How I Healed my Hypoglycemia

Guide To Beating Hypoglycemia

Here's Just A Tiny Glimpse Of The Topics Covered: The 3 main types of hypoglycemia and which type you're most likely suffering from. How snacking on chocolate bars can actually make you Fat and worsen your condition! (If you thought those delicious dark brown bars were great energy- boosters.think again!) The No. 1 question most folks have when it comes to hypoglycemia and hyperglycemia. Why you should insist on a 6-hour Gtt and not a 5-hour one. ( Why it might not be a good idea to consult a doctor to confirm your hypoglycemia. Aside from taking a Gtt, what other methods can you use to determine whether or not you're suffering from this condition? Well, refer Chapter 4, Pgs. 23-26 to take a revealing 67-question test especially designed to find out if you've got the symptoms. An inspiring motivational exercise that will help you effectively banish all of your negative thoughts that prevent you from having peace of mind. 2 good reasons why you should keep a food journal. 3 powerful nutrients that limit the effect of glucose on your blood sugar level. This is vital to a hypoglycemic as it helps slow down the absorption of sugar in the food. The secret impulse that literally forces you to say 'yes' to a candy bar or chocolate whenever you feel the hunger pangs gnawing at you. 2 ingredients that are lethal to a hypoglycemic. 'Hidden sugars' you must know to avoid buying products that can easily worsen your condition. 8 essential rules of food planning that are crucial to your speedy recovery from hypoglycemia. Leave out one of them and it could hurt your chances of recovering. How to create a healthy food plan that's suitable for both vegetarian and non- vegetarian hypoglycemics. Most food plans only focus on non-vegetarians, but this one works great for everybody!

Guide To Beating Hypoglycemia Summary

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Hypoglycemia and Brain Energetics

A small reserve of glucose is stored in the brain, as in other tissues, in the form of glycogen (Koizumi 1974). This glycogen store is localized primarily to astro-cytes. In contrast to ischemia, hypoglycemia causes a gradual consumption of brain glycogen (Feise et al. 1977 Agardh et al. 1978 Ratcheson et al. 1981 Choi et al. 2003). ATP depletion and onset of EEG isoelectricity were found to occur simultaneously with brain glycogen depletion (Lewis et al. 1974), suggesting a special role for this astrocyte energy store in maintaining brain function. More recent studies show that increasing brain glycogen stores can prolong brain activity during severe hypoglycemia (Suh et al. 2007a, b, c). Observations using an in vitro mouse optic nerve preparation provide insight into the means by which astrocyte glycogen stores may exert this effect (Wender et al. 2000 Brown et al. 2005 Tekkok et al. 2005). Under conditions of complete glucose deprivation, the mouse optic nerve is able to maintain...

Anatomical Distribution of Neuronal Injury After Severe Hypoglycemia

Not all neurons are equally sensitive to hypoglycemic injury, and studies using rodent models indicate a reproducible pattern of vulnerability. The most sensitive neuronal populations are, in order, those of the subiculum, the small and medium-size neurons of the caudate, CA1 hippocampus, dentate gyrus of the hippocampus, and superficial layers of the cortex (Auer et al. 1984a 1985a, b). This rank order of vulnerability is similar to that seen with global ischemia-reperfusion, but with some notable differences in ischemia, the dentate gyrus is much less vulnerable, and the deeper rather than the superficial layers of cortex are more vulnerable (Auer 1986). Electron microscopy studies of hippocampal neurons destined to undergo necrosis reveal early dendritic, axon-sparing lesions (Auer et al. 1985a, b). Swollen dendrites appear after 10 min of isoelectric EEG. After 30 min, swollen mitochondria and abnormal plasma membranes are seen in the cell body. One hour after the onset of...

The Hypoglycemic Neuronal Cell Death Pathway

Hypoglycemic neuronal death is not a direct result of energy failure, but results instead from a multi-step process (Fig. 14.1). Key steps identified in this process include glutamate receptor stimulation (Wieloch 1985 Wieloch et al. 1985 Butcher et al. 1987a, b Papagapiou and Auer 1990 Nellgard and Wieloch 1992), glucose re-perfusion (Suh et al. 2007a, b), production of reactive oxygen species (Patockova et al. 2003 McGowan et al. 2006 Suh et al. 2007a, b, 2008), Zn2+ release (Suh et al. 2004, 2008), mitochondrial permeability transition (Ferrand-Drake et al. 1999), and activation of poly(ADP-ribose) polymerase-1 (PARP-1) (Suh et al. 2003). Although the cause-effect relationships between some of these events remain uncertain, interceding at any one of these steps can prevent hypoglycemia-induced neuronal death. Fig. 14.1 Key events in hypoglycemia-induced neuronal death. Prolonged, severe hypoglycemia leads to the release and impaired re-uptake of glutamate and aspartate. With...

Summary of Hypoglycemia Induced Neuronal Cell Death

Severe hypoglycemia triggers the release and impaired uptake of glutamate and aspartate, which then activate NMDA and non-NMDA glutamate receptor subtypes. With glucose reperfusion, there is additional release of Zn2+ and nitric oxide and the production of superoxide. The superoxide production is mediated by NADPH oxidase and requires glucose for NADPH synthesis. Superoxide and nitric oxide together cause DNA damage, PARP-1 activation, and PARP-1-mediated neuronal death.

Hypoglycemic Brain Injury Epidemiology and Background

The normal range for blood glucose concentrations is 3.9-7.1 mM (1 mM 18 mg dL), and hypoglycemia is broadly defined as blood glucose concentrations below this range. Studies using mice and rats indicate that brain injury does not generally occur unless blood glucose concentrations fall below 1 mM and the cortical electroencephalogram (EEG) is isoelectric (silent) for at least 30 min (Auer et al. 1984a, b Auer et al. 1985a, b Suh et al. 2003). Case series suggest that a similar degree of hypoglycemia is required to induce brain injury in humans, although this may vary in infants and children, susceptible individuals, with repeated hypoglycemia, and with co-morbid factors (Kalimo and Olsson 1980 Malouf and Brust 1985 Auer et al. 1989 Langan et al. 1991 Ben-Ami et al. 1999 de Courten-Myers et al. 2000 Ennis et al. 2008). 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...

Review the mechanism of action for antagonists and side effects

P1-Blockade produces negative inotropic and chronotropic effects, decreasing cardiac output and myocardial oxygen requirements. p-Blockers also inhibit renin secretion and lipolysis. Since volatile anesthetics also depress contractility, intraoperative hypotension is a risk. p-Blockers can produce atrioventricular block. Abrupt withdrawal of these medications is not recommended because of up-regulation of the receptors myocardial ischemia and hypertension may occur. p-Blockade decreases the signs of hypoglycemia thus it must be used with caution in insulin-dependent patients with diabetes. p-Blockers may be cardioselective, with relatively selective B1 antagonist properties, or noncardioselective. Some p-Blockers have membrane-stabilizing (antiarrhythmic effects) some have sympathomimetic effects and are the drugs of choice in patients with left ventricular failure or bradycardia. p-Blockers interfere with the transmembrane movement of potassium thus potassium should be infused with...

Introduction

In the early 1980s it was recognized that excessive Ca2+ influx, presumably through voltage-gated Ca2+ channels, with a resultant increase in intracellular Ca2+, was associated with neuronal death from cerebral ischemia, hypoglycemia, and status epilepticus (Siejo 1981). Calcium activation of phospholipases, with arachidonic acid accumulation and its oxidation, generating free radicals, was thought to be a potential mechanism by which neuronal damage occurs. In cerebral ischemia and hypoglycemia, energy failure was thought to be the reason for excessive Ca2+ influx, whereas in status epilepticus it was thought that repetitive depolarizations were responsible (Siejo 1981). On the basis of these observations, Olney proposed the excitotoxic hypothesis, namely, that glutamate and aspartate, the principal excitatory neurotransmitters in the central nervous system, are responsible for the excitotoxic death of neurons (Olney 1985). Electron-microscopic studies in the early 1970s and 1980s...

Predisposing Conditions

Some supportive procedures that may cause ischemia have been associated with NEC. It includes umbilical and venous catheterization and exchange transfusion (2,6). Perinatal factors that cause hypoxia include respiratory distress syndrome, apnea, asphyxia, hypotension, congestive heart failure, patent ductus arteriosus, hypothermia, sepsis, hypoglycemia, and polycythemia. However, some infants with no risk factors develop NEC. Maternal complications associated with fetal distress and shock, such as prolonged rupture of membranes and maternal infection, frequently are observed in these infants (11).

Enhancers Of Insulin Release 21 Glucokinase activators

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) phenotypes associated with gene manipulation studies in mice. Recently, a potent GK activator RO0281675,1, which increased the enzymatic activity of recombinant human GK in a dose-dependent and stereospecific manner, was identified 1 . At a concentration of 3 mM, 1 increased the Vmax of GK by a factor of about 1.5 and decreased the substrate concentration at 0.5 Vmax ( S 05) for glucose from 8.6 to 2.0 mM. In numerous in vivo studies GK activators were shown to cause glucose-dependent insulin release in the pancreas, and also to increase glucose utilization in the liver.

Implementation Of An Acute Stroke Team And Acute Stroke Protocols

The overwhelming prerogative, in thrombolysis for acute ischemic stroke, is the need for rapid, yet complete, evaluation of potential therapeutic candidates within the 3-hour treatment window. Time is the acute stroke clinician's worst enemy.33 The acute stroke protocol should begin at the first of point of contact with the healthcare system the call to an ambulance dispatcher. Stroke symptoms should be recognized and given high priority for dispatch. Emergency medical technicians (EMTs) should be trained to identify potential thrombolysis candidates in the field by recognizing signs of stroke,73,74 and several simple scales have been created for this purpose.75-78 Prenotification by the EMTs, before hospital arrival, allows time for notification of the acute stroke team and preparation of the CT scanner before patient arrival, and has been associated with fewer in-hospital delays in treatment.79,80 The initial evaluation, after arrival in the emergency department, should include a...

Glucose6phosphatase inhibitors

In these patients, hypoglycemia is observed as one of many clinical features. Two series of compounds, characterized by the tetrahydrothienopyridines, 31 (IC50 350 nM) and the N,N-dibenzyl-N0-benzylidenehydrazines 32 (IC50 1 70 nM), have moderate in vitro activity, but no in vivo activity has been reported 39,40 .

Clinical Studies Of Sitagliptin

With an improvement in p-cell function. Sitagliptin was well-tolerated with a very low incidence of hypoglycemia, and, unlike many oral anti-hyperglycemic agents, was weight neutral. In addition to demonstration of efficacy in monotherapy trials, sitagliptin provided improved glycemic control when used in combination with pioglita-zone 42 or metformin 43 . In a 52-week non-inferiority study, patients taking metformin (> 1500mg day) were treated with either sitagliptin (100 mg) or glipizide (5mg titrated to a maximum dose of 20 mg daily), a sulfonylurea 44 . Both treatments resulted in an overall HbA1c decrease of 0.67 , demonstrating non-inferiority. A similar percentage of patients taking sitagliptin achieved HbA1c levels of < 7 (63 for the sitagliptin group and 59 for the glipizide group). While glucose lowering efficacy was similar, a much larger proportion of patients taking glipizide experienced hypoglycemic events (32 vs. 4.9 for those taking sitagliptin). In addition,...

Caspase Independent Programmed Cell Death

As mentioned previously, apoptosis and PCD have been used interchangeably, and until recently, necrosis was assumed to be a passive process of cell swelling and lysis, based on in vitro evidence. However, there has been for many years in vivo evidence in cerebral ischemia, status epilepticus and hypoglycemia that what was then called ischemic cell change and what we now describe as neuronal necrosis involves cell shrinkage and condensation, with nuclear pyknosis (shrinkage), scattered irregular chromatin clumps, and mitochondrial swelling, with disrupted cristae and flocculent densities (Fig. 4.6) (Brown and Brierley 1972, 1973 Griffiths et al. 1984 Auer et al. 1985a, b Ingvar et al. 1988 Colbourne et al. 1999 Fujikawa et al. 1999, 2000, 2002). As discussed in the section Morphological Classification of Cell Death, these changes were described independently by Wyllie (1981), and were recognized as being necrotic. Fig. 4.6 Early evidence that necrotic neurons are produced by cerebral...

Therapeutic significance

Relative to wild-type controls, DPP4-deficient mice are resistant to the development of obesity and hyperinsulinemia when fed a high-fat diet 28 . DPP4 knockout mice also show elevated GLP-1 levels and improved metabolic control. Relative to DPP4 positive controls, DPP4-deficient Fischer rats show improved glucose tolerance following an oral glucose challenge due to enhanced insulin release mediated by high levels of active GLP-1 29,30 . In these studies, the authors note that fasting and post-challenge glucose levels in both strains are similar, supporting previous assertions that hypoglycemia is unlikely during treatment with DPP4 inhibitors.

Preclinical Dpp4 Inhibitors

Rodent studies using NVP-DPP728 (6, IC50 7 nM) 54 and the structurally related K579 (7, IC50 5 nM) have demonstrated similar pharmacological effects as those seen with the inhibitors discussed above. In a comparative study, 7 appeared to provide better control of DPP4 activity and glucose excursions than did 6 55 . Combination of 7 with glibenclamide further enhanced the glucose control without significant hypoglycemia 56 .

Nuclear Receptor Based Lipid Mediators

Nuclear Hormone receptors There are several nuclear hormone receptors which are involved in the regulation of lipid metabolism. The liver X receptors (LXR), retinoid X receptors (RXR), and farnesoid X receptors (FXR) are activated by oxysterols, retinoids, and bile acids, respectively. RXR also forms heterodimers with peroxisome proliferator-activated receptors alpha, delta, and gamma (PPARs), with LXR alpha and beta, and FXR. All of these nuclear receptors have been targeted for drug development (40). Fibrates (e.g. fenofibrate, 17) are agonists of PPAR alpha, which results in the induction of a series of genes leading to a reduction in plasma triglyceride levels and an increase in HDL-cholesterol. The glitazones (e.g. rosiglitazone 18 and troglitazone 19) are agonists of PPAR gamma, which improve insulin sensitivity and are used as oral hypoglycemic agents. A high affinity PPAR gamma agonist, GI262570, 20 (pKi 8.9), has been reported to have potent

Describe an approach to the evaluation of postoperative hypertension and tachycardia

A hyperdynamic postoperative phase is not an uncommon event. Frequently observed and readily treatable causes include pain, hypoventilation, hypercarbia, hypothermia with shivering, bladder distention, and essential hypertension. Also consider hypoxemia, hyperthermia and its causes, anemia, hypoglycemia, tachydysrhythmias, withdrawal (e.g., drug and alcohol), myocardial ischemia, prior medications administered, and coexisting disease. Rarely the hyperdynamic state may reflect hyperthyroidism, pheochromocytoma, or malignant hyperthermia.

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...

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

Caspase Independent Pathways

Release of AIF can be suppressed by Bcl-2 (167), and crosstalk signaling between the AIF and the caspase-dependent cell death pathways likely occurs at various levels of signaling. Increased nuclear AIF has been reported after hypoxia-ischemia in immature rats (168 ), global ischemia in mature rats (169 ), and hypoglycemia (170). With NMDA-induced excitotoxicity in neurons, AIF translocation to the nucleus occurs rapidly and depends on activation of poly(ADP-ribose) polymerase (PARP) activity (171,172). In contrast, AMPA-induced injury is not dependent on PARP activation (173). PARP-1 normally participates in DNA repair by temporarily elongating the helical strands to permit access by other repair enzymes. However, hyperactivation of this DNA repair enzyme from excessive DNA damage leads to formation of an abundant amount of poly(ADP-ribose) (PAR) and consumption of NAD+. Moreover, hyperactivation of PARP-1 can cause mitochondrial state 4 respiration,...

Caspase Independent Cell Death and Its Regulators

AIF is one of the most important agents of caspase-independent cell death, and the study of the role and regulation of this pathway by PARP-1, cyclophilin A (CypA), and HSP-70 are active fields of research. AIF is a phylogenetically ancient flavoprotein NADH oxidase contained in the mitochondrial inter-membrane space, where its local redox function is essential for efficient oxidative phosphorylation and for antioxidant defense (Lipton and Bossy-Wetzel 2002 Vahsen et al. 2004). Upon induction of the death-promoting stimulus, AIF translocates from the mitochondria to the cytosol and then to the nucleus, where it associates with chromatin and causes peripheral chromatin condensation and high molecular weight DNA fragmentation (Ravagnan et al. 2002 van Loo et al. 2002 Daugas et al. 2000) Susin et al. 1999. AIF is essential for PCD during cavitation of embryoid bodies, as indicated by studies with AIF knockout mice (Joza et al. 2001). Translocation of AIF to the nucleus in neurons in...

Nondiabetic endocrine disease i

The signs and symptoms observed in patients with mild hypothyroidism are nonspecific, and clinical detection is extremely difficult. Patients with severe long-term untreated hypothyroidism may progress to myxedema coma, which is frequently fatal. Factors that may lead to myxedema coma in hypothyroid patients include cold exposure, infection, trauma, and administration of central nervous system depressants. Myxedema coma is characterized by hypoventilation, hypothermia, hypotension, hyponatremia, hypoglycemia, obtundation, and adrenal insufficiency.

Total Subtotal Pancreatectomy

A total pancreatectomy involves removal of the entire gland, the duodenum, distal stomach, distal bile duct, spleen, and the greater omentum (Fig. 3). This procedure was largely abandoned after a high mortality rate was observed both early and late. The metabolic changes that ensue are also challenging to control. As many as 50 of all of the late deaths that occur after total pancreatectomy are a result of iatrogenic hypoglycemia. Moreover, a survival benefit over the Whipple procedure has not been demonstrated for similar stage tumors of the proximal pancreas. Hence, the indication for a total pancreatectomy currently is the finding of carcinoma in the margin of a proximal pan-createctomy in a patient who can tolerate the metabolic demands of a complete resection.

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. When insulin was discovered in 1921, islet cell adenoma was joined by diabetic insulin treatment in reports of hypoglycemic brain damage (Bodechtel 1933 Baker 1938). Suicide or...

Substrate Utilization Defects

A multienzyme complex that participates in the p-oxidation of fatty acids and has 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase, and 3-ketoacyl-CoA thiolase activities provides another example of a nuclear-encoded mitochondrial disorder. This trifunctional protein (TP) has four a (HADHA) and four p (HADHB) subunits. The 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase active sites are part of the HADHA cluster, and the four HADHB subunits constitute the 3-ketoacyl-CoA thio-lase domain. The clinical features of TP deficiency are sudden infant death, coma, low blood sugar, liver failure, degeneration of skeletal muscles, and cardiomyopathy. Most mutations in the HADHA and HADHB genes, which are both located at chromosome 2p23, cause loss of the entire TP complex, whereas with some HADHA gene mutations only the 3-hydroxyacyl-CoA dehydrogenase activity is abolished. Interestingly, the phenotype is the same whether the loss of TP activity is partial or complete.

Models Of Preconditioning Crosstolerance

Numerous animal models have been described, in which brief episodes of global or focal ischemia are applied, followed by a more severe ischemic stress designed to kill neurons. In the classic experiment, brief global ischemia induced tolerance against subsequent global ischemia (3) in what is referred to as a global-global model of ischemic preconditioning. Subsequent studies have demonstrated that tolerance against focal ischemia can also be induced by brief focal ischemia (12), or focal-focal preconditioning. Furthermore, brief global ischemia has also been shown to reduce infarct size after focal ischemia induced by middle cerebral artery occlusion (global-focal) (13). Finally, transient focal ischemia increases tolerance against subsequent global ischemia. Interestingly, tolerance to ischemia in this focal-global paradigm develops in neurons within the region of focal ischemia (14) and in neurons outside the region of primary ischemia (15). Noxious stimuli other than ischemia can...

Cardiac Muscle Disorders Dilated Cardiomyopathy

And fatty acids by way of acetyl-CoA to CO2 and, concomitantly, by a chemios-motic process produce chemical energy in the form of ATP. A shortage of ATP impairs the extent of muscle activity. Specifically, when carnitine palmoyl-transferase II (CPTII), part of the complex that transfers long-chain fatty acids from the cytoplasm into mitochondria, is deficient, then cardiomyopathy occurs along with other complications including low plasma glucose concentration (hypoglycemia), vomiting, and coma. Severe cases with this enzyme deficiency result in early death. Also, individuals who lack the enzyme medium-chain (C4-C12) acyl-CoA dehydrogenase (MCACAD), which catalyzes the b-oxidation of fatty acids and leads to the production of acetyl CoA, occasionally have DCM as one of the symptoms (Table 13.4).

PARP1 activation Neuronal death

Hypoglycemia causes several-fold elevations in brain extracellular glutamate concentrations (Feise et al. 1977 Engelsen et al. 1986), and ablation of pre-synaptic glutamatergic terminals prevents both the rise of glutamate in the extracellular space and hypoglycemic neuronal death (Wieloch et al. 1985 Butcher et al. 1987a, b). Antagonists to both NMDA and non-NMDA glutamate receptors can also prevent hypoglycemic neuronal death (Wieloch 1985 Papagapiou and Auer 1990 Nellgard and Wieloch 1992). A unique feature of hypoglycemia is that, in addition to glutamate release, aspartate production and release result from the aspartate aminotransferase reaction glutamate + oxaloacetate aspartate + a-ketoglutarate (Sutherland et al. 2008). The absence of glucose carbon entry into the tricarboxylic acid (TCA) cycle during hypoglycemia leads to a net conversion of a-ketoglutarate to oxaloacetic acid. The result is a rise in tissue aspartate (Cravioto et al. 1951), and roughly 15-fold elevations in...

Superoxide Production is Triggered by Glucose Reperfusion

Superoxide production has been identified as a necessary event in excitotoxic neuronal death (Lafon-Cazal et al. 1993 Patel et al. 1996). Studies of hypoglycemic neuronal injury have identified two important features of this aspect of excitotoxicity (Suh et al. 2007a, b). First, studies using cultured neurons placed in glucose-free medium show that superoxide production is triggered when glucose is returned to the medium, and rather than during the glucose-free period itself (Fig. 14.2). Studies of hypoglycemia in the rat brain show the same pattern superoxide production is negligible during hypoglycemia, but occurs in vulnerable neuronal populations during the 30-60 min interval following normalization of plasma glucose concentrations (Fig. 14.2). A point of potential clinical importance is that the rate of superoxide formation, along with neuronal death, is substantially influenced by the blood glucose concentration achieved during this immediate post-hypoglycemic interval (Suh et...

Role of Zinc and Nitric Oxide

In rats subjected to hypoglycemia, zinc staining with (TSQ) showed depletion of presynaptic vesicular zinc from hippocampal mossy fiber terminals and accumulation of weakly bound zinc in hippocampal CA1 cell bodies induced at the time of glucose reperfusion (Fig. 14.5). The depletion in presynaptic, vesicular zinc was followed by accumulation of TSQ-stainable zinc in post-synaptic neuronal bodies (Suh et al. 2004). Intracerebroventricular injection of the zinc chelator, calcium ethylene-diamine tetraacetic acid (CaEDTA) blocked the zinc accumulation (Fig. 14.5) and reduced hypoglycemia-induced neuronal death. CaEDTA also attenuated the accumulation of poly(ADP-ribose), the enzymatic product of PARP-1 in hippocampal neurons (Suh et al. 2004). These results suggest that zinc translocation is an intermediary step linking hypoglycemia to PARP-1 activation and neuronal death. A key role for the vesicular zinc pool in this process is further suggested by reduced superoxide formation and...

Fundamental Research Advancing Telemedicine For Stroke Care

The first successful telemedicine systems for acute stroke consultation and treatment were reported at the University of Maryland Medical Center (9-14). Researchers created a test-bed to pilot projects that involved the technology's application (12). This group tested the advantages of real time, 2-way transmission of audio-video recording of a remotely located patient to stroke clinicians at the medical center, versus telephonic transmission of data alone. They found that 2-way audiovisual linkage added diagnostic and management certainty, provided prearrival time to prepare for treatment, and increased the number of patients with ischemic stroke treated with intravenous recombinant tissue plasminogen activator (Fig. 1) (10,11). Other important information gleaned from early study of this technology included clinician acceptance of the technology, patient and family satisfaction with remote specialty consultant care, and improved ability to diagnose and appropriately treat other...

Multiple Endocrine Neoplasia Type

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome that features tumors of the parathyroid, pituitary, and the islet cells of the pancreas. These tissues are part of the endocrine system, which produces and secretes various hormones. In response to different hormones, target cells control homeostatic processes, growth, development, and stress. Specifically, with regard to the sites of the MEN1 tumors, the parathyroid glands control levels of calcium and phosphate the pituitary glands regulate metabolic activities of other endocrine glands and growth and the pancreatic islet cells maintain blood glucose concentration. Depending on the site and the extent of the MEN1 tumors, symptoms may include excess calcium in the bloodstream (hypercalcemia), which causes kidney stone formation low blood sugar concentration (hypoglycemia), resulting in dizziness, confusion, weight loss, and glucose intolerance and disruption of the pituitary gland, accompanied by...

The Morphology of Seizure Induced Neuronal Death

Our current understanding of the morphology of seizure-induced neuronal death in the adult brain is in remarkable agreement with the ultrastructural morphology of cerebral ischemic and hypoglycemic neuronal death, both of which are excitotoxic in origin, and both of which show unmistakable earmarks of neuronal necrosis in vivo (Auer et al. 1985a, b Colbourne et al. 1999). This suggests that a common mechanism, presynaptic glutamate release from depolarization of neurons, as well as reversal of glutamate uptake by astrocytes, underlies these pathological conditions. After traumatic CNS injury in the adult rodent, ultrastructural photomicrographs (1) have been misinterpreted as showing apoptotic neurons (Colicos and Dash 1996) their Fig. 3B and 3C show microglia, Fig. 4B shows a microglial cell and Fig. 4B and 4C shows a necrotic neuron), (2) have suggested both necrotic and apoptotic morphology, predominantly the former, but with DNA laddering (Rink et al. 1995), which we have shown...

Telestroke In Clinical Practice Networks of Care

University of Maryland investigators reported 23 telemedicine consultations and 27 telephone consultations preceding transfer among patients with suspected acute stroke.36 Of the 23 telemedicine consultations, 2 were aborted because of technical difficulties, but 5 of the 21 patients receiving successful TeleStroke consultation received IV rt-PA. No patient experienced complications. Diagnoses included sub-arachnoid hemorrhage, intracerebral hemorrhage, seizure, hypoglycemia, and transient ischemic attack as well as acute ischemic stroke (both anterior and posterior circulations).

Discuss the considerations for fluid administration during craniotomy

The content of the fluids used during a craniotomy is also important. An isosmolar intravenous fluid should be chosen. Unless hypoglycemia is documented, glucose-containing solutions should be avoided. In both clinical and experimental settings in which glucose is used in the resuscitation fluids after head injury, outcome is worse. Saline is the appropriate fluid for use during craniotomy. Balanced salt solutions may be used if their osmolarity approximates or exceeds that of the serum. Ringer's lactate has a slight theoretic disadvantage because lactate is metabolized and the solution becomes hypotonic. Colloid solutions such as 5 albumin or 3 NaCl are equivalent solutions for acute volume replacement before packed red cell administration. Often 25 albumin is used for pressure support when blood replacement is not needed. Hetastarch solutions should be limited to 15 to 20 ml kg body weight during craniotomies because of concerns that larger quantities are associated with impaired...

Exenatide Antidiabetic [3741

Also moderates peak serum glucagon levels during hyperglycemic periods following meals, but does not interfere with glucagon release in response to hypoglycemia. The dosing regimen for exenatide is 5 or 10 mg twice daily, administered as a subcutaneous injection within an hour before morning and evening meals. Following subcutaneous administration, peak plasma concentrations of exenatide are reached in 2.1 h, and the plasma pharmacokinetic profile is dose proportional. Exenatide has an apparent volume of distribution of 28.3 L, a clearance rate of 9.1 L h, and an apparent in vivo half-life of 2.4 h. Exenatide levels are measurable for up to 10 h after administration. It is primarily excreted unchanged in the urine by glomerular filtration, after which it undergoes proteolytic degradation. The efficacy and safety of exenatide (5 or 10 mg as a twice-daily subcutaneous injection) has been evaluated in three 30-week double-blind, placebo-controlled clinical trials (n 1446). The primary...

Concluding Remarks

An underlying theme of this book is that acute pathological neurological processes, despite their apparent widely varying presentations, have at their core the central underlying triggering mechanism - excitotoxicity. That is because excessive neuronal depolarization, with excessive glutamate (GLU) release, both presynaptically and from reversal of astrocytic GLU uptake, occurs in each condition - cerebral ischemia, traumatic central nervous system (CNS) injury, hypoglycemia, and status epilepticus (SE). In a way, SE is the purest form of excitotoxicity, because the other processes have superimposed upon excessive neuronal depolarization an additional and modifying condition, be it reduced or absent cerebral blood flow (CBF) for a period of time, with or without reperfusion, traumatic impact to brain or spinal cord, or a low glucose concentration for a period of time, with or without resumption of a normal concentration. The excessive release of GLU activates an excessive number of...

Mitiglinide Antidiabetic [6367

Mitiglinide is a non-sulfonylurea hypoglycemic agent that has been developed and launched in Japan for the treatment of type-2 diabetes. Similar to the sulfonylurea insulinotropic drugs, mitiglinide adopts a U-shaped configuration in which the base of the U contains an amide linkage, and each branch of the U incorporates a hydrophobic side chain. This similarity in conformation suggests that mitiglinide also binds to the sulfonylurea receptor to cause the direct closing of ATP-sensitive potassium channels in pancreatic p-cells the result is stimulation of insulin secretion. In contrast to typical sulfonylurea agents that frequently cause hypoglycemia due to slowly reversed insulinotropic activity, mitiglinide's short duration of action should be advantageous in preventing this adverse effect. It also enjoys a rapid onset of insulin release. Mitiglinide can be prepared by several closely related methods, which involve either classical resolution of racemic intermediates, or...

Mitochondrial DNA Defects

Increased lactate concentration, and hypoglycemia. Second, mutations of the mitochondrial thymidine kinase gene (TK2,16q22.1) are responsible for severe loss of muscle mitochondrial DNA. The production of mitochondrial dNTPs depends on both of these kinases. Consequently, mutations that limit the supply of dNTPs constrain DNA replication and bring about DNA depletion. Presumably, under these conditions, there are too few active mitochondria to enable high-energy-demand tissues to function properly. At present, there is no explanation for the apparent tissue specificity of the different mutant kinases.

Alcohol and substance abuse

Special consideration must be given to the cardiovascular system of chronic alcohol users. Tachycardia, dysrhythmias, or cardiomegaly may indicate alcohol-related cardiac dysfunction and a 12-lead electrocardiogram (ECG) should be evaluated. Patients with alcohol-induced cardiac disease are less sensitive to endogenous or parenteral catecholamines. Hypokalemia and hypoglycemia are common, as are anemia, thrombocytopenia, and altered coagulation. These patients are often volume depleted and will require fluid resuscitation. Insert a urinary catheter to follow urine output. Intravascular monitoring should be individualized. Instrumentation of the esophagus should be avoided in patients with known liver disease because of the possibility of rupturing esophageal varices.

Counterregulatory Hormones

Hypoglycemia or stress can trigger the secretion of several hormones, including glucagon, the catecholamines such as epinephrine, growth hormone and Cortisol. These act to counter insulin's action in stimulating peripheral glucose disposal and inhibiting hepatic glucose output (89,90). Modulation of these counterregulatory hormones can impact glycemic control and or insulin action in diabetic patients. 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...

Non Chromosomal Syndromes Associations and Sequences

Eec Syndrom Foto

Another example of an infant with the typical macrosomia (birthweight of 3950 g), polycythemia (hematocrit 66 ) and hypoglycemia. Note the macroglossia, nevus flammeus over the glabellar region and the eyelids, and the prominent eyes with relative infraorbital hypoplasia. Figure 3.2. Another example of an infant with the typical macrosomia (birthweight of 3950 g), polycythemia (hematocrit 66 ) and hypoglycemia. Note the macroglossia, nevus flammeus over the glabellar region and the eyelids, and the prominent eyes with relative infraorbital hypoplasia.

Pharmacological Properties Of Qa

Modern medicine is declining and restricted. The utilization of sparteine as a uterus contracting drug has been abandoned for the same reasons. Sparteine, lupanine and 13-hydroxylupanine have hypotensive and CNS-depressant properties and furthermore, are hypoglycemic and, thus, might be interesting antidiabetic drugs. In addition to QA, the alkaloid-free fraction of L. albus seeds seems to have antidiabetic activities. Matrine and cytisine are amoebicidal matrine and 17-oxolupanine are effective inflammatory compounds. Some of these pharmacological properties can be explained through activation of the acetylcholine receptors and inhibition of K+ and Na+ -channels.48,52

Gpr119 Agonists Medicinal Chemistry

A key aspect of b-cell Gas-coupled receptors is their ability to enhance insulin release in a glucose-dependent fashion, and 6 has been used to show this is characteristic of GPR119. In both rat and mouse islets, 6 had no effect on insulin release at basal (5 mM) glucose concentrations but had GLP-1-like efficacy when the glucose concentration was > 8mM. Also, unlike the sulfonyl urea glyburide, 6 did not stimulate insulin release or cause hypoglycemia during a drug challenge to fasted mice.

The mechanism of GK activation by allostericsite binders

Regulation of GK activity via the allosteric site facilitates the explanation of the activated kinetic properties of certain GK mutations that have been identified in patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI). For example, in patients with mutations in one GK allele in which methionine was substituted for valine at residue 455 (V455M), tyrosine for cysteine at residue 214 (Y214C), or valine for alanine at residue 456 (A456V), improved GK activity was exhibited 13 . These residues, which seem to be included in the allosteric site regulatory domain, are important for the activity of GK and also may aid the design of specific GK activators.

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

Beckwith Wiedemann Syndrome

The major characteristic of the Beckwith-Wiedemann syndrome (BWS) is excessive fetal and postnatal growth. About 80 of BWS infants and children are greater than the 90th percentile for height and weight. After 6 years of age, overgrowth is not pronounced. Generally, the tongue is oversized. The abdominal body wall often fails to close at the base of the umbilical cord (omphalocele) because of enlarged internal organs (visceromegaly). Consequently, the intestines protrude from the body cavity at birth. About 60 of BWS patients have an abnormally low level of blood sugar (hypoglycemia) because an enlarged pancreas produces excess insulin. Hypoglycemia causes general weakness, increased appetite, and, occasionally, convulsions, coma, and irreversible brain damage. Wilms tumor, adrenocortical carcinoma, hepatoblastoma, rhabdomyosarcoma, or other cancers occur in 5 to 10 of BWS children. The incidence of severe BWS is about 1 in 14,000. About 15 of the cases of BWS are familial, which...

Recent Advances in Therapeutic Approaches to Type 2 Diabetes

The United Kingdom Prospective Diabetes Study (UKPDS), a long term study of Type 2 diabetics, has shown that rigorous management of blood glucose levels (measured as glycosylated hemoglobin, HbAic), and blood pressure substantially reduce the incidence of complications (3). The current therapeutic strategies for Type 2 diabetes are very limited, and involve insulin therapy and oral hypoglycemic agents (OHAs) such as sulfonylureas, metformin, and the thiazolidinediones. Combination therapy with one or more of these agents is now a viable option as target blood glucose levels become harder to maintain with monotherapy (3,4). While a wide variety of therapeutic approaches are now being examined for Type 2 diabetes, these can generality be classified in one of the following categories 1) insulin or insulin mimetics 2) agents which effect the secretion of insulin 3) inhibitors of hepatic glucose production 4) insulin sensitizers and 5) agents which inhibit glucose absorption. The current...

What is the most common replacement fluid used in children

A BSS such as lactated Ringer's (LR) with glucose (D5LR) or without glucose (LR) is recommended. Hypoglycemia may occur in healthy children undergoing minimally invasive 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 are the alleged benefits and risks of ginseng

Ginseng is a general tonic for improving well-being and stamina and may increase resistance to environmental stress. The active constituents of ginseng are ginsengosides these compounds may raise blood pressure and act as a central nervous system stimulant. Adrenal function and cortisol release may increase. Ginsengosides are reported to interfere with platelet aggregation and coagulation in vitro, but this effect has not been demonstrated in humans. Ginseng is also associated with hypoglycemia, interferes with warfarin, and may increase partial thromboplastin time.

Electron Transport Chain Defects

A deficiency of complex II (succinate dehydrogenase) in two siblings of a consanguineous marriage was associated with a homozygous mutation of the SDHA nuclear gene at chromosome 5p15 that encodes subunit A of the suc-cinate dehydrogenase complex. In these individuals, the onset of the disorder was in early childhood. Computed tomography scans showed a pattern of degeneration of the substantia nigra and basal ganglia that resembled Leigh syndrome. Similarly, individuals with mutations of the genes (SDHB, 1p36.13 SDHC, 1q21 SDHD, 11q23) for the other three subunits of complex II suffer from Leigh syndrome. And, mutations of the UQCRB gene at 8q22 that encodes a complex III, subunit cause, among other defects, hypoglycemia and lactic acidosis.

Necrotic Cell Death

Degradation and clumping of nuclear DNA, the formation of small, tightly wrapped membrane whorls, the rupture of the plasma membrane and the appearance of autophagosomes (Edinger and Thompson 2004). The word necrosis is derived from the Greek expression necros, standing for dead and was traditionally considered as the chaotic breakdown of the cell. In humans, necrotic cell death accompanies prolonged hypoxia, ischemia, hypoglycemia, toxin exposure, exposure to reactive oxygen metabolites, extreme changes in temperature, and nutrient deprivation (Nicotera et al. 1999). Necrosis is also involved in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis and epilepsy (Stefanis 2005). Necrotic cell death, unlike apoptosis, was thought to be a passive process, not requiring energy, synthesis of new proteins and specific regulatory mechanisms. However, recent findings in Drosophila and C. elegans have forced a shift of...

Summary And Outlook

T2D and associated morbidities are prevalent in an increasing proportion of populations of both the developed and the developing parts of the world. Major current therapies for T2D include sulfonylureas, metformin, and TZDs. Each of these therapies has limitations with regard to their efficacy or side-effect profile. Among the targets discussed in this chapter, the most advanced are those based on GLP-1 agonist activity, i.e., Exenatide, and DPPIV inhibitors. Both strategies are directed to potentiate the actions of GLP-1 on insulin secretion and have shown promise in Phase II III clinical trials. These agents may avoid complications related to hypoglycemia and also may limit the potential for weight gain, thus complementing existing therapies. The discovery of potent PTP1B inhibitors remains a challenge however, progress is being made and effective PTP1B inhibitors are expected to show beneficial effects in reducing insulin resistance and modulating weight gain, based on KO mice...

Stroke

The cellular mechanisms underlying the cascade of events from cerebral ischemia to neurodegeneration are not completely understood but are similar to those seen in hypoxic and hypoglycemic states (29). In general, impeded blood flow results in a decrease of energy levels in the cell in the form of decreased ATP. Cell membranes increase their permeability, cells swell, cation pumps fail, and neuronal depolarization occurs, resulting in a rise in intra-cellular calcium. Calcium in turn regulates many cellular processes, including neurotransmitter release, activation of receptors, and second messenger systems (30,31). The cell's attempt to sequester calcium leads to mitochondrial damage and free-radical formation. Tissue pH drops as the brain continues to function in an anaerobic state, leading finally to cell death. Along the way, gene programs are turned on, some of which are neurotoxic and others neuroprotective. Oncogenes, such as those belonging to the bcl-2 gene family, are...

Dumping syndrome

Late dumping occurs 2-4 h following a meal, and is a form of reactive hypoglycemia from excessive insulin release (13). Unlike early dumping symptoms, late dumping is relieved by ingestion of liquids that contain sugar. Dietary therapy is usually successful and revisional surgery almost never necessary.

Miscellaneous

The vital role of GK in glucose homeostasis has been established for some time. Developments over the last decade, including the discovery of the regulatory function of GKRP, identification of maturity-onset diabetes of the young (MODY-2-), permanent neonatal diabetes (PNDM-) and (Persistent Hyperinsulinemic Hypoglycemia of Infancy) PHHI-related GK mutations, and the identification of novel GKAs and their co-crystal structures with GK, have radically improved our knowledge of GK structure and function. The structural categories of GKAs revealed thus far can be categorized as either carbon nitrogen-centered, aromatic ring-centered activators, or a few special cases that do not fit into either category. These categories of GKAs seem to make comparable polar and non-polar interactions at the allosteric binding site, in spite of their considerable differences in structure. More significantly, in various animal models of T2D, GKAs have exhibited beneficial effects on glucose homeostasis,...

Vegf

Centrations, indicating that ARNT is crucial in the response to hypoxia and hypoglycemia. Furthermore, embryonic failure caused by defective angiogenesis was noted in Arnt- - embryos when tested in vivo, an result similar to that observed in mice bearing defective VEGF genes. These studies suggest that ARNT and HIF-1a may be key tran-scriptional regulators of downstream genes controlling angiogenesis in response to hypoxia or changes in nutrient concentration.

Their Hormones

The glucocorticoids are literally steroids (-oids) from the adrenal cortex (cortic) that affect blood glucose (gluc) levels. The major hormone in the glucocorticoid family is called cortisol (KOR-tih-sahl). Cortisol tends to protect our bodies against stress, reduce the symptoms of tissue inflammation, and raise blood glucose levels. Study suggestion What hormone have we already studied that also acts to raise blood glucose concentration

Calcium

Large increases in intracellular Ca+ during ischemia have been a central focus for initiating multiple mechanisms of injury. Loss of ATP results in an inability to actively extrude Ca2+ or to sequester Ca2+ in the ER. The large increase in intracellular Na+ causes a reversal of the Na+ Ca2+ exchanger on the cell membrane and results in a net influx of Ca2+. Because most neurons can survive brief periods of increased Ca2+, the downstream mechanisms of cell death appear to take many minutes or hours to become fully recruited and probably depend on compartmentalization of increased Ca2+. Early attempts to limit Ca2+ influx utilized inhibitors of voltage-dependent Ca2+ channels. However, these studies showed either no effect or modest protection from global ischemia (40-43). Subsequent attempts utilized antagonists of NMDA receptors. Results with these agents in models of global cerebral ischemia were generally disappointing in gerbil (44), rat (45), cat (46), dog (29,47), and monkey...

Insulins

Insulin - Therapy of insulin dependent diabetes mellitus (IDDM or Type I diabetes) attempts to replace insulin in a manner that mimics the physiologic pattern of release seen in the non-diabetic (7,8). In addition, insulin is used in the treatment of non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes) when oral therapy alone fails (9). While management of the acute symptoms of IDDM is generally achievable, the long-term complications of diabetes, including retinopathy, nephropathy, and neuropathy are not currently well-treated. However, there are clinical data suggesting that strict metabolic control in IDDM can improve long-term prognosis (10-12). Confirmation in longer term, large prospective studies of the effect of primary intervention with intensive insulin therapy has been shown to be feasible (13,14). Risk of symptomatic and severe hypoglycemic episodes associated with intensive insulin therapy is greater, however, than that seen with conventional treatment. New...

Gross Features

Since hypoglycemia leads to neither vascular occlusion nor lactic acidosis, infarction (pan-necrosis, with death of glia as well as neurons) is not seen in hypoglyce-mic brain damage. Instead, hypoglycemia leads to selective neuronal necrosis, meaning death of neurons but not glia and other supporting cells of the nervous system. Thus, depending on the degree of selective neuronal necrosis, the brain in hypoglycemic brain damage can be either normal or can show variable degrees of gross atrophy (Fig. 13.1). Cysts are not seen. The location of the gross atrophy is dictated by the brain areas that are vulnerable in hypoglycemic brain damage. These constitute the cerebral cortex, the stria-tum, the hippocampus and the thalamus. A metabolic release of aspartate underlies the selective neuronal death in hypoglycemia (Sandberg et al. 1986). Glucose transport is apparently better in the brainstem and cerebellum (LaManna and Harik 1985). Sparing of the brainstem and cerebellum from even a...

Light Microscopy

Within the hippocampus, the CA1 pyramidal cells are vulnerable, in common with ischemia. However, the signature lesion of dentate gyrus necrosis in the absence of severe necrosis of the CA1 and especially CA3 pyramidal cells, indicates hypogly-cemic brain damage as the etiology of the lesion in the hippocampus of the human. In rats, the lesion of the dentate is seen early, already after 10-20 minutes of coma, a comparably mild insult. The dentate gyrus lesions of rats and humans are compared (Fig. 13.2), both showing dentate necrosis as a feature of hypoglycemia, and CA1 necrosis, a feature in common with cerebral ischemia.

Electron Microscopy

The discovery by John Olney of the phenomenon of excitotoxicity in the late 1960s and early 1970s was a signal discovery (Olney 1969, 1971), a harbinger of our understanding of the nature of hypoglycemic neuronal death. Apparently unrelated to hypoglycemic brain damage at the time, the phenomenon of amino acid neurotoxicity to neurons, when the excitatory amino acid is present in the extracellular space in high concentrations, proved to be an essential key to our understanding of how nerve cells die after hypoglycemia. This connection was not initially obvious since hypoglycemia is a deficiency disorder where not enough of a substrate is present in the brain. How a molecular deficiency of glucose could lead to an excess of another metabolite was only apparent after the biochemistry of hypoglycemic brain damage was worked out by Siesjo and colleagues (Agardh et al. 1978). Already in 1951, aspartate was known to increase massively in hypoglycemic brains (Cravioto et al. 1951). We now...

Biochemical Features

The biochemistry of hypoglycemic brain damage has been reviewed previously (Auer and Siesj 1993 Suh et al. 2007b). Essentially, the brain maintains adequate energy by running a truncated version of the Krebs cycle in a new metabolic homeostasis (Sutherland et al. 2008) that becomes established with the onset of Fig. 13.3 Axon-sparing, dendritic lesion in hypoglycemia, analogous to that first described by Olney in glutamate excitotoxicity. The dendrites (d) and contained mitochondria (m) are swollen, sparing intermediate axons (a). Synapses are seen as dark densities. Dentate gyrus, hypoglycemia with 10 min electrocerebral silence. Bar 1 (mm EEG silence during profound hypoglycemia. Aspartate is increased as part of the new metabolic homeostasis, being produced by a shift in the aspartate-glutamate transaminase reaction to favor aspartate. Cellular leakage of this metabolically derived aspartate leads to its flooding the extracellular space, producing the axon-sparing lesions described...

Gonly HGGR

Fig. 14.2 Neuronal superoxide production occurs during glucose reperfusion (a) Panels show superoxide production in cultured mouse neurons as evidenced by ethidium (Et) fluorescence at time points after glucose deprivation (GD) and glucose reperfusion (GR). Top row shows neurons subjected to 2 h of GD followed by GR bottom row shows neurons subjected to GD during the entire 3 h interval. Scale bar 30 mm. Line graph shows the change in Et fluorescence over time in each of the labeled neurons, with values normalized to the background signal. (b) Neuronal superoxide production in rat hippocampus after sham hypoglycemia (HG), 60 min of HG without glucose reperfusion (HG only), or 30 min of HG plus 30 min of glucose reperfusion (GR). Reprinted with modifications from (Suh et al. 2007a, b, c) Fig. 14.2 Neuronal superoxide production occurs during glucose reperfusion (a) Panels show superoxide production in cultured mouse neurons as evidenced by ethidium (Et) fluorescence at time points...

PARP1 Activation

Rats subjected to severe hypoglycemia exhibit neuronal accumulation of poly(ADP-ribose), the metabolic product of PARP-1, during the first 3 h following glucose reperfusion (Suh et al. 2003). The accumulation of poly(ADP-ribose) occurs after the formation of nitrotyrosine, a marker of peroxynitrite formation (Fig. 14.4). Rats treated with PARP-1 inhibitors show a striking reduction in neuronal death, even with drug delivery delayed until 3 h after hypoglycemia (Suh et al. 2003). This reduction in cell death is associated with reduced cognitive impairment as assessed by the Morris water maze test of spatial learning and memory (Suh et al. 2003). Although PARP-1 activation can lead to mitochondrial permeability transition (Alano et al. 2004 Cipriani et al. 2005), it has also been reported that mitochondrial permeability transition can lead to DNA damage during hypoglycemia (Ferrand-Drake et al. 1999 Ferrand-Drake et al. 2003), which would place mitochondrial permeability transition...

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...

Side Effects

Effects of thalidomide on the endocrine system have been consistently observed in both clinical trials and animal experiments. These actions may be the result of an effect of the drug on the hypothalamus (82). In humans, a tendency to normalize hyperthyroid states has been noted. Iodine uptake by the thyroid gland was slightly decreased, and myxedema was occasionally observed. Increased urinary secretion of 17-hydroxycorti-costeroids associated with hypoglycemia has been reported. Thalidomide was found to antagonize the action of histamine, serotonin, acetylcholine, and prostaglandins in organ bath experiments, but had no influence on the uterine reaction to oxytocin, vasopressin, and histamine (82).

Hirsutism In Abdomen

Hirsute Stomach

Weight gain that is primarily centripetal, especially if associated with extremity wasting, purple striae, easy bruisability, moon facies, and rubor, suggests the presence of Cushing's syndrome, and these patients should be appropriately screened using 24-hour urinary-free cortisol levels or a cortisol level following an overnight dexamethasone suppression test. Other information that should be sought includes the patient's awareness of her body fat distribution, as women with PCOS have a greater prevalence of abdominal obesity (29). Weight gain may also be associated with carbohydrate craving and evidence of postprandial reactive hypoglycemia, particularly in mid-afternoons. For example, Holte and colleagues found that although insulin resistance in obese women with PCOS was reduced by weight loss to similar levels as BMI-matched controls, these patients continued to demonstrate an increased early insulin response to glucose, which could stimulate appetite and persistent weight gain...