomerular filtration pressure. This effect of hyperglycemia can be mimicked in vitro by incubating renal mesangial cells with elevated glucose levels that reduced cellular response to vasoconstriction. Several reports have suggested that the activation of PKC via the induction of prostaglandins may involve in this adverse effects of hyperglycemia (132,133).

Antileukocyte adhesion agents

We tested several commercially available antileukocyte adhesion agents in diabetic rats. We first evaluated the effectiveness of the sulphonylurea gliclazide for decreasing the adhesion of neutrophils to endothelial cells and leukocyte entrapment in the retinal microcirculation of streptozotocin (STZ)-induced diabetic rats. We showed that gliclazide attenuated retinal leukostasis irrespective of hyperglycemia in diabetic rats, whereas another sulphonylurea, glibenclamide, did not. This indicated that gliclazide, among the sulphonylurea drugs, might be selectively beneficial for preventing development of DR (Kinoshita et al., 2002). We also evaluated the effectiveness of topical nipradilol, a topical antiglaucoma ap-blocker and

AGE effects on the inner BRB

AGEs is the generic term that includes a number of compounds such as pentosidine, pyrraline, crossline, and N (epsilon)-(carboxymethyl) lysine. Interestingly, there are reports of the expression of receptors for AGEs, such as RAGE, on the cellular surface (Schmidt at al. 1992 Neeper et al., 1992). Under diabetic conditions, hyperglycemia promotes the production and accumulation of AGEs, and it is suggested that AGEs are closely related to the pericytes loss in diabetic retinopathy (Brownlee et al., 1988). As described previously, the retinal capillary is composed of endothelial cells, pericytes and glial cells, and it has been reported that the pericytes interacts with the endothelial cells to suppress the undesirable proliferation and prostacyclin production of endothelial cells and to protect these endothelial cells from harmful events (Yamagishi et al., 1993a Yamagishi et al., 1993b). Therefore, the loss of pericytes, observed during the early stage of diabetic retinopathy, can be...

Protein Kinase C Inhibitors

Hyperglycemia can activate PKC, which in turn increases oxidative stress. Inhibitors of PKC can restore vascular function and also increase mRNA expression of eNOS in aortic endothelial cells (143). Recently, an inhibitor of PKC, LY333531, has been developed it normalizes retinal blood flow and glomerular filtration rate in parallel with inhibition of PKC activity (169). LY333531 is discussed in detail in Chapter 2. Beckman and colleagues (170) found that this inhibitor of PKCP attenuated the impairment of endothelial-dependent vasodilation on healthy human subjects exposed to hyperglycemia.

Mechanisms responsible for a prothrombotic state associated with diabetes

Decreased activity of anti-thrombotic factors in blood can potentiate thrombosis. Of note, concentrations in blood of protein C and activity of anti-thrombin are decreased in diabetic subjects (88-91), although not universally (75). Unlike changes in concentrations of prothrombotic factors, altered concentrations and activity of anti-thrombotic factors appear to be reflections of the metabolic state typical of diabetes, either type 1 or type 2, especially hyperglycemia. Thus, decreased anti-thrombotic activity has been associated with nonenzymatic glycation of anti-thrombin. To recapitulate, functional activity of the prothrombinase complex and of thrombin itself are increased consistently in blood of people with diabetes. The increased activity is likely to be a reflection of increased procoagulant activity of platelets and monocytes in association with increased concentrations of fibrinogen, von Willebrand factor , and factor VII. Diminished activity in blood of anti-thrombotic...

Physiopathology of diabetes chronic complications

According to what has already been said, diabetes chronic complications occur as a consequence of persistent hyperglycemia (7). Hyperglycemia, in turn, promotes glucose auto-oxidation, AGEs formation and its interaction with RAGEs, activation of several isoformes of PKC, induction of poliol pathway and an increase of flux of hexosamine pathway (7). Recently, it was made a hypothesis according to which all these processes would be a consequence of an increase of superoxide production by respiratory mitochondrial chain during hyperglycemia (7,30). This way, reduction in superoxide production by mitochondria or an increase in its tax of decomposition by antioxidants could block many of hyperglycemia pathological consequences (7).

Role of the reninangiotensin system in cardiovascular disease in diabetes

As reviewed elsewhere in this book, multiple factors, including hyperglycemia, insulin resistance, dyslipidemia, hypercoagulability, and inflammation contribute to the pathogenesis of atherosclerosis in DM. Although there is considerable evidence for a role of the RAS in vascular remodeling, inflammation, thrombosis, and atherogeneis (81-83), the role of this system in atherosclerosis in the context of the other diabetes-associated cardiovascular risk factors is not fully understood. There is a growing body of evidence from both clinical studies and experiments in diabetic rodent models suggesting that the RAS contributes to CVD in both type 1 and type 2 diabetes.

Splanchnicmesenteric

Suggests experimental DAN may represent an example of distal axonopathy. Retrograde axonal transport of nerve growth factor was reduced (21). Aldose reduction inhibition was reported to partially reduce the development of these dystrophic changes (22). In a recent study, these workers reported that the changes were more prominent in the STZ-D rat and BB Wor rat, both models of hypoinsulinemic type 1 diabetes, than in the BBZDR Wor rat, a hyperglycemic and hyperinsulinemic type 2 diabetes model. They argued that hyperglycemia alone is not sufficient to produce sympathetic ganglionic neuroaxonal dystrophy, but rather that it may be the diabetes-induced superimposed loss of trophic support that ultimately causes these lesions (23). Similar findings to the pancreas have been reported (24). In a study of diabetes induced by STZ and occurring spontaneously in BB W rats, morphometric analysis of contacts between 3H norepinephrine-labeled sympathetic nerve terminals and a-cells in pancreases...

Esophageal Dysfunction

Autonomic neuropathy is the main pathogenetic suspect. Neuropathological esophageal abnormalities have been reported by Smith (8), who observed swelling, irregularity of caliber, and disruption of parasympathetic fibers in the esophageal wall and in the extrinsic trunks. The myenteric plexus appeared normal except for a lym-phocytic infiltration within the ganglia. Hyperglycemia might also be involved, it will be shown later for a number of motor gut disturbances.

Vitamin C and nitric oxide

Other studies demonstrated that vitamin C restores endothelium depending vasodilation in diabetic type 1 patients and in acute hyperglycemia in health humans, while studies realized with type 2 diabetics showed varied results (24). Several mechanisms may be responsible for such effects and, probably, they are related to vitamin C antioxidant activity (22).

Sex hormone effects on specific components in the vessel wall

The events leading to the retinal damage associated with hyperglycemia such as the breakdown of the blood retinal barrier, vessel basement membrane thickening, formation of microaneursyms, hemorrhages, cotton-wool spots, capillary obliteration and acellular capillaries can be traced to the damage occurring to micro-vessel endothelial cells, pericytes and their surrounding basement membrane. It has been noted that these sequelae develop as a result of the early loss of capillary endothelial cells and pericytes in the retina (Cunha-Vaz 2011).

Intracellular transportation of vitamin C

Glucose and DHA co-transportation by GLUT's in certain cellular types suggests a new causative mechanism of disease in these particular cellular types (25). Studies show an increase in free radicals production induced by hyperglycemia in target-organs affected by diabetes mellitus (25). Thus, it is suggested that free radicals production is the main causative pathway of diabetic complications (25). This way, it is probable that hyperglycemia results in a vitamin C deficiency in certain types of cells (such as peripheral neurons, pigmented cells and retinal vascular endothelial cells) which depend mainly or exclusively on GLUT carriers for vitamin C caption (25).

Genetic Susceptibility to Complications

As mentioned above, diabetes is associated with complications involving the eyes, kidneys, blood vessels, and heart. However, not all individuals with diabetes develop these complications. There is increasing evidence that there are genes other than those that increase susceptibility to developing the disease that may influence susceptibility to developing its complications. These genes are not yet identified, but they are likely to interact with other known risk factors for complications, including poor blood-sugar control and increased blood-pressure and blood-cholesterol levels. see also Complex Traits Disease, Genetics of Gene and Environment Gene Discovery Immune System Genetics Mitochondrial Diseases.

Dysmetabolic Metabolic Syndrome Syndrome X

Visceral adipose tissue is drained by the portal venous system and has a direct connection with the liver. Free fatty acids are quickly mobilized from these depots, compared with other peripheral fat stores. The lipolytic activity in visceral adipocytes is higher than in other fat depots, whereas, at the same time, the antilipolytic effect of insulin is more in the subcutaneous than the visceral fat. The concentration of free fatty acids in the portal system is thus elevated. This apparently results in stimulation of gluconeogenesis, resulting in hyperglycemia and increased triglyceride synthesis with associated dyslipidemia. Visceral obesity is also associated with increased levels of plasminogen activator inhibitor-1 (PAI-1) (135-140). PAI-1 lessens the fibrinolytic activity of tissue plasminogen by complexing with it. Low levels of plasminogen activator compared with PAI-1 are a risk factor for cardiovascular disease. PAI-1 is atherogenic, and its levels increase with...

Spinal Electrophysiology In Diabetes

There have been occasional reports of conduction slowing in the spinal cord of diabetic rats as early as 2 weeks after onset of hyperglycemia (49), although others reported that months of diabetes were required to show slowing in both ascending and descending tracts (50,51). Again, little is known about the pathogenesis of the disorder and the extent to which it mirrors the early metabolic and later structurally mediated aetiology of PNS conduction slowing has not been established, although conduction slowing in the PNS does appear to precede that in the CNS (51). It may be worth noting that glucose levels in spinal cerebrospinal fluid of diabetic rats are markedly lower than in plasma of the same animals (52), so that spinal axons and lower motor neuron cell bodies are exposed to less glycemic stress than their PNS counterparts.

Mechanisms responsible for hyperreactivity of platelets in people with diabetes

We have found that the osmotic effect of increased concentrations of glucose increase directly platelet reactivity (59). Exposure of platelets in vitro to increased concentrations of glucose is associated with increased activation of platelets in the absence and presence of added agonist. Exposure of platelets to isotonic concentrations of glucose or mannitol increases platelet reactivity to a similar extent (59). Thus, the osmotic effect of hypergly-cemia on platelet reactivity may contribute to the greater risk of death and reinfarction that has been associated with hyperglycemia in patients with diabetes and MI (60-62).

Glucocorticoid Coverage for Stress

A recent review (22) suggests that the conventional recommendations for stress doses of 200-300 mg of hydrocortisone for any procedure or medical illness should be discouraged. Excess amount and duration of the glucocorticoid may result in poor wound healing, immunosuppression, hyperglycemia, and excess sodium retention with volume overload. outcome studies. Previous recommendations of 100 mg iv hydrocortisone for minor procedures or illness, and 100 mg iv every 6 h for major surgery or illness appear excessive. Too much and too long administration of supplemental therapy may cause adverse effects such as delayed wound healing, immunosuppression, and hyperglycemia.

Expression of the Renin Angiotensin System in Diabetes

Acute hyperglycemia increases AGT expression in both liver and adipose tissue (63), suggesting that diabetes may increase AGT substrate availability. High glucose increases Ang II release from cardiomyocytes (64) and AT1 receptor expression in VSMC (65), suggesting that hyperglycemia may locally upregulate the RAS in vascular tissues.

Structural Abnormalities In Type 1 And Type 2

In the type 2 BBZDR Wor-rat the C-fiber population in sensory nerve is substantially less affected with normal axonal size and number (Fig. 6) even after 8 months exposure to severe hyperglycemia. Consequently the frequencies of denervated Schwann cell profiles and type 2 axon Schwann cell relationships are not different from nondiabetic

Oxidative And Nitrosative Induced Cell Death In Diabetic Neuropathy

Hyperglycemia promotes production of superoxides (O,,), increases flux through the Mt electron transport chain, and might be responsible for most of the key features of oxidative stress (20,23,54,55). In cell culture models of hyperglycemia, inhibition of formation prevents glucose-induced formation of advanced glycation end products (AGEs) and activation of protein kinase-C (56). O2 can also react with nitric oxide (NO) to form peroxynitrite (ONOO), which can damage intracellular lipids and proteins, resulting in lipid peroxidation, DNA fragmentation, and cell death. Accumulation of

Effects of HRT on Endothelial Function in Postmenopausal Women With Diabetes

Endothelial dysfunction is the hallmark of diabetes and is regarded as an early manifestation of atherogenesis. In postmenopausal women with diabetes, multiple pathophysiological processes may contribute to endothelial dysfunction. These are diabetes- related, as a result of hyperglycemia and obesity insulin resistance and menopause-related as a result of loss of the protective effect of estrogen, as discussed earlier.

Models of Autoimmunity

Diabetes, particularly type I (insulin-dependent diabetes mellitus, IDDM) has been associated with viral infections. A potential mechanism described above is molecular mimicry. The principle here is that a virus encoding a crossreacting epitope is also present in the pancreas of the genetically susceptible individual. Infection with a virus having the crossreacting protein and or epitope could initiate a crossreacting immune response. Here, the cell in the pancreas that contains the peptide in association with MHC molecules would be recognized by T cells and attacked. Two laboratories, those of Oldstone and Zinkernagle, have constructed transgenic mice to test this hypothesis. Lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) or nucleocapsid protein (NP) genes controlled by the insulin promoter were inserted into the germ line. Such transgenic mice expressed the viral GP or NP protein in the islet cells of the pancreas. These mice therefore consider the viral protein as...

Possible mechanisms of impaired endotheliumdependent vasodilation

Although the data are conflicting, overwhelming evidence presently suggests that DM is associated with an impairment of endothelial vasodilation. The mechanism(s) for this impairment is even less well understood. The most likely initial insult is hyperglycemia. Tesfamarian and colleagues took normal rabbit aortic rings and exposed them to high concentrations of glucose (up to 800 mg dL for 3 hours), resulting in a decrease in endothelium-dependent relaxation, in response to acetylcholine and ADP (52,53). This effect appears to be both concentration and time dependent. As stated earlier, this effect does not appear to be a result of the hyperosmolar effects of glucose because mannitol did not cause any such endothelium-dependent vasodilation (53). Bohlen and Lash (73) demonstrated that hyperglycemia at 300 and 500 mg dL suppressed the vasodilatory response to acetylcholine but not to nitroprusside. Similarly, Williams and colleagues (68) found that acute hyperglycemia attenuated...

Advanced Glycation end products AGEs

Best chemically characterized AGEs in human are carboxymethyllysine (CML), carboxyethyllysine (CEL), and pentosidine which act a markers for formation and accumulation of AGE in hyperglycemia. CML and other AGEs have been localized to retinal blood vessels of diabetes patients and were found to correlate with the degree of retinopathy suggesting the pathophysiological role of AGE's in diabetes Stitt AW, 2001 . Increased AGEs formation and accumulation has been found in retinal vessels of diabetic animals, in human serum with type 2 diabetes and in vitreous cavity of people with diabetic retinopathy Goh SY, 2008 Goldin A, 2006 .

Pathogenic implications of NO deficiency

Vascular deficiency of NO may be critical for pathogenesis of micro and macrovascular complications of non-controlled diabetes mellitus (15). This may be appreciated in the light of physiological importance of basal activity of NO in maintaining an appropriate arteriolar vasodilation, stabilizing platelets and preventing excessive activation and circulating leucocyte adhesion (15). Loss of such activity may clearly promote ischaemia by inducing arteriolar vasoconstriction and microvascular occlusion by activated adhering leucocytes and thrombosis (15). Besides, NO increases sodium-potassium pump activity in arterial wall and in axons of peripheral nerve (15). Reduction of sodium-potassium pump activity in endothelial capillary cells exposed to hyperglycemia could, in the same way, be attributed to a lesser production of NO (15).

Oxidative stress

Oxidative stress is believed to play a pivotal role in the development of diabetic retinopathy by damaging retinal cells Sato H, 2005 . However, the potential sources of ROS, is still unclear although a number of studies showed that high glucose and the diabetic state stimulate flux through the glycolytic pathway, increases cytosolic NADH, tissue lactate-to-pyruvate ratios, and tricarboxylic acid cycle flux thereby producing excess level of ROS Madsen-Bouterse SA, 2008 Ido Y, 1997 Obrosova IG, 2001 . ROS can be produced by activation of AGE, aldose reductase, hexosamine and PKC pathways induced by hyperglycemia, altered lipoprotein metabolism, excess level of excitatory amino acids and altered growth factor or cytokines chemokines activities Ola MS, 2006 Kanwar M, 2009 . Oxidative stress creates a vicious cycle of damage to macromolecules by amplifying the production of more ROS and activates other metabolic pathways that are detrimental to the

Hyperlipidaemia

Increased level of plasma lipid has been found to be involved in the pathogenesis of microvascular disease Ansquer JC, 2009 . High content of lipid in diabetic patients increases the risk of diabetic retinopathy and particularly diabetic macular edema van Leiden HA, 2002 . Still it is unclear how altered lipids level affect the onset and progression of diabetic retinopathy, may be through alterations in metabolic processes that alters concentration of serum compounds such as ketone bodies, acylcarnitine and oxidized fatty acids Adibhatla RM, 2007 . There is a growing body of evidence suggest that serum lipid fatty acid composition, concentration and tissue distribution contribute to the development and severity of this disease Berry EM, 1997 Kowluru RA, 2007 Nagao K, 2008 . The contribution of lipids fatty acid may be particularly important in the context of type I diabetes, where hypoglycemia and hyperglycemia co-exist.

Diabetic Nephropathy

The prevalence of diabetic nephropathy has increased dramatically and is now the first cause of end-stage renal disease requiring renal replacement therapy worldwide (72). Although the genetic background is important in determining susceptibility to diabetic nephropathy, exposure to chronic hyperglycemia leading to the subsequent activation of multiple pathogenic pathways appears to be the main initiating factor (2,3,4-6,41).

Diabetic Retinopathy

Diabetic retinopathy occurs in three-fourths of all persons with diabetes for more than 15 years (95) and is the most common cause of blindness in the industrialized world (96). It is primarily a disease of the intraretinal blood vessels, which become dysfunctional in response to hyperglycemia with progressive loss of retinal pericytes and eventually endothelial cells leading to capillary closure and widespread retinal ischemia (97).

Metabolic Factors

As hyperglycemia enhances AGE formation it is obvious that intensive treatment of hyperglycemia can modify the body AGE pool. Indeed, diabetic rats with good metabolic control exhibited lower levels of pentosidine, and lower intensity of collagen-linked fluorescence glycation and oxidation compared to rats with bad metabolic control (166). Skin collagen glycation, glycoxidation, and crosslinking were lower in a large group of type 1 diabetic patients under long-term intensive vs conventional treatment, as was shown in a cohort of patients studied in the DCCT (119).

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